WO2005097832A2 - Humanized anti-tgf-beta antibodies - Google Patents
Humanized anti-tgf-beta antibodies Download PDFInfo
- Publication number
- WO2005097832A2 WO2005097832A2 PCT/US2005/010994 US2005010994W WO2005097832A2 WO 2005097832 A2 WO2005097832 A2 WO 2005097832A2 US 2005010994 W US2005010994 W US 2005010994W WO 2005097832 A2 WO2005097832 A2 WO 2005097832A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- antibody
- tgf
- beta
- cancer
- antibodies
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/55—Fab or Fab'
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S435/00—Chemistry: molecular biology and microbiology
- Y10S435/81—Packaged device or kit
Definitions
- the present invention concerns humanized anti-TGF-beta antibodies and methods for preparing same and using same in methods for treating TGF-beta-related disorders.
- the antibodies are useful, for example, in immunoaffinity purifications, immunoassays, in vivo imaging, radioreceptor assays, and treatments where it is desired to antagonize TGF-beta activity, particularly TGF-betal activity.
- TGF-beta Transforming growth factor-beta
- the TGF-betas produced primarily by hematopoietic and tumor cells, can regulate, i.e., stimulate or inhibit, the growth and differentiation of cells from a variety of both normal and neoplastic tissue origins (Sporn et al., Science, 233: 532 (1986)) and stimulate the formation and elaboration of various stromal elements.
- TGF-beta is used in the treatment and prevention of diseases of the intestinal mucosa.
- WO 2001/24813 Of particular interest from an immunological viewpoint are the potent immunosuppressive activities of
- TGF-beta which include lymphokine-activated killer (LAK) and cytotoxic T lymphocyte (CTL) inhibition
- LAK lymphokine-activated killer
- CTL cytotoxic T lymphocyte
- TGF-beta stimulates stroma formation, and decreases immune surveillance of the tumor, suggests attractive models for neoplasm deregulation and proliferation (Roberts et al, Br. J. Cancer, supra).
- TGF-beta such as TGF-beta3.
- TGF-beta There are at least five forms of TGF-beta currently identified, TGF-betal, TGF-beta2, TGF-beta3,
- TGF-beta4 and TGF-beta5.
- Suitable methods are known for purifying this family of TGF-betas from various species such as human, mouse, green monkey, pig, bovine, chick, and frog, and from various body sources such as bone, platelets, or placenta, for producing it in recombinant cell culture, and for determining its activity. See, for example, Derynck et al, Nature, 316: 701-705 (1985); European Pat. Pub. Nos. 200,341 published December 10, 1986, 169,016 published January 22, 1986, 268,561 published May 25, 1988, and 267,463 published May 18, 1988; U.S. Pat. No.
- TGF-betal is a homodimer formed by dimerization of the carboxy-terminal 112 amino acids of a 390-amino-acid precursor (Derynck et al., Nature, supra).
- TGF-beta2 has a precursor form of 414 amino acids and is also processed to a homodimer from the carboxy-terminal 112 amino acids that shares approximately 70% homology with the active form of TGF-betal (Marquardt etal, J. Biol. Chem.. 262: 12127 (1987)).
- TGF-beta2 has been purified from porcine platelets (Seyedin et al, J. Biol.
- TGF-beta3, TGF-beta4, and TGF-beta5 which are the most recently discovered forms of TGF-beta, were identified by screening cDNA libraries. None of these three putative proteins has been isolated from natural sources, although Northern blots demonstrate expression of the corresponding mRNAs. Human and porcine TGF-beta3 have been cloned and are described as homodimers and expressed in Chinese hamster ovary cells (1988), ten Dijke et al, Proc. Natl. Acad. Sci. USA, 85: 4715 (1988); U.S. Pat. No. 4,886,747). See also WO 1992/00318 regarding TGF-beta3 proteins and antibodies thereto.
- TGF-betal differs from TGF-beta2 by 27 mainly conservative changes and from TGF-beta3 by 22 x mainly conservative changes. These differences have been related to the 3-D structure. Schlunegger and Grutter, Nature, 358: 430-434 (1992). , TGF-beta4 and TGF-beta5 were cloned from a chicken chondrocyte cDNA. library (Jakowlew et al, Molec. Endocrinol., Z: 1186-1195 (1988)) and from a frog oocyte cDNA library, respectively.
- the frog oocyte cDNA library can be screened using a probe derived from one or more sequences of another type of TGF-beta.
- TGF-beta4 mRNA is detectable in chick embryo chondrocytes, but is far less abundant than TGF-beta3 mRNA in developing embryos or in chick embryo fibroblasts.
- TGF-beta5 mRNA is expressed in frog embryos beyond the neurula state and in Xenopus tadpole (XTC) cells.
- XTC Xenopus tadpole
- TGF-beta2 used for treating hormonally responsive carcinoma and for production of antibodies.
- the heterodimer of TGF-betal and TGF- beta2, called TGF-betal.2 has been identified and its uses demonstrated, as disclosed in U.S. Pat. Nos. 4,931,548 and 5,304,541, the latter also disclosing an antibody thereto.
- WO 1990/00900 filed 20 Jul. 1989, discloses treatment of inflammatory disorders with homodimeric TGF-betal and -beta2, and the heterodimer TGF-betal.2.
- U.S. Pat. No. 5,462,925 discloses a heterodimer of TGF-beta2 and TGF-beta3.
- U.S. Pat. No. 5,780,436 discloses small peptide mimics of TGF-beta. Increased levels of TGF-beta activity are involved in a large number of pathologic conditions, including, but not limited to, the following: (i) fibrosis, scarring, and adhesion during wound healing; (ii) fibrotic diseases of the lungs, liver, and kidneys; (iii) atherosclerosis and arteriosclerosis; ( ⁇ ) certain types of cancer including cancer of tine prostate, neuroendocrine tumors of the digestive system, cancer of the cervix, glioblastomas, and gastric cancer; (v) angiopathy, vasculopathy, nephropathy; (vi) systemic sclerosis; (vii) viral infection such as hepatitis C and HIV; and (viii) immunological and inflammatory disorders and deficiencies such as rheumatoid axthritis.
- pathologic conditions including, but not limited to, the following: (i) fibro
- the modulation of immune and inflammatory responses by TGF-betas includes: (i) inhibition of proliferation of all T-cell subsets; (ii) inhibitory effects on proliferation and function of B lymphocytes; (iii) down-regulation of natural-killer cell activity and the T-cell response; (iv) regulation of cytokine production by immune cells; (v) regulation of macrophage function; and (vi) leukocyte recruitment and activation.
- cancer specifically, members of the TGF-beta family are known to have a number of biological activities related to tumorigenesis (including angiogenesis) and metastasis. TGF-beta inhibits the proliferation of many cell types including capillary endothelial cells and smooth muscle cells.
- TGF-beta downregulates integrin expression (alphalbetal, alpha2betal, and alphavbeta3 involved in endothelial cell migration). Integrins are involved in the migration of all cells, including metastatic ones. TGF-beta downregulates matrix metalloproteinase expression needed for both angiogenesis and metastasis. TGF-beta induces plasminogen activator inhibitor, which inhibits a proteinase cascade needed for angiogenesis and metastasis. TGF-beta induces normal cells to inhibit transformed cells.
- TGF-beta has been implicated in the pathogenesis of a variety of diseases, including cancer and fibrosis, and presents the rationale for evaluating TGF-beta signaling inhibitors as cancer therapeutics, biomarkers/diagnostics, the structures of small-molecule inhibitors that are in development, and the targeted drug discovery model that is being applied to their development.
- Early detection of cancer is very important (Ruth et al, Nature Reviews Cancer, 3: 243-252 (2003)), and the pathogenesis of cancer metastasis is being studied. Fidler, Nature Reviews Cancer, 3: 453-458 (2003).
- TGF-beta has emerged to be a major modulator of angiogenesis by regulating endothelial cell proliferation, migration, extracellular matrix (ECM) metabolism, and the expression of adhesion molecules. It is a potent growtri inhibitor of normal mammary epithelial cells and a number of breast cancer cell lines. TGF-beta appears to exert pleiotropic effects in the oncogenesis of breast cancers in a contextual manner, i.e., it suppresses tumorigenesis at an early stage by direct inhibition of angiogenesis and tumor cell growth. However, overproduction of XGF beta by an advanced tumor may accelerate disease progression through indirect stimulation of angiogenesis and immune suppression.
- the cell membrane antigen CD 105 (endoglin) binds TGF betal and TGF beta3 and is preferentially expressed in angiogenic vascular endothelial cells.
- the reduction of CD 105 levels in HUV ⁇ C leads to in vitro angiogenesis inhibition and massive cell mortality in the presence of TGF- betal.
- CD105 null mice die in utero with impaired vasculature, indicating the pivotal role of CD105 in vascular development. Li et al, Microsc. Res. Tech., 52:437-449 (2001). Abnormal angiogenesis but intact hematopoietic potential has been observed in TGF-beta type I receptor-deficient mice. Larsson et al., EMBO J..
- TGF-beta receptor type II deficiency resulted in defects of yolk sac hematopoiesis and vasculogenesis. Oshima et al, Developmental Biology, 179 (1): 297-302 (1996). Also, heart and liver defects and reduced transforming growth factor beta 2 sensitivity were observed in TGF-beta type III receptor-deficient embryos. Stenvers et al, Mol. Cell. Biol, 23 (12): 4371-4385 (2003). Further, targeted disruption of t ie mouse TGF-betal gene resulted in multifocal inflammatory disease. Shull et al, Nature, 359 (6397): 693-699 (1992).
- TGF-betal-null mouse Early-onset multifocal inflammation in the TGF-betal-null mouse was found to be lymphocyte mediated. Diebold et al, Proc. Natl. Acad. Sci. (USA). 92 (26): 12215-12219 (1995).
- the most important non-proliferative function of TGF-betas is in enhancing the formation of extracellular matrices. Although this is achieved primarily through the increased transcription of both collagen and fibronectin, trie inhibition of the proteases from degrading the matrix also contributes to its stability. Degradation of the extracellular matrix is inhibited by the decrease in the secretion of the proteases themselves and the simultaneous increase in the levels of protease inhibitors.
- WO 1984/001106 describes TGF-betal and its use for the promotion of cell proliferation and tissue repair, wound healing, and treatment of traumata.
- U.S. Pat. No. 4,806,523 discloses that TGF-betal and TGF- beta2 both possess anti-inflammatory activity and are inhibitors of mitogen-stimulated T-cell proliferation and B-cell activation. It also reports that TGF-beta is localized in centers of hematopoiesis and lymphopoiesis and that TGF-beta may, therefore, be useful for treating indications associated with malfunction or dysfunction of hematopoiesis or lymphopoiesis.
- TGF-beta2 has been shown to be the predominant isoform of TGF-beta in the neural retina, retinal pigment epittielium-choroid and vitreous of the human eye (Pfeffer et al. Exp. Eve Res.. 59: 323-333 (1994)) and found in human aqueous humour in specimens from eyes undergoing cataract extraction with intraocular lens implantation. ' Janipel et al, Current Eye Research. 9: 963-969 (1990). Non-transformed human retinal pigment epithelial cells predominantly secrete TGF-beta2. Kvanta, Ophthalmic Res., 26: 361-367 (1994).
- TGF-beta diseases that have potential for treatment with antibodies against TGF-beta include adult respiratory distress syndrome, cirrhosis of the liver, post-myocardial infarction, post-angioplasty restenosis, keloid scars, and scleroderma.
- the increased level of expression of TGF-beta2 in osteoporosis means that this is a disease potentially treatable by antibodies directed against TGF-beta2.
- TGF-beta2 Because of the involvement of TGF-beta in a large number of serious pathological conditions, there is considerable interest in developing inhibitors of TGF-beta. Many of the proposals for TGF-beta inhibitors have involved antibodies.
- TGF-beta is an immunosuppressive molecule and further, there is strong conservation of sequence between human and mouse TGF-beta molecules.
- Mouse and human TGF-betal only differ by one amino acid residue, an alanine (h ⁇ man)-to-serine (mouse) change at a buried residue. Derynck et al, J. Biol. Chem., 261: 4377-4379 (1986).
- Mouse and human TGF-beta2 only differ at three residues; residue 59 (T mouse, S human); residue 60 (K mouse, R human), and residue 94 (N mouse; K human). This makes it difficult to raise antibodies in mice against human TGF-beta. Further, any antibodies raised may only be directed against a restricted set of epitopes.
- Monoclonal antibodies against TGF-beta have been produced by immunizing chickens and immortalizing B cells, used for, e.g. diagnosis and passive treatment of disease as described in U.S. Pat. No. 6,143,559.
- Polyclonal antibodies binding to human TGF-betal and human TGF-beta2 against both neutralizing and non-neutralizing epitopes have been raised in rabbits (Danielpour et al, Growth Factors, 2: 61-71 (1989); Roberts et al. Growth Factors, 3: 277-286 (1990)), chickens (R&D Systems, Minneapolis) and turkeys (Danielpour et al, J.
- TGF-beta sequences have also been used as immunogens to raise neutralizing polyclonal antisera in rabbits- Ellingsworth et al, J. Biol. Chem., 261: 12362 (1986); Ellingsworth et al, Cell. Immunol, 114: 41 (1988); Border et al.
- TGF-betal Rabbit anti-TGF- beta serum is described in Roberts et al, Proc. Natl Acad. Sci. USA, 83: 4167-4171 (1986). In addition, RIAs against TGF-betal using rabbit antiserum have been established to quantitate the released protein during platelet aggregation. Assoian and Sporn, J. Cell Biol. 102: 12178-1223 (1986).
- a neutralizing mouse monoclonal antibody that binds both TGF-beta2 and TGF-beta3 isoforms is available commercially from Genzyme Diagnostics.
- a mouse monoclonal antibody directed against human TGF-betal is available from R&D Systems. This antibody only weakly neutralizes TGF-betal in a neutralization assay.
- Neutralizing mouse monoclonal antibodies have also been generated from mice immunized with human TGF-betal peptides comprising amino acid positions 48 to 60 (antibody reactive with TGF-betal, TGF-beta2 and TGF-beta3) and amino acid positions 86 to 101 (antibody specific for TGF-betal). Hoefer and Heat, Cancer Immunol Immunother., 41: 302-308 (1995).
- Phage antibody technology (WO 1992/01047; WO 1993/19172; WO 1992/20791; WO 1993/06213; and WO 1993/11236) offers the ability to isolate directly human antibodies against human TGF-beta. The isolation of anti-self antibodies from antibody segment repertoires displayed on phage has been described.
- antibodies with the 31G9 VH domain and variants of the domain more specifically, the antibody CS37 that comprises the 31G9 VH domain together with the CS37 VL and variants of this domain, including antibodies that: (i) compete in ELISA with CS37 for binding to TGF-beta 1, (ii) bind TGF-betal preferentially with respect to TGF-beta 3, and (iii) neutralize TGF-betal.
- U.S. Pat. No. 6,492,497 is based on identification of antibodies that are related to CS37, but that have unexpectedly advantageous properties with respect to binding and neutralization of TGF-betal. They do not bind to, or neutralize, TGF-beta2 or TGF-beta3.
- the epitope for these antibodies lies in the C-terminal region of TGF-betal (residues 83-112) and includes the loop consisting of residues 92-98 of TGF-betal, also known as finger 2, a region that has been identified as interacting with the receptor for TGF-beta.
- a monoclonal antibody against human TGF-beta-1 that is highly specific and can be used for tumor diagnosis and for affinity chromatography is disclosed by JP 95068278 B2 published July 26, 1995.
- Use of TGF-beta and its antagonists for modulating blood pressure, and for treating hypertension and hypotension, respectively, is disclosed in WO 1991/19513.
- WO 1991/15223 discloses a purified respiratory burst suppression factor that may be incubated with turkey anti-TGF-beta antibody that specifically binds TGF-betal.
- the antibody completely neutralized the activity of TGF-betal on activated macrophages, but had no effect on the activity of the respiratory burst suppression factor on the macrophages.
- Suppressing TGF-beta activity and extracellular matrix accumulation in diagnosis and treatment of fibrotic diseases s ⁇ ch ⁇ as " glomeful nephr ⁇ t ⁇ s by contact with an ECM-producing activity suppressor, such as anti- TGF-beta antibody, is disclosed in WO 1991/04748 and WO 1993/10808.
- Antibodies against a linear peptide from TGF-beta, and cells producing the antibodies are also disclo sed.
- U.S. Pat. No. 5,888,705 discloses a method of inducing the proliferation of human adult pancreatic cells or the differentiation thereof by contacting primary cultures of such cells with hepatocyte rowth factor alone or in combination with anti-TGF-beta antibodies.
- WO 2001/66140 discloses the use of TGF-beta antagonists such as antibodies to treat or prevent loss of renal function.
- WO 2000/40227 discloses methods for treating conditi s associated with the accumulation of excess extracellular matrix using agents that inhibit TGF-beta such as antibodies.
- Antibodies to TGF-beta are disclosed as ameliorating tu " bular apoptosis in unilateral ureteral obstruction, in Miyajima et al, Kidney International. 58: 2301-2313 (2000).
- Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal anti-TGF-beta antibody in db/db diabetic mice is disclosed in Ziyadeh et al, Proc. Natl Acad. Sci. USA, 9J (14): S015-8020 (2000).
- TGF-beta was found to be a key mediator in hyperglycemia and diabetic kidney disease.
- Use of TGF-beta in diabetic nephropathy is disclosed in Border et al, Diabetes Metab. Rev., 12/4: 309-339 (1996).
- U.S. Pat. No. 5,662,904 describes a composition for use in treating wounds to inhibit scar tissue formation.
- compositions comprising at least two antibodies for use in promoting wound healing of fibrotic disorders, where the first antibody is specific for a single epitope on TGF betal and the second antibody is specific for a single epitope on TGF beta2.
- U.S. Pat. No. 5,958,411 discloses methods for treating a CNS pathology by administering neutralizing anti-TGF-beta antibodies.
- U.S. Pat. No. 5,616,561 describes a method for treating; tissue damage caused by radiation using a TGF- beta antagonist such as antibodies.
- No. 6,500,920 discloses a peptide of 10-25 amino acids comprising amino acids 49-58 of a TGF-beta2, wherein the peptide is capable of inhibiting specific binding of a TGF-beta to a TGF-beta receptor on a cell.
- TGF-beta disclose monoclonal antibodies to TGF-beta, including ones that neutralize the activity of TGF-betal and TGF-beta2, and their use in therapeutic applications for treating indications where there is an overproduction of TGF-beta (e.g., acute liver injury, interstitial lung fibrosis, liver cirrhosis, chronic hepatic fibrosis " , arid fibrotic sl ⁇ disorders such as scleroderma) and for diagnosing o>r treating malignancies (e.g., sarcomas and melanomas) and metastatic cancers.
- TGF-beta e.g., acute liver injury, interstitial lung fibrosis, liver cirrhosis, chronic hepatic fibrosis " , arid fibrotic sl ⁇ disorders such as scleroderma
- malignancies e.g., sarcomas and melanomas
- metastatic cancers e.
- New antibodies for treating disorders associated with TGF-beta3, e.g., osteoporosis, AIDS, cancer, etc., are disclosed in WO 1992/00330 and U.S. Pat. No. 5,262,319. Such antibodies bind to human TGF-beta3 and exhibit no cross-reactivity with TGF-betal and beta2.
- U.S. Pat. No. 6,509,318 discloses a family of small peptides found to be inhibitory to TGF-beta activity for uses such as scar tissue inhibition during wound healing.
- Use of a compound (e.g. an antibody) that can inhibit the biological activity of TGF-beta on pre- damaged neurons for treating cerebral disorders, e.g. cerebral ischemia is disclosed in WO 2000/13705.
- a monoclonal antibody recognizing all three isoforms of TGF-beta that can inhibit the biological activity of TGF-beta on pre-damaged neurons, useful for treating cerebral disorders, is disclosed in WO 2000/54804. Such antibody was used to neutralize endogenous TGF-beta during the main period of ontogenetic cell death of ciliary ganglia (CG) and dorsal root ganglia (DRG) as well as spinal motoneurons in chick embryos.
- CG ciliary ganglia
- DRG dorsal root ganglia
- spinal motoneurons spinal motoneurons in chick embryos.
- Diagnosing and predicting the likelihood of development of tamoxif en-sensitive or tamoxifen-resistant breast cancer using an antibody specific to angiogenic factors or receptors, such as am antibody specific to TGF- beta3, is disclosed in WO 2000/34788.
- EP 945464 Bl discloses specific binding members for human TGF-beta, that is, specific binding members comprising human antibody-antigen binding domains specific for human TTGF-beta that bind specifically isoforms TGF-beta2 and TGF-betal, or both, preferentially compared with TGF-beta3.
- Specific binding members may be isolated and utilized in the treatment of disease, particularly fibrotic disease and also immune/inflammatory diseases.
- Antibodies against TGF-beta have been shown to be effective in the treatment of glomerulonephritis (Border et al, Diabetes Metab. Rev., supra); neural scarring (Logan et al, Eur. J.
- TGF-beta3 acts antagonistically to TGF-betal and TGF-beta2 in dermal scarring (Shah et al, 1995 supra).
- Arteaga et al, J. Clin. Invest.. 92: 2569-2576 (1993) discloses that anti-TGHF-beta antibodies inhibit breast cancer cell tumorigenicity and increase mouse spleen natural killer cell activity.
- Anti-fibrotic agents for wound healing and treatment of fibrotic disorders, including anti-TGF-betas are described in WO 1993/19769.
- Specific sequences of anti-TGF-beta2 are described in EP 853,661B1.
- TGF-beta antibodies against TGF-beta
- Other applications where antibodies against TGF-beta have shown promise of therapeutic efficacy include the use of antibodies against TGF-beta for the treatment of eye diseases involving ocular fibrosis, including proliferative retinopathy (Pena et al, Invest. Ophthalmology. Vis. Sci., 35: 2804-2808 (1994)), prevention of cataracts (WO 1995/13827), retinal detachment, and post glaucoma drainage surgery (Khaw et al, Eye, 8: 188-195 (1994)). Connor et al, J. Clin.
- TGF-beta2 showed that much higher levels of TGF-beta2 were present in vitreous aspirates from patients with intraocular fibrosis associated with proliferative retinopathy compared with patients with uncomplicated retinal detachment without ocular fibrosis and that the biological activity of this TGF-beta2 could be neutralized with antibodies directed against TGF-beta2.
- the use of antibodies against TGF-beta for the treatment of diseases has been the subject of patent applications for fibrotic disease (WO 1991/04748); macrophage-deficiency diseases (WO 1993/14782); macrophage pathogen infections (WO 1993/17708; U.S. Pat. No.
- TGF-beta antibody-treated stem cell composition capable of survival for 14 da ⁇ s in vitro or ex vivo, and rapid in vivo hematopoietic system repopulation are described in WO 2000/43499. Scrip 2580 pl4, October 04, 2000 reported that Cambridge Antibody Technology (CAT) and Genzyme were working together to develop human monoclonal antibodies against TGF-beta.
- CAT Cambridge Antibody Technology
- CAT was to develop a human analogue of ID 11 using its phage display technology.
- anti-TGF-beta Several other clinical indications for anti-TGF-beta treatment, including ophthalmic indications, post-surgical scarring, fibrosis of major organs, such as the lungs, kidneys and liver, and certain cancers, will also be considered as well as treatment of malignant brain tumors by inhibiting the growth of TGE-beta2.
- CAT-152 anti-TGF-beta2
- CAT-192 anti-TGF-betal
- a method for quantifying TGF-beta using anti-TGF-beta antibody is disclosed in WO 1995/19987.
- a new assay for determining active TGF-beta in a sample using eukaryotic cells that contain a TGF-beta- responsive expression vector is described in WO 2000/00641.
- This assay includes one for determining the levels of TGF-beta isoforms in a sample, wherein cryosections are pre-incubated with ant ⁇ -TGF-beta isoform neutralizing antibodies.
- TGF-beta immunoassays using TGF-beta antibodies are described, for example, in JP 2126157 and JP 92041307 B published July 7, 1992. Darland and D'Amore, J. Clin.
- Invest., 103: 157-158 (1999) discloses that vessel development proceeds from a stage of growth-factor dependence where loss of a survival factor leads to apoptos ⁇ s. Vessel stabilization is marked by investment with mural cells, local activation of TGF-beta, and basement membrane production. It poses several questions regarding what is the role of growth factors in the adult vascular, including VEGF and TGF-beta. Benjamin et al, J. Clin. Invest., 103: 159-165 (1999) discloses selective ablation of immature blood vessels in established human tumors follows VEGF withdrawal. Methods of making chimeric and humanized antibodies are described in, and ottier references in this area include, for example, U.S. Pat. No.
- TGF-beta molecules there is a need to control TGF-beta molecules to prevent their deleterious effects in diseases such as those set forth above.
- monoclonal antibodies of high affinity that bind to TGF- beta specifically and that neutralize TGF-beta activity so as to act as a TGF-beta antagonist.
- the apparent loss of TGF-beta regulation by neoplastic cells coupled with the suppression of immune function and the TG-T-beta- induced stroma formation makes potential intervention with TGF-beta antagonists an attractive option for cancer therapy.
- TGF-beta antibodies are useful in diagnostic assays and immunoaffinity purification.
- the present invention provides a humanized antibody that binds a TGF-beta comprising a variable heavy (V H ) domain that comprises non-human hypervariable region residues incorporated into a human V H domain, said variable domain comprising a framework region (FR) substitution in SEQ ID NO:6 at a position selected from the group consisting of 48, 49, 67, 69, 71, 73, and 78, utilizing the numbering system set forth in Kabat et al, Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991).
- the antibody includes an intact IgGl antibody or antibody fragment such as a Fab.
- the humanized antibody comprises FR substitutions at positions 49, 67, and 71, wherein more preferably at position 49 the alanine is changed to a glycine, at position 67 the phenylalanine is changed to an alanine, and at position 71 the arginine is changed to an alanine.
- the humanized antibody comprises FR substitutions at positions 48,
- the humanized antibody comprises FR substitutions at positions 49, 69, and 7 , wherein more preferably at position 49 the alanine is changed to a glycine, at position 69 the isoleucine is changed to a leucine, and at position 71 the arginine is changed to an alanine.
- an additional FR substitution is at position 73, more preferably wherein at position 73 the asparagine is changed to a lysine.
- the humanized antibody comprises FR substitutions at positions 49, 71, and 73, wherein more preferably at position 49 the alanine is changed to a glycine, at position 7 1 the arginine is changed to an alanine, and at position 73 the asparagine is changed to a lysine.
- the humanized antibody comprises FR substitutions at positions 49, 71, and 78, wherein more preferably at position 49 the alanine is changed to a glycine, at position 71 the arginine is changed to an alanine, and at position 78 the leucine is changed to an alanine.
- any of the antibodies above comprises variable light (V L ) domain complementarity-determining-region (CDR) residues RASQSVLYSSNQKNYLA (SEQ ID NO:36); WASTRES (SEQ ID NO:38); and HQYLSSDT (SEQ ID NO:40), or comprises V L domain CDR residues wherein the first CDR (CDR LI) is reverted to the sequence of human germline kappa locus L8 L9: RASQGISSYLA (SEQ ID NO:37) and/or the second CDR (CDR L2) is reverted to the sequence of human germline kappa locus L8/L9/L14/L15: YASSLQS (SEQ ID NO:39).
- V L variable light domain complementarity-determining-region residues
- any of the antibodies above comprises V H domain complementarity-determining-region (CDR) residues GYAFTNYLIE (SEQ ID NO:41), VNNPGSGGSNYNEKFKG (SEQ ID NO:42), or VINPGSGGSNYNEKFKG (SEQ ID NO:43); and SGGFYFDY (SEQ ID NO:44).
- the invention provides any of the antibodies above conjugated with a cytotoxic agent, or not so conjugated.
- the invention provides a composition comprising such antibodies and a carrier.
- the invention provides an isolated nucleic acid encoding the humanized antibody, a vector comprising such nucleic acid, and a host cell comprising such nucleic acid.
- the invention provides a process of producing a humanized antibody comprising culturing the host cell comprising the nucleic acid encoding the antibody so that the nucleic acid is expressed and the antibody produced, and preferably recovered from the host cell culture, more preferably from the host cell culture medium.
- the host cell may be co-transfected with a vector comprising nucleic acid encoding the variable heavy domain and with a vector comprising nucleic acid encoding the variable light domain.
- the invention provides a method of treating a TGF-beta disorder in a mammal, preferably a primate, and more preferably a human, comprising administering to the mammal an effective amount of the humanized antibody.
- the invention provides a method for detecting a TGF-beta in a body sample that comprises contacting the humanized antibody with the body sample and determining whether antibody binding to the TGF-beta has occurred.
- a method for detecting a TGF-beta in a body sample that comprises contacting the humanized antibody with the body sample and determining whether antibody binding to the TGF-beta has occurred.
- the invention also provides an article of manufacture comprising a container containing the humanized antibody and instructions directing a user to treat a TGF-beta disorder in a mammal, preferably a human, with the antibody.
- This article may also comprise a container containing a therapeutic agent other than the humanized antibody, wherein the instructions direct the user to treat the disorder with the antibody in combination with the agent.
- this invention provides a method of treating cancer in a mammal comprising administering to the mammal an effective amount of a TGF-beta antibody and an antibody that binds to vascular endothelial growth factor.
- the mammal is human.
- the TGF-beta antibody binds to any one or more of the following: TGF-betal, TGF-beta2, and TGF-beta3.
- the antibody binds to TGF-betal, or to both TGF-betal and TGF-beta2.
- Figures 1A and IB depict alignments of the amino acid sequences of the variable light (V ) (Fig. 1A) and variable heavy (Vjj) (Fig. IB) domains of murine monoclonal antibody 2G7 (SEQ ID NOS: 1 and 2, respectively); V L and V H domains of humanized huxTGFB version (V5H.V5L) (SEQ ID NOS: 3 and 4, respectively), and human V and VH consensus frameworks (hum ⁇ l, light kappa subgroup I; hu lll, heavy subgroup III) (SEQ ID NOS: 5 and 6, respectively).
- CDRs Complementarity Determining Regions
- Figure 2 shows the DNA sequences (SEQ ID NOS: 12-17) encoding the various CDR regions (SEQ ID NOS: 18-23).
- Figure 3 shows the amino acid sequences of 709.landH.IgGl (SEQ ID NO:24); of H2NI.V5L (SEQ ID NO:25), of V11H.V11L (SEQ ID NO:26), of V5H.V5L (SEQ ID NO:27), of chimL.chimH (SEQ ID NO:28), and of V5H.glL2 (SEQ ID NO:29).
- Figure 4 shows the nucleic acid sequences without and with signal sequences encoding the sequences of Figure 3 (SEQ ID NOS:30-35).
- Figure 5 shows the binding curves of 2G7 IgG variant humanized antibodies to TGF-beta.
- Figure 6 shows the sequence of the plasmid pDRl (SEQ ID NO:45; 5391 bp) for expression of immunoglobulin light chains as described in Example 2.
- pDRl contains sequences encoding an irrelevant antibody, i.e., the light chain of a humanized anti-CD3 antibody (Shalaby et al, J. Exp. Med., 175: 217-225 (1992)), the start and stop codons for which are indicated in bold and underlined.
- Figure 7 shows the sequence of plasmid pDR2 (SEQ ID NO:46; 6135 bp) for expression of immunoglobulin heavy chains as described in Example 2.
- pDR2 contains sequences encoding an irrelevant antibody, i.e., the heavy chain of a humanized anti-CD3 antibody (Shalaby et al, supra), the start and stop codons for which are indicated in bold and underlined.
- Figure 8 shows the binding curves of 2G7 germ-line revertant humanized antibodies to TGF-beta.
- Figure 9 shows the blocking results of a mouse mesangial cell proliferation assay of TGF-betal antibody 2G7 and several humanized TGF-beta variant antibodies.
- Figures 10A-10C show neutralization of TGF-beta3 in three different concentrations, respectively, in a
- 3T3 fibroblast proliferation assay by three humanized antibodies against TGF-beta (H2NI.V5L, H2NI.glL2, and V5H.glL2) and 2G7 murine antibody.
- Figures 11A-11C show neutralization of TGF-beta2 in three different concentrations, respectively, in a 3T3 fibroblast proliferation assay by the four antibodies shown in Figure 10.
- Figures 12A-12C show neutralization of TGF-betal in three different concentrations, respectively, in a
- FIG. 14A shows neutralization of 2 ng/ml TGFbetal, beta2, and beta3, respectively, in a 3T3 fibroblast proliferation assay by the four antibodies shown in Figure 10.
- Figures 14A-14D show neutralization of the three TGF-beta isoforms in a 3T3 fibroblast proliferation assay by humanized antibody H2NI.V5L ( Figure 14A), humanized antibody H2NI.glL2 ( Figure 14B), 2G7 murine antibody ( Figure 14C), and humanized antibody V5H.glL2 ( Figure 14D).
- Figures 15 A and 15B show ELISA results of production and inhibition of TGF-beta by normal and tumor epithelial cells.
- Figure 15 A show in vitro production of TGF-betal by normal epithelial cells (EpC) (C57) and by tumor EpC (4T1 model).
- Figure 15B shows the effect of anti-TGF-beta antibody 2G7 in vivo on the serum TGF-betal levels in the tumor EpC versus IgG control antibody (isotype-matched IgG, which is an anti-ragweed antibody) in normal and tumor EpC. This same IgG control is used for the remaining figures, and in Figure 28 an IgG control is used that may or may not be the same.
- Figures 16A and 16B show the effect of anti-TGF-beta antibody 2G7 on secondary lung tumors versus
- Figure 16A shows histology scores with grade and number of lobes affected for both IgG control antibody and TGF-beta antibody 2G7
- Figure 16B shows tissue weights in grams and percentage body weight for the same control and TGF-beta antibody 2G7.
- Figure 17 shows the effect of anti-TGF-beta antibody 2G7 on quantification of lung tumors by uCT versus IgG control, both by tumor volume and tumor number.
- Figures 18A and 18B show the effect of anti-TGF-beta antibody 2G7 and chemotherapy in the 4T1 breast cancer model versus IgG control.
- Figure 18A shows tumor volume as a function of time after cell injection for IgG with saline control, IgG and docetaxel (TAXOTERE®) control, and anti-TGF-beta 2G7 and docetaxel (TAXOTERE®).
- Figure 18B shows tissue weight for brain, lung, spleen, and tumor for the two controls (IgG with and without TAXOTERE® docetaxel) and the anti-TGF-beta with docetaxel (TAXOTERE®).
- Figure 19 shows plasma VEGF levels (pg/ml) in mice without tumors (Normal), or in mice with 4T1 mammary tumors treated with either control IgG (control) or anti-TGF-beta (2G7).
- Figures 20A and 20B show the effect of TGF-beta antibody 2G7 in a different breast cancer model PymT.
- Figure 20A shows tumor volume as a function of days of tumor growth for the TGF-beta antibody and an IgG control
- Figure 20B shows tumor weight for the TGF-beta antibody and IgG control.
- Figures 21A and 21B show a mouse melanoma model B16 and the effect of TGF-beta antibody 2G7 versus IgG control.
- Figure 21 A shows the percentage of mice with lung tumors for surface and pathology for the control and TGF-beta antibody
- Figure 21B shows the lung tumor number for surface, cleared, and CT for the control and TGF-beta antibody.
- Figure 22 shows the effect of the TGF-beta antibody 2G7 on B16 tumor growth (volume) over 14 days after inoculation versus the control IgG.
- Figure 23 shows the effect of the TGF-beta antibody 2G7 on B16 (E6) visible lung metastasis count versus the IgG control
- Figure 24 shows the effect of the TGF-beta antibody 2G7 on B16 tumor growth (volume) over 17 days after inoculation versus the IgG control.
- Figure 25 shows the effect of the TGF-beta antibody 2G7 on B16 primary tumor weight versus the IgG control.
- Figure 26 shows the effect of the TGF-beta antibody 2G7 on B16 (E7) visible lung metastasis count versus the IgG control.
- Figure 27 shows the effect of the TGF-beta antibody 2G7, the murine monoclonal anti-VEGF antibody A461, and a combination of the two antibodies on tumor volume in a human lung cell Calu-6 mouse xenograft versus the IgG control over a period of time up to day 42. Treatment with the various agents is started at day 2.
- Figure 28 shows final tumor weights for the Calu-6 experiment in Figure 27 for the three types of antibody treatments and an IgG control.
- TGF-beta and "transforming growth factor-beta” are used interchangeably herein and refer to the family of molecules described hereinabove that have either the full-length, native amino acid sequence of any of the TGF-betas from humans, including the latent forms and associated or unassociated complex of precursor and mature TGF-beta ("latent TGF-beta").
- TGF-beta herein will be understood to be a reference to any one of the currently identified forms, including TGF-betal, TGF-beta2, TGF-beta3, TGF- beta4, and TGF-beta5 and latent versions thereof, as well as to human TGF-beta species identified in the future, including polypeptides derived from the sequence of any known TGF-beta and being at least about 75%, preferably at least about 80%, more preferably at least about 85%, still more preferably at least about 90%, and even more preferably at least about 95% homologous with the sequence.
- TGF-betal refers to the TGF-betas defined in the literature, e.g., Derynck et al, Nature, supra, Seyedin et al, J. Biol Chem., 262, supra, and deMartin et al., supra.
- TGF-beta refers to the gene encoding human TGF-beta.
- Preferred TGF-beta is native- sequence human TGF-beta.
- TGF-beta family are defined as those that have nine cysteine residues in the mature portion of the molecule, share at least 65% homology with other known TGF-beta sequences in the mature region, and may compete for the same receptor. In addition, they all appear to be encoded as a larger precursor that shares a region of high homology near the N-terminus and shows conservation of three cysteine residues in the portion of the precursor that will later be removed by processing. Moreover, the TGF-betas appear to have a processing site with four or five amino acids.
- a "native-sequence" polypeptide is one that has the same amino acid sequence as a polypeptide (e.g.,
- TGF-betal TGF-betal derived from nature.
- native-sequence polypeptides can be isolated from nature or can be produced by recombinant or synthetic means.
- a native-sequence polypeptide can have the amino acid sequence of naturally occurring human polypeptide, murine polypeptide, or polypeptide from any other mammalian species.
- amino acid sequence variant refers to polypeptides having amino acid sequences that differ to some extent from a native-sequence polypeptide.
- amino acid sequence variants will possess at least about 70% homology with the native-sequence polypeptide or portion thereof that is being compared with the variant, and preferably, they will be at least about 80%, more preferably at least about 90%, and still more preferably at least about 95% homologous with such native-sequence polypeptide or portion.
- the amino acid sequence variants possess substitutions, deletions, and/or insertions at certain positions within the native amino acid sequence.
- "Homology” is defined as the percentage of residues in the amino acid sequence variant that are identical after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent homology. Methods and computer programs for the alignment are well known in the art.
- antibody herein is used in the broadest sense and specifically covers intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g. bispecific antibodies) formed from at least two intact antibodies, and antibody fragments, so long as they exhibit the desired biological activity.
- monoclonal antibody refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts.
- Monoclonal antibodies are highly specific, being directed against a single antigenic site. Furthermore, in contrast to polyclonal antibody preparations that include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. In addition to their specificity, the monoclonal antibodies are advantageous in that they may be synthesized uncontaminated by other antibodies.
- the modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
- the monoclonal antibodies to be used in accordance with the present invention may be made by the hybridoma method first described by Kohler et al, Nature, 256:495 (1975), or may be made by recombinant DNA methods (see, e.g., U.S. Patent No. 4,816,567).
- the "monoclonal antibodies” may also be isolated from phage antibody libraries using the techniques described in Clackson et al, Nature, 352: 624-628 (1991) and Marks et al, J. Mol Biol, 222: 581-597 (1991), for example.
- the monoclonal antibodies herein specifically include "chimeric" antibodies in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (U.S. Patent No. 4,816,567; and Morrison et al, Proc. Natl Acad. Sci. USA, 81:6851-6855 (1984)).
- Chimeric antibodies of interest herein include “primatized” antibodies comprising variable-domain antigen-binding sequences derived from a non-human primate (e.g. Old World Monkey, Ape etc) and human constant-region sequences.
- Antibody fragments comprise a portion of an intact antibody, preferably comprising the antigen- binding or variable region thereof. Examples of antibody fragments include Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules; and multispecific antibodies formed from antibody fragment(s).
- An "intact” antibody is one that comprises an antigen-binding variable region as well as a light-chain constant domain (CL) and. heavy-chain constant domains, CHL CJJ2 and CH3.
- the constant domains may be native-sequence constant domains (e.g. human native-sequence constant domains) or amino acid sequence variants thereof.
- the intact antibody has one or more effector functions.
- Antibody effector functions refer to those biological activities attributable to the Fc region (a native- sequence Fc region or amino acid sequence variant Fc region) of an antibody. Examples of antibody effector functions include Clq binding; complement-dependent cytotoxicity; Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; down-regulation of cell-surface receptors (e.g. B-cell receptor; BCR); etc.
- intact antibodies can be assigned to different "classes”.
- IgA immunoglobulin-dependent cell-mediated cytotoxicity
- ADCC antibody-dependent cell-mediated cytotoxicity
- NK cells Natural Killer (NK) cells, neutrophils, and macrophages) recognize bound antibody on a target cell and subsequently cause lysis of the target cell.
- ADCC activity of a molecule of interest may be assessed in vitro, such as that described in US Patent No. 5,500,362 or 5,821,337.
- Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells.
- PBMC peripheral blood mononuclear cells
- NK Natural Killer
- ADCC activity of the molecule of interest may be assessed in vivo, e.g., in an animal model such as that disclosed in Clynes et al, Proc. Nat Acad. Sci. (USA), 95:652-656 (1998).
- Human effector cells are leukocytes that express one or more FcRs and perform effector functions. Preferably, the cells express at least Fc ⁇ Rffl and perform ADCC effector function. Examples of human leukocytes that mediate ADCC include peripheral blood mononuclear cells (PBMC), natural killer (NK) cells, monocytes, cytotoxic T cells, and neutrophils, with PBMCs and NK cells being preferred.
- PBMC peripheral blood mononuclear cells
- NK natural killer cells
- monocytes cytotoxic T cells
- neutrophils neutrophils
- the effector cells may be isolated from a native source thereof, e.g. from blood or PBMCs as described herein.
- the terms "Fc receptor” or “FcR” are used to describe a receptor that binds to the Fc region of an antibody.
- the preferred FcR is a native-sequence human FcR.
- a preferred FcR is one that binds an IgG antibody (a gamma receptor) and includes receptors of the Fc ⁇ RI, Fc ⁇ RII, and Fc ⁇ RIII subclasses, including allelic variants and alternatively spliced forms of these receptors.
- Fc ⁇ RII receptors include Fc ⁇ RIIA (an "activating receptor") and Fc ⁇ RIIB (an "inhibiting receptor”), which have similar amino acid sequences that differ primarily in the cytoplasmic domains thereof.
- Activating receptor Fc ⁇ RIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain.
- ITAM immunoreceptor tyrosine-based activation motif
- Inhibiting receptor Fc ⁇ RIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain (see review in Daeron, Annu. Rev. Immunol 15: 203-234 (1997)). FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol. 9: 457- 492 (1991); Capel et al, Immunomethods. 4: 25-34 (1994); and de Haas et al, J. Lab. Clin. Med., 126: 330-41 (1995). Other FcRs, including those to be identified in the future, are encompassed by the term "FcR" herein.
- ITIM immunoreceptor tyrosine-based inhibition motif
- the term also includes the neonatal receptor, FcRn, which is responsible for the transfer of maternal IgGs to the fetus.
- FcRn neonatal receptor
- “Complement-dependent cytotoxicity” or “CDC” refers to the ability of a molecule to lyse a target in the presence of complement.
- the complement activation pathway is initiated by the binding of the first component of the complement system (Clq) to a molecule (e.g. an antibody) complexed with a cognate antigen.
- a CDC assay e.g.
- “Native antibodies” are usually heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light (L) chains and two identical heavy (H) chains. Each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide linkages varies among the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges.
- Each heavy chain has at one end a variable domain (VJJ) followed by a number of constant domains.
- Each light chain has a variable domain at one end (VL) and a constant domain at its other end.
- the constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light-chain variable domain is aligned with the variable domain of the heavy chain.
- Particular amino acid residues are believed to form an interface between the light-chain and heavy-chain variable domains.
- the term "variable” refers to the fact that certain portions of the variable domains differ extensively in sequence among antibodies and are used in the binding and specificity of each particular antibody for its particular antigen. However, the variability is not evenly distributed throughout the variable domains of antibodies.
- variable domains both in the light-chain and the heavy-chain variable domains.
- the more highly conserved portions of variable domains are called the framework regions (FRs).
- the variable domains of native heavy and light chains each comprise four FRs, largely adopting a ⁇ -sheet configuration, connected by three hypervariable regions, which form loops connecting, and in some cases forming part of, the ⁇ -sheet structure.
- the hypervariable regions in each chain are held together in close proximity by the FRs and, with the hypervariable regions from the other chain, contribute to the formation of the antigen-binding site of antibodies (see Kabat et al, supra).
- the constant domains are not involved directly in binding an antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody-dependent cellular cytotoxicity (ADCC).
- the term "hypervariable region” when used herein refers to the amino acid residues of an antibody that are responsible for antigen binding.
- the hypervariable region generally comprises amino acid residues from a "complementarity-determining region" or "CDR" (e.g.
- “Framework Region” or "FR” residues are those variable-domain residues other than the hypervariable region residues as herein defined. Papain digestion of antibodies produces two identical antigen-binding fragments, called “Fab” fragments, each with a single antigen-binding site, and a residual "Fc” fragment, whose name reflects its ability to crystallize readily. Pepsin treatment yields an F(ab')2 fragment that has two antigen-binding sites and is still capable of cross-linking antigen. "Fv” is the minimum antibody fragment that contains a complete antigen-recognition and antigen- binding site. This region consists of a dimer of one heavy-chain and one light-chain variable domain in tight, non-covalent association.
- variable domain interacts to define an antigen-binding site on the surface of the VH-VL dimer.
- the six hypervariable regions confer antigen-binding specificity to the antibody.
- a single variable domain or half of an Fv comprising only tliree hypervariable regions specific for an antigen
- the Fab fragment also contains the constant domain of the light chain and the first constant domain
- CHI heavy chain Fab' fragments differ from Fab fragments by the addition of a few residues at the carboxy terminus of the heavy-chain CHI domain including one or more cysteines from the antibody hinge region.
- Fab'-SH is the designation herein for Fab' in which the cysteine residue(s) of the constant domains bear at least one free thiol group.
- F(ab')2 antibody fragments originally were produced as pairs of Fab' fragments that have hinge cysteines between them. Other chemical couplings of antibody fragments are also known.
- the "light chains" of antibodies from any vertebrate species can be assigned to one of two clearly distinct types, called kappa (K) and lambda ( ⁇ ), based on the amino acid sequences of their constant domains.
- Single-chain Fv or “scFv” antibody fragments comprise the VJJ and VL domains of antibody, wherein these domains are present in a single polypeptide chain.
- the Fv polypeptide further comprises a polypeptide linker between the VJJ and VL domains that enables the scFv to form the desired structure for antigen binding.
- scFv see Pl ⁇ ckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer- Verlag, New York, pp. 269-315 (1994).
- Anti-TGF-beta antibody scFv fragments are described in WO 1993/16185; U.S. Pat.
- diabodies refers to small antibody fragments with two antigen-binding sites, which fragments comprise a variable heavy domain (VJJ) connected to a variable light domain (VL) in the same polypeptide chain (VJJ - VL).
- VJJ variable heavy domain
- VL variable light domain
- VJJ - VL variable light domain
- Humanized forms of non-human (e.g., rodent) antibodies are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin.
- humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a hypervariable region of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit, or non-human primate having the desired specificity, affinity, and capacity.
- donor antibody such as mouse, rat, rabbit, or non-human primate having the desired specificity, affinity, and capacity.
- framework region " (FR) fesfdue T ⁇ f the human immunoglobulin are replaced by corresponding non-human residues.
- humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine antibody performance.
- the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FRs are those of a human immunoglobulin sequence.
- the humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.
- Fc immunoglobulin constant region
- An "isolated" antibody is one that has been identified and separated and/or recovered from a component of its natural environment. Contaminant components of its natural environment are materials that would interfere with diagnostic or therapeutic uses for the antibody, and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes.
- the antibody will be purified (1) to greater than 95% by weight of antibody as determined by the Lowry method, and most preferably more than 99% by weight, (2) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (3) to homogeneity by SDS-PAGE under reducing or nonreducing conditions using Coomassie blue or, preferably, silver stain.
- Isolated antibody includes the antibody in situ within recombinant cells since at least one component of the antibody's natural environment will not be present. Ordinarily, however, isolated antibody will be prepared by at least one purification step.
- An antibody “that binds" an antigen of interest, e.g.
- TGF-beta antigen is one capable of binding that antigen with sufficient affinity such that the antibody is useful as a therapeutic agent in targeting a cell expressing the antigen.
- the antibody is one that binds TGF-beta
- it will usually preferentially bind TGF- beta as opposed to other members of the TGF-beta superfamily, and may be one that does not significantly cross-react with other proteins of such family such as BMPs, activin, etc.
- the extent of binding of the antibody to these non-TGF-beta proteins will be less than 10% as determined by fluorescence- activated cell sorting (FACS) analysis or radioimmunoprecipitation (RIA).
- an antibody having a "biological characteristic" of a designated antibody is one that possesses one or more of the biological characteristics of that antibody that distinguish it from other antibodies that bind to the same antigen (e.g. TGF-beta).
- an antibody with a biological characteristic of 2G7 may block activation of a TGF-beta, and/or bind the same epitope in the extracellular domain of TGF-beta as that bound by 2G7.
- the expression “monoclonal antibody 2G7” refers to an antibody that has antigen-binding residues of, or derived from, the murine 2G7 antibody of the Examples below.
- the monoclonal antibody 2G7 may be murine monoclonal antibody 2G7 or a variant thereof, such as humanized antibody 2G7, possessing antigen-binding amino acid residues of murine monoclonal antibody 2G7.
- humanized 2G7 antibodies are provided in Example 2 below. Unless indicated otherwise, the expression
- rhuMAb 2G7 when used herein refers to an antibody comprising the variable light (VL) and variable heavy (VH) sequences of SEQ ID NOS:l and 2, respectively, fused to human light and heavy IgGl (non-A allotype) constant-region sequences optionally expressed by a Chinese Hamster Ovary (CHO) cell.
- a “growth-inhibitory agent” when used herein refers to a compound or composition that inhibits growth of a cell, especially a TGF-beta-expressing cancer cell either in vitro or in vivo. Thus, the growth-inhibitory agent may be one that significantly reduces the percentage of TGF-beta-expressing cells in S phase.
- growth-inhibitory agents include agents that block cell-cycle progression (at a place other than S phase), such as agents that induce Gl arrest and M-phase arrest.
- Classical M-phase blockers include the vincas (vincristine and vinblastine), taxanes, and topo II inhibitors such as doxorubicin, epirubicin, daunorubicin, etoposide, and bleomycin.
- Those agents that arrest Gl also spill over into S-phase arrest, for example, DNA-alkylating agents such as tamoxifen, prednisone, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5-fluorouracil, and ara-C.
- growth-inhibitory antibodies are those that bind to TGF-beta and inhibit the growth of cancer cells overexpressing TGF-beta.
- Preferred growth-inhibitory anti-TGF-beta antibodies inhibit growth of SK-BR-3 breast tumor cells in cell culture by greater than 20%, and preferably greater than 50% (e.g.
- the SK-BR-3 cell growth-inhibition assay is described in more detail in that patent.
- An antibody that "induces cell death" is one that causes a viable cell to become nonviable.
- the cell is generally one that expresses the TGF-beta receptor, especially where the cell overexpresses the TGF-beta receptor.
- the cell is a cancer cell, e.g.
- the cell may be a SK-BR-3, BT474, Calu 3, MDA- MB-453, MDA-MB-361 or SKOV3 cell.
- Cell death in vitro may be determined in the absence of complement and immune effector cells to distinguish cell death induced by antibody-dependent cell-mediated cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC).
- ADCC antibody-dependent cell-mediated cytotoxicity
- CDC complement-dependent cytotoxicity
- the assay for cell death may be performed using heat-inactivated serum (i.e. in the absence of complement) and in the absence of immune effector cells.
- Preferred cell-death-inducing antibodies are those that induce PI uptake in the PI uptake assay in BT474 cells (see below).
- An antibody that "induces apoptosis" is one that induces programmed cell death as determined by binding of annexin V, fragmentation of DNA, cell shrinkage, dilation of endoplasmic reticulum, cell fragmentation, and/or formation of membrane vesicles (called apoptotic bodies).
- the cell is usually one that overexpresses the TGF-beta receptor.
- the cell is a tumor cell, e.g., a breast, ovarian, stomach, endometrial, salivary gland, lung, kidney, colon, thyroid, pancreatic or bladder cell.
- the cell may be a SK-BR-3, BT474, Calu 3 cell, MDA-MB-453, MDA-MB-361 or SKOV3 cell.
- Various methods are available for evaluating the cellular events associated with apoptosis.
- phosphatidyl serine (PS) translocation can be measured by annexin binding; DNA fragmentation can be evaluated through DNA laddering; and nuclear/chromatin condensation along with D1STA fragmentation can be evaluated by any increase in hypodiploid cells.
- the antibody that induces apoptosis is one that results in about 2- to 50-fold, preferably about 5- to 50-fold, and most preferably about 10- to 50-fold, induction of annexin binding relative to untreated cells in an annexin-binding assay using BT474 cells (see below).
- the pro-apoptotic antibody will be one that further blocks TGF-beta binding (e.g.2G7 antibody); i.e.
- the antibody shares a biological characteristic with an antibody to TGF-beta.
- the antibody is one that does not significantly block TGF-beta.
- the antibody may be one that, while inducing apoptosis, does not induce a large reduction in the percent of cells in S phase (e.g. one that only induces about 0-10% reduction in the percent of these cells rel tive to control).
- the "epitope 2G7" is the region in the extracellular domain of TGF-beta to which the anti ody 2G7
- TGF-beta antibody refers to an antibody that binds to any of the isoforms of TGF-beta, preferably binding to either TGF-betal, TGF-beta2, or TGF-beta3, or to any combination thereof, more preferably at least TGF-betal, or at least TGF-beta2, and most preferably TGF-betal, or TGF-betal together with TGF-beta2.
- the antibody may bind to at least TGF-beta3.
- Treatment refers to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those already with the disorder as well as those in which the disorder is to be prevented. Hence, the mammal to be treated herein may have been diagnosed as having the disorder or may be predisposed or susceptible to the disorder.
- “Mammal” for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cows, etc.
- the mammal is a primate, such as a monkey, ape, or human, for example, and most preferably a human-.
- TGF-beta disorders or “TGF-beta-related disorders” refers to any disorder, disease, or condition that would benefit from treatment with the anti-TGF-beta antibody. This includes chronic and acute disorders or diseases including those pathological conditions that predispose the mammal to the disorder in question.
- Disorders to be treated herein include diseases characterized by accumulation of extracellular matrix, diseases caused by circulating TGF-beta or TGF-beta activated at a local site, conditions caused by suppression of the immune system due to endogenous TGF-beta production, acute immune deficiencies resulting from severe injuries, burns, and illnesses such as viral or bacterial infections, multi-organ systemic illnesses due to TGF-beta production or overproduction, and TGF-beta-producing tumors.
- Non-limiting specific examples include neuronal, glial, astrocytal, hypothalamic and other glandular, macrophagal, epithelial, stromal and " blastocoelic disorders, fibrosis, scarring, tissue damage such as caused by radiation, and adhesion during wound healing, fibrotic skin disorders such as scleroderma, CNS pathology scar tissue, dermal scarring, keloid scarring, and neural scarring, fibrotic diseases of the peritoneal cavity, lungs, liver, and kidneys such as chronic hepatic fibrosis, acute liver injury, interstitial lung and renal fibrosis, and liver cirrhosis, cystic fibrosis, vascular disorders, e.g., cardiac fibrosis, arterial injury such as atherosclerosis and arteriosclerosis, benign and malignant tumors, certain leukemias not inhibited by TGF-beta, and malignancies (e.g., sarcomas, carcinomas, and melanomas), including
- the disorder is fibrosis, an arterial injury, an infection, rheumatoid arthritis, diabetes or a diabetic condition, or a malignancy, such as cancer that expresses TGF-beta, more preferably wherein the cancer is characterized by excessive activation of TGF-beta.
- cancer may overexpress TGF-beta, or alternatively not be characterized by overexpression of TGF-beta.
- the term "effective amount" refers to an amount of a drug effective to treat a disease or disorder in a mammal
- the therapeutic ally effective amount of the drug may reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to so e extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and/or relieve to some extent one or more of the symptoms associated with the cancer.
- the drug may prevent growth and/or kill existing cancer cells, it may be cytostatic and/or cytotoxic.
- efficacy can, for example, be measured by assessing the time to disease progression (TTP) and/or determining the response rate (RR).
- TTP time to disease progression
- RR response rate
- cancer and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.
- cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More particular examples of such cancers include squamous cell cancer (e.g.
- lung cancer including small- cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary-gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, as well as head and neck cancer.
- lung cancer including small- cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver
- a "TGF-beta-expressing cancer” is one that produces sufficient levels of TGF-beta at the surface of cells thereof, such that an anti-TGF-beta antibody can bind thereto and have a therapeutic effect with respect to the cancer.
- a cancer "characterized by excessive activation" of a TGF-beta receptor is one in which the extent of TGF-beta receptor activation in cancer cells significantly exceeds the level of activation of that receptor in non- cancerous cells of the same tissue type. Such excessive activation may result from overexpression of the TGF- beta receptor and/or greater than normal levels of a TGF-beta ligand available for activating the TGF-beta receptor in the cancer cells.
- Such excessive activation may cause and/or be caused by the malignant state of a cancer cell.
- the cancer will be subjected to a diagnostic or prognostic assay to determine whether amplification and/or overexpression of a TGF-beta receptor is occurring that results in such excessive activation of the TGF-beta receptor.
- the cancer may be subjected to a diagnostic or prognostic assay to determine whether amplification and/or overexpression of a TGF-beta ligand is occurring in the cancer that attributes to excessive activation of the receptor.
- excessive activation of the receptor may result from an autocrine-stimulatory pathway.
- TGF-beta receptor In an "autocrine"-stimulatory pathway, self-stimulation occurs by virtue of the cancer cell producing both a TGF-beta ligand and its cognate TGF-beta receptor.
- the cancer may express or overexpress TGF-beta receptor and also express or overexpress a TGF-beta ligand (e.g. TGF-betal).
- a cancer that "overexpresses" a TGF-beta receptor is one that has significantly higher levels of a TGF- beta receptor, at the cell surface thereof, compared to a non-cancerous cell of the same tissue type. Such overexpression may be caused by gene amplification or by increased transcription or translation.
- TGF-beta receptor overexpression may be determined in a diagnostic or prognostic assay by evaluating increased levels of the TGF-beta protein present on the surface of a cell (e.g. via an immunohistochemistry assay; IHC).
- TGF-beta-encoding nucleic acid may be measured levels of TGF-beta-encoding nucleic acid in the cell, e.g. via fluorescent in situ hybridization (FISH; see WO 1998/45479 published October, 1998), southern blotting, or polymerase chain reaction (PCR) techniques, such as real-time quantitative PCR (RT-PCR).
- FISH fluorescent in situ hybridization
- PCR polymerase chain reaction
- RT-PCR real-time quantitative PCR
- TGF-beta receptor overexpression by measuring shed antigen (e.g., TGF-beta extracellular domain) in a biological fluid such as serum (see, e.g., U. S. Patent No. 4,933,294 issued June 12, 1990; WO 1991/05264 published April 18, 1991; U.S. Patent 5,401,638 issued March 28, 1995; and Sias et al. J.
- a cancer that is "not characterized by overexpression of the TGF-beta receptor” is one that, in a diagnostic assay, does not express higher than normal levels of TGF-beta receptor compared to a non- cancerous cell of the same tissue type.
- a cancer that "overexpresses" a TGF-beta ligand is one that produces significantly higher levels of that ligand compared to a non-cancerous cell of the same tissue type. Such overexpression may be caused by gene amplification or by increased transcription or translation.
- Overexpression of the TGF-beta ligand may be determined diagnostically by evaluating le els of the ligand (or nucleic acid encoding it) in the patient, e.g.
- a "hormone-independent” cancer is one in which proliferation thereof is not dependent on the presence of a hormone that binds to a receptor expressed by cells in the cancer. Such cancers do not undergo clinical regression upon administration of pharmacological or surgical strategies that reduce the hormone concentration in or near the tumor.
- hormone-independent cancers include androgen-independent prostate cancer, estrogen-independent breast cancer, endometrial cancer, and ovarian cancer. Such cancers may begin as hormone-dependent tumors and progress from a hormone-sensitive stage to a hormone-refractory tumor following anti-hormonal therapy.
- cytotoxic agent refers to a substance that inhibits or prevents the function of 211 131 cells and/or causes destruction of cells. The term is intended to include radioactive isotopes (e.g. At , 1 ,
- chemotherapeutic agent is a chemical compound useful in the treatment of cancer.
- chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide (CYTOXANTM); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimetliylolomelamine; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; ⁇ nitrosureas such as carmustine
- paclitaxel TAXOL ® , Bristol-Myers Squibb Oncology, Princeton, NJ
- docetaxel TXOTERE®, Rh ⁇ ne-Poulenc Rorer, Antony, France
- chlorambucil gemcitabine
- 6-thioguanine mercaptopurine
- methotrexate platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoic acid; esperamicins; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above.
- anti-hormonal agents that act to regulate or inhibit hormone action on tumors
- SERMs selective estrogen receptor modulators
- tamoxifen including NOLVADEX® tamoxifen
- raloxifene including NOLVADEX® tamoxifen
- droloxifene 4-hydroxytamoxifen
- trioxifene keoxifene
- LY117018 onapristone
- aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® megestrol acetate, AROMASIN® exemestane, formestanie, fadrozole, RIVISOR® vorozole, FEMARA® letrozole, and ARIMIDEX® anastrozole
- anti-androgens such as flutamide, nil
- EGFR-targeted drug refers to a therapeutic agent that binds to EGFR and, optionally, inhibits EGFR activation.
- agents include antibodies and small molecules that bind to EGFR.
- antibodies that bind to EGFR include MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB8507), MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see U.S. Patent No.
- a "therapeutic agent other than the humanized antibody” refers to any agent that is effective in treating a TGF-beta disorder other than the antibodies herein, and include those types listed below.
- An "anti-angiogenic agent” refers to a compound that blocks, or interferes with, to some degree, the development of blood vessels.
- the anti-angiogenic factor may be, e.g., a small molecule or antibody that binds a growth factor or growth factor receptor involved in promoting angiogenesis.
- VEGF vascular endothelial growth factor
- Examples include antagonists to vascular endothelial growth factor (VEGF), such as antibodies that specifically bind VEGF, e.g., AVASTIN®.
- VEGF vascular endothelial growth factor
- Antibodies that bind to VEGF include chimeric, human and humanized antibodies as well as fragments, and also include antibodies that block or neutralize VEGF or block VEGF binding to one or more VEGF receptors, preferably both receptors.
- regulators of immune function in a mammal refers to cytokines and growth factors that regulate a mammal's immune function, including interleukins, tumor necrosis factor, lymphotoxin, epidermal growth factor, platelet-derived growth factor, TGF- ⁇ , macrophage-migration-inhibitory factor, macrophage-activation factor, fibroblast growth factor, macrophage-activating factors, interferons, and colony- stimulating factors. These regulators may be derived from natural sources, formed by leukocytes, synthesized by chemical methods if appropriate, or prepared recombinantly. Preferred are EL- 1, TL-2, IL-6, and IFN- ⁇ .
- cytokine is a generic term for proteins released by one cell population that act on another cell as intercellular mediators.
- lymphokines include lymphokines, mono ines, and traditional polypeptide hormones. Included among the cytokines are growth hormone such as human growth hormone, N- methionyl human growth hormone, and bovine growth hormone; parathyroid hormone; thyroxine; insulin; proinsulin; relaxin; prorelaxin; glycoprotein hormones such as follicle-stimulating hormone (FSH), thyroid- stimulating hormone (TSH), and luteinizing hormone (LH); hepatic growth factor; fibroblast growth factor; prolactin; placental lactogen; tumor necrosis factor- ⁇ and - ⁇ ; mullerian-inhibiting substance; mouse gonadotropin-associated peptide; inhibin; activin; vascular endothelial growth factor; integrin; thrombopoietin (TPO); nerve growth factors such as NGF- ⁇ ; platelet
- cytokine includes proteins from natural sources or from recombinant cell culture and biologically active equivalents of the native-sequence cytokines.
- prodrug refers to a precursor or derivative form of a pharmaceutically active substance that is less cytotoxic to tumor cells compared to the parent drug and is capable of being enzymatically activated or converted into the more active parent form. See, e.g., Wilman, "Prodrugs in Cancer Chemotherapy" Biochemical Society Transactions, 14, pp.
- the prodrugs of this invention include, but are not limited to, phosphate-containing prodrugs, thiophosphate-containing prodrugs, sulfate-containing prodrugs, peptide- containing prodrugs, D-amino acid-modified prodrugs, glycosylated prodrugs, ⁇ -lactam-containing prodrugs, optionally substituted phenoxyacetamide-containing prodrugs or optionally substituted phenylacetamide- containing prodrugs, 5-fluorocytosine, and other 5-fluorouridine prodrugs that can be converted into the more active cytotoxic free drug.
- a "liposome” is a small vesicle composed of various types of lipids, phospholipids, and/or surfactant that is useful for delivery of a drug (such as the anti-TGF-beta antibodies disclosed herein and, optionally, a chemotherapeutic agent) to a mammal
- a drug such as the anti-TGF-beta antibodies disclosed herein and, optionally, a chemotherapeutic agent
- the components of the liposome are comrrionly arranged in a bilayer formation, similar to the lipid arrangement of biological membranes.
- package insert is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications, and/or warnings concerning the use of such therapeutic products .
- a "cardioprotectant” is a compound or composition that prevents or reduces myocardial dysfunction
- cardiomyopathy and/or congestive heart failure associated with administration of a drug, such as an anthracycline antibiotic and/or an anti-TGF-beta antibody, to a patient.
- the cardioprotectant may, for example, block or reduce a free-radical-mediated cardiotoxic effect and/or prevent or reduce oxidative-stress injury.
- cardioprotectants encompassed by the present definition include the iron-chelating agent dexrazoxane (TCRF-187) (Seifert ' et al. The Annals of Pharmacotherapy, 28: 1063-1072 (1994)); a. lipid- lowering agent and/or anti-oxidant such as probucol (Singal et al, J.
- amifostine (aminothiol 2-[(3-aminopropyl)amino]ethanethiol-dihydrogen phosphate ester, also called WR-2721, and the dephosphorylated cellular uptake form thereof called WR-1065) and 5-3-(3- methylaminopropylamino)propylphosphorothioic acid (WR-151327), see Green et al, Cancer Research, 54: 738-741 (1994); digoxin (Bristow, M.R. In: Bristow MR, ed.
- beta-blockers such as metoprolol (Hjalmarson et al, Drugs, 4J:Suppl 4:31-9 (1994); and Shaddy et al, Am.
- vitamin E ascorbic acid (vitamin C); free-radical scavengers such as oleanolic acid, ursolic acid, and N-acetylcysteine (NAC); spin-trapping compounds such as alpha- phenyl-tert-butyl nitrone (PBN) (Paracchini et al, Anticancer Res., 13: 1607-1612 (1993)); selenoorganic compounds such as P251 (Elbesen); and the like.
- PBN alpha- phenyl-tert-butyl nitrone
- P251 Elbesen
- an "isolated" nucleic acid molecule is a nucleic acid molecule that is identified and separated from at least one contaminant nucleic acid molecule with which it is ordinarily associated in the natural source of the antibody-encoding nucleic acid.
- An isolated nucleic acid molecule is other than in the form or setting in which it is found in nature. Isolated nucleic acid molecules therefore are distinguished from the nucleic acid molecule as it exists in natural cells.
- an isolated nucleic acid molecule includes a nucleic acid molecule contained in cells that ordinarily express the antibody where, for example, the nucleic acid molecule is in a cxiromosomal location different from that of natural cells.
- control sequences refers to DNA sequences necessary for the expression of an operably linked coding sequence in a particular host organism.
- the control sequences that are suitable for prokaryotes include a promoter, optionally an operator sequence, and a ribosome-birading site.
- Eukaryotic cells are known to utilize promoters, polyadenylation signals, and enhancers.
- Nucleic acid is "operably linked” when it is placed into a functional relationship with another nucleic acid sequence.
- DNA for a presequence or secretory leader is operably linked to DN-A for a polypeptide if it is expressed as a preprotein that participates in the secretion of the polypeptide; a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence; or a ribosome- binding site is operably linked to a coding sequence if it is positioned so as to facilitate translation-.
- "operably linked" means that the DNA sequences being linked are contiguous, and, in the case of a secretory leader, contiguous and in reading phase. However, enhancers do not have to be contiguous. Linking is accomplished by ligation at convenient restriction sites.
- the synthetic oligonucleotide adaptors or linkers are used in accordance with conventional practice.
- the expressions "cell,” “cell line,” and “cell culture” are used interchange ably and all such designations include progeny.
- the words “transformants” and “transformed cells” include the primary subject cell and cultures derived therefrom without regard for the number of transfers. It is also understood that all progeny may not be precisely identical in DNA content, due to deliberate or inadvertent mutations. Mutant progeny that have the same function or biological activity as screened for in thte originally transformed cell are included. Where distinct designations are intended, it will be clear from the context.
- body sample refers to any liquid or biological sample that contains or may contain the TGF-beta to be detected.
- the sample includes fluids such as human or animal body fluids, e.g., blood, serum, urine, amniotic fluid, tissue extracts, cerebrospinal fluid, and the like.
- the samples may require special treatment such as extraction before being analyzed, depending on the tendency of the components contained therein toward lability, aggregation, or absorption by the storage container.
- II. Production of Humanized anti-TGF-beta Antibodies Methods for humanizing non-human antibodies have been described in the art. Preferably, a humanized antibody has one or more amino acid residues introduced into it from a source that is non-human.
- humanized antibodies are typically human antibodies in which some hypervariable region residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies.
- Another method for making humanized antibodies is described in U.S. Patent Publication 2003/0017534 published January 23, 2003, wherein humanized antibodies and antibody preparations are produced from transgenic non-human animals.
- the non-human animals are genetically engineered to contain. one or more humanized immunoglobulin loci that are capable of undergoing gene rearrangement and gene conversion in the transgenic non-human animals to produce diversified humanized immunoglobulins.
- the choice of human variable domains, both light and heavy, to be used in making the humanized antibodies is very important to reduce antigenicity.
- the sequence of the variable domain of a rodent antibody is screened against the entire library of known human variable- domain sequences.
- the human sequence that is closest to that of the rodent is then accepted as the human framework region (FR) for the humanized antibody (Sims et al, J. Immunol, 151: 2296 (1993); Chothia et al, J. Mol. Biol, 196: 901 (1987)).
- Another method uses a particular framework region derived from the consensus sequence of all human antibodies of a particular subgroup of light or heavy chains. The same framework may be used for several different humanized antibodies (Carter et al, Proc. Natl Acad. Sci.
- humanized antibodies are prepared by a process of analysis of the parental sequences and various conceptual humanized products using three-dimensional models of the parental and humanized sequences. Three-dimensional immunoglobulin models are commonly available and are familiar to those skilled in the art. Computer programs are available that illustrate and display probable three-dimensional conformational structures of selected candidate immunoglobulin sequences.
- the humanized antibody herein comprises non-human hypervariable region residues incorporated into a human variable heavy domain and further comprises a framework region (FR) substitution at a position selected from the group consisting of 48, 49, 67, 69, 71, 73, and 78, utilizing the variable domain numbering system set forth in Kabat et al, supra.
- the humanized antibody comprises FR substitutions at two or more of positions 48, 49, 67, 69, 71, 73, and 78; and in other embodiments, at three or four or more of such positions.
- the antibody comprises FR substitutions at positions 49, 67 and 71, or positions 48, 49 and 71, or positions 49, 69, and 71, or positions 49, 69, 71, and 73, or positions 49, 71, and 73, or positions 49, 71, and 78. It is preferred that there are fewer rather than more framework substitutions to minimize immunogenicity, but efficacy is also a very important consideration.
- the amino acids actually substituted are those that are preferably conserved so as not to change the immunogenicity or efficacy.
- the change is preferably from valine to isoleucine, at position 49, the change is preferably from alanine to glycine, at position 67, the change is preferably phenylalanine to alanine, at position 69, the change is preferably phenylalanine to alanine, at position 71, the change is preferably arginine to alanine, at position 73, the change is preferably asparagine to lysine, and at position 78, the change is preferably leucine to alanine.
- An exemplary humanized antibody of interest herein comprises variable heavy-domain complementarity-determining residues GYAFTNYLIE (SEQ ID NO:41); VNNPGSGGSNYNEKFKG (SEQ ID NO:42) or VTNPGSGGSNYNEKFKG (SEQ ID NO:43); and/or SGGFYFDY (SEQ ID NO:44), optionally comprising amino acid modifications of those CDR residues, e.g. where the modifications essentially maintain or improve affinity of the antibody.
- the antibody variant of interest may have from about one to about seven or about five amino acid substitutions in the above variable heavy CDR sequences.
- Such antibody variants may be prepared by affinity maturation, e.g., as described below.
- the residues are two or more of GYAFTNYLIE (SEQ ID NO:41); VNNPGSGGSNYNEKFKG (SEQ ID NO:42) or
- the most preferred humanized antibody comprises the variable heavy-domain amino acid sequence in SEQ ID NO:4 or the one with GYAFTNYLIE (SEQ ID NO:41); V ⁇ NPGSGGSNYNEKFKG (SEQ ID NO:43); and SGGFYFDY (SEQ ID NO:44).
- the humanized antibody may comprise variable light-domain complementarity-determining residues
- Such humanized antibodies optionally comprise amino acid modifications of the above CDR residues, e.g. where the modifications essentially maintain or improve affinity of the antibody.
- the antibody variant of interest may have from about one to about seven or about five amino acid substitutions in the above variable light CDR sequences.
- Such antibody variants may be prepared by affinity maturation, e.g., as described below.
- the residues are two or more of RASQSVLYSSNQKNYLA (SEQ ID NO:36); WASTRES (SEQ ID NO:38); and/or HQYLSSDT (SEQ ID NO:40), most preferably all three.
- the most preferred humanized antibody comprises the variable light- domain amino acid sequence in SEQ ID NO:3.
- the present application also contemplates affinity-matured antibodies that bind TGF-beta.
- the parent antibody may be a human antibody or a humanized antibody, e.g., one comprising the variable light and/or heavy sequences of SEQ ID NOS:3 and 4, respectively (i.e. Version 5).
- the affinity-matured antibody preferably binds to TGF-beta with an affinity superior to that of murine 2G7 or variant 5 (e.g. from about two- or about four-fold, to about 100-fold or about 1000-fold improved affinity, e.g. as assessed using a TGF-beta- extracellular domain (ECD) ELISA).
- TGF-beta- extracellular domain (ECD) ELISA TGF-beta- extracellular domain
- the humanized antibody or affinity-matured antibody may be an antibody fragment, such as a Fab, that is optionally conjugated with one or more cytotoxic agent(s) in order to generate an immunoconjugate.
- the humanized antibody or affinity-matured antibody may be an intact antibody, such as an intact IgGl antibody.
- Various techniques have been developed for the production of antibody fragments of humanized antibodies. Traditionally, these fragments were derived via proteolytic digestion of intact antibodies (see, e.g., Morimoto etal, Journal of Biochemical and Biophysical Methods, 24:107-117 (1992); and Brennan et al, Science. 229:81 (1985)). However, these fragments can now be produced directly by recombinant host cells. For example, the antibody fragments can be isolated from the antibody phage libraries discussed above.
- Fab'-SH fragments can be directly recovered from E. coli and chemically coupled to form F(ab')2 fragments (Carter et al, Bio/Technology, 10:163-167 (1992)).
- F(ab')2 fragments can be isolated directly from recombinant host cell culture.
- the antibody of choice is a single-chain Fv fragment (scFv). See WO 1993/16185; U.S. Patent No. 5,571,894; and U.S. Patent No. 5,587,458.
- the antibody fragment may also be a "linear antibody", e.g., as described in U.S.
- Such linear antibody fragments may be monospecific or bispecific.
- Bispecific antibodies are antibodies that have binding specificities for at least two different epitopes.
- Exemplary bispecific antibodies may bind to two different epitopes of the TGF-beta protein.
- Other such antibodies may combine a TGF-beta binding site with binding site(s) for HER-2, EGFR, ErbB, ErbB3, and/or ErbB4.
- an anti-TGF-beta arm may be combined with an arm that binds to a triggering molecule on a leukocyte such as a T-cell receptor molecule (e.g. CD2 or CD3), or Fc receptors for IgG (Fc ⁇ R), such as
- Bispecific antibodies may also be used to localize cytotoxic agents to cells that express TGF- beta. These antibodies possess a TGF-beta-binding arm and an arm that binds the cytotoxic agent (e.g. saporin, anti-interferon- ⁇ , vinca alkaloid, ricin A chain, methotrexate, or radioactive isotope hapten). Bispecific antibodies can be prepared as full-length antibodies or antibody fragments (e.g. F(ab') 2 bispecific antibodies).
- WO 1996/16673 describes a bispecific anti-TGF-beta/anti-Fc ⁇ RIII antibody and U.S. Patent No. 5,837,234 discloses a bispecific anti-TGF-beta/anti-Fc ⁇ RI antibody.
- a bispecific anti-TGF-beta/Fc ⁇ antibody is shown in WO 1998/02463.
- U.S. Patent No. 5,821,337 teaches a bispecific anti-TGF-beta/anti-CD3 antibody. Methods for making bispecific antibodies are known in the art.
- antibody-variable domains with the desired binding specificities are fused to immunoglobulin constant-domain sequences.
- the fusion preferably is with an immunoglobulin heavy-chain constant domain, comprising at least part of the hinge, CH2, and CH3 regions. It is preferred to have the first heavy-chain constant region (CHI) containing the site necessary for light-chain binding, present in at least one of the fusions.
- CHI first heavy-chain constant region
- the bispecific antibodies are composed of a hybrid immunoglobulin heavy chain with a first binding specificity in one arm, and a hybrid immunoglobulin heavy- chain-light-chain pair (providing a second binding specificity) in the other arm.
- the interface between a pair of antibody molecules can be engineered to maximize the percentage of heterodimers that are recovered from recombinant cell culture.
- the preferred interface comprises at least a part of the CH3 domain of an antibody constant domain.
- bispecific antibodies include cross-linked or "heteroconjugate" antibodies.
- one of the antibodies in the heteroconjugate can be coupled to avidin, the other to biotin.
- Such antibodies have, for example, been proposed to target immune system cells to unwanted cells (U.S. Patent No. 4,676,980), and for treatment of HIV infection (WO 1991/00360, WO 1992/200373, and EP 03089).
- Heteroconjugate antibodies may be made using any convenient cross-linlang methods. Suitable cross-linking agents are well known in the art, and are disclosed, for example, in U.S. Patent No. 4,676,980, along with a number of cross-linking techniques. Techniques for generating bispecific antibodies from antibody fragments have also been described in the literature. For example, bispecific antibodies can be prepared using chemical linkage.
- F(ab')2 fragments These fragments are reduced in the presence of the dithiol complexing agent sodium arsenite to stabilize vicinal dithiols and prevent intermolecular disulfide formation.
- the Fab' fragments generated are then converted to thionitrobenzoate (TNB) derivatives.
- TNB thionitrobenzoate
- One of the Fab'-TNB derivatives is then reconverted to the Fab -thiol by reduction with mercaptoethylamine and is mixed with an equimolar amount of the other Fab'- TNB derivative to form the bispecific antibody.
- the bispecific antibodies produced can be used as agents for the selective immobilization of enzymes. Recent progress has facilitated the direct recovery of Fab'-SH fragments from E.
- bispecific antibody F(ab')2 Each Fab' fragment was separately secreted from E. coli and subjected to directed chemical coupling in vitro to form the bispecific antibody.
- the bispecific antibody thus formed was able to bind to cells overexpressing the TGF-beta receptor and normal human T cells, as well as trigger the lytic activity of human cytotoxic lymphocytes against human breast tumor targets.
- TGF-beta receptor and normal human T cells
- bispecific antibodies have been produced using leucine zippers.
- the leucine zipper peptides from the Fos and Jun proteins were linked to the Fab' portions of two different antibodies by gene fusion.
- the antibody homodimers were reduced at the hinge region to form monomers and then re-oxidized to form the antibody heterodimers.
- This method can also be utilized for the production of antibody homodimers.
- the "diabody” technology described by Hollinger et al, Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993) has provided an alternative mechanism for making bispecific antibody fragments.
- the fragments comprise a heavy-chain variable domain (VJJ) connected to a light-chain variable domain (VL) by a linker that is too short to allow pairing between the two domains on the same chain. Accordingly, the VH and VL domains of one fragment are forced to pair with the complementary VL and VJJ domains of another fragment, thereby forming two antigen- binding sites.
- VJJ heavy-chain variable domain
- VL light-chain variable domain
- Another strategy for making bispecific antibody fragments by the use of single-chain Fv (sFv) dimers has also been reported. See Gruber et al, J. Immunol, 152:5368 (1994). Antibodies with more than two valencies are contemplated. For example, trispecific antibodies can be prepared. Tutt et al, J. Immunol.
- the antibody is thus able to block the activity of all endogenous TGF-beta 3 produced by tumors and suppressor lymphoid cells (T cells).
- One way to measure such neutralization is by H- thymidine uptake inhibition of a mink lung fibroblast cell line, e.g., Mv-3D9, wherein as the concentration of the antibody is increased, the activity of the TGF-beta is steadily decreased, either linearly or non-linearly.
- the mink lung cell line is very sensitive to the growth-inhibitory effects of TGF-beta and is a relatively easy assay to perform.
- the assay is performed by incubating the cells with a mixture of a TGF-beta and the antibody in minimal essential media containing 2mM glutamine and 5% fetal bovine serum for 18-24 hours at 3 37°C in 5% C0 2 and then pulsing with 1 ⁇ Ci of H-thymidine in 20 ⁇ l and harvesting after four hours at 37°C.
- the antibody will be able to inhibit cell proliferation by TGF-beta to a greater extent than monoclonal antibody 2G7.
- Another way to assess growth-inhibitory effects of the antibody is to test whether it inhibits TGF-beta in a mouse mesangial cell-proliferation assay as set forth in the Examples below.
- the antibodies herein are also useful in a receptor-binding or radioreceptor assay in a conventional manner, as by incubating a mixture of radiolabeled TGF-beta (e.g., radioiodinated rhTGF-betal) and the antibody with cells containing the TGF-beta receptor (e.g., mink lung fibroblast cells such as the MvlLu cell line, which is available from the ATCC as ATCC No. CCL-64), and determining if the antibody blocks binding of the labeled TGF-beta to the receptor.
- TGF-beta receptor e.g., mink lung fibroblast cells such as the MvlLu cell line, which is available from the ATCC as ATCC No. CCL-64
- loss of membrane integrity as indicated by, e.g., PI, trypan blue or 7AAD uptake may be assessed relative to control.
- the preferred assay is the PI uptake assay using BT474 cells. According to this
- D-MEM Dulbecco's Modified Eagle Medium
- F-12 50:50
- heat-inactivated FBS heat-inactivated FBS
- 2 mM L-glutamine 2 mM L-glutamine.
- the BT474 cells are seeded at a density of 3 x 10 per dish in 100 x 20-mm dishes and allowed to attach overnight. The medium is then removed and replaced with fresh medium alone or medium containing 10 ⁇ g/ml of the appropriate monoclonal antibody. The cells are incubated for a 3-day time period.
- Those antibodies that induce statistically significant levels of cell death as determined by PI uptake may be selected as cell-death-inducing antibodies.
- an annexin-binding assay using BT474 cells is available. The BT474 cells are cultured and seeded in dishes as discussed in the preceding paragraph.
- the medium is then removed and replaced with fresh medium alone or medium containing 10 ⁇ g/ml of the monoclonal antibody. Following a three-day incubation period, monolayers are washed with PBS and detached 2+ by trypsinization. Cells are then centrifuged, resuspended in Ca binding buffer and aliquoted into tubes as discussed above for the cell-death assay. Tubes then receive labeled annexin (e.g. annexin V-FTIC) (l ⁇ g/ml). Samples may be analyzed using a FACSCANTM flow cytometer and FACSCONVERTTM CellQuest software (Becton Dickinson).
- annexin e.g. annexin V-FTIC
- Those antibodies that induce statistically significant levels of annexin binding relative to control are selected as apoptosis-inducing antibodies.
- a DNA-staining assay using BT474 cells is available.
- BT474 cells that have been treated with the antibody of interest as described in the preceding two paragraphs are incubated with 9 ⁇ g/ml HOECHST 33342TM fluorescence probe for 2 hr at 37°C, then analyzed on an EPICS ELITETM flow cytometer (Coulter Corporation) using MODFIT LTTM software (Verity Software House).
- Antibodies that induce a change in the percentage of apoptotic cells that is 2-fold or greater (and preferably 3- fold or greater) than untreated cells (up to 100% apoptotic cells) may be selected as pro-apoptotic antibodies using this assay.
- a routine cross-blocking assay such as that described in Antibodies. A Laboratory Manual, Cold Spring Harbor Laboratory, Ed Harlow and David Lane (1988), can be performed.
- epitope mapping can be performed by methods known in the art.
- the invention also pertains to immunoconjugates comprising an antibody conjugated to a cytotoxic agent such as a chemotherapeutic agent, toxin (e.g. a small-molecule toxin or an enzymatically active toxin of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof), or a radioactive isotope (i.e., a radioconjugate).
- a cytotoxic agent such as a chemotherapeutic agent, toxin (e.g. a small-molecule toxin or an enzymatically active toxin of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof), or a radioactive isotope (i.e., a radioconjugate).
- chemotherapeutic agent e.g. a small-molecule toxin or an enzymatically active toxin of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof
- the antibody is conjugated to one or more maytansine molecules (e.g. about 1 to about 10 maytansine molecules per antibody molecule).
- Maytansine may, for example, be converted to May-SS-Me, which may be reduced to May-SH3 and reacted with modified antibody (Chari et al, Cancer Research, 52: 127-131 (1992)) to generate a maytansinoid-antibody immunoconjugate.
- Another immunoconjugate of interest comprises an anti-TGF-beta antibody conjugated to one or more calicheamicin molecules.
- the calicheamicin family of antibiotics is capable of producing double-stranded DNA breaks at sub-picomolar concentrations.
- Structural analogues of calicheamicin that may be used include, but are not limited to, ⁇ i , ⁇ 2 , ⁇ 3 , N-acetyl- ⁇ i , PSAG and ⁇ ⁇ (Hinman et al. Cancer Research. 53: 3336-3342 (1993) and Lode et al. Cancer Research, 58: 2925-2928 (1998)). See, also, US Patent Nos. 5,714,586; 5,712,374; 5,264,586; and 5,773,001 expressly incorporated herein by reference.
- Enzymatically active toxins and fragments thereof that can be used include diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, ge ⁇ onin, mitogellin, restrictocin, phenomycin, enomycin and the tricothecenes.
- the present invention further contemplates an immunoconjugate formed between an antibody and a compound with nucleofytic activity (e.g. a ribonuclease or a DNA endonuclease such as a deoxyribonuclease; DNase).
- a compound with nucleofytic activity e.g. a ribonuclease or a DNA endonuclease such as a deoxyribonuclease; DNase.
- a variety of radioactive isotopes are available for the production of radioconjugated anti-TGF-beta ant *i-bod Ai-es.
- E Dxampl Ies i -ncl 1ud Ae A At.
- Conjugates of the antibody and cytotoxic agent may be made using a variety of bifunctional protein coupling agents such as N-succinimidyl-3-(2-pyridyldithiol) propionate (SPDP), succinimidyl-4-(N- malei ⁇ domethyl) cyclohexane-1-carboxylate, iminothiolane (LT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HC1), active esters (such as disuccinimidyl suberate), aldehydes (such as glutareldehyde), bis-azido compounds (such as bis (p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as tolyene 2,6-diisocyanate), and bis- active fluorine compounds (such as l
- a ricin immunotoxin can be prepared as described in Vitetta et al. Science, 238: 1098 (1987).
- Carbon- 14-labeled l-isothiocyanatobenzyl-3- methyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionucleotide to the antibody. See WO 1994/11026.
- the linker may be a "cleavable linker" facilitating release of the cytotoxic drug in the cell.
- an acid-labile linker, peptidase-sensitive linker, dimethyl linker, or disulfide-containing linker (Chari et al. Cancer Research.
- a fusion protein comprising the anti-TGF-beta antibody and cytotoxic agent may be made, e.g. by recombinant techniques or peptide synthesis.
- the antibody may be conjugated to a "receptor” (such as streptavidin) for utilization in tumor pretargeting wherein the antibody-receptor conjugate is administered to the patient, followed by removal of unbound conjugate from the circulation using a clearing agent and then administration of a "ligand” (e.g. avidin) that is conjugated to a cytotoxic agent (e.g. a radionucleotide).
- a receptor such as streptavidin
- the antibodies of the present invention may also be used in ADEPT by conjugating the antibody to a prodrug-activating enzyme that converts a prodrug (e.g. a peptidyl chemotherapeutic agent, see WO 1981/01145) to an active anti-cancer drug.
- a prodrug e.g. a peptidyl chemotherapeutic agent, see WO 1981/01145
- the enzyme component of the immunoconjugate useful for ADEPT includes any enzyme capable of acting on a prodrug in such a way so as to convert it into its more active, cytotoxic form.
- Enzymes that are useful in the method of this invention include, but are not limited to, alkaline phosphatase useful for converting phosphate-containing prodrugs into free drugs; arylsulfatase useful for converting sulfate-containing prodrugs into free drugs; cytosine deaminase useful for converting non-toxic 5- fluorocytosine into the anti-cancer drug, 5-fluorouracil; proteases, such as serratia protease, thermolysin, subtilisin, carboxypeptidases and cathepsins (such as cathepsins B and L), that are useful for converting peptide- containing prodrugs into free drugs; D-alanylcarboxypeptidases, useful for converting prodrugs that contain D- amino acid substituents; carbohydrate-cleaving enzymes such as ⁇ -galactosidase and neuraminidase useful for converting glycosylated prodrugs into free drugs; ⁇ -
- antibodies with enzymatic activity can be used to convert the prodrugs of the invention into free active drugs (see, e.g., Massey, Nature, 328:457-458 (1987)).
- Antibody-abzyme conjugates can be prepared as described herein for delivery of the abzyme to a tumor cell population.
- the enzymes useful in this invention can be covalently bound to the anti-TGF-beta antibodies by techniques well known in the art such as the use of the heterobifunctional crosslinking reagents discussed above.
- fusion proteins comprising at least the antigen-binding region of an antibody of the invention linked to at least a functionally active portion of a suitable enzyme can be constructed using recombinant DNA techniques well known in the art (see, e.g., Neuberger et al, Nature, 312: 604-608 (1984)).
- Other modifications of the antibody are contemplated herein.
- the antibody may be linked to one of a variety of nonproteinaceous polymers, e.g. , polyethylene glycol, polypropylene glycol, polyoxyalkylenes, or copolymers of polyethylene glycol and polypropylene glycol.
- the antibody also may be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively), in colloidal drug-delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules), or in macroemulsions.
- colloidal drug-delivery systems for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules
- macroemulsions for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules.
- the anti-TGF-beta antibodies disclosed herein may also be formulated as immunoliposomes.
- Liposomes containing the antibody are prepared by methods known in the art, such as described in Epstein et al, Proc. Natl Acad. Sci. USA, 82:3688 (1985); Hwang et al, Proc. Natl Acad. Sci. USA.22:4030 (1980); U.S. Pat. Nos. 4,485,045 and 4,544,545; and WO 1997/38731 published October 23, 1997. Liposomes with enhanced circulation time are disclosed in U.S. Patent No. 5,013,556. Particularly useful liposomes can be generated by the reverse-phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol and PEG-derivatized phosphatidylethanolamine (PEG- PE).
- PEG- PE PEG-derivatized phosphatidylethanolamine
- Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter.
- Fab' fragments of the antibody of the present invention can be conjugated to the liposomes as described in Martin et al. J. Biol Chem.. 257: 286-288 (1982) via a disulfide-interchange reaction.
- a chemotherapeutic agent is optionally contained within the liposome. See Gabizon et al, J. National Cancer Inst. 81.(19): 1484 (1989). III.
- the invention also provides isolated nucleic acid encoding the humanized anti-TGF-beta antibody, vectors and host cells comprising the nucleic acid, and recombinant techniques for the production of the antibody.
- the nucleic acid encoding it is isolated and inserted into a replicable vector for further cloning (amplification of the DNA) or for expression.
- DNA encoding the monoclonal antibody is readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of the antibody). Many vectors are available.
- the vector components generally include, but are not limited to, one or more of the following: a signal sequence, an origin of replication, one or more marker genes, an enhancer element, a promoter, and a transcription-termination sequence.
- a signal sequence an origin of replication
- marker genes an enhancer element
- a promoter an enhancer element
- a transcription-termination sequence a transcription-termination sequence.
- the anti-TGF-beta antibody of this invention may be produced recombinantly not only directly, but also as a fusion polypeptide with a heterologous polypeptide, which is preferably a signal sequence or other polypeptide having a specific cleavage site at the N-terminus of the mature protein or polypeptide.
- the heterologous signal sequence selected preferably is one that is recognized and processed (i.e., cleaved by a signal peptidase) by the host cell.
- the signal sequence is substituted by a prokaryotic signal sequence selected, for example, from the group of the alkaline phosphatase, penicillinase, lpp, or heat-stable enterotoxin II leaders.
- a prokaryotic signal sequence selected, for example, from the group of the alkaline phosphatase, penicillinase, lpp, or heat-stable enterotoxin II leaders.
- yeast secretion the native signal sequence may be substituted by, e.g., the yeast invertase leader, ⁇ -factor leader (including Saccharomyces and Kluyveromyces ⁇ -factor leaders), acid-phosphatase leader, the C. albicans glucoamylase leader, or the signal described in WO 1990/13646.
- mammalian signal sequences as well as viral secretory leaders, for example, the herpes simplex gD signal, are available.
- the DNA for such precursor region is ligated in reading frame to DNA encoding the anti-TGF-beta antibody.
- Origin of replication component Both expression and cloning vectors contain a nucleic acid sequence that enables the vector to replicate in one or more selected host cells. Generally, in cloning vectors this sequence is one that enables the vector to replicate independently of the host chromosomal DNA, and includes origins of replication or autonomously replicating sequences. Such sequences are well known for a variety of bacteria, yeast, and viruses.
- the origin of replication from the plasmid pBR322 is suitable for most Gram-negative bacteria, the 2 ⁇ plasmid origin is suitable for yeast, and various viral origins (SV40, polyoma, adenovirus, VSV or BPV) are useful for cloning vectors in mammalian cells.
- the origin of replication component is not needed for mammalian expression vectors (the SV40 origin may typically be used only because it contains the early promoter).
- Selection gene component may contain a selection gene, also termed a selectable marker.
- Typical selection genes encode proteins that (a) confer resistance to antibiotics or other toxins, e.g., ampicillin, neomycin, methotrexate, or tetracycline, (b) complement auxofrophic deficiencies, or (c) supply critical nutrients not available from complex media, e.g., the gene encoding D-alanine racemase for Bacilli.
- antibiotics or other toxins e.g., ampicillin, neomycin, methotrexate, or tetracycline
- b complement auxofrophic deficiencies
- c supply critical nutrients not available from complex media, e.g., the gene encoding D-alanine racemase for Bacilli.
- One example of a selection scheme utilizes a drug to arrest growth of a host cell. Those cells that are successfully transformed with a heterologous gene produce a protein conferring drug resistance and thus survive the selection regimen. Examples of such dominant selection use the drugs neomycin, mycophenolic acid and
- suitable selectable markers for mammalian cells are those that enable the identification of cells competent to take up the anti-TGF-beta antibody-encoding nucleic acid, such as DHFR, thymidine kinase, metallothionein-I and -II, preferably primate metallothionein genes, adenosine deaminase, ornithine decarboxylase, etc.
- DHFR thymidine kinase
- metallothionein-I and -II preferably primate metallothionein genes, adenosine deaminase, ornithine decarboxylase, etc.
- DHFR selection gene are first identified by culturing all of the transformants in a culture medium that contains methotrexate (Mtx), a competitive antagonist of DHFR.
- Mtx methotrexate
- An appropriate host cell when wild-type DHFR is employed is the Chinese hamster ovary (CHO) cell line deficient in DHFR activity.
- host cells particularly wild-type hosts that contain endogenous DHFR transformed or co- transformed with DJNA sequences encoding anti-TGF-beta antibody, wild-type DHFR protein, and another selectable marker such as aminoglycoside 3'-phosphotransferase (APH) can be selected by cell growth in medium containing a selection agent for the selectable marker such as an aminoglycosidic antibiotic, e.g., kanamycin, neomycin, or G418. See U.S. Patent No. 4,965,199.
- a suitable selection gene for use in yeast is the trpl gene present in the yeast plasmid YRp7 (Stinchcomb et al, Nature, 282:39 (1979)).
- the trpl gene provides a selection marker for a mutant strain of yeast lacking the ability to grow in tryptophan, for example, ATCC No. 44076 or PEP4-1. Jones, Genetics, 85: 12 (1977).
- the presence of the trpl lesion in the yeast host cell genome then provides an effective environment for detecting transformation by growth in the absence of tryptophan.
- LeM2-deficient yeast strains (ATCC 20,622 or 38,626) are complemented by known plasmids bearing the Leu2 gene.
- vectors derived from the 1.6- ⁇ m circular plasmid pKDl can be used for transformation of Kluyveromyces yeasts.
- an expression system for large-scale production of recombinant calf chymosin was reported for K. lactis. Van den Berg, Bio/Technology, 8:135 (1990).
- Stable multi-copy expression vectors for secretion of mature recombinant human serum albumin by industrial strains of Kluyveromyces have also been disclosed. Fleer et al, Bio/Technology, 9: 968-975 (1991).
- Promoter component Expression and cloning vectors usually contain a promoter that is recognized by the host organism and is operably linked to the anti-TGF-beta antibody-encoding nucleic acid.
- Promoters suitable for use with prokaryotic hosts include the phoA promoter, ⁇ -lactamase and lactose promoter systems, alkaline phosphatase, a tryptophan (trp) promoter system, and hybrid promoters such as the tac promoter.
- trp tryptophan
- Other known bacterial promoters are suitable. Promoters for use in bacterial systems also will contain a Shine-Dalgarno (S.D.) sequence operably linked to the DNA encoding the anti-TGF-beta antibody.
- Promoter sequences are known for eukaryotes. Virtually all eukaryotic genes have an AT-rich region located approximately 25 to 30 bases upstream from the site where transcription is initiated. Another sequence found 70 to 80 bases upstream from the start of transcription of many genes is a CNCAAT (SEQ ID NO:47) region where N may be any nucleotide. At the 3' end of most eukaryotic genes is an AATAAA (SEQ ID NO:48) sequence that may be the signal for addition of the poly A tail to the 3' end of the coding sequence. All of these sequences are suitably inserted into eukaryotic expression vectors.
- suitable promoting sequences for use with yeast hosts include the promoters for 3- phosphoglycerate inase or other glycolytic enzymes, such as enolase, glyceraldehyde-3-phosphate dehydrogenase, hexokinase, pyruvate decarboxylase, phosphofructokinase, glucose-6-phosphate isomerase, 3- phosphoglycerate mutase, pyruvate kinase, triosephosphate isomerase, phosphoglucose isomerase, and glucokinase.
- promoters for 3- phosphoglycerate inase or other glycolytic enzymes such as enolase, glyceraldehyde-3-phosphate dehydrogenase, hexokinase, pyruvate decarboxylase, phosphofructokinase, glucose-6-phosphate isomerase, 3- phosphoglycerate mutase,
- yeast promoters which are inducible promoters having the additional advantage of transcription controlled by growth conditions, are the promoter regions for alcohol dehydrogenase 2, isocytochrome C, acid phosphatase, degradative enzymes associated with nitrogen metabolism, metallothionein, glyceraldehyde-3- phosphate dehydrogenase, and enzymes responsible for maltose and galactose utilization.
- Suitable vectors and promoters for use in yeast expression are further described in EP 73,657.
- Yeast enhancers also are advantageously used with yeast promoters.
- Anti-TGF-beta antibody transcription from vectors in mammalian host cells is controlled, for example, by promoters obtained from the genomes of viruses such as polyoma virus, fowlpox virus, adenovirus (such as Adeno virus 2), bovine papilloma virus, avian sarcoma virus, cytomegalovirus, a retrovirus, hepatitis-B virus and most preferably Simian Virus 40 (SV40), heterologous mammalian promoters, e.g., the actin promoter or an immunoglobulin promoter, and heat-shock promoters, provided such promoters are compatible with the host cell systems.
- viruses such as polyoma virus, fowlpox virus, adenovirus (such as Adeno virus 2), bovine papilloma virus, avian sarcoma virus, cytomegalovirus, a retrovirus, hepatitis-B virus and most preferably Simian
- the early and late promoters of the SV40 virus are conveniently obtained as an SV40 restriction fragment that also contains the S V40 viral origin of replication.
- the immediate early promoter of the human cytomegalovirus is conveniently obtained as a Hindlll E restriction fragment.
- a system for expressing DNA in mammalian hosts using the bovine papilloma virus as a vector is disclosed in U.S. Patent No. 4,419,446. A modification of this system is described in U.S. Patent No. 4,601,978.
- Enhancer element component Transcription of a DNA encoding the anti-TGF-beta antibody of this invention by higher eukaryotes is often increased by inserting an enhancer sequence into the vector. Many enhancer sequences are now known from mammalian genes (globin, elastase, albumin, ⁇ -fetoprotein, and insulin).
- an enhancer from a eukaryotic cell virus examples include the SV40 enhancer on the late side of the replication origin (bp 100-270), the cytomegalovirus early-promoter enhancer, the polyoma enhancer on the late side of the replication origin, and adenovirus enhancers. See also Yaniv, Nature, 297:17-18 (1982) on enhancing elements for activation of eukaryotic promoters.
- the enhancer may be spliced into the vector at a position 5' or 3' to the anti-TGF-beta antibody-encoding sequence, but is preferably located at a site 5' from the promoter.
- Transcription termination component Expression vectors used in eukaryotic host cells (for example, yeast, fungi, insect, plant, animal, human, or nucleated cells from other multicellular organisms) will also contain sequences necessary for the termination of transcription and for stabilizing the mRNA. Such sequences are commonly available from the 5' end, occasionally 3' end, of untranslated regions of eukaryotic or viral DNAs or cDNAs. These regions contain nucleotide segments transcribed as polyadenylated fragments in the untranslated portion of the mRNA encoding anti-TGF-beta antibody.
- One useful transcription termination component is the bovine growth hormone polyadenylation region. See WO 1994/11026 and the expression vector disclosed therein.
- Suitable host cells for cloning or expressing the DNTA in the vectors herein are the prokaryote, yeast, or higher eukaryote cells described above.
- Suitable prokaryotes for this purpose include eubacteria, such as Gram- negative or Gram-positive organisms, for example, Enterobacteriaceae such as Escherichia, e.g., E. coli, Enterobacter, Erwinia, Klebsiella, Proteus, Salmonella, e.g., Salmonella typhimurium, Serratia, e.g., Serratia marcescans, and Shigella, as well as Bacilli such as B. subtilis and B.
- Enterobacteriaceae such as Escherichia, e.g., E. coli, Enterobacter, Erwinia, Klebsiella, Proteus
- Salmonella e.g., Salmonella typhimurium
- Serratia e.g
- E. coli cloning host is E. coli 294 (ATCC 31 ,446), although other strains such as E. coli B, E. coli X1776 (ATCC 31,537), and E. coli W3110 (ATCC 27,325) are suitable. These examples are illustrative rather than limiting.
- eukaryotic microbes such as filamentous fungi or yeast are suitable cloning or expression hosts for anti-TGF-beta antibody-encoding vectors.
- Saccliaromyces cerevisiae or common baker's yeast, is the most commonly used among lower eukaryotic host microorganisms.
- Kluyveromyces hosts such as, e.g., K. lactis, K.fragilis (ATCC 12,424), K. bulgaricus (ATCC 16,045), K. wickeramii (ATCC 24,178), K.
- waltii ATCC 56,500
- K. drosophilarum ATCC 36,906
- K. thermotolerans K. marxianus
- yarrowia EP 402,226
- Pichia pastoris EP 183,070
- Candida Trichoderma reesia
- Neurospora crassa Schwanniomyces such as Schwanniomyces occidentalis
- filamentous fungi such as, e.g., Neurospora, Penicillium, Tolypocladium, and Aspergillus hosts such as A. nidulans and A. niger.
- Suitable host cells for the expression of glycosylated anti-TGF-beta antibody are derived from multicellular organisms.
- invertebrate cells include plant and insect cells.
- Numerous baculoviral strains and variants and corresponding permissive insect host cells from hosts such as Spodopterafrugiperda (caterpillar), Aedes aegypti (mosquito), Aedes albopictus (mosquito), Drosophila melanogaster (fruitfly), and Bombyx mori have been identified.
- a variety of viral strains for transfection are publicly available, e.g., the L- 1 variant of Autographa califomica NPV and the Bm-5 strain of Bombyx mori NPV, and such viruses may be used as the virus herein according to the present invention, particularly for transfection of Spodopterafrugiperda cells.
- Plant cell cultures of cotton, corn, potato, soybean, petunia, tomato, and tobacco can also be utilized as hosts. However, interest has been greatest in vertebrate cells, and propagation of vertebrate cells in culture
- mice sertoli cells TM4, Mather, Biol Reprod., 23:243-251 (1980)
- monkey kidney cells CV1 ATCC CCL 70); African green monkey kidney cells (VERO-76, ATCC CRL-1587); human cervical carcinoma cells (HELA, ATCC CCL 2); canine kidney cells (MDCK, ATCC CCL 34); buffalo rat liver cells (BRL 3A, ATCC CRL 1442); human lung cells (W138, ATCC CCL 75); human liver cells (Hep G2, HB 8065); mouse mammary tumor (MMT 060562, ATCC CCL51 ); TRI cells (Mather et al, Annals N.Y. Acad. Sci..).
- Host cells are transformed with the above-described expression or cloning vectors for anti-TGF-beta antibody production and cultured in conventional nutrient media modified as appropriate for inducing promoters, selecting transformants, or amplifying the genes encoding the desired sequences. (viii) Culturing the host cells
- the host cells used to produce the anti-TGF-beta antibody of diis invention may be cultured in a variety of media.
- 30,985 may be used as culture media for the host cells. Any of these media may be supplemented as necessary with hormones and/or other growth factors (such as insulin, transferrin, or epidermal growth factor), salts (such as sodium chloride, calcium, magnesium, and phosphate), buffers (such as HEPES), nucleotides (such as adenosine and thymidine), antibiotics (such as GENTAMYCINTM drug), trace elements (defined as inorganic compounds usually present at final concentrations in the micromolar range), and glucose or an equivalent energy source. Any other necessary supplements may also be included at appropriate concentrations that would be known to those skilled in the art.
- growth factors such as insulin, transferrin, or epidermal growth factor
- salts such as sodium chloride, calcium, magnesium, and phosphate
- buffers such as HEPES
- nucleotides such as adenosine and thymidine
- antibiotics such as GENTAMYCINTM drug
- trace elements defined as inorganic
- the culture conditions such as temperature, pH, and the like, are those previously used with the host cell selected for expression, and will be apparent to the ordinarily skilled artisan.
- the antibody can be produced intracellularly or in the periplasmic space, or directly secreted into the medium. If the antibody is produced intracellularly, as a first step, die particulate debris, either host cells or lysed fragments, is removed, for example, by centrifugation or ultrafiltration. Carter et al, Bio/Technology, 10:163-167 (1992) describes a procedure for isolating antibodies that are secreted to the periplasmic space of E. coli.
- cell paste is thawed in the presence of sodium acetate (pH 3.5), EDTA, and phenylmethylsulfonylfluoride (PMSF) over about 30 min.
- Cell debris can be removed by centrifugation.
- supernatants from such expression systems are generally first concentrated using a commercially available protein concentration filter, for example, an AMICONTM or MILLIPORE PELLICONTM ultrafiltration unit.
- a protease inhibitor such as phenylmethylsulphonyl fluoride (PMSF) may be included in any of the foregoing steps to inhibit proteolysis, and antibiotics may be included to prevent the growth of adventitious contaminants.
- the antibody composition prepared from the cells can be purified using, for example, hydroxylapatite chromatography, gel electrophoresis, dialysis, and affinity chromatography, with affinity chromatography being the preferred purification technique.
- affinity chromatography is the preferred purification technique.
- the suitability of protein A as an affinity ligand depends on the species and isotype of any immunoglobulin Fc domain that is present in the antibody.
- Protein A can be used to purify antibodies that are based on human ⁇ l, ⁇ 2, or ⁇ 4 heavy chains (Lindmark et al, J. Immunol Meth., 62: 1-13 (1983)). Protein G is recommended for all mouse isotypes and for human ⁇ 3 (Guss et al, EMBO J., 5:15671575 (1986)).
- the matrix to which the affinity ligand is attached is most often agarose, but other matrices are available.
- Mechanically stable matrices such as controlled-pore glass or poly(styrenedivinyl)benzene allow for faster flow rates and shorter processing times than can be achieved with agarose.
- the antibody comprises a C H 3 domain
- the BAKERBOND ABXTM resin J. T. Baker, Phillipsburg, NJ is useful for purification.
- the mixture comprising the antibody of interest and contaminants may be subjected to low-pH hydrophobic-interaction chromatography using an elution buffer at a pH between about 2.5-4.5, preferably performed at low-salt concentrations (e.g., from about 0-0.25M salt).
- elution buffer at a pH between about 2.5-4.5, preferably performed at low-salt concentrations (e.g., from about 0-0.25M salt).
- Therapeutic formulations of the antibodies used in accordance with the present invention are prepared for storage by mixing an antibody having the desired degree of purity with optional pharmaceutically acceptable carriers, excipients, or stabilizers (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the form of lyophilized formulations or aqueous solutions.
- Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low-molecular-weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine
- Preferred lyophilized anti-TGF-beta antibody formulations are described in WO 1997/04801, expressly incorporated herein by reference.
- the formulation herein may also contain more than one active compound as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other.
- VEGF vascular endothelial growth factor
- the composition may further comprise a chemotherapeutic agent, cytotoxic agent, cytokine, growth-inhibitory agent, anti-hormonal agent, TGF-beta- targeted drug, anti-angiogenic agent, and/or cardioprotectant.
- chemotherapeutic agent cytotoxic agent, cytokine, growth-inhibitory agent, anti-hormonal agent, TGF-beta- targeted drug, anti-angiogenic agent, and/or cardioprotectant.
- the active ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymefhylcellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug-delivery systems (for example, liposomes, albumin microspheres, ⁇ ucroemulsions, nano-particles and nanocapsules) or in macroemulsions.
- colloidal drug-delivery systems for example, liposomes, albumin microspheres, ⁇ ucroemulsions, nano-particles and nanocapsules
- Sustained-release preparations may be prepared.
- sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g. films, or microcapsules.
- sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No.
- copolymers of L-glutamic acid and ⁇ ethyl-L-glutar ⁇ ate non-degradable ethylene- vinyl acetate
- degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOTTM (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate)
- poly-D-(-)-3- hydroxybutyric acid The formulations to be used for in vivo administration must be sterile. This is readily accomplished by filtration through sterile filtration membranes. V.
- the anti-TGF-beta antibodies may be used to treat various diseases or disorders.
- exemplary conditions or disorders include benign or malignant tumors; leukemias and lymphoid malignancies; and other disorders such as neuronal, glial, astrocytal, hypothalamic, glandular, macrophagal, epithelial, stromal, blastocoelic, inflammatory, angiogenic and immunologic disorders.
- the disorder to be treated is a TGF-beta disorder, most preferably cancer.
- cancers to be treated herein include, but are not limited to, carcinoma, blastoma, and sarcoma, and certain leukemia or lymphoid malignancies. More particular examples of such cancers include squamous cell cancer (e.g.
- lung cancer including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, as well as head and neck cancer.
- lung cancer including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer,
- the cancer will be one that expresses (and may overexpress) a TGF-beta receptor.
- TGF-beta receptor(s) examples include squamous cell cancer (e.g.
- lung cancer including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, as well as head and neck cancer.
- lung cancer including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer,
- the cancer to be treated by the antibody herein may be any cancer, not simply those that express or overexpress a TGF-beta receptor. If the cancer to be treated herein may be one characterized by excessive activation of a TGF-beta receptor, such excessive activation may be attributable to overexpression or increased production of the TGF- beta receptor.
- a diagnostic or prognostic assay will be performed to determine whether the patient's cancer is characterized by excessive activation of a TGF-beta receptor. For example, TGF-beta gene amplification and/or overexpression of a TGF-beta receptor in the cancer may be determined.
- TGF-beta receptor overexpression or amplification may be evaluated using an in vivo diagnostic assay, e.g. by administering a molecule (such as an antibody) that binds the molecule to be detected and is tagged with a detectable label (e.g. a radioactive isotope) and externally scanning the patient for localization of the label.
- a detectable label e.g. a radioactive isotope
- the L-929 assay system is a convenient in vitro assay that permits rapid measurement of the activity of the antibody herein optionally in conjunction with an appropriate regulator of immune function. Its degree of correlation with the in vivo tumor-necrosis assay of Carswell et al, Proc. INatl. Acad. Sci. USA, 22:3666 (1975) is at present unknown; however, as it utilizes murine tumor cells specifically, the correlation is expected to be high.
- the proteins tumor necrosis factor (TNF- ⁇ ) and lymphotoxin (TNF-beta) give activity in this assay.
- the assay is similar in concept to that disclosed in U.S. Pat. No.
- L-929 assay has been shown to correlate (for TNF- ⁇ derived from HL-60 cells) with human tumor cell line cytotoxicity.
- L-929 assay system herein, L-929 cells are prepared overnight as monolayers in microtiter plates. The best samples are diluted twofold across the plate, UV irradiated, and then added onto the prepared cell monolayers. The culture media in the wells are then brought to 1 ⁇ g/ml actinomycin D. The plates are allowed to incubate 18 hours at 37°C and the plates are scored visually under the microscope. Each well is given a 25, 50, 75, or 100% mark signifying the extent of cell death in the well
- One unit of TNF activity is defined as the reciprocal of the dilution at which 50% killing occurs.
- Preparations may also be tested for activity using the ability of the anti-TGF-beta antibody to kill or repress the growth of tumors and to protect the animal bearing the tumor -from mortality.
- Balb/c mice are injected subcutaneously with various types of tumor cells to create a localized tumor.
- Tumor cell lines include
- MethA mouse fibrosarcoma obtained as a cell suspension from ascites flviid, and MCF-7, a human breast 3 carcinoma that is administered as a 1-mm clump of cells.
- female Balb/c mice (19-22 g) are injected subcutaneously by a 26-gauge needle with either suspension containing 5 x 10 fibrosarcoma cells in 0.1 ml of medium or with the MCF-7 clumps.
- the fibrosarcoma suspension is prepared from 8-day-old ascites fluid by cell counting and dilution with serum-free medium.
- 1 ⁇ g per mouse of TNF- ⁇ is injected intravenously, and administration of the TNF- ⁇ is repeated, if desired, on subsequent days. Results are assessed by measuring tumor volume and by survival rate. The test is repeated using separate sequential injections of 1 ⁇ g per mouse of TNF- ⁇ and 10 mg/kg per mouse of antibody 4A11. The test antibody is compared against these agents for activity.
- expression of the liormone e.g.
- an immunoconjugate comprising the anti-TGF-beta antibody conjugated with a cytotoxic agent is administered to the patient.
- the immunoconjugate and/or TGF-beta protein to which it is bound is/are internalized by the cell, resulting in increased therapeutic efficacy of the immunoconjugate in killing the cancer cell to which it binds.
- the cytotoxic agent targets or interferes with nucleic acid in the cancer cell.
- cytotoxic agents include maytansinoids, calicheamicins, ribonucleases, and DNA endonucleases.
- the anti-TGF-beta antibodies or immunoconjugates are administered to a human patient in accordance with known methods, such as intravenous administration, e.g., as a bolus or by continuous infusion over a period of time, by intramuscular, intraperitoneal, intracerobrospinal, subcutaneous, intra-articular, intrasynovial, intrathecal, oral, topical, or inhalation routes.
- Intravenous, intraperitoneal, or subcutaneous administration of the antibody is preferred, with subcutaneous or intraperitoneal routes being particular preferred.
- a preferred administration schedule is about 2-3 times per week, depending on the particular mammal being treated, the type of antibody, and otiier factors well known to the practitioner. However, other administration schedules are operable herein.
- Other therapeutic regimens may be combined with the administration of the anti-TGF-beta antibody.
- the combined administration includes co-administration, using separate formulations or a single pharmaceutical formulation, and consecutive administration in either order, wherein preferably there is a time period while both (or all) active agents simultaneously exert their biological activities.
- the patient is treated with two different anti-TGF-beta antibodies. It may also be desirable to combine administration of the anti-TGF-beta antibody or antibodies with administration of an antibody directed against another tumor-associated antigen.
- the other antibody in this case may, for example, bind to an antigen such as HER-2, EGFR, ErbB3, ErbB4, vascular endothelial growth factor (VEGF), or a B-cell surface marker or antigen (an antigen expressed on the surface of a IB cell that can be targeted with an antagonist that binds thereto), such as, for example, the CD10, CD19, CD20, CD21, CD22, CD23, CD24, CD37, CD40, CD53, CD72, CD73, CD74, CDw75, CDw76, CD77, CDwT ⁇ , CD79a, CD79b, CD80, CD81, CD82, CD83, CDw84, CD85 and CD86 leukocyte surface markers (for descriptions, see The Leukocyte Antigen Facts Book, 2 nd Edition.
- an antigen such as HER-2, EGFR, ErbB3, ErbB4, vascular endothelial growth factor (VEGF), or a B-cell surface marker or antigen (an antigen
- B-cell surface markers include RP105, FcRH2, B-cell CR2, CCR6, P2X5, HLA-DOB, CXCR5, FCER2, BR3, Btig, NAG14, SLGC16270, FcRHl, IRTA2, ATWD578, FcRH3, IRTAl, FcRH6, BCMA, and 239287.
- the B-cell surface marker of particular interest is preferentially exipressed on B cells compared to other non-B-cell tissues of a mammal and may be expressed on both precursor B cells and mature B cells.
- the preferred B-cell surface markers herein are CD20 and CD22.
- the TGF-beta antibody may be combined with an anti-angiogenic agent, which acts to inhibit angiogenesis.
- an anti-angiogenic agent which acts to inhibit angiogenesis.
- An example is an antagonist to VEGF, such as an antibody, e.g., AVASTINTM.
- the treatment of the present invention involves the combined administration of a-n anti-TGF-beta antibody (or antibodies) and one or more regulators of immune function in a mammal, such a_s cytokines, as well as chemotherapeutic agents or growth-inhibitory agents, including co-administration of cocktails of different chemotherapeutic agents.
- Preferred chemotherapeutic agents include taxanes (such as paclitaxel and docetaxel) and/or anthracycline antibiotics.
- Preparation and dosing schedules for such chemotherapeutic agents may be used according to manufacturers' instructions or as determined empirically by the skilled practitioner. Preparation and dosing schedules for such chemotherapy are also described in Chemotherapy Service, Ed., M.C. Perry, Williams & Wilkins, Baltimore, MD (1992).
- the antibody may be combined with an anti-hormonal compound, e.g., an anti-estrogen compound such as tamoxifen or an aromatase inhibitor such as anastrozole; an anti-progesterone such as onapristone (see, ET 616 812); or an anti-androgen such as flutamide, in dosages known for such molecules.
- an anti-hormonal compound e.g., an anti-estrogen compound such as tamoxifen or an aromatase inhibitor such as anastrozole; an anti-progesterone such as onapristone (see, ET 616 812); or an anti-androgen such as flutamide, in dosages
- the patient may previously have been subjected to anti-hormonal therapy and, after the cancer becomes hormone independent, the anti-TGF-beta antibody (and optionally other agents as described herein) may be administered to the patient.
- the anti-TGF-beta antibody and optionally other agents as described herein
- a cardioprotectant to prevent or reduce myocardial dysfunction associated with the therapy
- cytokines one or more cytokines
- the patient may be subjected to surgical removal of cancer cells and/or radiation therapy.
- the anti-TGF-beta antibodies herein may also be combined with an EGFR-targeted drug such as those discussed above in the definitions section resulting in a complementary, and potentially synergistic, therapeutic effect.
- Suitable dosages for any of the above co-administered agents are those presently used and may be lowered due to the combined action (synergy) of the agent and anti-TGF-beta antibody.
- the appropriate dosage of antibody will depend on the type of disease to be treated, as defined above, the severity and course of the disease, whether the antibody is administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history and response to the antibody, and the discretion of the attending physician.
- the antibody is suitably administered to the patient at one time or over a series of treatments.
- about ! ⁇ g/kg to 15 mg/kg (e.g. 0.1-20mg/kg) of antibody is an initial candidate dosage for administration to the patient, whether, for example, by one or more separate administrations, or by continuous infusion.
- a typical daily dosage might range from about 1 ⁇ g/kg to 100 mg/kg or more, depending on the factors mentioned above.
- Tor repeated administrations over several days or longer, depending on the condition, the treatment is sustained until a desired suppression of disease symptoms occurs.
- the preferred dosage of the antibody will be in the range from about 0.05mg/kg to about lOmg/kg.
- one or more doses of about 0.5mg/kg, 2.0mg/kg, 4.0mg kg or lOmg/kg (or any combination thereof) may be administered to the patient.
- Such doses may be administered intermittently, e.g. every week or every three weeks (e.g. such that the patient receives from about two to about twenty, e.g. about six doses, of the anti-TGF- beta antibody).
- An initial higher loading dose, followed by one or more lower doses, may be administered.
- An exemplary dosing regimen comprises administering an initial loading dose of about 4 mg/kg, followed by a weekly maintenance dose of about 2 mg/kg of the anti-TGF-beta antibody.
- other dosage regimens may be useful.
- the antibody is suitably administered serially or in combination with radiological treatments—irradiation or introduction of radioactive substances-such as those referred to in UZCC (Ed.), Klinische Onkologie, Springer- Verlag (1982).
- radiological treatments irradiation or introduction of radioactive substances-such as those referred to in UZCC (Ed.), Klinische Onkologie, Springer- Verlag (1982).
- the present application contemplates administration of the antibody by gene therapy.
- Such administration of nucleic acid encoding the antibody is encompassed by the expression "administering a therapeutically effective amount of an antibody”. See, for example, WO 1996/07321 published March 14, 1996 concerning the use of gene therapy to generate intracellular antibodies.
- nucleic acid (optionally contained in a vector) into the patient's cells
- in vivo and ex vivo the nucleic acid is injected directly into the patient, usually at the site where the antibody is required.
- ex vivo treatment the patient's cells are removed, the nucleic acid is introduced into these isolated cells, and the modified cells are administered to the patient either directly or, for example, encapsulated within porous membranes that are implanted into the patient (see, e.g. U.S. Patent Nos. 4,892,538 and 5,283,187).
- techniques available for introducing nucleic acids into viable cells There are a variety of techniques available for introducing nucleic acids into viable cells.
- the techniques vary depending upon whether the nucleic acid is transferred into cultured cells in vitro, or transferred in vivo in the cells of the intended host.
- Techniques suitable for the transfer of nucleic acid into mammalian cells in vitro include the use of liposomes, electroporation, micro injection, cell fusion, DEAE-dextran, the calcium-phosphate precipitation method, etc.
- a commonly used vector for ex vivo delivery of the gene is a retrovirus.
- the currently prefened in vivo nucleic acid transfer techniques include transfection with viral vectors (such as adenovirus, Herpes simplex I virus, or adeno-associated virus) and lipid-based systems (useful lipids for lipid-mediated transfer of the gene are DOTMA, DOPE and DC-Choi, for example).
- viral vectors such as adenovirus, Herpes simplex I virus, or adeno-associated virus
- lipid-based systems useful lipids for lipid-mediated transfer of the gene are DOTMA, DOPE and DC-Choi, for example.
- an agent that targets the target cells such as aji antibody specific for a cell-surface membrane protein or the target cell, a ligand for a receptor on the target cell, etc.
- proteins that bind to a cell-surface membrane protein associated with endocytosis may be used for targeting and/or to facilitate uptake, e.g.
- capsid proteins or fragments thereof tropic for a particular cell type antibodies for proteins that undergo internalization in cycling, and proteins that target intracellular localization and enhance intracellular half-life.
- the technique of receptor-mediated endocytosis is described, for example, by Wu et al, J. Biol Chem., 262:4429-4432 (1987) and Wagner et al. , Proc. Natl Acad. Sci. USA, 82:3410-3414 (1990).
- Wu et al J. Biol Chem., 262:4429-4432 (1987) and Wagner et al. , Proc. Natl Acad. Sci. USA, 82:3410-3414 (1990).
- cancer such as lung cancer, melanoma, breast cancer, kidney cancer, colorectal cancer, pancreatic cancer, or prostate cancer
- a mammal preferably a human
- administering to the mammal an effective amount of a TGF-beta antibody and an antibody that binds to VEGF, optionally along with any other suitable agent as herein set forth.
- the TGF-beta antibody is a monoclonal antibody, more preferably ifbinds to any one or more of the following: TGF-betal, TGF-beta2, and TGF-beta3, and still more preferably binds to at least TGF-betal, or both TGF-betal and TGF-beta2, and most preferably is the humanized antibody as set forth herein.
- the antibody that binds to VEGF is a monoclonal antibody and more preferably it blocks or neutralizes VEGF and/or blocks VEGF binding to one or both of its receptors.
- an article of manufacture containing materials useful for t-he treatment of the disorders described above comprises a container and a label or package insert on or associated with the container.
- Suitable containers include, for example, bottles, vials, syringes, etc.
- the containers may be formed from a variety of materials such as glass or plastic.
- the container holds a composition that is effective for treating the condition and may have a sterile access port (for example, the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
- At least one active agent in the composition is the humanized anti-TGF-beta antibody herein.
- the label or package insert indicates that the composition is used for treating the condition of choice, such as cancer.
- the label or package insert indicates that the composition comprising the antibody can be used to treat a TGF-beta disorder, for example, to treat cancer that expresses a TGF-beta receptor.
- the label or package insert may indicate that the patient to be treated is one having cancer characterized by excessive activation of a TGF-beta receptor.
- the label or package insert may also indicate that the composition can be used to treat cancer, wherein the cancer is not characterized by overexpression of a TGJF- beta receptor.
- the package insert may indicate that the antibody or composition can. be used to treat breast cancer (e.g.
- the article of manufacture may comprise (a) a first container with a composition contained therein, wherein the composition comprises the humanized antibody herein, and (b) a second container witli a composition contained therein, wherein the composition comprises a therapeutic agent other than the humanized antibody.
- the article of manufacture in this embodiment of the invention may further comprise a package insert indicating that the first and second compositions can be used in combination to treat a TGF-beta disorder such as cancer.
- Such therapeutic agent may be any of the adjunct therapies described in the preceding section (e. _, a chemotherapeutic agent, an anti-angiogenic agent, an anti-hormonal compound, a cardioprotectant, and/or a regulator of immune function in a mammal, including a cytokine).
- the article of manufacture may further comprise a second (or third) container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.
- the antibodies e.g. the humanized anti-TGF-beta antibodies
- the antibodies may " be used as affinity-purification agents.
- the antibodies are immobilized on a solid phase such as a SEPHADEXTM resin or filter paper, using methods well known in the art.
- the immobilized antibody is contacted with a sample containing the TGF-beta protein (or fragment thereof) to be purified, and thereafter the support is washed with a suitable solvent that will remove substantially all the material in the sample except the TGF-beta protein, which is bound to the immobilized antibody.
- Anti-TGF-beta antibodies may also be useful in diagnostic assays for TGF-beta protein, e.g., detecting its expression in specific cells, tissues, or serum.
- the antibody typically will be labeled with a detectable moiety.
- Numerous labels are available that can be generally grouped into the following categories: 35 14 125 3 131 (a) Radioisotopes, such as S, C, I, H, and I.
- the antibody can be labeled with the radioisotope using the techniques described in Current Protocols in Immunology. Volumes 1 and 2, Coligen et al, Ed.
- Fluorescent labels such as rare-earth chelates (europium chelates) or fluorescein and its derivatives, rhodamine and its derivatives, dansyl, Lissamine, phycoeryfhrin and Texas Red are available. The fluorescent labels can be conjugated to the antibody using the techniques disclosed in Current Protocols in Immunology, supra, for example. Fluorescence can be quantified using a fluorimeter.
- fluorescent labels such as rare-earth chelates (europium chelates) or fluorescein and its derivatives, rhodamine and its derivatives, dansyl, Lissamine, phycoeryfhrin and Texas Red are available. The fluorescent labels can be conjugated to the antibody using the techniques disclosed in Current Protocols in Immunology, supra, for example. Fluorescence can be quantified using a fluorimeter.
- Various enzyme-substrate labels are available and U.S. Patent No. 4,275,149 provides a review of some of these.
- the enzyme generally catalyzes a chemical alteration of the chromogenic substrate that can be measured using various techniques.
- the enzyme may catalyze a color change in a substrate, which can be measured spectrophotomerrically.
- the enzyme may alter the fluorescence or chemiluminescence of the substrate. Techniques for quantifying a change in fluorescence are described above.
- the chemiluminescent substrate becomes electronically excited by a chemical reaction and may then emit light that can be measured (using a chemiluminometer, for example) or donates energy to a fluorescent acceptor.
- Examples of enzymatic labels include luciferases (e.g., firefly luciferase and bacterial luciferase; U.S.
- Patent No. 4,737,456 luciferin, 2,3-dihydrophthalazinediones, malate dehydrogenase, urease, peroxidase such as horseradish peroxidase (HRPO), alkaline phosphatase, ⁇ -galactosidase, glucoamylase, lysozyme, saccharide oxidases (e.g., glucose oxidase, galactose oxidase, and glucose-6-phosphate dehydrogenase), heterocyclic oxidases (such as unease and xanthine oxidase), lactoperoxidase, microperoxidase, and the like.
- HRPO horseradish peroxidase
- alkaline phosphatase alkaline phosphatase
- ⁇ -galactosidase glucoamylase
- lysozyme saccharide oxidases
- enzyme-substrate combinations include, for example: (i) Horseradish peroxidase (HRPO) with hydrogen peroxidase as a substrate, wherein the hydrogen peroxidase oxidizes a dye precursor (e.g., orthophenylene diamine (OPD) or 3,3',5,5'-tetramethyl benzidine hydrochloride (TMB)); (ii) alkaline phosphatase (AP) with para-nitrophenyl phosphate as chromogenic substrate; and (iii) ⁇ -D-galactosidase ( ⁇ -D-Gal) with a chromogenic substrate (e.g., p-nitrophenyl- ⁇ -D-galactosidase) or fluorogenic substrate 4-methylumbelliferyl- ⁇ -D-galactosidase.
- HRPO Horseradish peroxidase
- OPD orthophenylene diamine
- TMB 3,3',5,5'-tetramethyl benzidine
- the label is indirectly conjugated with the antibody.
- the antibody can be conjugated with biotin, and any of the three broad categories of labels mentioned above can be conjugated with avidin, or vice versa. Biotin binds selectively to avidin, and thus, the label can be conjugated with the antibody in this indirect manner.
- the antibody is conjugated with a small hapten (e.g., digoxin) and one of the different types of labels mentioned above is conjugated with an anti- hapten antibody (e.g., anti-digoxin antibody).
- a small hapten e.g., digoxin
- an anti- hapten antibody e.g., anti-digoxin antibody
- the anti-TGF-beta antibody need not be labeled, and the presence thereof can be detected using a labeled antibody that binds to the TGF-beta antibody.
- the antibodies of the present invention may be employed in any known assay method, such as competitive-binding assays, direct and indirect sandwich assays, and immunoprecipitation assays.
- the tumor sample may be fresh or frozen or may be embedded in paraffin and fixed with a preservative such as formalin, for example.
- the antibodies may also be used for in vivo diagnostic assays. Generally, the antibody is labeled with a ,- j , , HI . 99__, 14 ⁇ 131 125 ⁇ 3 TT 32 radical 35 ⁇ , ⁇ , , , ,. . radionuchde (such as In, Tc, C, I, I, H, P or S) so that, for example, a tumor can be localized using immunoscintiography.
- the antibodies of the present invention can be provided in a kit, i.e., a packaged combination of reagents in predetermined amounts with instructions for performing the diagnostic assay.
- the kit will include substrates and cofactors required by the enzyme (e.g., a substrate precursor that provides the detectable chromophore or fluorophore).
- substrates and cofactors required by the enzyme e.g., a substrate precursor that provides the detectable chromophore or fluorophore
- other additives may be included such as stabilizers, buffers (e.g., a block buffer or lysis buffer) and the like.
- the relative amounts of the various reagents may be varied widely to provide for concentrations in solution of the reagents that substantially optimize the sensitivity of the assay.
- the reagents may be provided as dry powders, usually lyophilized, including excipients that on dissolution will provide a reagent solution having the appropriate concentration.
- the antibody herein is also useful for in vivo imaging, where the labeled antibody is administered to a host, preferably the bloodstream, and the presence and location of the labeled antibody in the host is assayed. This imaging technique is suitably used in the staging and treatment of neoplasms.
- the antibody is suitably labeled with any moiety that is detectable in a host, including non-radioactive indicators detectable by, e.g., nuclear magnetic resonance, or other means known in the art.
- the label is a radiolabel, including iodine, e.g., 251 and 311, selenium, bifunctional chelates, copper, e.g., 7Cu, technetium, e.g., i i 9mTc, and rhenium, e.g., 86Re and 88Re.
- the radioisotope is conjugated to the protein by any means, including metal-chelating compounds or lactoperoxidase, or iodogen techniques for iodination.
- Murine monoclonal antibody 2G7 was deposited with the American Type Culture Collection, 10801 University Boulevard, Manassas, VA 20110-2209, USA (ATCC) as HB 10240 on 9/28/89; and murine monoclonal antibody 4A11 was deposited as ATCC HB 10241 on 9/28/89. Further details of the invention are illustrated by the following non-limiting Examples. The disclosures of all citations in the specification are expressly incorporated herein by reference.
- TGF-betal Purified TGF-betal was iodinated by a modified procedure using CHLORAMINE TTM n-chloro-para- toluene sulfonamide sodium salt (Greenwood et al, Biochem. J., 89: 114 (1963)). Briefly, 10 ⁇ g of purified 125 rTGF-betal was labeled with 1 mCi of Na I on ice using three sequential additions of 20 ⁇ l of 0.1 mg/ml
- the wells were washed with PBST, blocked with PBS containing 0.1% gelatin (called PBSG), washed with PBST, and incubated with hybridoma supernatants for four hours at 22°C.
- the wells were washed with PBST, and 175 approximately 75,000 CPM/well of I-rTGF-betal, in 100 ⁇ l of 0.1% gelatin in PBST, was added and 125 incubated for two hours at 22°C.
- the plates were washed with PBST, and bound I-rTGF-betal was quantitated on a GAMMAMASTERTM counter (LKB , Sweden). IV.
- A-SEPHAROSETM agarose (Repligen, Cambridge, MA) coated with rabbit anti-mouse IgG (Boehringer Mannheim Biochemicals, Indianapolis, IN) and subsequently washed 3 X with PBST.
- the complexes were dissociated from the protein A-SEPHAROSETM agarose with reducing sample buffer, electrophoresed into 12% SDS-polyacrylamide gel (SDS-PAGE), and exposed to autoradiography.
- V. Affinity Determination of TGF-beta Monoclonal Antibodies The solid-phase radioimmunoassay procedure described by Mariani et al, J. Immunol. Methods.
- TGF-beta-specific monoclonal antibodies were used to determine the affinities of the TGF-beta-specific monoclonal antibodies. Briefly, purified anti-TGF-beta monoclonal antibodies were coated on EVIMULONTM 2 "REMOVAWELL”TM microtiter strips in pH 9.6 carbonate buffer for 18 hours at 4°C. The wells were washed and blocked as described above.
- rTGF-beta monoclonal antibodies and controls were incubated with either rTGF-betal, native porcine TGF-beta2 (R & D Systems), or rTGF-beta3 (Derynck et al, Nature, supra) at a final concentration of 1000-2000 pg/ml for 18 hours at 4°C. Fifty ⁇ l of these mixtures were added to 96- well microtiter plates followed by 1 x 10 Mv-3D9 cells, in 50 ⁇ l of minimal essential media containing 2 mM glutamine and 5% fetal bovine serum, and incubated for 18-24 hours at 37° C in 5% C0 2 .
- the wells were pulsed with 1 ⁇ Ci of H- thymidine in 20 ⁇ l and harvested after four hours at 37° C and counted in a scintillation counter. The percent 3 inhibition of H-thymidine uptake for each dilution of TGF-beta standard was used to calculate the TGF-beta activity in pg/ l of the negative ⁇ c ⁇ ntf ⁇ l monoclonal antibody and TGF-beta-specific-monoclonal-antibody- treated samples.
- VIII. Isotyping of Monoclonal Antibodies Isotyping of TGF-betal-reactive monoclonal antibodies was performed using the PANDEXTM fluorescence screen machine technology.
- Rat-anti-mouse-IgG-antisera-coated polystyrene particles were used to bind the monoclonal antibody from culture supernatant dispensed into PANDEXTM 96-well assay plates. The plates were washed and FITC-conjugated-rat-monoclonal-anti-mouse-isotype-specific reagents (Becton Dickinson Monoclonal Center) added. The bound fluorescence was quantitated by the PANDEXTM fluorescence screen machine technology.
- IX. Epitope Analysis Purified anti-rTGF-betal monoclonal antibodies were coupled to horseradish peroxidase (HRP) by the method of Nakane and Kawaoi, J.
- rTGF-betal -coated plates were incubated with 50 ⁇ g/ml of purified anti-rTGF-betal or negative control in PBS for two hours at 22° C. A predetermined dilution of the anti-rTGF-beta monoclonal antibody-HRP conjugate was then added to the plates and incubated for one hour at 22° C. The plates were washed and substrate was added and reactivity quantitated as described above. The percent blocking of the heterologous anti-rTGF-betal monoclonal antibodies was compared to the autologous, positive blocking control X.
- mice were immunized with rTGF-betal (produced and purified as described by Derynck et al, Nature, supra) by subcutaneous and intraperitoneal routes using a variety of immunogen preparations, doses, and schedules and using both complete and incomplete Freund's adjuvant. The immunization schedules were continued for up to 11 weeks. Several mice responded with measurable but low anti-rTGF-betal liters and two of these mice were sacrificed and their spleens used for fusions.
- the fused cells were plated into a total of 134496-well microtiter plates at a density of 2 x 10 cells/well followed by HAT selection (Littlefield, J.W., Science, 145: 709 (1964)) on day 1 post-fusion. 1190 of the wells were reactive with immobilized recombinant TGF-betal in the ELISA test. Eighteen of these cultures remained stable when expanded and cell lines were cryopreserved. These parental cultures 125 were isotyped and assayed for their ability to capture I-rTGF-betal and to neutralize in vitro TGF-betal activity.
- a competitive inhibition assay was used to determine the affinity of interaction between TGF-betal and each of the monoclonal antibodies.
- Monoclonal antibodies 2G7 and 4A11 had equally higher affinities, which were 1.2 x 10 1/mole.
- Immunoprecipitation experiments were also performed to determine the ability of the monoclonal antibodies selected to recognize and precipitate TGF-beta2 in solution. The autoradiograph showed that, in 125 contrast to rTGF-betal, only antibody 2G7 immunoprecipitated I-TGF-beta2 to any measurable degree.
- *Mab 456 is a control antibody that reacts with CD4.
- the data indicate that the epitopes recognized by these two monoclonal antibodies are distinct but are either in close proximity or somehow affect the binding of one another from a distance. From both the immunoprecipitation and cross-blocking experiments, 12H5 appears to be a distinct epitope, although some blocking was observed. This conclusion is also supported by the neutralization data below.
- the antibodies 2G7, 4A11 and 12H5 all reacted in an indirect immunoblot with the TGF-betal dimer (non-reduced) form. 2G7 gave a much stronger band than either 4A11 or 12H5. As in the immunoprecipitation experiment, control antibody 6G 12 was negative. This pattern of reactivity was also observed in a direct Western blot with HRP conjugates of these monoclonal antibodies.
- the protocol employing foot-pad immunizations coupled with fusions of the draining lymph nodes was performed after multiple unsuccessful attempts at breaking tolerance to rTGF-betal using a variety of immunization procedures and dosing schedules in Balb/c and C3H mice with complete and incomplete Freund's adjuvant.
- TGF-beta antibodies neutralized rTGF-betal activity in vitro, while only one of the two neutralized both TGF-beta2 and TGF-beta3 activity in the mink lung fibroblast cell assay.
- the TGF-betal-neutralizing antibodies also blocked radioiodinated rTGF-betal binding in a radioreceptor assay, indicating that the in vitro neutralization of rTGF-betal activity may be due to receptor blocking.
- variable domains of murine monoclonal antibody 2G7 were first cloned into a vector that allows production of a mouse/human chimeric Fab fragment.
- Total RNA was isolated from the hybridoma cells using a STRAGENETM RNA extraction kit following manufacturer's protocols.
- the variable domains were amplified by RT-PCR, gel purified, and inserted into a derivative of a pUCl 19-based plasmid containing a human kappa constant domain and human C H 1 domain as previously described (Carter et al,. Proc. Natl. Acad. Sci. (USA). 89: 4285 (1992) and U.S. Pat. No. 5,821,337).
- the resultant plasmid was transformed into E. coli strain 16C9 for expression of the Fab fragment. Growth of cultures, induction of protein expression, and purification of Fab fragment were as previously described (Werther et al,. J. Immunol, 157: 4986-4995 (1996); Presta et al, Cancer Research, 5 : 4593-4599 (1997)). DNA sequencing of the chimeric clone allowed identification of the CDR residues (Kabat et al. , supra).
- a NUNC MAXISORPTM plate was coated with 1 microgram per ml of TGF-beta extracellular domain (ECD; produced as described in WO 1990/14357) in 50 mM of carbonate buffer, pH 9.6, overnight at 4° C, and then blocked with ELISA diluent (0.5% BSA, O.05% POLYSORBATETM 20 non-ionic surfactant, PBS) at room temperature for 1 hour. Serial dilutions of samples in ELISA diluent were incubated on the plates for 2 hours.
- ECD TGF-beta extracellular domain
- Fab fragment was detected with biotinylated murine anti-human kappa antibody (ICN 634771) followed by streptavidin-conjugated horseradish peroxidase (Sigma) and using 3,3',5,5'-tetramethyl benzidine (Kirkegaard & Perry Laboratories, Gaithersburg, MD) as substrate. Absorbance was read at 450 nm. Binding of the CDR-swap Fab was significantly reduced compared to binding of the chimeric Fab fragment. To restore binding of the humanized Fab, mutants were constructed using DNA from the CDR-swap as template.
- Versions 3 and 4 were used as intermediates to obtain the humanized Fab versions bearing later numbers. Version 5, with the changes AlaH49Gly, PheH67Ala, and ArgH71Ala, appears to have binding restored to that of the original chimeric 2G7 Fab fragment, as do Versions 709 and 11 ( Figure 5). Versions 710 and 712 are expected to have similar binding to the chimeric fragment, but version 712 has an additional framework mutation that might not be desirable due to the possibility of increased immunogenicity. Additional FR or CDR residues, such as L3, L24, L54, and/or H35, may be modified (e.g.
- substitutions that might be desirable to enhance stability are the substitution of leucine or isoleucine for methionine to decrease oxidation, or the change of asparagines in the CDRs to other residues to decrease the possibility of de-amidation.
- the humanized antibody may be affinity matured (see above) to further improve or refine its affinity and/or other biological activities.
- Plas ids for expression of full-length IgG's were constructed by sirbcloning the VL and VH domains of chimeric 2G7 Fab as well as humanized Fab versions 5, 709, and 11 into previously described pRK vectors for mammalian cell expression (Gorman et al., DNA Prot. Eng. Tech.. 2:3-10 (1990)). Briefly, each Fab construct was digested with EcoRV and Blpl to excise a VL fragment, which was cloned into the EcoRW/Blpl sites of plasmid pDRl (see Figure 6) for expression of the complete light chain (VL-CL domains).
- each Fab construct was digested with PvwII and Apal to excise a VH fragment, which was cloned into the PvuWAp ⁇ l sites of plasmid pDR2 (see Figure 7) for expression of the complete heavy chain (VH-CH1-CH2- CH3 domains).
- transient transfections were performed by co-transfecting a light-chain-expressing plasmid and a heavy-chain-expressing plasmid into an adenovirus-transformed human embryonic kidney cell line, 293 (Graham et al. J. Gen. Virol, 36:59-74 (1977)). Briefly, 293 cells were split on the day prior to transfection, and plated in serum-containing medium.
- a calcium phosphate precipitate was prepared from double- stranded DNA of the light and heavy chains, along with pADVANTAGETM vector DNA (Promega, Madison, WI), and added dropwise to the plates.
- Cells were incubated overnight at 37° C, then washed with PBS and cultured in serum-free medium for 4 days at which time conditioned medium was harvested.
- Antibodies were purified from culture supernatants using protein A-SEPHAROSE CL-4BTM agarose, then buffer-exchanged into 10 mM sodium succinate, 140 mM NaCl, pH 6.0, and concentrated using a CENTRICON-10 T I microconcentrator (Amicon).
- the name for the germline sequence used for CDR LI is L8/L9, as set forth in Figure 4 of Cox et al, Eur. J. Immunol, 24: 827-836 (1994) and in Figure 2e of Schable and Zachau, Biol Chem. Hoppe-Seyler, 374: 1001-1022 (1993).
- the germline sequence is named L8/L9/L14/L15 (see Cox et al, supra, and Schable and Zachau, supra). Reversions to the sequence of human germline (gl) kappa locus were made in all the CDR's, but only the germline revertants set forth above showed binding (see Figure 8).
- V5H.glL2 with CDR L2 reverted to the sequence of the human germline kappa locus, still binds to TGF-beta as well as V5H.V5L.
- a mouse mesangial cell-proliferation assay was used to test a control antibody and several humanized antibodies (V5H.V5L, V5H.gl L2, H2NI.V5L, V5H.glLlglL2, and H2Nl.glLlglL2).
- the protocol is as follows: On day 1: Mouse mesangial cells were plated on a 96- well plate in Media (a 3:1 mixture of Dulbecco's modified Eagle's medium and Ham's F12 medium-95%-fetal bovine serum-5%-supplemented with 14 mM HEPES buffer) and grown overnight. i On day 2: TGF-beta with three different concentrations (100 ng, 10 ng and 1 ng) and five different types of humanized TGF antibody (20 ⁇ g/ml) were diluted in serum-free Media and added to the cells. A mouse TGF antibody was used as a control (2G7).
- reaction buffer CELLTITER 96 AQUEOUS ONE SOLUTION REAGENTTM buffer (Promega Inc. Cat number G3580)
- OD absorbance
- H2NI.V5L (20 ⁇ g/ml) completely blocked cell inhibition induced by TGF-beta at 1 ng/ml level, which is the same result as using the chimeric mouse control (see Figure 9). Version 5 (V5H.V5L) also blocked cell inhibition similarly to the control.
- Various humanized antibodies were tested for their activity in neutralizing various TGF-betas versus
- humanized antibodies V5H.V5L, V5H.glL2, H2NLV5L, H2NI.glL2, and Versions 709, 710, and 711 are the most preferred humanized versions since they bind TGF-beta comparably as the chimeric antibody (chimH.chimL; 2G7 Fab fragment) and/or neutralize TGF-beta or block cell inhibition induced by
- TGF-betas in vitro and have the fewest framework changes of all the humanized antibodies tested, which would minimize the risk of an immune response in patients.
- H2NI.V5L is a particularly preferred antibody, as it appears to be superior in neutralization activity of all three TGF-beta isoforms (TGF-beta 1,2,3) and might have improved stability due to the changes in the CDR H2.
- those humanized antibodies herein that exhibit improved ability to block activity of all tliree TGF-beta ligands in vitro compared to the mouse monoclonal antibody 2G7 are expected to work better than 2G7 in the various indications below by virtue of their superior ability to inhibit pan-TGF-beta-induced effects, as shown in the assay for TGF-beta-induced fibroblast proliferation ( Figures 10-14).
- Example 3 Therapy of Relapsed or Refractory Prostate Cancer
- the antibody herein is a full-length, humanized monoclonal antibody (produced in CHO cells) directed against TGF-beta. It is indicated as a single agent for treatment of hormone-refractory (androgen-independent) prostate cancer patients.
- Primary endpoints for efficacy include overall survival compared to best available care (Mitoxantrone/Prednisone), when used as a single agent, and safety.
- Secondary efficacy endpoints include: time-to-disease progression, response rate, quality of life, pain and/or duration of response.
- the antibody is administered intravenously (IV) weekly or every three weeks at 2 or 4 mg/kg, respectively, until disease progression.
- the antibody is supplied as a multi-dose liquid formulation (20-mL fill at a concentration of 20mg/mL or higher concentration).
- the antibody is also indicated in combination with chemotherapy for treatment of hormone-refractory (androgen-independent) prostate cancer patients.
- Primary endpoints for efficacy include overall survival compared to chemotherapy, and safety.
- Secondary efficacy endpoints include: time-to-disease progression, response rate, quality of life, pain and/or duration of response.
- the antibody is administered intravenously (IV) weekly or every three weeks at 2 or 4 mg/kg, respectively, until disease progression.
- the antibody is supplied as a multi-dose liquid formulation (20mL fill at a concentration of 20mg/mL or higher concentration).
- E -2, IL-12, G-CSF or GM-CSF an anti-androgen (such as flutamide or cyproterone acetate); leuprolide; suramin; a chemotherapeutic agent such as vinblastine, estramustine, mitoxantrone, liarozole (a retinoic acid metabolism-blocking agent), cyclophosphamide, anthracycline antibiotics such as doxorubicin, a taxane (e.g.
- paclitaxel or docetaxel or methotrexate, or any combination of the above, such as vinblastine/estramustine or cyclophosphamide/doxorubicin/methotrexate; prednisone; hydrocortizone; or combinations thereof.
- Standard doses for these various drugs can be administered, e.g. 40 mg/m 2 /wk docetaxel (TAXOTERE®); 6 (AUC) carboplatin; and 200mg/m 2 paclitaxel (TAXOL®).
- Example 4 Therapy of Breast Cancer
- the antibody herein is indicated as a single agent for treatment of breast cancer patients, especially but not limited to metastatic patients.
- Primary endpoints for efficacy include response rate and safety.
- Secondary efficacy endpoints include: overall survival, time-to-disease progression, quality of life, and/or duration of response.
- the humanized antibody herein is administered intravenously (IV) weekly or every three weeks at 2 or 4 mg/kg, respectively, until disease progression.
- the antibody is supplied as a multi-dose liquid formulation (20 mL fill at a concentration of 20 mg/mL or higher concentration).
- the humanized antibody herein is also indicated in combination with chemotherapy for treatment of breast cancer patients.
- Primary endpoints for efficacy include overall survival compared to chemotherapy alone, and safety. Secondary efficacy endpoints include: time-to-disease progression, response rate, quality of life, and/or duration of response.
- the humanized antibody is administered intravenously (IV) weekly or every three weeks at 2 or 4 mg/kg, respectively, until disease progression.
- the antibody is supplied as a multi-dose liquid formulation (20-mL fill at a concentration of 20mg/mL or higher concentration).
- paclitaxel or docetaxel navelbine, xeloda, mitomycin C, a platinum compound, oxaliplatin, gemcitabine, or combinations of two or more of these such as doxorubicin/cyclophosphomide; HERCEPTIN® anti-HER-2 antibody, or an anti-ErbB antibody that induces apoptosis such as 7C2 or 7F3, including humanized or affinity- matured variants thereof; 2C4 or humanized 2C4; another anti-TGF-beta antibody (e.g. a monoclonal TGF-beta antibody); an anti-estrogen (e.g. tamoxifen); an aromatase inhibitor (e.g.
- anastrozole a farnesyl transferase inhibitor
- an anti-angiogenic agent e.g. an anti-VEGF antibody
- an EGFR-targeted drug e.g. C225 or ZD1839
- a cytokine e.g. IL-2, IL-12, G-CSF or GrM-CSF
- Standard dosages for such additional drugs may be used.
- the humanized antibody herein is additionally indicated in combination with HERCEPTIN® anti- HER-2 antibody or rhuMAb 2C4 for treatment of breast cancer patients, especially those with metastasis.
- Primary endpoints for efficacy include response rate, and safety.
- RhuMAb 2C4 is administered intravenously (IV) weekly or every three weeks at 2 or 4 mg/kg, respectively, until disease progression.
- the antibody rhuMAb 2C4 is supplied as a multi-dose liquid formulation (20mL fill at a concentration of 20mg/mL or higher concentration).
- HERCEPTIN® anti-HER-2 antibody is administered IV as an initial loading dose of 4 mg/kg followed by a weekly maintenance dose of 2 mg/kg.
- HERCEPTIN® anti-HER-2 antibody is supplied as a lyophilized powder.
- Each vial of HERCEPTIN® anti-HER-2 antibody contains 440 mg HERCEPTIN® anti-HER-2 antibody, 9.9 mg L-histidine HC1, 6.4 mg L-histidine, 400 mg ⁇ - ⁇ -trehalose dihydrate, and 1.8 mg POLYSORBATE 20TM surfactant.
- BWFI Bacterio static Water for Injection
- mice Using the murine antibody 2G7 in the 4T1 epithelial cells from a spontaneous mouse mammary tumor model of breast cancer, cells (1.5x10 ) were injected into the mammary fat of mice (day 0). In this model, a palpable primary tumor appears by one week; secondary metastases appear in the lungs by week 2, in the liver by week 3, and in the bone between weeks 4 and 5. Tissues are harvested at week 5.
- the 2G7 antibody and two control IgG antibodies were injected intraperitoneally into mice at 25mg/kg 3x/week and serum TGF-beta production by the 4T1 cells was measured in the tissue culture media (or blood for the in vivo studies) by a commercial ELISA from R&D systems.
- Figure 15A shows TGF-beta production by the 4T1 cells and normal mouse epithelial cells C57 as a control by ELISA in vitro.
- Figure 15B shows the effect on serum TGF-beta production by 4T1 cells in vivo of the 2G7 antibody in mice with tumors (+ anti-TGFbeta) versus mice without tumors (- Con) treated with control (Con) antibodies (isotype-matched IgG, which is an anti-ragweed antibody), and versus mice with tumors (+ Con) treated with control antibodies.
- Figure 16A shows the histology scores and Figure 16B shows the tissue weights for secondary lung tumors produced by the tumor cell model used for Figure 15 with the anti-ragweed IgG control and anti-TGF- beta 2G7 as given to the mice per the description for Figure 15, indicating that anti-TGF-beta lowered the grade, the number of lobes affected, the tissue weight in grams, and the lung weights as a percentage of body weight versus the control. Secondary lung tumors were detected by ex vivo computed tomography scanning.
- Figure 17 shows the quantification of lung tumors of the above mouse model by uCT, indicating tumor volume and number, with anti-TGF-beta 2G7 showing lower tumor volume than the IgG control, with both 2G7 and the control given to the mice per the description for Figure 15 (i.e., 25mg/kg 3x/week intraperitoneally) .
- Figure 18A shows the tumor volume in the above mouse model as a function of time in days after cell injection using 25mg/kg 3x/week intraperitoneally of the IgG control with saline or with taxol, and 25mg/kg 3x/week intraperitoneally of anti-TGF-beta 2G7 with taxol, indicating that the latter was most effective in reducing tumor volume.
- Figure 18B shows that the anti-TGF-beta antibody 2G7 with chemotherapy reduced tissue weight— lung, spleen, and tumors-over both the IgG/saline control and the IgG/chemotherapy controls. Further, the 2G7 antibody decreased systemic levels of vascular endothelial growth factor (VEGF) versus the IgG control in this mouse model.
- Figure 19 shows plasma VEGF levels (pg/ml) in mice without tumors (Normal), or in mice with 4T1 mammary tumors treated with either control IgG (control) or anti-TGF- beta 2G7 (aTGF-b) (25kg/kg 3x/week intraperitoneally for control and anti-TGF-beta). Each point represents an individual mouse.
- VEGF vascular endothelial growth factor
- the bar indicates the mean for the group.
- the 2G7 antibody was found to decrease circulating levels of free TGF-betal and systemic VEGF levels and have a small but significant transitory ability to decrease primary tumor growth versus controls.
- Early treatment with 2G7 decreased secondary lung tumors.
- early treatment with the 2G7 antibodies overcame much of the breast tumor-induced bone destruction occurring in this model, using the same scanning as for lungs. See Table 4.
- ttabecular number refers to the number of ttabeculae (the small spicules of bone which extend into the marrow cavity), and trabecular thickness refers to the average thickness of these ttabeculae. Both of these parameters indicate quantity of bone and are determined using micro-computed tomography and an algorithm to quantitate various bone parameters (Table 4). Table 4 Measurement of Bone Regeneration
- FIG. 20A shows the effect of anti-TGF-beta 2G7 versus the IgG control on tumor volume as a function of days of tumor growth in the PymT model, indicating that the 2G7 antibody reduced tumor volume over time versus the IgG control.
- Figure 20B shows that tumor weight was also reduced with the TGF-beta antibody 2G7 versus the IgG control. It was also found that there are decreased VEGF levels in PyMT tumors relative to Her2 tumors.
- the humanized versions of the 2G7 antibodies herein will act similarly to 2G7 in terms of tumor growth and metastasis.
- Her+ epithelial cells did not synthesize high levels of TGF-beta in vitro, were growth inhibited by TGF-beta in vitro (Siegel et al, Transforming growth factor beta signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis. -Proc Natl Acad Sci U S A, 100(14):8430-5 (2003)), and were not growth inhibited by anti-TGF-beta tteatn ⁇ ent in vivo.
- VEGF levels were increased in this model when anti-TGF-beta antibody 2G7 was given versus an IgG control Staining of three of the breast tumor models (4T1, PyMt and Her2) for basement membrane (collagen IV), endothelial cells (CD31), or vessel-supporting cells called pericytes (SMA or NG2) revealed differences in these model systems in terms of these tliree components.
- These components may be predictive with regards to sensitivity of tumors to anti-TGF-beta tteatment.
- TGF-beta Given the proposed bi-functional nature of the role of TGF-beta in cancer, use of a diagnostic to determine how/if the patient will respond may prove to be useful in the application of TGF-beta inhibitory sttategies for the tteatment of cancer. For example, determining whether or not a given patient's cancer cells remain sensitive to the growth-inhibitory effects of TGF-beta may " be important.
- TGF-beta isoforms, TGF-betal , -2, and/or -3, especially those with higher expression levels, with a particular focus on TGF-betal .
- a This would cover a number of different types of cancer, including, but not limited to: breast, pancreas, prostate, kidney, lung, and skin (melanoma). It was found that there was significant overexpression in these tumor types of TGF-betal in comparison to matched normal tissue samples of the same tissue type. b.
- TGF-betal Her2-negative breast cancers as opposed to Her2-positive breast cancers, as the former may respond better to antibody tteatment as indicated by higher expression of TGF-betal. In this regard, it was found that there was significant overexpression in these tumor types of TGF- betal in comparison to matched normal tissue samples of the same tissue type. 2) As a corollary to #1, tumor cell production, independent of whether TGF-beta is also made in the sttoma/environment. 3) Mutation in, and decreased expression of, one or more TGF-beta receptors, especially, but not limited to, TGF-betal RI or TGF-betaRII (type-IIR).
- TGF-betal RI TGF-betaRII
- TGF-beta signaling pathway including, but not limited to: SMADs/phosphoSMADs, c-myc, CDC25A, pl5INK4B, p21WAFl/CiPl, and p27KlPl.
- Alterations in other signaling pathways known to impact TGF-b activity including, but not limited to: FoxGl, Jagged/Notch, CDK2, and CDK4, and especially Her2/neu, Estrogen Receptor levels, Ras activity, phosphatidylinositol 3-kinase (PI3K), AKT and MAPK activity, as well as p53 status.
- markers may be used to evaluate (within the tumor and/or in the periphery) biological activity of anti-TGF-beta antibodies in patients before and after treatment, including, but not limited to: 1) TGF-beta levels, in the tumor or in the circulation (as shown by Figure 15B as well as by immunohistochemisfry (IHC) data showing TGF-betal protein ex-pression in stained tissue sections of tumor xenografts Colo205 and Calu6 tumors, HPAC tumors, and a human tumor sample of ductal breast adenocarcinoma).
- TGF-beta levels in the tumor or in the circulation
- IHC immunohistochemisfry
- VEGF levels in the tumor or in the circulation (as shown by Figure 19, and also by the data showing that VEGF levels are increased in the Her2-positive model when 2G7 is provided versus the control).
- BMCs blood mononuclear cells
- Indicators of immune cell function especially NK, T-cell, and macrophage activity.
- NSCLC non-small cell lung cancer
- Secondary efficacy endpoints include: overall survival, time-to-disease progression, quality of life, and/or duration of response.
- the humanized antibody is administered intravenously (IV) weekly or every three weeks at 2 or 4 mg/kg, respectively, until disease progression.
- the antibody is supplied as a multi-dose liquid formulation (20-mL fill at a concentration of 20 mg/mL or higher concentration).
- the humanized antibody is also indicated in combination with chemotherapy for tteatment of metastatic non-small cell lung cancer patients.
- Primary endpoints for efficacy include overall survival compared to standard therapy, and safety.
- Secondary efficacy endpoints include: time-to-disease progression, response rate, quality of life and/or duration of response.
- the humanized antibody is administered intravenously (TV) weekly or every tiiree weeks at 2 or 4 mg/kg, respectively, until disease progression.
- the antibody is supplied as a multi-dose liquid formulation (20-mL fill at a concentration of 20 mg/mL or higher concentration) -
- additional drugs that can be combined with the antibody herein to treat lung cancer include chemotherapeutic agents such as carboplatin, a taxane (e.g.
- paclitaxel or docetaxel gemcitabine, navelbine, cisplatin, oxaliplatin, or combinations of any of these such as carboplatin/docetaxel; HERCEPTEN(S> anti-HER-2 antibody, or an anti-ErbB antibody that induces apoptosis such as 7C2 or 7F3, including humanized or affinity- matured variants uiereof; 2C4 or humanized 2C4; another anti-TGF-beta antibody (e.g. a monoclonal TGF-beta antibody); a farnesyl transferase inhibitor; an anti-angiogenic agent (e.g. an anti-VEGF antibody); an EGFR- targeted drug (e.g. C225 or ZD1839); a cytokine (e.g. IL-2, IL-12, G-CSF or GM-CSF); or combinations of the above.
- Example 6 Therapy of Colorectal Cancer The humanized antibody herein is indicated as a single agent for treatment of metastatic c lorectal cancer.
- Primary endpoints for efficacy include response rate and safety. Secondary efficacy endpoints include: overall survival, time-to-disease progression, quality of life, and/or duration of response.
- the humanized antibody is administered intravenously (IV) weekly or every tiiree weeks at 2 or 4 mg/kg, respectively, until disease progression.
- the antibody is supplied as a multi-dose liquid formulation (20-mL fill at a concentration of 20 mg/mL or higher concentration).
- the humanized antibody is also indicated in combination with chemotherapy for treatment of metastatic colorectal cancer patients.
- Primary endpoints for efficacy include overall survival compared to standard therapy, and safety.
- Secondary efficacy endpoints include: time-to-disease progression, response rate, quality of life, and/or duration of response.
- the humanized antibody is administered intravenously (IV) weekly or every three weeks at 2 or 4 mg/kg, respectively, until disease progression.
- the antibody is supplied as a multi-dose liquid formulation (20-mL fill at a concentration of 20 mg/mL or higher concentration).
- chemotherapeutic agents used to treat colorectal cancer that can be combined with the humanized antibody that binds TGF-beta include 5-fluorouracil (5-FU), leucovorin (LV), CPT-11, levamisole, or combinations of any two or more of these, e.g., 5-FU/LV/CPT-ll.
- Standard dosages of such chemotherapeutic agents can be administered.
- Other drugs that may be combined with the anti-TGF-beta antibody to treat colorectal cancer include a farnesyl fransferase inhibitor; an anti-angiogenic agent (e.g. an anti- VEGF antibody); an EGFR-targeted drug (e.g. C225 or ZD1839); a cytokine (e.g.
- IL-2 IL-2, IL-12, G-CSF or GM- CSF
- HERCEPTIN® anti-HER-2 antibody or an anti-ErbB antibody that induces apoptosis such as 7C2 or 7F3, including humanized or affinity-matured variants thereof; 2C4 or humanized 2C4; another anti-TGF-beta antibody (e.g. a monoclonal TGF-beta antibody); or combinations of the above.
- the antibody can be tested in colon cancer models (e.g., HT29 and HCT116) and expected to work.
- Example 7 Therapy of Melanoma
- the results with monoclonal antibody 2G7 in this Example suggest that the humanized antibodies herein would be useful for treatment of malignant melanoma.
- the murine anti-TGF-betal antibody 2G7 was tested in animal models of melanoma. Specifically, in syngeneic C57black6 mice injected subcutaneously with mouse melanoma cells (B16F10 or B16B16), tteatment with anti-TGF-beta (2G7) at 25mg/kg 3x/week intraperitoneally decreased primary tumor size relative to treatment with the isotype-matched IgG control (anti- ragweed antibody) (at 25mg/kg 3x/week intraperitoneally) ( Figures 22, 24, and 25).
- Calu-6 CM cells induced VEGF and SMA expression in fibroblasts in vitro, an effect which was inhibited by tteatment with the murine anti-TGF-beta 2G7 antibody.
- Xenotransplants of these cells were made into nude mice (see, e.g., Gourdeau et al, Mol Cancer Ther., 3:1375-1384 (2004)) and the tumor volume was tested after treatment with the control IgG2b antibody used in the B 16 experiment above (at 25 mg/kg 3x/week intraperitoneally), along an anti-VEGF antibody (A461) (at 5 mg/kg 3x ⁇ veek intraperitoneally), murine anti- TGF-beta antibody 2G7 (at 25 mg/kg 3x/week intraperitoneally), and the combination of 2G7 and A461 (dosing as above).
- the control IgG2b antibody used in the B 16 experiment above (at 25 mg/kg 3x/week intraperitoneally), along an anti-VEGF antibody (A461) (at 5 mg/kg 3x ⁇ veek intraperitoneally), murine anti- TGF-beta antibody 2G7 (at 25 mg/kg 3x/week intraperitoneally), and the combination of 2G
- the tumor volume and tumor weight results show that the combination of 2G7 and the anti-VEGF antibody was the most superior treatment, followed by the 2G7 antibody.
- the results show that the two antibodies (anti-TGF-beta and anti-VEGF) are additive and/or synergize with one another. Based on these data, it is expected that the humanized antibodies herein will also reduce primary and secondary tumors involved in malignant melanoma.
- the humanized antibody H2NI.V5L may be tested in two models in which efficacy was shown with the murine antibody 2G7: 1) mouse melanoma cells (B16) into syngeneic mice and 2) Calu-6 (human NSCLC) tumor cells as xenottansplants into nude mice.
- B16 mouse melanoma cells
- Calu-6 human NSCLC tumor cells
- xenottansplants into nude mice.
- B 16 model cells are implanted subcutaneously into mice.
- treatment with various anti-TGF-beta antibodies including H2NI.V5L (25 mg/kg 3x/week) or control antibodies (25 mg/kg 3x week) starts when a palpable tumor is present. Tumors are measured 2-3 x per week. Prior to testing any antibodies, the ability of H2NI.
- H2NI.V5L to inhibit TGF-beta-induced fibroblast (NIH3T3) cell growth is ascertained. If the mouse Fc part of H2NI.V5L is not required for activity in mice, then it is expected that H2NI.V5L will have the same activity as, or better activity than, the original mouse monoclonal 2G7 in mice. If the mouse Fc part of the antibody is required for activity in mice, then H2NI. V5L is not expected to be as effective as the original mouse monoclonal 2G7 in the mouse studies. However, H2NI.V5L (and the other humanized antibodies as claimed herein) are expected to remain effective in humans, since the human Fc will be active therein.
- Example 8 Pharmaco inetics of 2G7 Antibody in Normal and Tumor-bearing Mice
- the purpose herein is to evaluate the pharmacokinetic (PK) characteristics of the murine anti-TGF- beta 2G7 in normal v. tumor-bearing mice.
- the antibody clearance was about 2-fold faster, which is not likely a factor at this dose level.
- the bioavailability of greater than 95% indicates that IP or SC administration is an appropriate route for therapies.
- the 2-3 day half-life supports a 2-3 x weekly dosing regimen.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Immunology (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Heart & Thoracic Surgery (AREA)
- Neurosurgery (AREA)
- Hematology (AREA)
- Biomedical Technology (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Neurology (AREA)
- Cardiology (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Abstract
Description
Claims
Priority Applications (11)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
MXPA06011199A MXPA06011199A (en) | 2004-03-31 | 2005-03-31 | Humanized anti-tgf-beta antibodies. |
KR1020067022715A KR101245983B1 (en) | 2004-03-31 | 2005-03-31 | Humanized anti-TGF-beta antibodies |
CN2005800176135A CN1961003B (en) | 2004-03-31 | 2005-03-31 | Humanized anti-TGF-beta antibodies |
EP05732737.1A EP1740615B1 (en) | 2004-03-31 | 2005-03-31 | Humanized anti-tgf-beta antibodies |
AU2005230848A AU2005230848B9 (en) | 2004-03-31 | 2005-03-31 | Humanized anti-TGF-beta antibodies |
NZ550217A NZ550217A (en) | 2004-03-31 | 2005-03-31 | Humanized anti-TGF-beta antibodies |
BRPI0508761-9A BRPI0508761A (en) | 2004-03-31 | 2005-03-31 | humanized antibody, composition comprising a humanized antibody, isolated nucleic acid, vector, host cell, humanized antibody production process, tgf-beta dysfunction treatment method, tgf-beta detection method, manufactured article and method of treating cancer |
JP2007506586A JP5128935B2 (en) | 2004-03-31 | 2005-03-31 | Humanized anti-TGF-β antibody |
CA2561686A CA2561686C (en) | 2004-03-31 | 2005-03-31 | Humanized anti-tgf-beta antibodies |
ES05732737.1T ES2527292T3 (en) | 2004-03-31 | 2005-03-31 | Humanized anti-TGF-beta antibodies |
IL178409A IL178409A (en) | 2004-03-31 | 2006-09-28 | Humanized anti-tgf-beta antibodies |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US55829004P | 2004-03-31 | 2004-03-31 | |
US60/558,290 | 2004-03-31 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2005097832A2 true WO2005097832A2 (en) | 2005-10-20 |
WO2005097832A3 WO2005097832A3 (en) | 2005-12-01 |
Family
ID=34965114
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2005/010994 WO2005097832A2 (en) | 2004-03-31 | 2005-03-31 | Humanized anti-tgf-beta antibodies |
Country Status (15)
Country | Link |
---|---|
US (2) | US7527791B2 (en) |
EP (1) | EP1740615B1 (en) |
JP (1) | JP5128935B2 (en) |
KR (1) | KR101245983B1 (en) |
CN (1) | CN1961003B (en) |
AU (1) | AU2005230848B9 (en) |
BR (1) | BRPI0508761A (en) |
CA (1) | CA2561686C (en) |
ES (1) | ES2527292T3 (en) |
IL (1) | IL178409A (en) |
MX (1) | MXPA06011199A (en) |
NZ (1) | NZ550217A (en) |
RU (1) | RU2386638C2 (en) |
WO (1) | WO2005097832A2 (en) |
ZA (1) | ZA200608130B (en) |
Cited By (30)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007076391A1 (en) * | 2005-12-23 | 2007-07-05 | Eli Lilly And Company | Tgf-beta binding compositions |
WO2008063776A2 (en) | 2006-10-12 | 2008-05-29 | Genentech, Inc. | Antibodies to lymphotoxin-alpha |
JP2008237098A (en) * | 2007-03-27 | 2008-10-09 | National Institute Of Advanced Industrial & Technology | Animal model for analyzing metastasis of breast cancer to lung and/or liver |
US7619069B2 (en) | 2005-04-22 | 2009-11-17 | Eli Lilly And Company | Antibodies to TGF-beta 1 |
US7723486B2 (en) | 2005-02-08 | 2010-05-25 | Optein, Inc. | Antibodies to TGF-β |
WO2013014262A1 (en) | 2011-07-27 | 2013-01-31 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for diagnosing and treating myhre syndrome |
US8642034B2 (en) | 2006-10-03 | 2014-02-04 | Genzyme Corporation | Use of TGF-β antagonists to treat infants at risk of developing bronchopulmonary dysplasia |
US9468612B2 (en) | 2011-10-26 | 2016-10-18 | Seattle Children's Hospital | Cysteamine in the treatment of fibrotic disease |
US9518112B2 (en) | 2012-03-08 | 2016-12-13 | Ludwig Institute For Cancer Research Ltd | TGF-β1 specific antibodies and methods and uses thereof |
WO2016201282A2 (en) | 2015-06-12 | 2016-12-15 | Ludwig Institute For Cancer Research Ltd | TGF-β3 SPECIFIC ANTIBODIES AND METHODS AND USES THEREOF |
WO2017075433A1 (en) | 2015-10-30 | 2017-05-04 | The Regents Of The University Of California | Transforming growth factor-beta-responsive polypeptides and their methods for use |
WO2017201036A1 (en) | 2016-05-17 | 2017-11-23 | Genentech, Inc. | Stromal gene signatures for diagnosis and use in immunotherapy |
WO2019090263A1 (en) | 2017-11-06 | 2019-05-09 | Genentech, Inc. | Diagnostic and therapeutic methods for cancer |
US10633437B2 (en) | 2010-09-01 | 2020-04-28 | Genzyme Corporation | Treatment of myocardial infarction using TGF-β antagonists |
WO2020095104A1 (en) | 2018-11-05 | 2020-05-14 | Ludwig Institute For Cancer Research Ltd. | HUMANIZED AND VARIANT TGF-β3 SPECIFIC ANTIBODIES AND METHODS AND USES THEREOF |
WO2020095113A1 (en) | 2018-11-05 | 2020-05-14 | Ludwig Institute For Cancer Research Ltd | Humanized and variant tgf-beta1 specific antibodies and methods and uses thereof |
US10766955B2 (en) | 2017-01-20 | 2020-09-08 | Sanofi | Anti-TGF-β antibodies and their use |
WO2020201362A2 (en) | 2019-04-02 | 2020-10-08 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods of predicting and preventing cancer in patients having premalignant lesions |
US10844115B2 (en) | 2017-01-20 | 2020-11-24 | Genzyme Corporation | Bone-targeting antibodies |
US11253546B2 (en) | 2014-12-15 | 2022-02-22 | The Regents Of The University Of California | Bispecific OR-gate chimeric antigen receptor responsive to CD19 and CD20 |
US11325970B2 (en) | 2015-03-04 | 2022-05-10 | Genzyme Corporation | Modified-IgG antibodies that bind transforming growth factor-β1 with high affinity, avidity and specificity |
US11325971B2 (en) | 2015-03-04 | 2022-05-10 | Genzyme Corporation | scFv-Fc dimers that bind transforming growth factor-β1 with high affinity, avidity and specificity |
WO2022115611A1 (en) | 2020-11-25 | 2022-06-02 | Catamaran Bio, Inc. | Cellular therapeutics engineered with signal modulators and methods of use thereof |
US11384350B2 (en) | 2014-12-15 | 2022-07-12 | The Regents Of The University Of California | Cytotoxic molecules responsive to intracellular ligands for selective T cell mediated killing |
US11518803B2 (en) | 2016-06-08 | 2022-12-06 | UCB Biopharma SRL | Antagonist antibodies that bind to human TGFB1, TGFB2 and to TGFB3 and their use for the treatment of lung fibrosis |
WO2023020592A1 (en) * | 2021-08-18 | 2023-02-23 | 丹生医药技术(上海)有限公司 | TGF-β/VEGF BI-FUNCTIONAL ANTIBODY FUSION PROTEIN |
WO2023080900A1 (en) | 2021-11-05 | 2023-05-11 | Genentech, Inc. | Methods and compositions for classifying and treating kidney cancer |
WO2024077166A1 (en) | 2022-10-05 | 2024-04-11 | Genentech, Inc. | Methods and compositions for classifying and treating lung cancer |
WO2024077095A1 (en) | 2022-10-05 | 2024-04-11 | Genentech, Inc. | Methods and compositions for classifying and treating bladder cancer |
US12049496B2 (en) | 2017-01-20 | 2024-07-30 | Sanofi | Anti-TGF-beta antibodies and their use |
Families Citing this family (662)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7211644B1 (en) * | 1996-08-27 | 2007-05-01 | University Of South Florida | Diagnostic markers of human female infertility |
US6683156B1 (en) | 1996-08-27 | 2004-01-27 | University Of South Florida | Method for diagnosing selected adenocarcinomas |
US8106001B2 (en) * | 1996-08-27 | 2012-01-31 | University Of South Florida | Diagnostic markers of human female infertility |
US6294662B1 (en) | 1996-08-27 | 2001-09-25 | University Of South Florida | Nucleic acids encoding an endometrial bleeding associated factor (ebaf) |
US20080267946A1 (en) * | 2005-03-08 | 2008-10-30 | Medigenes Co., Ltd | Pharmaceutical Composition for Treating Avellino Cornea Dystrophy Comprising an Antibody Against Tgf-Beta |
US7741448B2 (en) * | 2005-06-21 | 2010-06-22 | Medical & Biological Laboratories Co., Ltd. | Antibody having inhibitory effect on amyloid fibril formation |
BRPI0707679A2 (en) * | 2006-02-01 | 2011-05-10 | Tjhe Johns Hopkins University | polypeptide conjugate - Nucleic acid for immunoprophylaxis or immunotherapy for neoplastic or infectious disorders |
EP1998810A4 (en) | 2006-03-13 | 2009-09-02 | Univ Johns Hopkins | Augmentation of endothelial thromboresistance |
MX2009008230A (en) * | 2007-01-30 | 2010-03-08 | Epivax Inc | Regulatory t cell epitopes, compositions and uses thereof. |
US20100291024A1 (en) * | 2007-03-30 | 2010-11-18 | Xuebin Qin | Methods and compositions for the treatment of proliferative and pathogenic diseases |
KR20100063048A (en) * | 2007-07-31 | 2010-06-10 | 더 존스 홉킨스 유니버시티 | Polypeptide-nucleic acid conjugate for immunoprophylaxis or immunotherapy for neoplastic or infectious disorders |
SG193868A1 (en) | 2007-09-26 | 2013-10-30 | Chugai Pharmaceutical Co Ltd | Modified antibody constant region |
EP2212431A4 (en) * | 2007-10-16 | 2011-05-11 | Nuvelo Inc | Antibodies to irem-1 |
AU2009225590B2 (en) | 2008-03-20 | 2013-05-02 | Stephen H. Bartelmez | Enhancing vessel lesion homing and repair potential of stem cells |
CA2718120A1 (en) * | 2008-03-31 | 2009-10-08 | Genentech, Inc. | Compositions and methods for treating and diagnosing asthma |
US20110053804A1 (en) * | 2008-04-03 | 2011-03-03 | Sloan-Kettering Institute For Cancer Research | Gene Signatures for the Prognosis of Cancer |
EP2310006A4 (en) * | 2008-07-03 | 2012-04-25 | Mayo Foundation | Treating cancer |
US20110135651A1 (en) * | 2008-08-19 | 2011-06-09 | Children's Hospital Medical Center | Method and composition for enhancing hematopoietic stem cell mobilization |
US8685932B2 (en) | 2008-12-16 | 2014-04-01 | Option Pharmaceuticals, Llc | Targeted transforming growth factor-beta-bound IgG for Treatment of Diseases |
PE20120770A1 (en) | 2009-03-25 | 2012-07-10 | Genentech Inc | ANTI alpha5ß1 ANTIBODIES WITH ACTIVITY ON GLIOBLASTOMAS |
ES2598006T3 (en) * | 2009-04-24 | 2017-01-24 | Vanderbilt University | Anti-TGF-beta antibodies for bone growth induction |
CN102712945B (en) | 2009-08-18 | 2016-11-02 | 哈佛大学校长及研究员协会 | Treatment proliferative disease and the method and composition of pathogenic conditions |
RU2587619C2 (en) | 2010-02-18 | 2016-06-20 | Дженентек, Инк. | Neuregulin antagonists and use thereof in treating malignant growth |
BR112012020790B1 (en) * | 2010-02-18 | 2021-09-28 | The Regents Of The University Of California | ISOLATED ANTIBODY ANTI-INTEGRIN ALFAVBETA8 AND PHARMACEUTICAL COMPOSITION |
PT2542590T (en) * | 2010-03-05 | 2017-08-31 | Univ Johns Hopkins | Compositions and methods for targeted immunomodulatory antibodies and fusion proteins |
TR201816180T4 (en) | 2010-03-12 | 2018-11-21 | Genzyme Corp | Combination therapy to treat breast cancer. |
BR112012022044A2 (en) | 2010-03-24 | 2020-08-25 | Genentech Inc | ''antibody, immunoconjugate, pharmaceutical formulation, antibody use, treatment method, isolated bispecific antibody and host cell''. |
KR101885388B1 (en) | 2010-06-18 | 2018-08-03 | 제넨테크, 인크. | Anti-axl antibodies and methods of use |
WO2011161189A1 (en) | 2010-06-24 | 2011-12-29 | F. Hoffmann-La Roche Ag | Anti-hepsin antibodies and methods of use |
BR112013000340A2 (en) | 2010-07-09 | 2016-05-31 | Genentech Inc | isolated antibody that binds neuropillin-1 (nrp1), isolated nucleic acid, host cell, method of producing an antibody, immunoconjugate and method of detecting nrp1 in a biological sample |
WO2012010582A1 (en) | 2010-07-21 | 2012-01-26 | Roche Glycart Ag | Anti-cxcr5 antibodies and methods of use |
CA2806855A1 (en) | 2010-08-03 | 2012-02-09 | F. Hoffmann - La Roche Ag | Chronic lymphocytic leukemia (cll) biomarkers |
CA2805564A1 (en) | 2010-08-05 | 2012-02-09 | Stefan Jenewein | Anti-mhc antibody anti-viral cytokine fusion protein |
EP2603525A1 (en) | 2010-08-13 | 2013-06-19 | F.Hoffmann-La Roche Ag | Antibodies to il-1beta and il-18, for treatment of disease |
EP3333194B1 (en) | 2010-08-13 | 2021-03-17 | Roche Glycart AG | Anti-fap antibodies and methods of use |
KR101653030B1 (en) | 2010-08-13 | 2016-08-31 | 로슈 글리카트 아게 | Anti-tenascin-c a2 antibodies and methods of use |
DK2612151T3 (en) | 2010-08-31 | 2017-10-02 | Genentech Inc | BIOMARKETS AND METHODS OF TREATMENT |
CN103228674B (en) | 2010-11-10 | 2019-07-05 | 霍夫曼-拉罗奇有限公司 | Method and composition for neural disease immunotherapy |
EP3447491A3 (en) | 2010-12-16 | 2019-06-05 | F. Hoffmann-La Roche AG | Diagnosis and treatments relating to th2 inhibition |
TWI477513B (en) | 2010-12-20 | 2015-03-21 | 建南德克公司 | Anti-mesothelin antibodies and immunoconjugates |
SG191219A1 (en) | 2010-12-22 | 2013-07-31 | Genentech Inc | Anti-pcsk9 antibodies and methods of use |
RU2013135175A (en) | 2011-01-03 | 2015-02-10 | Ф. Хоффманн-Ля Рош Аг | PHARMACEUTICAL COMPOSITION OF ANTIBODY COMPLEX AGAINST DIGOXYGENIN AND DIGOXIGENIN CONJUGATED WITH PEPTIDE |
JP2014511147A (en) | 2011-02-10 | 2014-05-12 | ロシュ グリクアート アーゲー | Improved immunotherapy |
DK3489255T3 (en) | 2011-02-10 | 2021-08-23 | Roche Glycart Ag | Mutated interleukin-2 polypeptides |
US9289513B2 (en) | 2011-03-23 | 2016-03-22 | Option Pharmaceuticals, Llc | Targeted cytokine for treatment of musculoskeletal diseases |
PT2691417T (en) | 2011-03-29 | 2018-10-31 | Roche Glycart Ag | Antibody fc variants |
KR20140021589A (en) | 2011-04-07 | 2014-02-20 | 제넨테크, 인크. | Anti-fgfr4 antibodies and methods of use |
EA201892619A1 (en) | 2011-04-29 | 2019-04-30 | Роше Гликарт Аг | IMMUNOCONJUGATES CONTAINING INTERLEUKIN-2 MUTANT POLYPETIPS |
US8679767B2 (en) | 2011-05-12 | 2014-03-25 | Genentech, Inc. | Multiple reaction monitoring LC-MS/MS method to detect therapeutic antibodies in animal samples using framework signature peptides |
DK2710035T3 (en) | 2011-05-16 | 2017-06-19 | Hoffmann La Roche | FGFR1 agonists and methods of use |
EP2714735B1 (en) * | 2011-06-03 | 2021-07-21 | XOMA Technology Ltd. | Antibodies specific for tgf-beta |
CA2837914A1 (en) | 2011-06-15 | 2012-12-20 | F. Hoffmann-La Roche Ag | Anti-human epo receptor antibodies and methods of use |
AR086823A1 (en) | 2011-06-30 | 2014-01-22 | Genentech Inc | ANTI-C-MET ANTIBODY FORMULATIONS, METHODS |
EP2744824A1 (en) | 2011-08-17 | 2014-06-25 | F.Hoffmann-La Roche Ag | Neuregulin antibodies and uses thereof |
EP2748195A1 (en) | 2011-08-23 | 2014-07-02 | Roche Glycart AG | Anti-mcsp antibodies |
MX349095B (en) | 2011-08-23 | 2017-07-11 | Roche Glycart Ag | Bispecific antigen binding molecules. |
US20130078250A1 (en) | 2011-08-23 | 2013-03-28 | Oliver Ast | Bispecific t cell activating antigen binding molecules |
HUE038225T2 (en) | 2011-08-23 | 2018-10-29 | Roche Glycart Ag | Bispecific t cell activating antigen binding molecules |
CA2844143C (en) | 2011-08-23 | 2018-07-31 | Roche Glycart Ag | Fc-free antibodies comprising two fab fragments and methods of use |
KR101870555B1 (en) | 2011-08-23 | 2018-06-22 | 로슈 글리카트 아게 | Bispecific antibodies specific for t-cell activating antigens and a tumor antigen and methods of use |
MX2014003094A (en) | 2011-09-15 | 2014-04-25 | Genentech Inc | Methods of promoting differentiation. |
KR20140064971A (en) | 2011-09-19 | 2014-05-28 | 제넨테크, 인크. | Combination treatments comprising c-met antagonists and b-raf antagonists |
US20130089562A1 (en) | 2011-10-05 | 2013-04-11 | Genenthech, Inc. | Methods of treating liver conditions using notch2 antagonists |
EP3461839A1 (en) | 2011-10-14 | 2019-04-03 | F. Hoffmann-La Roche AG | Anti-htra1 antibodies and methods of use |
EP2766000A2 (en) | 2011-10-15 | 2014-08-20 | F.Hoffmann-La Roche Ag | Scd1 antagonists for treating cancer |
WO2013059531A1 (en) | 2011-10-20 | 2013-04-25 | Genentech, Inc. | Anti-gcgr antibodies and uses thereof |
SG11201401815XA (en) | 2011-10-28 | 2014-05-29 | Genentech Inc | Therapeutic combinations and methods of treating melanoma |
CN104066748A (en) | 2011-11-21 | 2014-09-24 | 霍夫曼-拉罗奇有限公司 | Purification of anti-c-met antibodies |
WO2013078286A1 (en) * | 2011-11-22 | 2013-05-30 | Cornell University | Methods for stimulating hematopoietic recovery by inhibiting tgf beta signaling |
US20140335084A1 (en) | 2011-12-06 | 2014-11-13 | Hoffmann-La Roche Inc. | Antibody formulation |
CN113881702A (en) | 2011-12-22 | 2022-01-04 | 弗·哈夫曼-拉罗切有限公司 | Expression vector element combinations, novel production cell production methods and their use in the recombinant production of polypeptides |
RU2625033C2 (en) | 2011-12-22 | 2017-07-11 | Ф. Хоффманн-Ля Рош Аг | Display system based on full length antibody for eukaryotic cells, and its application |
EP2794878B1 (en) | 2011-12-22 | 2020-03-18 | F.Hoffmann-La Roche Ag | Expression vector organization, novel production cell generation methods and their use for the recombinant production of polypeptides |
WO2013096791A1 (en) | 2011-12-23 | 2013-06-27 | Genentech, Inc. | Process for making high concentration protein formulations |
US20150011431A1 (en) | 2012-01-09 | 2015-01-08 | The Scripps Research Institute | Humanized antibodies |
CN104520321A (en) | 2012-01-09 | 2015-04-15 | 斯克利普斯研究所 | Ultralong complementarity determining regions and uses thereof |
IN2014DN05885A (en) | 2012-01-18 | 2015-06-05 | Hoffmann La Roche | |
EP2804630B1 (en) | 2012-01-18 | 2017-10-18 | F. Hoffmann-La Roche AG | Methods of using fgf19 modulators |
KR102148303B1 (en) | 2012-02-11 | 2020-08-26 | 제넨테크, 인크. | R-spondin translocations and methods using the same |
CA2860600C (en) | 2012-02-15 | 2022-07-26 | F. Hoffmann-La Roche Ag | Fc-receptor based affinity chromatography |
US10259626B2 (en) | 2012-03-08 | 2019-04-16 | Selig Sealing Products, Inc. | Container sealing member with protected security component and removal tab |
PE20141909A1 (en) | 2012-03-13 | 2014-11-29 | Hoffmann La Roche | COMBINED THERAPY FOR THE TREATMENT OF OVARIAN CANCER |
EP2831115A1 (en) | 2012-03-27 | 2015-02-04 | F. Hoffmann-La Roche AG | Diagnosis and treatments relating to her3 inhibitors |
AR090549A1 (en) | 2012-03-30 | 2014-11-19 | Genentech Inc | ANTI-LGR5 AND IMMUNOCATE PLAYERS |
CA2867824A1 (en) | 2012-05-01 | 2013-11-07 | Genentech, Inc. | Anti-pmel17 antibodies and immunoconjugates |
WO2013170191A1 (en) | 2012-05-11 | 2013-11-14 | Genentech, Inc. | Methods of using antagonists of nad biosynthesis from nicotinamide |
MX2014014086A (en) | 2012-05-23 | 2015-01-26 | Genentech Inc | Selection method for therapeutic agents. |
BR112014031310A2 (en) | 2012-06-15 | 2017-07-25 | Genentech Inc | anti-pcsk9 antibodies, formulations, dosage and methods of use |
CN104428006B (en) | 2012-07-04 | 2017-09-08 | 弗·哈夫曼-拉罗切有限公司 | The antigen-antibody conjugate of covalent attachment |
WO2014006123A1 (en) | 2012-07-04 | 2014-01-09 | F. Hoffmann-La Roche Ag | Anti-biotin antibodies and methods of use |
WO2014006118A1 (en) | 2012-07-04 | 2014-01-09 | F. Hoffmann-La Roche Ag | Anti-theophylline antibodies and methods of use |
ES2743401T3 (en) | 2012-07-05 | 2020-02-19 | Hoffmann La Roche | Expression and secretion system |
EA201590174A1 (en) | 2012-07-09 | 2015-09-30 | Дженентек, Инк. | IMMUNOCONGATES CONTAINING ANTI-CD22 ANTIBODIES |
MX2015000315A (en) | 2012-07-09 | 2015-07-06 | Genentech Inc | Immunoconjugates comprising anti-cd22 antibodies. |
US20140030280A1 (en) | 2012-07-09 | 2014-01-30 | Genentech, Inc. | Anti-cd79b antibodies and immunoconjugates |
MX2015000314A (en) | 2012-07-09 | 2015-04-10 | Genentech Inc | Immunoconjugates comprising anti - cd79b antibodies. |
ES2896493T3 (en) | 2012-07-13 | 2022-02-24 | Roche Glycart Ag | Bispecific anti-VEGF/anti-ANG-2 antibodies and their use in the treatment of ocular vascular diseases |
WO2014025813A1 (en) | 2012-08-07 | 2014-02-13 | Genentech, Inc. | Combination therapy for the treatment of glioblastoma |
AR092044A1 (en) | 2012-08-07 | 2015-03-18 | Roche Glycart Ag | IMPROVED IMMUNOTHERAPY |
BR112015002085A2 (en) | 2012-08-08 | 2017-12-19 | Roche Glycart Ag | protein, polynucleotide, vector, host cell, method for producing protein, pharmaceutical composition, protein use, method of treatment and invention |
CN109705218B (en) | 2012-08-09 | 2022-07-19 | 罗切格利卡特公司 | ASGPR antibodies and uses thereof |
US20140044675A1 (en) | 2012-08-10 | 2014-02-13 | Roche Glycart Ag | Interleukin-2 fusion proteins and uses thereof |
RU2015117393A (en) | 2012-10-08 | 2016-12-10 | Роше Гликарт Аг | Deprived fc antibodies containing two Fab fragments, and methods for their use |
US20140120116A1 (en) * | 2012-10-26 | 2014-05-01 | The Chinese University Of Hong Kong | Treatment of cancer using smad3 inhibitor |
WO2014071358A2 (en) | 2012-11-05 | 2014-05-08 | Foundation Medicine, Inc. | Novel ntrk1 fusion molecules and uses thereof |
SG11201502538TA (en) | 2012-11-08 | 2015-05-28 | Hoffmann La Roche | Her3 antigen binding proteins binding to the beta-hairpin of her3 |
TWI657095B (en) | 2012-11-13 | 2019-04-21 | 美商建南德克公司 | Anti-hemagglutinin antibodies and methods of use |
WO2014107739A1 (en) | 2013-01-07 | 2014-07-10 | Eleven Biotherapeutics, Inc. | Antibodies against pcsk9 |
WO2014113729A2 (en) | 2013-01-18 | 2014-07-24 | Foundation Mecicine, Inc. | Methods of treating cholangiocarcinoma |
WO2014116749A1 (en) | 2013-01-23 | 2014-07-31 | Genentech, Inc. | Anti-hcv antibodies and methods of using thereof |
KR20150134319A (en) * | 2013-01-28 | 2015-12-01 | 에베크 인코포레이티드 | Humanized Anti-HMGB1 Antibody or Antigen-Binding Fragment Thereof |
KR20150118159A (en) | 2013-02-22 | 2015-10-21 | 에프. 호프만-라 로슈 아게 | Methods of treating cancer and preventing drug resistance |
CA2896259A1 (en) | 2013-02-26 | 2014-09-04 | Roche Glycart Ag | Anti-mcsp antibodies |
KR20150122203A (en) | 2013-02-26 | 2015-10-30 | 로슈 글리카트 아게 | Bispecific t cell activating antigen binding molecules |
KR20210094673A (en) | 2013-02-26 | 2021-07-29 | 로슈 글리카트 아게 | Bispecific t cell activating antigen binding molecules |
CN105143270B (en) | 2013-02-26 | 2019-11-12 | 罗切格利卡特公司 | Bispecific T cell activation antigen binding molecules |
RU2015137610A (en) | 2013-03-06 | 2017-04-10 | Дженентек, Инк. | METHODS FOR TREATMENT AND PREVENTION OF DRUG RESISTANCE OF MALIGNANT TUMORS |
KR20150127203A (en) | 2013-03-14 | 2015-11-16 | 제넨테크, 인크. | Combinations of a mek inhibitor compound with an her3/egfr inhibitor compound and methods of use |
US9562099B2 (en) | 2013-03-14 | 2017-02-07 | Genentech, Inc. | Anti-B7-H4 antibodies and immunoconjugates |
CA2905070A1 (en) | 2013-03-14 | 2014-09-25 | Genentech, Inc. | Methods of treating cancer and preventing cancer drug resistance |
EP2968552B1 (en) | 2013-03-14 | 2020-03-11 | The Scripps Research Institute | Targeting agent antibody conjugates and uses thereof |
KR20150127199A (en) | 2013-03-14 | 2015-11-16 | 제넨테크, 인크. | Anti-b7-h4 antibodies and immunoconjugates |
PE20151750A1 (en) | 2013-03-15 | 2015-12-07 | Genentech Inc | COMPOSITIONS AND METHODS FOR THE DIAGNOSIS AND TREATMENT OF HEPATIC CANCER |
BR112015021521A2 (en) | 2013-03-15 | 2017-10-10 | Genentech Inc | anti-crth2 antibodies and methods for their use |
MX2015012872A (en) | 2013-03-15 | 2016-02-03 | Ac Immune Sa | Anti-tau antibodies and methods of use. |
US20160143910A1 (en) | 2013-03-15 | 2016-05-26 | Constellation Pharmaceuticals, Inc. | Methods of treating cancer and preventing cancer drug resistance |
CN110079599B (en) | 2013-03-15 | 2024-06-04 | 豪夫迈·罗氏有限公司 | Biomarkers and methods for treating PD-1 and PD-L1 related disorders |
UA118028C2 (en) | 2013-04-03 | 2018-11-12 | Рош Глікарт Аг | Bispecific antibodies specific for fap and dr5, antibodies specific for dr5 and methods of use |
EP2992011B1 (en) | 2013-04-29 | 2017-12-13 | F. Hoffmann-La Roche AG | Fcrn-binding abolished anti-igf-1r antibodies and their use in the treatment of vascular eye diseases |
RU2019108429A (en) | 2013-04-29 | 2019-05-06 | Ф. Хоффманн-Ля Рош Аг | MODIFIED ASYMMETRIC ANTIBODIES CONNECTING FC-RECEPTOR AND METHODS OF THEIR APPLICATION |
MY172430A (en) | 2013-04-29 | 2019-11-25 | Hoffmann La Roche | Human fcrn-binding modified antibodies and methods of use |
AR096364A1 (en) | 2013-05-20 | 2015-12-23 | Genentech Inc | ANTITRANSPHERINE RECEIVING ANTIBODIES AND METHODS OF USE |
CN105814074B (en) | 2013-07-18 | 2020-04-21 | 图鲁斯生物科学有限责任公司 | Humanized antibodies with ultralong complementarity determining regions |
EP3022224A2 (en) | 2013-07-18 | 2016-05-25 | Fabrus, Inc. | Antibodies with ultralong complementarity determining regions |
HUE058243T2 (en) | 2013-08-01 | 2022-07-28 | Five Prime Therapeutics Inc | Afucosylated anti-fgfr2iiib antibodies |
US10456470B2 (en) | 2013-08-30 | 2019-10-29 | Genentech, Inc. | Diagnostic methods and compositions for treatment of glioblastoma |
US10617755B2 (en) | 2013-08-30 | 2020-04-14 | Genentech, Inc. | Combination therapy for the treatment of glioblastoma |
KR20160055252A (en) | 2013-09-17 | 2016-05-17 | 제넨테크, 인크. | Methods of using anti-lgr5 antibodies |
JP2016537965A (en) | 2013-10-11 | 2016-12-08 | ジェネンテック, インコーポレイテッド | NSP4 inhibitors and methods of use |
CA2925598A1 (en) | 2013-10-18 | 2015-04-23 | Genentech, Inc. | Anti-rspo antibodies and methods of use |
KR20160068802A (en) | 2013-10-23 | 2016-06-15 | 제넨테크, 인크. | Methods of diagnosing and treating eosinophilic disorders |
CN111499742B (en) | 2013-11-21 | 2024-05-07 | 豪夫迈·罗氏有限公司 | Anti-alpha-synuclein antibodies and methods of use |
AU2014362238A1 (en) | 2013-12-13 | 2016-06-09 | Genentech, Inc. | Anti-CD33 antibodies and immunoconjugates |
MX2016007887A (en) | 2013-12-17 | 2016-10-28 | Genentech Inc | Methods of treating her2-positive cancers using pd-1 axis binding antagonists and anti-her2 antibodies. |
SG11201604979WA (en) | 2013-12-17 | 2016-07-28 | Genentech Inc | Combination therapy comprising ox40 binding agonists and pd-1 axis binding antagonists |
BR112016013741A2 (en) | 2013-12-17 | 2017-10-03 | Genentech Inc | USES OF PD-1 AXIS LEADING ANTAGONISTS AND AN ANTI-CD20 ANTIBODY, AND KITS COMPRISING THEM |
LT3736292T (en) | 2013-12-17 | 2024-07-25 | Genentech, Inc. | Anti-cd3 antibodies and methods of use |
BR112016013562A2 (en) | 2013-12-20 | 2017-10-03 | Hoffmann La Roche | HUMANIZED ANTI-TAU(PS422) ANTIBODIES, THEIR USES, AND PHARMACEUTICAL FORMULATIONS |
TWI728373B (en) | 2013-12-23 | 2021-05-21 | 美商建南德克公司 | Antibodies and methods of use |
RU2694981C2 (en) | 2014-01-03 | 2019-07-18 | Ф. Хоффманн-Ля Рош Аг | Covalently linked conjugates chelicar-antibody against chelicar and use thereof |
EP3960768A1 (en) | 2014-01-03 | 2022-03-02 | F. Hoffmann-La Roche AG | Bispecific anti-hapten/anti-blood brain barrier receptor antibodies, complexes thereof and their use as blood brain barrier shuttles |
JP6521464B2 (en) | 2014-01-03 | 2019-05-29 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | Covalently linked polypeptide toxin-antibody conjugates |
BR112016015589A2 (en) | 2014-01-06 | 2017-10-31 | Hoffmann La Roche | monovalent transit modules for the blood-brain barrier |
KR20160107190A (en) | 2014-01-15 | 2016-09-13 | 에프. 호프만-라 로슈 아게 | Fc-region variants with modified fcrn- and maintained protein a-binding properties |
CA2935393A1 (en) | 2014-01-24 | 2015-07-30 | Genentech, Inc. | Methods of using anti-steap1 antibodies and immunoconjugates |
DK3102595T3 (en) | 2014-02-06 | 2019-02-04 | Hoffmann La Roche | Interleukin-2 fusion proteins and their applications |
KR20210121288A (en) | 2014-02-08 | 2021-10-07 | 제넨테크, 인크. | Methods of treating alzheimer's disease |
TWI785472B (en) | 2014-02-08 | 2022-12-01 | 美商建南德克公司 | Methods of treating alzheimer's disease |
EP3825332A1 (en) | 2014-02-12 | 2021-05-26 | F. Hoffmann-La Roche AG | Anti-jagged1 antibodies and methods of use |
CR20160379A (en) | 2014-02-21 | 2016-10-07 | Genentech Inc | BISPECIFIC ANTIBODIES ANTI-IL 13 / IL-17 AND ITS USES |
ES2897765T3 (en) | 2014-03-14 | 2022-03-02 | Hoffmann La Roche | Methods and compositions for the secretion of heterologous polypeptides |
WO2015140591A1 (en) | 2014-03-21 | 2015-09-24 | Nordlandssykehuset Hf | Anti-cd14 antibodies and uses thereof |
MA39776A (en) | 2014-03-24 | 2017-02-01 | Hoffmann La Roche | Cancer treatment with c-met antagonists and correlation of the latter with hgf expression |
PT3126394T (en) | 2014-03-31 | 2019-12-19 | Hoffmann La Roche | Anti-ox40 antibodies and methods of use |
MX2016012779A (en) | 2014-03-31 | 2017-04-27 | Genentech Inc | Combination therapy comprising anti-angiogenesis agents and ox40 binding agonists. |
SG10202107077QA (en) | 2014-04-02 | 2021-07-29 | Hoffmann La Roche | Method for detecting multispecific antibody light chain mispairing |
ES2845650T3 (en) | 2014-04-18 | 2021-07-27 | Acceleron Pharma Inc | Procedures to increase red blood cell levels and treat sickle cell disease |
WO2015164615A1 (en) | 2014-04-24 | 2015-10-29 | University Of Oslo | Anti-gluten antibodies and uses thereof |
CA2946662A1 (en) | 2014-05-22 | 2015-11-26 | Genentech, Inc. | Anti-gpc3 antibodies and immunoconjugates |
EP3146071B1 (en) | 2014-05-23 | 2020-09-02 | F. Hoffmann-La Roche AG | Mit biomarkers and methods using the same |
MX2016016233A (en) | 2014-06-11 | 2017-03-31 | Genentech Inc | Anti-lgr5 antibodies and uses thereof. |
EP3154566B1 (en) | 2014-06-13 | 2022-08-03 | Acceleron Pharma Inc. | Actrii antagonist for the treatment or prevention of a cutaneous ulcer in a subject that has anemia |
WO2015191986A1 (en) | 2014-06-13 | 2015-12-17 | Genentech, Inc. | Methods of treating and preventing cancer drug resistance |
MX2016015280A (en) | 2014-06-26 | 2017-03-03 | Hoffmann La Roche | Anti-brdu antibodies and methods of use. |
AR100978A1 (en) | 2014-06-26 | 2016-11-16 | Hoffmann La Roche | ANTI-Tau HUMANIZED ANTIBODY BRAIN LAUNCHERS (pS422) AND USES OF THE SAME |
EP3680336A1 (en) | 2014-07-03 | 2020-07-15 | F. Hoffmann-La Roche AG | Polypeptide expression systems |
CN106488775A (en) | 2014-07-11 | 2017-03-08 | 基因泰克公司 | NOTCH approach suppresses |
MX2017000419A (en) | 2014-07-11 | 2017-08-16 | Genentech Inc | Anti-pd-l1 antibodies and diagnostic uses thereof. |
EP3169801A1 (en) | 2014-07-14 | 2017-05-24 | F. Hoffmann-La Roche AG | Diagnostic methods and compositions for treatment of glioblastoma |
HUE044814T2 (en) | 2014-08-04 | 2019-11-28 | Hoffmann La Roche | Bispecific t cell activating antigen binding molecules |
KR102615681B1 (en) | 2014-08-28 | 2023-12-18 | 바이오아트라, 인코퍼레이티드 | Conditionally active chimeric antigen receptors for modified t-cells |
PE20170670A1 (en) | 2014-09-12 | 2017-06-06 | Genentech Inc | ANTI-CLL-1 ANTIBODIES AND IMMUNOCONJUGATES |
DK3191135T3 (en) | 2014-09-12 | 2020-10-12 | Genentech Inc | Anti-HER2 antibodies and immunoconjugates |
CN113698488A (en) | 2014-09-12 | 2021-11-26 | 基因泰克公司 | anti-B7-H4 antibodies and immunoconjugates |
RU2727663C2 (en) | 2014-09-17 | 2020-07-22 | Дженентек, Инк. | Immunoconjugates, containing antibodies against her2 and pyrrolbenzodiazepines |
CA3069221C (en) | 2014-09-23 | 2023-04-04 | Genentech, Inc. | Methods of using anti-cd79b immunoconjugates |
JP2017536102A (en) | 2014-10-16 | 2017-12-07 | ジェネンテック, インコーポレイテッド | Anti-alpha-synuclein antibodies and methods of use |
US10626176B2 (en) | 2014-10-31 | 2020-04-21 | Jounce Therapeutics, Inc. | Methods of treating conditions with antibodies that bind B7-H4 |
RU2017119231A (en) | 2014-11-03 | 2018-12-06 | Дженентек, Инк. | METHODS AND BIOMARKERS FOR PREDICTING EFFICIENCY AND EVALUATING TREATMENT WITH OX40 AGONIST |
CA2966523A1 (en) | 2014-11-03 | 2016-05-12 | Genentech, Inc. | Assays for detecting t cell immune subsets and methods of use thereof |
CA2966558C (en) | 2014-11-05 | 2024-03-12 | Genentech, Inc. | Methods of producing two chain proteins in bacteria |
MX2017005925A (en) | 2014-11-05 | 2017-11-08 | Genentech Inc | Methods of producing two chain proteins in bacteria. |
SG11201703376QA (en) | 2014-11-06 | 2017-05-30 | Genentech Inc | Combination therapy comprising ox40 binding agonists and tigit inhibitors |
WO2016071377A1 (en) | 2014-11-06 | 2016-05-12 | F. Hoffmann-La Roche Ag | Fc-region variants with modified fcrn- and protein a-binding properties |
WO2016073157A1 (en) | 2014-11-06 | 2016-05-12 | Genentech, Inc. | Anti-ang2 antibodies and methods of use thereof |
CN107108720A (en) | 2014-11-06 | 2017-08-29 | 豪夫迈·罗氏有限公司 | Fc region variants and its application method that FCRN with change is combined |
EP3552488A1 (en) | 2014-11-10 | 2019-10-16 | F. Hoffmann-La Roche AG | Animal model for nephropathy and agents for treating the same |
EA201791029A1 (en) | 2014-11-10 | 2017-12-29 | Дженентек, Инк. | ANTIBODIES AGAINST INTERLEUKIN-33 AND THEIR APPLICATION |
PL3224275T3 (en) | 2014-11-14 | 2020-09-07 | F.Hoffmann-La Roche Ag | Antigen binding molecules comprising a tnf family ligand trimer |
US20160166685A1 (en) | 2014-11-17 | 2016-06-16 | Genentech, Inc. | Combination therapy comprising ox40 binding agonists and pd-1 axis binding antagonists |
US10508151B2 (en) | 2014-11-19 | 2019-12-17 | Genentech, Inc. | Anti-transferrin receptor antibodies and methods of use |
EP3221361B1 (en) | 2014-11-19 | 2021-04-21 | Genentech, Inc. | Anti-transferrin receptor / anti-bace1 multispecific antibodies and methods of use |
CN107108745B (en) | 2014-11-19 | 2021-01-12 | 基因泰克公司 | Antibodies against BACE1 and their use for immunotherapy of neurological diseases |
PL3789402T3 (en) | 2014-11-20 | 2022-10-17 | F. Hoffmann-La Roche Ag | Combination therapy of t cell activating bispecific antigen binding molecules and pd-1 axis binding antagonists |
MX2017006626A (en) | 2014-11-20 | 2017-08-21 | Hoffmann La Roche | Common light chains and methods of use. |
MA41119A (en) | 2014-12-03 | 2017-10-10 | Acceleron Pharma Inc | METHODS OF TREATMENT OF MYELODYSPLASIC SYNDROMES AND SIDEROBLASTIC ANEMIA |
EA201790984A1 (en) | 2014-12-05 | 2018-05-31 | Дженентек, Инк. | ANTI-CD79B ANTIBODIES AND METHODS OF THEIR APPLICATION |
RU2017120039A (en) | 2014-12-10 | 2019-01-10 | Дженентек, Инк. | ANTIBODIES TO HEMATOENCEPHALIC BARRIER RECEPTORS AND METHODS OF APPLICATION |
BR112017011170A2 (en) | 2014-12-18 | 2018-02-27 | Hoffmann La Roche | method for determining the complement-dependent cytotoxicity of a composition |
KR20230044338A (en) | 2014-12-19 | 2023-04-03 | 추가이 세이야쿠 가부시키가이샤 | Anti-c5 antibodies and methods of use |
US20160200815A1 (en) | 2015-01-05 | 2016-07-14 | Jounce Therapeutics, Inc. | Antibodies that inhibit tim-3:lilrb2 interactions and uses thereof |
AU2016206682B2 (en) | 2015-01-14 | 2021-11-11 | The Brigham And Women's Hospital, Inc. | Treatment of cancer with anti-LAP monoclonal antibodies |
US20180016327A1 (en) | 2015-01-22 | 2018-01-18 | Chugai Seiyaku Kabushiki Kaisha | A Combination of Two or More Anti-C5 Antibodies and Methods of Use |
CN107108729A (en) | 2015-02-05 | 2017-08-29 | 中外制药株式会社 | The antibody of antigen-binding domains comprising ion concentration dependence, FC region variants, the binding antibodies of IL 8, and its application |
WO2016149276A1 (en) | 2015-03-16 | 2016-09-22 | Genentech, Inc. | Methods of detecting and quantifying il-13 and uses in diagnosing and treating th2-associated diseases |
WO2016146833A1 (en) | 2015-03-19 | 2016-09-22 | F. Hoffmann-La Roche Ag | Biomarkers for nad(+)-diphthamide adp ribosyltransferase resistance |
DK3274370T3 (en) | 2015-03-23 | 2020-02-17 | Bayer Pharma AG | ANTI-CEACAM6 ANTIBODIES AND APPLICATIONS THEREOF |
US10023635B2 (en) | 2015-03-23 | 2018-07-17 | Jounce Therapeutics, Inc. | Antibodies to ICOS |
WO2016161410A2 (en) | 2015-04-03 | 2016-10-06 | Xoma Technology Ltd. | Treatment of cancer using inhibitors of tgf-beta and pd-1 |
EP3889171A1 (en) | 2015-04-06 | 2021-10-06 | Acceleron Pharma Inc. | Tgf-beta superfamily type i and type ii receptor heteromultimers and uses thereof |
MA41919A (en) | 2015-04-06 | 2018-02-13 | Acceleron Pharma Inc | ALK4 HETEROMULTIMERS: ACTRIIB AND THEIR USES |
EP3280736A1 (en) | 2015-04-07 | 2018-02-14 | F. Hoffmann-La Roche AG | Antigen binding complex having agonistic activity and methods of use |
IL254887B2 (en) | 2015-04-07 | 2023-11-01 | Alector Llc | Anti-sortilin antibodies and methods of use thereof |
PL3286315T3 (en) | 2015-04-24 | 2021-11-02 | F. Hoffmann-La Roche Ag | Methods of identifying bacteria comprising binding polypeptides |
JP2018520642A (en) | 2015-05-01 | 2018-08-02 | ジェネンテック, インコーポレイテッド | Mask anti-CD3 antibody and method of use thereof |
WO2016179194A1 (en) | 2015-05-04 | 2016-11-10 | Jounce Therapeutics, Inc. | Lilra3 and method of using the same |
WO2016183104A1 (en) | 2015-05-11 | 2016-11-17 | Genentech, Inc. | Compositions and methods of treating lupus nephritis |
MX2017014381A (en) | 2015-05-12 | 2018-03-02 | Genentech Inc | Therapeutic and diagnostic methods for cancer. |
CN107771182A (en) | 2015-05-29 | 2018-03-06 | 豪夫迈·罗氏有限公司 | The anti-Ebola virus glycoproteins antibody of humanization and application method |
CN107532217A (en) | 2015-05-29 | 2018-01-02 | 豪夫迈·罗氏有限公司 | Treatment and diagnostic method for cancer |
WO2016196679A1 (en) | 2015-06-02 | 2016-12-08 | Genentech, Inc. | Compositions and methods for using anti-il-34 antibodies to treat neurological diseases |
MA44955A (en) | 2015-06-05 | 2019-03-20 | Ac Immune Sa | ANTI-TAU BODIES AND THEIR METHODS OF USE |
CN107750164A (en) | 2015-06-08 | 2018-03-02 | 豪夫迈·罗氏有限公司 | Use anti-OX40 antibody and the method for the axle binding antagonists treating cancers of PD 1 |
CN107810011A (en) | 2015-06-08 | 2018-03-16 | 豪夫迈·罗氏有限公司 | Use the method for anti-OX40 antibodies for treating cancer |
EP3307771A2 (en) | 2015-06-12 | 2018-04-18 | Alector LLC | Anti-cd33 antibodies and methods of use thereof |
US11174313B2 (en) | 2015-06-12 | 2021-11-16 | Alector Llc | Anti-CD33 antibodies and methods of use thereof |
CN108064246A (en) | 2015-06-15 | 2018-05-22 | 基因泰克公司 | Antibody and immune conjugate |
PT3310814T (en) | 2015-06-16 | 2023-10-02 | H Hoffnabb La Roche Ag | Humanized and affinity matured antibodies to fcrh5 and methods of use |
JP2018526972A (en) | 2015-06-16 | 2018-09-20 | ジェネンテック, インコーポレイテッド | Anti-CD3 antibody and method of use |
US10501545B2 (en) | 2015-06-16 | 2019-12-10 | Genentech, Inc. | Anti-CLL-1 antibodies and methods of use |
EP3310812A2 (en) | 2015-06-17 | 2018-04-25 | H. Hoffnabb-La Roche Ag | Anti-her2 antibodies and methods of use |
CN107771076A (en) | 2015-06-17 | 2018-03-06 | 豪夫迈·罗氏有限公司 | Use the axle binding antagonists of PD 1 and the method for Taxane treatment Locally Advanced or metastatic breast cancer |
TW201718010A (en) * | 2015-06-19 | 2017-06-01 | 健臻公司 | Method of treating primary focal segmental glomerulosclerosis |
CN107921145A (en) | 2015-06-23 | 2018-04-17 | 拜耳医药股份有限公司 | The antibody drug conjugate of KSP inhibitor and anti-TWEAKR antibody(ADC) |
EP3744732A1 (en) | 2015-06-24 | 2020-12-02 | F. Hoffmann-La Roche AG | Humanized anti-tau(ps422) antibodies and methods of use |
IL302486A (en) | 2015-06-24 | 2023-06-01 | Hoffmann La Roche | Anti-transferrin receptor antibodies with tailored affinity |
US20170029520A1 (en) | 2015-06-29 | 2017-02-02 | Genentech, Inc. | Compositions and methods for use in organ transplantation |
CA3162816A1 (en) | 2015-06-29 | 2017-01-05 | Ventana Medical Systems, Inc. | Materials and methods for performing histochemical assays for human pro-epiregulin and amphiregulin |
AU2016301380B2 (en) | 2015-08-04 | 2021-07-01 | Acceleron Pharma Inc. | Methods for treating myeloproliferative disorders |
CN105384825B (en) | 2015-08-11 | 2018-06-01 | 南京传奇生物科技有限公司 | A kind of bispecific chimeric antigen receptor and its application based on single domain antibody |
TW202342532A (en) | 2015-09-18 | 2023-11-01 | 日商中外製藥股份有限公司 | Il-8-binding antibodies and uses thereof |
CA2999369C (en) | 2015-09-22 | 2023-11-07 | Spring Bioscience Corporation | Anti-ox40 antibodies and diagnostic uses thereof |
JP6959912B2 (en) | 2015-09-23 | 2021-11-05 | ジェネンテック, インコーポレイテッド | Optimized variant of anti-VEGF antibody |
JP6955487B2 (en) | 2015-09-24 | 2021-10-27 | アブビトロ, エルエルシー | HIV antibody composition and usage |
BR112018005862A2 (en) | 2015-09-25 | 2018-10-16 | Genentech, Inc. | antibodies, isolated antibodies, polynucleotide, vector, host cell, antibody production method, immunoconjugate, composition, uses of antibodies, methods for treating or retarding the progression of a cancer and a disease and for increasing, enhancing or stimulating a response or immune function and kit |
AR106188A1 (en) | 2015-10-01 | 2017-12-20 | Hoffmann La Roche | ANTI-CD19 HUMANIZED HUMAN ANTIBODIES AND METHODS OF USE |
MA43345A (en) | 2015-10-02 | 2018-08-08 | Hoffmann La Roche | PYRROLOBENZODIAZEPINE ANTIBODY-DRUG CONJUGATES AND METHODS OF USE |
WO2017055392A1 (en) | 2015-10-02 | 2017-04-06 | F. Hoffmann-La Roche Ag | Anti-cd3xcd44v6 bispecific t cell activating antigen binding molecules |
EP3913000A1 (en) | 2015-10-02 | 2021-11-24 | F. Hoffmann-La Roche AG | Bispecific anti-cd19xcd3 t cell activating antigen binding molecules |
CA2990755A1 (en) | 2015-10-02 | 2017-04-06 | F. Hoffman-La Roche Ag | Bispecific anti-ceaxcd3 t cell activating antigen binding molecules |
WO2017055393A1 (en) | 2015-10-02 | 2017-04-06 | F. Hoffmann-La Roche Ag | Anti-cd3xtim-3 bispecific t cell activating antigen binding molecules |
WO2017055385A1 (en) | 2015-10-02 | 2017-04-06 | F. Hoffmann-La Roche Ag | Anti-cd3xgd2 bispecific t cell activating antigen binding molecules |
AR106365A1 (en) | 2015-10-02 | 2018-01-10 | Hoffmann La Roche | BISPECIFIC MOLECULES OF ANTIGEN BINDING TO T-CELL ACTIVATORS |
CN107949574A (en) | 2015-10-02 | 2018-04-20 | 豪夫迈·罗氏有限公司 | Bispecific T cell activation antigen binding molecules |
US20180282410A1 (en) | 2015-10-02 | 2018-10-04 | Hoffmann-La Roche Inc. | Anti-cd3xrob04 bispecific t cell activating antigen binding molecules |
MX2018003822A (en) | 2015-10-02 | 2018-06-22 | Hoffmann La Roche | Bispecific anti-human cd20/human transferrin receptor antibodies and methods of use. |
AR106189A1 (en) | 2015-10-02 | 2017-12-20 | Hoffmann La Roche | BIESPECTIFIC ANTIBODIES AGAINST HUMAN A-b AND THE HUMAN TRANSFERRINE RECEIVER AND METHODS OF USE |
HUE056033T2 (en) | 2015-10-02 | 2022-01-28 | Hoffmann La Roche | Anti-pd1 antibodies and methods of use |
MA43354A (en) | 2015-10-16 | 2018-08-22 | Genentech Inc | CONJUGATE DRUG CONJUGATES WITH CLOUDY DISULPHIDE |
MA45326A (en) | 2015-10-20 | 2018-08-29 | Genentech Inc | CALICHEAMICIN-ANTIBODY-DRUG CONJUGATES AND METHODS OF USE |
AU2016342269A1 (en) | 2015-10-22 | 2018-03-29 | Jounce Therapeutics, Inc. | Gene signatures for determining icos expression |
EP4015533A1 (en) | 2015-10-29 | 2022-06-22 | F. Hoffmann-La Roche AG | Anti-variant fc-region antibodies and methods of use |
EP3184547A1 (en) | 2015-10-29 | 2017-06-28 | F. Hoffmann-La Roche AG | Anti-tpbg antibodies and methods of use |
CA3001362C (en) | 2015-10-30 | 2020-10-13 | Genentech, Inc. | Anti-htra1 antibodies and methods of use thereof |
JP2018534930A (en) | 2015-10-30 | 2018-11-29 | ジェネンテック, インコーポレイテッド | Anti-factor D antibodies and conjugates |
JP6998869B2 (en) | 2015-11-08 | 2022-02-04 | ジェネンテック, インコーポレイテッド | Screening method for multispecific antibody |
US10988543B2 (en) | 2015-11-11 | 2021-04-27 | Opi Vi—Ip Holdco Llc | Humanized anti-tumor necrosis factor alpha receptor 2 (anti-TNFR2) antibodies and methods of use thereof to elicit an immune response against a tumor |
BR112018010410A8 (en) | 2015-11-23 | 2019-02-26 | Five Prime Therapeutics Inc | method for treating cancer in a subject, composition and methods of increasing the number of nk cells and increasing the number of one or more pd-11 positive cells |
CA3005975A1 (en) | 2015-11-23 | 2017-06-01 | Acceleron Pharma Inc. | Methods for treating eye disorders |
EP3178848A1 (en) | 2015-12-09 | 2017-06-14 | F. Hoffmann-La Roche AG | Type ii anti-cd20 antibody for reducing formation of anti-drug antibodies |
CA2997406C (en) | 2015-12-09 | 2024-05-28 | F. Hoffmann-La Roche Ag | Type ii anti-cd20 antibody for reducing formation of anti-drug antibodies or cytokine release |
BR112018009067A8 (en) | 2015-12-18 | 2019-02-26 | Chugai Pharmaceutical Co Ltd | anti-c5 antibodies and methods of use |
WO2017118307A1 (en) | 2016-01-05 | 2017-07-13 | 江苏恒瑞医药股份有限公司 | Pcsk9 antibody, antigen-binding fragment thereof, and medical uses thereof |
WO2017118675A1 (en) | 2016-01-08 | 2017-07-13 | F. Hoffmann-La Roche Ag | Methods of treating cea-positive cancers using pd-1 axis binding antagonists and anti-cea/anti-cd3 bispecific antibodies |
BR112018014762A2 (en) | 2016-01-20 | 2018-12-26 | Genentech Inc | method of treating (early) alzheimer's disease |
KR102500659B1 (en) | 2016-02-29 | 2023-02-16 | 제넨테크, 인크. | Therapeutic and diagnostic methods for cancer |
CN109153719B (en) | 2016-03-15 | 2022-12-30 | 中外制药株式会社 | Methods of treating cancer using PD-1 axis binding antagonists and anti-GPC 3 antibodies |
CA3012422A1 (en) | 2016-03-22 | 2017-09-28 | F. Hoffmann-La Roche Ag | Protease-activated t cell bispecific molecules |
EP4273551A3 (en) | 2016-03-25 | 2024-01-17 | F. Hoffmann-La Roche AG | Multiplexed total antibody and antibody-conjugated drug quantification assay |
EP3231813A1 (en) | 2016-03-29 | 2017-10-18 | F. Hoffmann-La Roche AG | Trimeric costimulatory tnf family ligand-containing antigen binding molecules |
US20170319688A1 (en) | 2016-04-14 | 2017-11-09 | Genentech, Inc. | Anti-rspo3 antibodies and methods of use |
JP7503887B2 (en) | 2016-04-15 | 2024-06-21 | ジェネンテック, インコーポレイテッド | Methods for monitoring and treating cancer - Patents.com |
CN109154027A (en) | 2016-04-15 | 2019-01-04 | 豪夫迈·罗氏有限公司 | For monitoring and the method for the treatment of cancer |
CN109071635B (en) | 2016-05-02 | 2023-09-01 | 豪夫迈·罗氏有限公司 | Contorsbody-single stranded target conjugates |
CN109071652B (en) | 2016-05-11 | 2022-09-23 | 豪夫迈·罗氏有限公司 | Antigen binding molecules comprising TNF family ligand trimers and tenascin binding modules |
EP3243836A1 (en) | 2016-05-11 | 2017-11-15 | F. Hoffmann-La Roche AG | C-terminally fused tnf family ligand trimer-containing antigen binding molecules |
EP3455252B1 (en) | 2016-05-11 | 2022-02-23 | F. Hoffmann-La Roche AG | Modified anti-tenascin antibodies and methods of use |
EP3243832A1 (en) | 2016-05-13 | 2017-11-15 | F. Hoffmann-La Roche AG | Antigen binding molecules comprising a tnf family ligand trimer and pd1 binding moiety |
US11254742B2 (en) | 2016-05-13 | 2022-02-22 | Bioatla, Inc. | Anti-Ror2 antibodies, antibody fragments, their immunoconjugates and uses thereof |
WO2017201449A1 (en) | 2016-05-20 | 2017-11-23 | Genentech, Inc. | Protac antibody conjugates and methods of use |
JP7022080B2 (en) | 2016-05-27 | 2022-02-17 | ジェネンテック, インコーポレイテッド | Biochemical analytical methods for the characterization of site-specific antibody-drug conjugates |
EP3252078A1 (en) | 2016-06-02 | 2017-12-06 | F. Hoffmann-La Roche AG | Type ii anti-cd20 antibody and anti-cd20/cd3 bispecific antibody for treatment of cancer |
CA3059010A1 (en) | 2016-06-02 | 2018-12-06 | F. Hoffmann-La Roche Ag | Type ii anti-cd20 antibody and anti-cd20/cd3 bispecific antibody for treatment of cancer |
JP7043425B2 (en) | 2016-06-06 | 2022-03-29 | ジェネンテック, インコーポレイテッド | Silvestrol Antibodies-Drug Conjugates and Usage |
EP3464345A1 (en) | 2016-06-06 | 2019-04-10 | F. Hoffmann-La Roche AG | Fusion proteins for ophthalmology with increased eye retention |
EP3472210A1 (en) | 2016-06-17 | 2019-04-24 | Life Technologies Corporation | Site-specific crosslinking of antibodies |
JP7133477B2 (en) | 2016-06-24 | 2022-09-08 | ジェネンテック, インコーポレイテッド | Anti-polyubiquitin multispecific antibody |
CN109415435B (en) | 2016-07-04 | 2024-01-16 | 豪夫迈·罗氏有限公司 | Novel antibody forms |
EP3496739B1 (en) | 2016-07-15 | 2021-04-28 | Acceleron Pharma Inc. | Compositions comprising actriia polypeptides for use in treating pulmonary hypertension |
WO2018014260A1 (en) | 2016-07-20 | 2018-01-25 | Nanjing Legend Biotech Co., Ltd. | Multispecific antigen binding proteins and methods of use thereof |
MA45811A (en) | 2016-07-27 | 2019-06-05 | Acceleron Pharma Inc | METHODS AND COMPOSITIONS OF TREATMENT OF DISEASE. |
WO2018027204A1 (en) | 2016-08-05 | 2018-02-08 | Genentech, Inc. | Multivalent and multiepitopic anitibodies having agonistic activity and methods of use |
CA3026050A1 (en) | 2016-08-05 | 2018-02-08 | Chugai Seiyaku Kabushiki Kaisha | Composition for prophylaxis or treatment of il-8 related diseases |
EP3497129A1 (en) | 2016-08-08 | 2019-06-19 | H. Hoffnabb-La Roche Ag | Therapeutic and diagnostic methods for cancer |
JP7093767B2 (en) | 2016-08-11 | 2022-06-30 | ジェネンテック, インコーポレイテッド | Pyrrolobenzodiazepine prodrug and its antibody conjugate |
US11701384B2 (en) | 2016-09-02 | 2023-07-18 | The Regents Of The University Of California | Methods and compositions involving interleukin-6 receptor alpha-binding single chain variable fragments |
SG10201607778XA (en) | 2016-09-16 | 2018-04-27 | Chugai Pharmaceutical Co Ltd | Anti-Dengue Virus Antibodies, Polypeptides Containing Variant Fc Regions, And Methods Of Use |
CN116731197A (en) | 2016-09-19 | 2023-09-12 | 豪夫迈·罗氏有限公司 | Complement factor based affinity chromatography |
KR102557643B1 (en) | 2016-09-23 | 2023-07-20 | 제넨테크, 인크. | Use of IL-13 antagonists to treat atopic dermatitis |
EP3519437B1 (en) | 2016-09-30 | 2021-09-08 | F. Hoffmann-La Roche AG | Bispecific antibodies against p95her2 |
WO2018067740A1 (en) | 2016-10-05 | 2018-04-12 | Acceleron Pharma, Inc. | Compositions and method for treating kidney disease |
JP7050770B2 (en) | 2016-10-05 | 2022-04-08 | エフ・ホフマン-ラ・ロシュ・アクチェンゲゼルシャフト | Method for preparing antibody drug conjugate |
CN110418851A (en) | 2016-10-06 | 2019-11-05 | 基因泰克公司 | The treatment of cancer and diagnostic method |
WO2018068201A1 (en) | 2016-10-11 | 2018-04-19 | Nanjing Legend Biotech Co., Ltd. | Single-domain antibodies and variants thereof against ctla-4 |
CN110267678A (en) | 2016-10-29 | 2019-09-20 | 霍夫曼-拉罗奇有限公司 | Anti- MIC antibody and application method |
HRP20211703T1 (en) | 2016-11-02 | 2022-02-04 | Jounce Therapeutics, Inc. | Antibodies to pd-1 and uses thereof |
CN109906030B (en) | 2016-11-04 | 2022-03-18 | 安健基因公司 | Genetically modified non-human animals and methods for producing heavy chain-only antibodies |
KR20190074300A (en) | 2016-11-15 | 2019-06-27 | 제넨테크, 인크. | Dosage for treatment with anti-CD20 / anti-CD3 bispecific antibodies |
TW201829463A (en) | 2016-11-18 | 2018-08-16 | 瑞士商赫孚孟拉羅股份公司 | Anti-hla-g antibodies and use thereof |
KR102645073B1 (en) | 2016-12-07 | 2024-03-11 | 제넨테크, 인크. | Anti-tau antibodies and methods of using the same |
AU2017373889A1 (en) | 2016-12-07 | 2019-06-06 | Ac Immune Sa | Anti-Tau antibodies and methods of use |
AU2017370942A1 (en) | 2016-12-07 | 2019-06-13 | Progenity Inc. | Gastrointestinal tract detection methods, devices and systems |
WO2018109058A1 (en) | 2016-12-16 | 2018-06-21 | H. Lundbeck A/S | Agents, uses and methods |
CA3039430A1 (en) | 2016-12-19 | 2018-06-28 | F. Hoffmann-La Roche Ag | Combination therapy with targeted 4-1bb (cd137) agonists |
KR20190093588A (en) | 2016-12-20 | 2019-08-09 | 에프. 호프만-라 로슈 아게 | Combination therapy of anti-CD20 / anti-CD3 bispecific antibodies and 4-1BB (CD137) agonists |
BR112019009839A2 (en) | 2016-12-21 | 2019-09-17 | Hoffmann La Roche | method for enzymatic production of an antibody and antibody |
AU2017384276B9 (en) | 2016-12-21 | 2020-11-26 | F. Hoffmann-La Roche Ag | In vitro glycoengineering of antibodies |
MX2019006123A (en) | 2016-12-21 | 2019-08-12 | Hoffmann La Roche | Method for in vitro glycoengineering of antibodies. |
CN110494453B (en) | 2017-02-10 | 2023-05-26 | 豪夫迈·罗氏有限公司 | Anti-tryptase antibodies, compositions thereof and uses thereof |
CN110546277B (en) | 2017-03-01 | 2024-06-11 | 豪夫迈·罗氏有限公司 | Diagnostic and therapeutic methods for cancer |
AR111249A1 (en) | 2017-03-22 | 2019-06-19 | Genentech Inc | OPTIMIZED ANTIBODY COMPOSITIONS FOR THE TREATMENT OF OCULAR DISORDERS |
EP3600441A1 (en) | 2017-03-22 | 2020-02-05 | Genentech, Inc. | Hydrogel cross-linked hyaluronic acid prodrug compositions and methods |
CN110494446A (en) | 2017-03-28 | 2019-11-22 | 基因泰克公司 | The method for treating neurodegenerative disease |
EP3601345A1 (en) | 2017-03-29 | 2020-02-05 | H. Hoffnabb-La Roche Ag | Bispecific antigen binding molecule for a costimulatory tnf receptor |
WO2018178074A1 (en) | 2017-03-29 | 2018-10-04 | F. Hoffmann-La Roche Ag | Trimeric antigen binding molecules specific for a costimulatory tnf receptor |
EP3601346A1 (en) | 2017-03-29 | 2020-02-05 | H. Hoffnabb-La Roche Ag | Bispecific antigen binding molecule for a costimulatory tnf receptor |
WO2018187191A1 (en) | 2017-04-03 | 2018-10-11 | Jounce Therapeutics, Inc | Compositions and methods for the treatment of cancer |
JP7247101B2 (en) | 2017-04-03 | 2023-03-28 | エフ・ホフマン-ラ・ロシュ・アクチェンゲゼルシャフト | Antibody that binds to STEAP-1 |
KR20190121816A (en) | 2017-04-03 | 2019-10-28 | 에프. 호프만-라 로슈 아게 | Immunoconjugates of Anti-PD-1 Antibodies with Mutant IL-2 or IL-15 |
CN110382525B (en) | 2017-04-03 | 2023-10-20 | 豪夫迈·罗氏有限公司 | Immunoconjugates |
HUE060019T2 (en) | 2017-04-05 | 2023-01-28 | Hoffmann La Roche | Anti-lag3 antibodies |
CA3059615A1 (en) | 2017-04-21 | 2018-10-25 | Genentech, Inc. | Use of klk5 antagonists for treatment of a disease |
AU2018256934B2 (en) | 2017-04-27 | 2021-10-14 | Anaptysbio, Inc. | Antibody agents directed against Lymphocyte Activation Gene-3 (LAG-3) and uses thereof |
EP3401328A1 (en) | 2017-05-10 | 2018-11-14 | Bayer Pharma Aktiengesellschaft | One step antibody humanization by golden gate based germline framework region shuffling |
EP3625251A1 (en) | 2017-05-15 | 2020-03-25 | University Of Rochester | Broadly neutralizing anti-influenza monoclonal antibody and uses thereof |
KR20200006538A (en) | 2017-05-16 | 2020-01-20 | 파이브 프라임 테라퓨틱스, 인크. | Anti-FGFR2 Antibody in Combination with Chemotherapy in Cancer Treatment |
CN111492245A (en) | 2017-07-21 | 2020-08-04 | 基因泰克公司 | Methods of treatment and diagnosis of cancer |
CN117700548A (en) | 2017-08-03 | 2024-03-15 | 艾利妥 | anti-CD 33 antibodies and methods of use thereof |
EP3444275A1 (en) | 2017-08-16 | 2019-02-20 | Exiris S.r.l. | Monoclonal antibody anti-fgfr4 |
MX2020002241A (en) | 2017-08-28 | 2020-09-03 | Angiex Inc | Anti-tm4sf1 antibodies and methods of using same. |
WO2019045086A1 (en) * | 2017-08-29 | 2019-03-07 | 林化成株式会社 | USE FOR SPECIFIC ANTIBODY FOR ACTIVE OR LATENT TGF-β1 |
AU2018338859A1 (en) | 2017-09-29 | 2020-02-06 | Chugai Seiyaku Kabushiki Kaisha | Multispecific antigen-binding molecule having blood coagulation factor VIII (FVIII) cofactor function-substituting activity, and pharmaceutical formulation containing said molecule as active ingredient |
WO2019075090A1 (en) | 2017-10-10 | 2019-04-18 | Tilos Therapeutics, Inc. | Anti-lap antibodies and uses thereof |
JP2021500930A (en) | 2017-11-01 | 2021-01-14 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | COMP Body-Multivalent Target Binding Substance |
EP3704155A2 (en) | 2017-11-01 | 2020-09-09 | F. Hoffmann-La Roche AG | Combination therapy with targeted ox40 agonists |
BR112020008031A2 (en) | 2017-11-01 | 2020-10-27 | F. Hoffmann-La Roche Ag | multispecific antibody, method for preparing multispecific antibody, set of nucleic acids, expression vector, host cell and pharmaceutical composition |
CN107827983B (en) * | 2017-11-06 | 2020-09-25 | 中国药科大学 | Targeting ARTN single-chain antibody, preparation method and application |
EP3502140A1 (en) | 2017-12-21 | 2019-06-26 | F. Hoffmann-La Roche AG | Combination therapy of tumor targeted icos agonists with t-cell bispecific molecules |
BR112020011469A2 (en) | 2017-12-21 | 2020-11-24 | F. Hoffmann-La Roche Ag | antibodies, bispecific antigen binding molecule, one or more isolated polynucleotides, one or more vectors, host cell, method for producing an antibody, pharmaceutical composition, use of the antibody, method of treating a disease and invention |
WO2019126472A1 (en) | 2017-12-22 | 2019-06-27 | Genentech, Inc. | Use of pilra binding agents for treatment of a disease |
EP3728318A2 (en) | 2017-12-22 | 2020-10-28 | Jounce Therapeutics, Inc. | Antibodies for lilrb2 |
CA3078849A1 (en) | 2017-12-28 | 2019-07-04 | Nanjing Legend Biotech Co., Ltd. | Antibodies and variants thereof against pd-l1 |
US11905327B2 (en) | 2017-12-28 | 2024-02-20 | Nanjing Legend Biotech Co., Ltd. | Single-domain antibodies and variants thereof against TIGIT |
JP7490565B2 (en) | 2017-12-29 | 2024-05-27 | アレクトル エルエルシー | Anti-TMEM106B antibodies and methods of use thereof |
CN111699200B (en) | 2018-01-15 | 2023-05-26 | 南京传奇生物科技有限公司 | Single domain antibodies and variants thereof against PD-1 |
EP3740505A1 (en) | 2018-01-16 | 2020-11-25 | Lakepharma Inc. | Bispecific antibody that binds cd3 and another target |
CN111971301A (en) | 2018-01-31 | 2020-11-20 | 艾莱克特有限责任公司 | anti-MS 4A4A antibodies and methods of use thereof |
CA3089287A1 (en) | 2018-02-08 | 2019-08-15 | Genentech, Inc. | Bispecific antigen-binding molecules and methods of use |
TWI829667B (en) | 2018-02-09 | 2024-01-21 | 瑞士商赫孚孟拉羅股份公司 | Antibodies binding to gprc5d |
KR20230142806A (en) | 2018-02-09 | 2023-10-11 | 제넨테크, 인크. | Therapeutic and diagnostic methods for mast cell-mediated inflammatory diseases |
WO2019165434A1 (en) | 2018-02-26 | 2019-08-29 | Genentech, Inc. | Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies |
EP3765489A1 (en) | 2018-03-13 | 2021-01-20 | F. Hoffmann-La Roche AG | Therapeutic combination of 4-1 bb agonists with anti-cd20 antibodies |
AU2019235330A1 (en) | 2018-03-13 | 2020-07-16 | F. Hoffmann-La Roche Ag | Combination therapy with targeted 4-1BB (CD137) agonists |
US20200040103A1 (en) | 2018-03-14 | 2020-02-06 | Genentech, Inc. | Anti-klk5 antibodies and methods of use |
CA3093729A1 (en) | 2018-03-15 | 2019-09-19 | Chugai Seiyaku Kabushiki Kaisha | Anti-dengue virus antibodies having cross-reactivity to zika virus and methods of use |
EP3775184A1 (en) | 2018-03-29 | 2021-02-17 | F. Hoffmann-La Roche AG | Modulating lactogenic activity in mammalian cells |
JP7346790B2 (en) | 2018-03-30 | 2023-09-20 | ナンジン レジェンド バイオテック カンパニー,リミテッド | Single domain antibodies against LAG-3 and their uses |
WO2019192432A1 (en) | 2018-04-02 | 2019-10-10 | 上海博威生物医药有限公司 | Lymphocyte activation gene-3 (lag-3) binding antibody and use thereof |
TW202011029A (en) | 2018-04-04 | 2020-03-16 | 美商建南德克公司 | Methods for detecting and quantifying FGF21 |
EP3552631A1 (en) | 2018-04-10 | 2019-10-16 | Inatherys | Antibody-drug conjugates and their uses for the treatment of cancer |
AR114284A1 (en) | 2018-04-13 | 2020-08-12 | Hoffmann La Roche | HER2 TARGETING ANTIGEN BINDING MOLECULES COMPOSING 4-1BBL |
AR114789A1 (en) | 2018-04-18 | 2020-10-14 | Hoffmann La Roche | ANTI-HLA-G ANTIBODIES AND THE USE OF THEM |
AR115052A1 (en) | 2018-04-18 | 2020-11-25 | Hoffmann La Roche | MULTI-SPECIFIC ANTIBODIES AND THE USE OF THEM |
JP7402541B2 (en) | 2018-05-03 | 2023-12-21 | ユニバーシティ オブ ロチェスター | Anti-influenza neuraminidase monoclonal antibody and its use |
PE20210342A1 (en) | 2018-05-25 | 2021-02-23 | Alector Llc | ANTI-SIRPA ANTIBODIES AND METHODS OF USING THEM |
JP2021525806A (en) | 2018-06-01 | 2021-09-27 | タユー ファシャ バイオテック メディカル グループ カンパニー, リミテッド | Compositions for treating diseases or conditions and their use |
US20210238308A1 (en) | 2018-06-04 | 2021-08-05 | Chugai Seiyaku Kabushiki Kaisha | Antigen-binding molecule showing changed half-life in cytoplasm |
US20230009902A1 (en) | 2018-06-20 | 2023-01-12 | Progenity, Inc. | Treatment of a disease or condition in a tissue orginating from the endoderm |
KR20210024550A (en) | 2018-06-23 | 2021-03-05 | 제넨테크, 인크. | PD-1 axis binding antagonist, platinum agent, and method of treating lung cancer using topoisomerase II inhibitor |
JP2021529556A (en) | 2018-06-29 | 2021-11-04 | ジェンサン バイオファーマ、 インコーポレイテッドGensun Biopharma, Inc. | Antitumor antagonist |
US20210277113A1 (en) | 2018-06-29 | 2021-09-09 | Alector Llc | Anti-SIRP-Beta1 Antibodies and Methods of Use Thereof |
CN112703038A (en) | 2018-07-10 | 2021-04-23 | 赛诺菲 | Anti-cancer combination therapy targeting CD38 and TGF-beta |
LT3618928T (en) | 2018-07-13 | 2023-04-11 | Alector Llc | Anti-sortilin antibodies and methods of use thereof |
CN112839644A (en) | 2018-07-18 | 2021-05-25 | 豪夫迈·罗氏有限公司 | Methods of treating lung cancer with PD-1 axis binding antagonists, antimetabolites, and platinum agents |
KR20200010103A (en) * | 2018-07-19 | 2020-01-30 | (주)셀트리온 | Stable Liquid Pharmaceutical Formulation |
CN112839960A (en) | 2018-08-10 | 2021-05-25 | 中外制药株式会社 | anti-CD 137 antigen binding molecules and uses thereof |
TW202019968A (en) | 2018-08-13 | 2020-06-01 | 美商英伊布里克斯公司 | Ox40-binding polypeptides and uses thereof |
TW202021618A (en) | 2018-08-17 | 2020-06-16 | 美商23與我有限公司 | Anti-il1rap antibodies and methods of use thereof |
BR112021003843A2 (en) | 2018-08-28 | 2021-05-25 | Ambrx, Inc. | anti-cd3 antibody folate biconjugates and their uses |
CA3108808A1 (en) | 2018-08-31 | 2020-03-05 | Alector Llc | Anti-cd33 antibodies and methods of use thereof |
GB201814281D0 (en) | 2018-09-03 | 2018-10-17 | Femtogenix Ltd | Cytotoxic agents |
AU2019342099A1 (en) | 2018-09-19 | 2021-04-08 | Genentech, Inc. | Therapeutic and diagnostic methods for bladder cancer |
CA3111809A1 (en) | 2018-09-21 | 2020-03-26 | Genentech, Inc. | Diagnostic methods for triple-negative breast cancer |
US20200109200A1 (en) | 2018-10-09 | 2020-04-09 | Genentech, Inc. | Methods and systems for determining synapse formation |
TW202035445A (en) | 2018-10-10 | 2020-10-01 | 美商帝洛斯療法股份有限公司 | Anti-lap antibody variants and uses thereof |
JP2022504822A (en) | 2018-10-11 | 2022-01-13 | インヒブルクス インコーポレイテッド | DLL3 single domain antibody and therapeutic composition thereof |
US11208485B2 (en) | 2018-10-11 | 2021-12-28 | Inhibrx, Inc. | PD-1 single domain antibodies and therapeutic compositions thereof |
CA3114693A1 (en) | 2018-10-11 | 2020-04-16 | Inhibrx, Inc. | 5t4 single domain antibodies and therapeutic compositions thereof |
CA3115082A1 (en) | 2018-10-11 | 2020-04-16 | Inhibrx, Inc. | B7h3 single domain antibodies and therapeutic compositions thereof |
JP2022512744A (en) | 2018-10-18 | 2022-02-07 | ジェネンテック, インコーポレイテッド | Diagnosis and treatment for sarcomatoid kidney cancer |
WO2020086858A1 (en) | 2018-10-24 | 2020-04-30 | Genentech, Inc. | Conjugated chemical inducers of degradation and methods of use |
US20210395390A1 (en) | 2018-10-31 | 2021-12-23 | Bayer Aktiengesellschaft | Reversal agents for neutralizing the therapeutic activity of anti-fxia antibodies |
JP2022506156A (en) | 2018-11-05 | 2022-01-17 | ジェネンテック, インコーポレイテッド | Method for producing double-stranded protein in prokaryotic host cell |
KR20210095165A (en) | 2018-11-19 | 2021-07-30 | 프로제너티, 인크. | Methods and devices for treating diseases with biopharmaceuticals |
JP2022513708A (en) | 2018-12-05 | 2022-02-09 | モルフォシス・アーゲー | Multispecific antigen-binding molecule |
BR112021010908A2 (en) | 2018-12-06 | 2021-08-31 | Genentech, Inc. | METHOD FOR TREATMENT OF DIFFUSED LARGE B-CELL LYMPHOMA, KIT AND IMMUNOCONJUGATE |
CN113227119A (en) | 2018-12-10 | 2021-08-06 | 基因泰克公司 | Photocrosslinked peptides for site-specific conjugation to Fc-containing proteins |
AR117327A1 (en) | 2018-12-20 | 2021-07-28 | 23Andme Inc | ANTI-CD96 ANTIBODIES AND METHODS OF USE OF THEM |
AR117453A1 (en) | 2018-12-20 | 2021-08-04 | Genentech Inc | CF OF MODIFIED ANTIBODIES AND METHODS TO USE THEM |
EP3898673A1 (en) | 2018-12-21 | 2021-10-27 | 23Andme, Inc. | Anti-il-36 antibodies and methods of use thereof |
BR112021012040A2 (en) | 2018-12-21 | 2021-11-03 | Ose Immunotherapeutics | Bifunctional anti-PD-1/SIRPA molecule |
WO2020127628A1 (en) | 2018-12-21 | 2020-06-25 | F. Hoffmann-La Roche Ag | Tumor-targeted superagonistic cd28 antigen binding molecules |
EP3898984A1 (en) | 2018-12-21 | 2021-10-27 | Genentech, Inc. | Methods of producing polypeptides using a cell line resistant to apoptosis |
AU2019406453A1 (en) | 2018-12-21 | 2021-07-22 | Ose Immunotherapeutics | Bifunctional molecule directed against human PD-1 |
US20230071889A1 (en) | 2018-12-21 | 2023-03-09 | Ose Immunotherapeutics | Bifunctional anti-pd-1/il-7 molecule |
CN113286821A (en) | 2018-12-21 | 2021-08-20 | 豪夫迈·罗氏有限公司 | Tumor-targeting agonistic CD28 antigen binding molecules |
TWI829831B (en) | 2018-12-21 | 2024-01-21 | 瑞士商赫孚孟拉羅股份公司 | Antibodies binding to cd3 |
JP2022515543A (en) | 2018-12-30 | 2022-02-18 | エフ.ホフマン-ラ ロシュ アーゲー | Anti-rabbit CD19 antibody and how to use |
SG11202106700WA (en) | 2019-01-07 | 2021-07-29 | Inhibrx Inc | Polypeptides comprising modified il-2 polypeptides and uses thereof |
JP2022518399A (en) | 2019-01-14 | 2022-03-15 | ジェネンテック, インコーポレイテッド | How to Treat Cancer with PD-1 Axial Binding Antagonists and RNA Vaccines |
CN113330030A (en) | 2019-01-17 | 2021-08-31 | 拜耳公司 | Method for determining whether a subject is suitable for treatment with an agonist of soluble guanylate cyclase (sGC) |
CN113329763A (en) | 2019-01-22 | 2021-08-31 | 豪夫迈·罗氏有限公司 | Immunoglobulin a antibodies and methods of making and using |
WO2020153467A1 (en) | 2019-01-24 | 2020-07-30 | 中外製薬株式会社 | Novel cancer antigens and antibodies of said antigens |
GB201901197D0 (en) | 2019-01-29 | 2019-03-20 | Femtogenix Ltd | G-A Crosslinking cytotoxic agents |
WO2020165374A1 (en) | 2019-02-14 | 2020-08-20 | Ose Immunotherapeutics | Bifunctional molecule comprising il-15ra |
CN113710706A (en) | 2019-02-27 | 2021-11-26 | 豪夫迈·罗氏有限公司 | Administration for anti-TIGIT antibody and anti-CD 20 antibody or anti-CD 38 antibody treatment |
MX2021010441A (en) | 2019-03-01 | 2021-09-21 | Allogene Therapeutics Inc | Dll3 targeting chimeric antigen receptors and binding agents. |
KR20210138588A (en) | 2019-03-08 | 2021-11-19 | 제넨테크, 인크. | Methods for detecting and quantifying membrane-associated proteins on extracellular vesicles |
CA3130446A1 (en) | 2019-03-14 | 2020-09-17 | Genentech, Inc. | Treatment of cancer with her2xcd3 bispecific antibodies in combination with anti-her2 mab |
BR112021018684A2 (en) | 2019-03-21 | 2021-11-23 | Allogene Therapeutics Inc | Methods to increase the efficiency of tcr¿¿+ cell depletion |
EP3952996A1 (en) | 2019-04-12 | 2022-02-16 | F. Hoffmann-La Roche AG | Bispecific antigen binding molecules comprising lipocalin muteins |
EP3956364A1 (en) | 2019-04-19 | 2022-02-23 | F. Hoffmann-La Roche AG | Anti-mertk antibodies and their methods of use |
KR20220004028A (en) | 2019-04-26 | 2022-01-11 | 알로젠 테라퓨틱스 인코포레이티드 | Methods for making allogeneic CAR T cells |
WO2020226986A2 (en) | 2019-05-03 | 2020-11-12 | Genentech, Inc. | Methods of treating cancer with an anti-pd-l1 antibody |
CN114040926A (en) | 2019-05-04 | 2022-02-11 | 印希比股份有限公司 | Polypeptide binding to CD123 and uses thereof |
KR20220004751A (en) | 2019-05-04 | 2022-01-11 | 인히브릭스, 인크. | CLEC12a binding polypeptides and uses thereof |
WO2020227072A1 (en) | 2019-05-04 | 2020-11-12 | Inhibrx, Inc. | Cd33-binding polypeptides and uses thereof |
BR112021022815A2 (en) | 2019-05-14 | 2021-12-28 | Genentech Inc | Methods to treat follicular lymphoma, kits, immunoconjugates and polatuzumab vedotin |
US20200392229A1 (en) | 2019-06-11 | 2020-12-17 | Alector Llc | Methods of use of anti-sortilin antibodies |
TW202115124A (en) | 2019-06-26 | 2021-04-16 | 瑞士商赫孚孟拉羅股份公司 | Novel antigen binding molecules binding to cea |
WO2020260326A1 (en) | 2019-06-27 | 2020-12-30 | F. Hoffmann-La Roche Ag | Novel icos antibodies and tumor-targeted antigen binding molecules comprising them |
CN114340735A (en) | 2019-06-28 | 2022-04-12 | 璟尚生物制药公司 | Antitumor antagonist composed of mutated TGF beta 1-RII extracellular domain and immunoglobulin scaffold |
TW202115115A (en) | 2019-07-02 | 2021-04-16 | 瑞士商赫孚孟拉羅股份公司 | Immunoconjugates |
AR119393A1 (en) | 2019-07-15 | 2021-12-15 | Hoffmann La Roche | ANTIBODIES THAT BIND NKG2D |
CA3145885A1 (en) | 2019-07-31 | 2021-02-04 | Jeonghoon Sun | Anti-ms4a4a antibodies and methods of use thereof |
CN114174342A (en) | 2019-07-31 | 2022-03-11 | 豪夫迈·罗氏有限公司 | Antibodies that bind to GPRC5D |
CN114174338A (en) | 2019-07-31 | 2022-03-11 | 豪夫迈·罗氏有限公司 | Antibodies that bind to GPRC5D |
US20210032322A1 (en) | 2019-08-01 | 2021-02-04 | Vaccinex, Inc. | Combined inhibition of semaphorin-4d and tgf-beta and compositions therefor |
TWI780464B (en) | 2019-08-06 | 2022-10-11 | 香港商新旭生技股份有限公司 | Antibodies that bind to pathological tau species and uses thereof |
WO2021030251A1 (en) | 2019-08-12 | 2021-02-18 | Purinomia Biotech, Inc. | Methods and compositions for promoting and potentiating t-cell mediated immune responses through adcc targeting of cd39 expressing cells |
TW202118512A (en) | 2019-09-12 | 2021-05-16 | 美商建南德克公司 | Compositions and methods of treating lupus nephritis |
EP4031579A2 (en) | 2019-09-18 | 2022-07-27 | F. Hoffmann-La Roche AG | Anti-klk7 antibodies, anti-klk5 antibodies, multispecific anti-klk5/klk7 antibodies, and methods of use |
AU2020348393A1 (en) | 2019-09-20 | 2022-02-24 | Genentech, Inc. | Dosing for anti-tryptase antibodies |
PE20221110A1 (en) | 2019-09-27 | 2022-07-11 | Genentech Inc | DOSE ADMINISTRATION FOR TREATMENT WITH ANTI-TIGIT AND ANTI-PD-L1 ANTAGONIST ANTIBODIES |
US20220281997A1 (en) | 2019-09-27 | 2022-09-08 | Nanjing GenScript Biotech Co., Ltd. | Anti-VHH Domain Antibodies and Use Thereof |
CN114746119A (en) | 2019-09-27 | 2022-07-12 | 詹森生物科技公司 | anti-CEACAM antibodies and uses thereof |
CA3153880A1 (en) | 2019-10-18 | 2020-06-09 | Juana Elva HERNANDEZ MONTALVO | Methods of using anti-cd79b immunoconjugates to treat diffuse large b-cell lymphoma |
EP4055388A1 (en) | 2019-11-06 | 2022-09-14 | Genentech, Inc. | Diagnostic and therapeutic methods for treatment of hematologic cancers |
CN114641270A (en) | 2019-11-15 | 2022-06-17 | 豪夫迈·罗氏有限公司 | Prevention of visible particle formation in aqueous protein solutions |
CN115151307A (en) | 2019-12-13 | 2022-10-04 | 艾莱克特有限责任公司 | Anti-merk antibodies and methods of use thereof |
PE20221511A1 (en) | 2019-12-13 | 2022-10-04 | Genentech Inc | ANTI-LY6G6D ANTIBODIES AND METHODS OF USE |
EP4309722A2 (en) | 2019-12-13 | 2024-01-24 | Biora Therapeutics, Inc. | Ingestible device for delivery of therapeutic agent to the gastrointestinal tract |
MX2022007635A (en) | 2019-12-18 | 2022-07-19 | Hoffmann La Roche | Antibodies binding to hla-a2/mage-a4. |
EP4076660A1 (en) | 2019-12-20 | 2022-10-26 | Novartis AG | Uses of anti-tgf-beta antibodies and checkpoint inhibitors for the treatment of proliferative diseases |
IL294131A (en) | 2019-12-23 | 2022-08-01 | Genentech Inc | Apolipoprotein l1-specific antibodies and methods of use |
BR112022011723A2 (en) | 2019-12-27 | 2022-09-06 | Chugai Pharmaceutical Co Ltd | ANTI-CTLA-4 ANTIBODY AND USE THEREOF |
KR20220107251A (en) | 2020-01-09 | 2022-08-02 | 에프. 호프만-라 로슈 아게 | Novel 4-1BBL Trimer-Containing Antigen Binding Molecules |
CN110818795B (en) | 2020-01-10 | 2020-04-24 | 上海复宏汉霖生物技术股份有限公司 | anti-TIGIT antibodies and methods of use |
WO2022050954A1 (en) | 2020-09-04 | 2022-03-10 | Genentech, Inc. | Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies |
WO2021194481A1 (en) | 2020-03-24 | 2021-09-30 | Genentech, Inc. | Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies |
WO2021155071A1 (en) | 2020-01-29 | 2021-08-05 | Inhibrx, Inc. | Cd28 single domain antibodies and multivalent and multispecific constructs thereof |
CA3164559A1 (en) | 2020-01-31 | 2021-08-05 | Lars Mueller | Methods of inducing neoepitope-specific t cells with a pd-1 axis binding antagonist and an rna vaccine |
AU2021220887A1 (en) | 2020-02-10 | 2022-09-29 | Shanghai Escugen Biotechnology Co., Ltd. | CLDN18.2 antibody and use thereof |
KR20220140786A (en) | 2020-02-10 | 2022-10-18 | 상하이 에스쿠겐 바이오테크놀로지 컴퍼니 리미티드 | Claudin 18.2 Antibodies and Their Uses |
TW202144395A (en) | 2020-02-12 | 2021-12-01 | 日商中外製藥股份有限公司 | Anti-CD137 antigen-binding molecule for use in cancer treatment |
CR20220396A (en) | 2020-02-14 | 2022-11-14 | Jounce Therapeutics Inc | Antibodies and fusion proteins that bind to ccr8 and uses thereof |
WO2021173889A1 (en) | 2020-02-26 | 2021-09-02 | Ambrx, Inc. | Uses of anti-cd3 antibody folate bioconjugates |
KR20220148209A (en) | 2020-02-28 | 2022-11-04 | 상하이 헨리우스 바이오테크, 인크. | Anti-CD137 constructs and uses thereof |
AU2021228078A1 (en) | 2020-02-28 | 2022-09-22 | Shanghai Henlius Biotech, Inc. | Anti-CD137 constructs, multispecific antibody and uses thereof |
JP2023517345A (en) | 2020-03-13 | 2023-04-25 | ジェネンテック, インコーポレイテッド | Anti-interleukin-33 antibody and uses thereof |
CA3169626A1 (en) | 2020-03-19 | 2021-09-23 | Genentech, Inc. | Isoform-selective anti-tgf-beta antibodies and methods of use |
CA3169967A1 (en) | 2020-03-24 | 2021-09-30 | Genentech, Inc. | Tie2-binding agents and methods of use |
EP4127153A2 (en) | 2020-03-26 | 2023-02-08 | Genentech, Inc. | Modified mammalian cells having reduced host cell proteins |
WO2021202590A1 (en) | 2020-03-31 | 2021-10-07 | Alector Llc | Anti-mertk antibodies and methods of use thereof |
JP2023519930A (en) | 2020-04-01 | 2023-05-15 | ユニバーシティ オブ ロチェスター | Monoclonal Antibodies Against Hemagglutinin (HA) and Neuraminidase (NA) of Influenza H3N2 Virus |
CN115698717A (en) | 2020-04-03 | 2023-02-03 | 基因泰克公司 | Methods of treatment and diagnosis of cancer |
WO2021209402A2 (en) | 2020-04-15 | 2021-10-21 | F. Hoffmann-La Roche Ag | Immunoconjugates |
EP4139359A1 (en) | 2020-04-24 | 2023-03-01 | Genentech, Inc. | Methods of using anti-cd79b immunoconjugates |
JP2023523480A (en) | 2020-04-28 | 2023-06-06 | ザ ロックフェラー ユニバーシティー | Neutralizing anti-SARS-COV-2 antibodies and methods of use thereof |
CN115885050A (en) | 2020-04-28 | 2023-03-31 | 基因泰克公司 | Methods and compositions for non-small cell lung cancer immunotherapy |
EP4146283A1 (en) | 2020-05-03 | 2023-03-15 | Levena (Suzhou) Biopharma Co., Ltd. | Antibody-drug conjugates (adcs) comprising an anti-trop-2 antibody, compositions comprising such adcs, as well as methods of making and using the same |
EP4149421A1 (en) | 2020-05-15 | 2023-03-22 | F. Hoffmann-La Roche AG | Prevention of visible particle formation in parenteral protein solutions |
EP4153130A1 (en) | 2020-05-19 | 2023-03-29 | F. Hoffmann-La Roche AG | The use of chelators for the prevention of visible particle formation in parenteral protein solutions |
CA3178417A1 (en) | 2020-05-29 | 2021-12-02 | Yu Chen | Anti-cd200r1 antibodies and methods of use thereof |
CN116529260A (en) | 2020-06-02 | 2023-08-01 | 当康生物技术有限责任公司 | anti-CD 93 constructs and uses thereof |
EP4157462A1 (en) | 2020-06-02 | 2023-04-05 | Dynamicure Biotechnology LLC | Anti-cd93 constructs and uses thereof |
US20230340081A1 (en) | 2020-06-08 | 2023-10-26 | Hoffmann-La Roche Inc. | Anti-hbv antibodies and methods of use |
CN115698719A (en) | 2020-06-12 | 2023-02-03 | 基因泰克公司 | Methods and compositions for cancer immunotherapy |
MX2022015877A (en) | 2020-06-16 | 2023-01-24 | Genentech Inc | Methods and compositions for treating triple-negative breast cancer. |
AU2021293507A1 (en) | 2020-06-18 | 2023-02-02 | F. Hoffmann-La Roche Ag | Treatment with anti-TIGIT antibodies and PD-1 axis binding antagonists |
WO2021255146A1 (en) | 2020-06-19 | 2021-12-23 | F. Hoffmann-La Roche Ag | Antibodies binding to cd3 and cea |
PE20230470A1 (en) | 2020-06-19 | 2023-03-14 | Hoffmann La Roche | BINDING MOLECULES TO THE FC DOMAIN OF IMMUNE ACTIVATION |
AR122658A1 (en) | 2020-06-19 | 2022-09-28 | Hoffmann La Roche | ANTIBODIES THAT BIND TO CD3 |
CN115916826A (en) | 2020-06-19 | 2023-04-04 | 豪夫迈·罗氏有限公司 | Antibodies that bind to CD3 and FolR1 |
EP4168444A1 (en) | 2020-06-19 | 2023-04-26 | F. Hoffmann-La Roche AG | Protease-activated t cell bispecific antibodies |
US11780920B2 (en) | 2020-06-19 | 2023-10-10 | Hoffmann-La Roche Inc. | Antibodies binding to CD3 and CD19 |
EP4168443A1 (en) | 2020-06-22 | 2023-04-26 | Almirall S.A. | Anti-il-36 antibodies and methods of use thereof |
JP2023530760A (en) | 2020-06-23 | 2023-07-19 | エフ・ホフマン-ラ・ロシュ・アクチェンゲゼルシャフト | Agonist CD28 antigen-binding molecules targeting Her2 |
WO2021262783A1 (en) | 2020-06-24 | 2021-12-30 | Genentech, Inc. | Apoptosis resistant cell lines |
WO2021260064A1 (en) | 2020-06-25 | 2021-12-30 | F. Hoffmann-La Roche Ag | Anti-cd3/anti-cd28 bispecific antigen binding molecules |
TW202216745A (en) | 2020-07-02 | 2022-05-01 | 美商英伊布里克斯公司 | Polypeptides comprising modified il-2 polypeptides and uses thereof |
EP4178529A1 (en) | 2020-07-07 | 2023-05-17 | F. Hoffmann-La Roche AG | Alternative surfactants as stabilizers for therapeutic protein formulations |
JP2023534458A (en) | 2020-07-17 | 2023-08-09 | ジェネンテック, インコーポレイテッド | Anti-Notch2 antibody and method of use |
PE20231104A1 (en) | 2020-07-21 | 2023-07-19 | Genentech Inc | BRM ANTIBODY CONJUGATED CHEMICAL DEGRADATION INDUCERS AND METHODS THEREOF |
GB2597532A (en) | 2020-07-28 | 2022-02-02 | Femtogenix Ltd | Cytotoxic compounds |
TW202221029A (en) | 2020-07-29 | 2022-06-01 | 美商當康生物科技有限公司 | Anti-cd93 constructs and uses thereof |
CA3192344A1 (en) | 2020-08-28 | 2022-03-03 | Genentech, Inc. | Crispr/cas9 multiplex knockout of host cell proteins |
US20230331867A1 (en) | 2020-09-04 | 2023-10-19 | Novarock Biotherapeutics, Ltd. | Nectin-4 antibodies and uses thereof |
US11970539B2 (en) | 2020-09-14 | 2024-04-30 | Ichnos Sciences SA | Antibodies that bind to IL1RAP and uses thereof |
AU2021343834A1 (en) | 2020-09-15 | 2023-04-13 | Bayer Aktiengesellschaft | Novel anti-A2AP antibodies and uses thereof |
MX2023003756A (en) | 2020-10-05 | 2023-04-24 | Genentech Inc | Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies. |
CA3190782A1 (en) | 2020-10-20 | 2022-04-28 | F. Hoffmann-La Roche Ag | Combination therapy of pd-1 axis binding antagonists and lrrk2 inhibitors |
TW202233671A (en) | 2020-10-20 | 2022-09-01 | 美商建南德克公司 | Peg-conjugated anti-mertk antibodies and methods of use |
WO2022093981A1 (en) | 2020-10-28 | 2022-05-05 | Genentech, Inc. | Combination therapy comprising ptpn22 inhibitors and pd-l1 binding antagonists |
EP4240766A2 (en) | 2020-11-04 | 2023-09-13 | Genentech, Inc. | Subcutaneous dosing of anti-cd20/anti-cd3 bispecific antibodies |
CA3196191A1 (en) | 2020-11-04 | 2022-05-12 | Chi-Chung Li | Dosing for treatment with anti-cd20/anti-cd3 bispecific antibodies and anti-cd79b antibody drug conjugates |
IL302396A (en) | 2020-11-04 | 2023-06-01 | Genentech Inc | Dosing for treatment with anti-cd20/anti-cd3 bispecific antibodies |
WO2022098870A1 (en) | 2020-11-04 | 2022-05-12 | The Rockefeller University | Neutralizing anti-sars-cov-2 antibodies |
KR20230109674A (en) | 2020-11-16 | 2023-07-20 | 에프. 호프만-라 로슈 아게 | FAB high mannose sugar form |
AU2021392039A1 (en) | 2020-12-02 | 2023-06-29 | Alector Llc | Methods of use of anti-sortilin antibodies |
MX2023006480A (en) | 2020-12-04 | 2023-06-19 | Hoffmann La Roche | Ph-dependent mutant interleukin-2 polypeptides. |
US20220184124A1 (en) | 2020-12-14 | 2022-06-16 | Allogene Therapeutics, Inc. | Methods and reagents for characterizing car t cells for therapies |
KR20230120665A (en) | 2020-12-17 | 2023-08-17 | 에프. 호프만-라 로슈 아게 | Anti-HLA-G Antibodies and Uses Thereof |
WO2022148853A1 (en) | 2021-01-11 | 2022-07-14 | F. Hoffmann-La Roche Ag | Immunoconjugates |
EP4277926A1 (en) | 2021-01-15 | 2023-11-22 | The Rockefeller University | Neutralizing anti-sars-cov-2 antibodies |
TW202245811A (en) | 2021-02-03 | 2022-12-01 | 美商異基因治療有限公司 | Formulations and processes for car t cell drug products |
KR20230147662A (en) | 2021-02-19 | 2023-10-23 | 인히브릭스, 인크. | Preparation of DR5 binding polypeptide |
WO2022180145A2 (en) | 2021-02-26 | 2022-09-01 | Bayer Aktiengesellschaft | Inhibitors of il-11 or il-11ra for use in the treatment of abnormal uterine bleeding |
JP2024509169A (en) | 2021-03-03 | 2024-02-29 | ソレント・セラピューティクス・インコーポレイテッド | Antibody-drug conjugates including anti-BCMA antibodies |
US20240141048A1 (en) | 2021-03-05 | 2024-05-02 | Dynamicure Biotechnology Llc | Anti-vista constructs and uses thereof |
CA3209640A1 (en) | 2021-03-09 | 2022-09-15 | F. Hoffmann-La Roche Ag | Combination therapy of pd-1-targeted il-2 variant immunoconjugates and fap/4-1bb binding molecules |
WO2022189380A1 (en) | 2021-03-09 | 2022-09-15 | F. Hoffmann-La Roche Ag | Combination therapy of pd-1-targeted il-2 variant immunoconjugate and anti-tyrp1/anti-cd3 bispecific antibodies |
JP2024512377A (en) | 2021-03-12 | 2024-03-19 | ジェネンテック, インコーポレイテッド | Anti-KLK7 antibodies, anti-KLK5 antibodies, multispecific anti-KLK5/KLK7 antibodies, and methods of use |
BR112023018621A2 (en) | 2021-03-15 | 2023-10-24 | Hoffmann La Roche | METHODS TO TREAT LUPUS NEPHRITIS, DEPLETION OF PERIPHERAL B CELLS, KITS TO TREAT LUPUS NEPHRITIS AND ANTI-CD20 TYPE II ANTIBODIES |
EP4308606A1 (en) | 2021-03-18 | 2024-01-24 | Alector LLC | Anti-tmem106b antibodies and methods of use thereof |
WO2022197877A1 (en) | 2021-03-19 | 2022-09-22 | Genentech, Inc. | Methods and compositions for time delayed bio-orthogonal release of cytotoxic agents |
EP4314063A1 (en) | 2021-03-23 | 2024-02-07 | Alector LLC | Anti-tmem106b antibodies for treating and preventing coronavirus infections |
US20240150466A1 (en) | 2021-03-25 | 2024-05-09 | Dynamicure Biotechnology Llc | Anti-igfbp7 constructs and uses thereof |
BR112023018061A2 (en) | 2021-03-30 | 2023-10-03 | Bayer Ag | ANTI-SEMA3A ANTIBODIES AND USES THEREOF |
EP4314032A1 (en) | 2021-03-30 | 2024-02-07 | F. Hoffmann-La Roche AG | Protease-activated polypeptides |
TW202304979A (en) | 2021-04-07 | 2023-02-01 | 瑞士商諾華公司 | USES OF ANTI-TGFβ ANTIBODIES AND OTHER THERAPEUTIC AGENTS FOR THE TREATMENT OF PROLIFERATIVE DISEASES |
AR125344A1 (en) | 2021-04-15 | 2023-07-05 | Chugai Pharmaceutical Co Ltd | ANTI-C1S ANTIBODY |
IL307501A (en) | 2021-04-19 | 2023-12-01 | Hoffmann La Roche | Modified mammalian cells |
CA3217803A1 (en) | 2021-04-30 | 2022-11-03 | F. Hoffmann-La Roche Ag | Dosing for treatment with anti-cd20/anti-cd3 bispecific antibody |
AU2021443318A1 (en) | 2021-04-30 | 2023-09-07 | F. Hoffmann-La Roche Ag | Dosing for combination treatment with anti-cd20/anti-cd3 bispecific antibody and anti-cd79b antibody drug conjugate |
EP4334343A2 (en) | 2021-05-06 | 2024-03-13 | The Rockefeller University | Neutralizing anti-sars- cov-2 antibodies and methods of use thereof |
IL308351A (en) | 2021-05-12 | 2024-01-01 | Genentech Inc | Methods of using anti-cd79b immunoconjugates to treat diffuse large b-cell lymphoma |
KR20240007928A (en) | 2021-05-14 | 2024-01-17 | 제넨테크, 인크. | Agonist of TREM2 |
CN117396599A (en) | 2021-05-21 | 2024-01-12 | 基因泰克公司 | Modified cells for production of recombinant products of interest |
AR126009A1 (en) | 2021-06-02 | 2023-08-30 | Hoffmann La Roche | CD28 ANTIGEN-BINDING AGONIST MOLECULES THAT TARGET EPCAM |
WO2022255440A1 (en) | 2021-06-04 | 2022-12-08 | Chugai Seiyaku Kabushiki Kaisha | Anti-ddr2 antibodies and uses thereof |
BR112023025738A2 (en) | 2021-06-09 | 2024-02-27 | Hoffmann La Roche | COMBINATION OF A BRAF INHIBITOR AND A PD-1 AXIS BINDING ANTAGONIST, USE OF A COMBINATION OF A BRAF INHIBITOR AND A PD-1 AXIS BINDING ANTAGONIST, METHOD FOR THE TREATMENT OR PROPHYLAXIS OF CANCER, PHARMACEUTICAL COMPOSITION AND INVENTION |
WO2022266223A1 (en) | 2021-06-16 | 2022-12-22 | Alector Llc | Bispecific anti-mertk and anti-pdl1 antibodies and methods of use thereof |
EP4355783A1 (en) | 2021-06-16 | 2024-04-24 | Alector LLC | Monovalent anti-mertk antibodies and methods of use thereof |
EP4355785A1 (en) | 2021-06-17 | 2024-04-24 | Amberstone Biosciences, Inc. | Anti-cd3 constructs and uses thereof |
BR112023023480A2 (en) | 2021-06-25 | 2024-01-30 | Chugai Pharmaceutical Co Ltd | USE OF ANTI-CTLA-4 ANTIBODY |
BR112023022992A2 (en) | 2021-06-25 | 2024-01-23 | Chugai Pharmaceutical Co Ltd | ANTI-CTLA-4 ANTIBODY |
CR20240074A (en) | 2021-07-14 | 2024-03-08 | Genentech Inc | Anti-c-c motif chemokine receptor 8 (ccr8) antibodies and methods of use |
WO2023004305A1 (en) | 2021-07-20 | 2023-01-26 | Inhibrx, Inc. | Cd8-targeted modified il-2 polypeptides and uses thereof |
WO2023004304A1 (en) | 2021-07-20 | 2023-01-26 | Inhibrx, Inc. | Cd8-binding polypeptides and uses thereof |
EP4373576A1 (en) | 2021-07-22 | 2024-05-29 | Genentech, Inc. | Brain targeting compositions and methods of use thereof |
EP4373859A1 (en) | 2021-07-22 | 2024-05-29 | F. Hoffmann-La Roche AG | Heterodimeric fc domain antibodies |
AU2022318255A1 (en) | 2021-07-27 | 2024-01-18 | Morphosys Ag | Combinations of antigen binding molecules |
WO2023012147A1 (en) | 2021-08-03 | 2023-02-09 | F. Hoffmann-La Roche Ag | Bispecific antibodies and methods of use |
WO2023019239A1 (en) | 2021-08-13 | 2023-02-16 | Genentech, Inc. | Dosing for anti-tryptase antibodies |
CN117858905A (en) | 2021-08-19 | 2024-04-09 | 豪夫迈·罗氏有限公司 | Multivalent anti-variant FC region antibodies and methods of use |
IL310382A (en) | 2021-08-27 | 2024-03-01 | Genentech Inc | Methods of treating tau pathologies |
EP4396223A1 (en) | 2021-08-30 | 2024-07-10 | Genentech, Inc. | Anti-polyubiquitin multispecific antibodies |
WO2023031366A1 (en) | 2021-09-02 | 2023-03-09 | Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts | Anti-cecam6 antibodies with reduced side-effects |
TW202321308A (en) | 2021-09-30 | 2023-06-01 | 美商建南德克公司 | Methods for treatment of hematologic cancers using anti-tigit antibodies, anti-cd38 antibodies, and pd-1 axis binding antagonists |
WO2023056069A1 (en) | 2021-09-30 | 2023-04-06 | Angiex, Inc. | Degrader-antibody conjugates and methods of using same |
AR127269A1 (en) | 2021-10-08 | 2024-01-03 | Chugai Pharmaceutical Co Ltd | ANTI-HLA-DQ2.5 ANTIBODY FORMULATION |
WO2023062048A1 (en) | 2021-10-14 | 2023-04-20 | F. Hoffmann-La Roche Ag | Alternative pd1-il7v immunoconjugates for the treatment of cancer |
AU2022362681A1 (en) | 2021-10-14 | 2024-04-04 | F. Hoffmann-La Roche Ag | New interleukin-7 immunoconjugates |
WO2023069919A1 (en) | 2021-10-19 | 2023-04-27 | Alector Llc | Anti-cd300lb antibodies and methods of use thereof |
WO2023086807A1 (en) | 2021-11-10 | 2023-05-19 | Genentech, Inc. | Anti-interleukin-33 antibodies and uses thereof |
TW202337494A (en) | 2021-11-16 | 2023-10-01 | 美商建南德克公司 | Methods and compositions for treating systemic lupus erythematosus (sle) with mosunetuzumab |
WO2023094569A1 (en) | 2021-11-26 | 2023-06-01 | F. Hoffmann-La Roche Ag | Combination therapy of anti-tyrp1/anti-cd3 bispecific antibodies and tyrp1-specific antibodies |
TW202333787A (en) | 2021-12-01 | 2023-09-01 | 日商中外製藥股份有限公司 | Method for preparing antibody-containing formulation |
AR127887A1 (en) | 2021-12-10 | 2024-03-06 | Hoffmann La Roche | ANTIBODIES THAT BIND CD3 AND PLAP |
WO2023109900A1 (en) | 2021-12-17 | 2023-06-22 | Shanghai Henlius Biotech, Inc. | Anti-ox40 antibodies, multispecific antibodies and methods of use |
CA3240565A1 (en) | 2021-12-17 | 2023-06-22 | Wenfeng Xu | Anti-ox40 antibodies and methods of use |
CA3242658A1 (en) | 2022-01-05 | 2023-07-13 | Bryan R. Becklund | Gamma delta t-cell-binding polypeptides and uses thereof |
TW202334193A (en) | 2022-01-05 | 2023-09-01 | 美商英伊布里克斯公司 | Gamma delta t-cell-targeted modified il-2 polypeptides and uses thereof |
US20230322958A1 (en) | 2022-01-19 | 2023-10-12 | Genentech, Inc. | Anti-Notch2 Antibodies and Conjugates and Methods of Use |
AR128330A1 (en) | 2022-01-26 | 2024-04-17 | Genentech Inc | CHEMICAL DEGRADATION INDUCERS CONJUGATED WITH ANTIBODY AND METHODS OF THESE |
AR128331A1 (en) | 2022-01-26 | 2024-04-17 | Genentech Inc | CHEMICAL DEGRADATION INDUCTORS CONJUGATED WITH ANTIBODIES AND METHODS OF THESE |
WO2023147399A1 (en) | 2022-01-27 | 2023-08-03 | The Rockefeller University | Broadly neutralizing anti-sars-cov-2 antibodies targeting the n-terminal domain of the spike protein and methods of use thereof |
WO2023173026A1 (en) | 2022-03-10 | 2023-09-14 | Sorrento Therapeutics, Inc. | Antibody-drug conjugates and uses thereof |
WO2023170247A1 (en) | 2022-03-11 | 2023-09-14 | Mablink Bioscience | Antibody-drug conjugates and their uses |
US20230414750A1 (en) | 2022-03-23 | 2023-12-28 | Hoffmann-La Roche Inc. | Combination treatment of an anti-cd20/anti-cd3 bispecific antibody and chemotherapy |
AR128876A1 (en) | 2022-03-28 | 2024-06-19 | Hoffmann La Roche | ENHANCED FOLR1 PROTEASE ACTIVATABLE T LYMPHOCYTE BISPECIFIC ANTIBODIES |
WO2023191816A1 (en) | 2022-04-01 | 2023-10-05 | Genentech, Inc. | Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies |
TW202404636A (en) | 2022-04-08 | 2024-02-01 | 美商英伊布里克斯公司 | Dr5 agonist and plk1 inhibitor or cdk inhibitor combination therapy |
WO2023198727A1 (en) | 2022-04-13 | 2023-10-19 | F. Hoffmann-La Roche Ag | Pharmaceutical compositions of anti-cd20/anti-cd3 bispecific antibodies and methods of use |
WO2023201299A1 (en) | 2022-04-13 | 2023-10-19 | Genentech, Inc. | Pharmaceutical compositions of therapeutic proteins and methods of use |
US20230407252A1 (en) | 2022-04-28 | 2023-12-21 | Allogene Therapeutics, Inc. | Methods for donor cell analysis |
WO2023212298A1 (en) | 2022-04-29 | 2023-11-02 | Broadwing Bio Llc | Bispecific antibodies and methods of treating ocular disease |
WO2023212293A1 (en) | 2022-04-29 | 2023-11-02 | Broadwing Bio Llc | Complement factor h related 4-specific antibodies and uses thereof |
WO2023212294A1 (en) | 2022-04-29 | 2023-11-02 | Broadwing Bio Llc | Angiopoietin-related protein 7-specific antibodies and uses thereof |
TW202406934A (en) | 2022-05-03 | 2024-02-16 | 美商建南德克公司 | Anti-ly6e antibodies, immunoconjugates, and uses thereof |
TW202406933A (en) | 2022-05-05 | 2024-02-16 | 美商英伊布里克斯公司 | Albumin-binding polypeptides and uses thereof |
WO2023219613A1 (en) | 2022-05-11 | 2023-11-16 | Genentech, Inc. | Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies |
WO2023230432A1 (en) | 2022-05-23 | 2023-11-30 | Inhibrx, Inc. | Dr5 agonist and iap antagonist combination therapy |
WO2023235699A1 (en) | 2022-05-31 | 2023-12-07 | Jounce Therapeutics, Inc. | Antibodies to lilrb4 and uses thereof |
WO2023240058A2 (en) | 2022-06-07 | 2023-12-14 | Genentech, Inc. | Prognostic and therapeutic methods for cancer |
WO2023239803A1 (en) | 2022-06-08 | 2023-12-14 | Angiex, Inc. | Anti-tm4sf1 antibody-drug conjugates comprising cleavable linkers and methods of using same |
WO2023240218A1 (en) | 2022-06-09 | 2023-12-14 | Allogene Therapeutics Inc. | Methods for detecting genomic abnormalities in cells |
TW202409086A (en) | 2022-06-11 | 2024-03-01 | 美商英伊布里克斯公司 | Fcrn-binding polypeptides and uses thereof |
WO2023245008A1 (en) | 2022-06-13 | 2023-12-21 | Genentech, Inc. | Methods of delaying or preventing the onset of alzheimer's disease using crenezumab |
WO2024015897A1 (en) | 2022-07-13 | 2024-01-18 | Genentech, Inc. | Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies |
WO2024020432A1 (en) | 2022-07-19 | 2024-01-25 | Genentech, Inc. | Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies |
WO2024020564A1 (en) | 2022-07-22 | 2024-01-25 | Genentech, Inc. | Anti-steap1 antigen-binding molecules and uses thereof |
WO2024020579A1 (en) | 2022-07-22 | 2024-01-25 | Bristol-Myers Squibb Company | Antibodies binding to human pad4 and uses thereof |
WO2024026471A1 (en) | 2022-07-29 | 2024-02-01 | Alector Llc | Cd98hc antigen-binding domains and uses therefor |
TW202405020A (en) | 2022-07-29 | 2024-02-01 | 美商阿列克特有限責任公司 | Transferrin receptor antigen-binding domains and uses therefor |
TW202415679A (en) | 2022-07-29 | 2024-04-16 | 美商阿列克特有限責任公司 | Anti-gpnmb antibodies and methods of use thereof |
US20240085403A1 (en) | 2022-08-16 | 2024-03-14 | Allogene Therapeutics, Inc. | Method for inhibiting adventitious viral infection |
WO2024049949A1 (en) | 2022-09-01 | 2024-03-07 | Genentech, Inc. | Therapeutic and diagnostic methods for bladder cancer |
WO2024054929A1 (en) | 2022-09-07 | 2024-03-14 | Dynamicure Biotechnology Llc | Anti-vista constructs and uses thereof |
WO2024068572A1 (en) | 2022-09-28 | 2024-04-04 | F. Hoffmann-La Roche Ag | Improved protease-activatable t cell bispecific antibodies |
WO2024068705A1 (en) | 2022-09-29 | 2024-04-04 | F. Hoffmann-La Roche Ag | Protease-activated polypeptides |
WO2024077239A1 (en) | 2022-10-07 | 2024-04-11 | Genentech, Inc. | Methods of treating cancer with anti-c-c motif chemokine receptor 8 (ccr8) antibodies |
WO2024086796A1 (en) | 2022-10-20 | 2024-04-25 | Alector Llc | Anti-ms4a4a antibodies with amyloid-beta therapies |
WO2024091991A1 (en) | 2022-10-25 | 2024-05-02 | Genentech, Inc. | Therapeutic and diagnostic methods for multiple myeloma |
US20240165227A1 (en) | 2022-11-04 | 2024-05-23 | Gilead Sciences, Inc. | Anticancer therapies using anti-ccr8 antibody, chemo and immunotherapy combinations |
WO2024102734A1 (en) | 2022-11-08 | 2024-05-16 | Genentech, Inc. | Compositions and methods of treating childhood onset idiopathic nephrotic syndrome |
WO2024100170A1 (en) | 2022-11-11 | 2024-05-16 | F. Hoffmann-La Roche Ag | Antibodies binding to hla-a*02/foxp3 |
US20240226313A1 (en) | 2022-11-17 | 2024-07-11 | Sanofi | Ceacam5 antibody-drug conjugates and methods of use thereof |
WO2024118593A1 (en) | 2022-11-28 | 2024-06-06 | Allogene Therapeutics Inc. | Claudin 18.2 targeting chimeric antigen receptors and binding agents and uses thereof |
WO2024129594A1 (en) | 2022-12-12 | 2024-06-20 | Genentech, Inc. | Optimizing polypeptide sialic acid content |
WO2024148232A2 (en) | 2023-01-06 | 2024-07-11 | Alector Llc | Anti-il18 binding protein antibodies and methods of use thereof |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1993016185A2 (en) | 1992-02-06 | 1993-08-19 | Creative Biomolecules, Inc. | Biosynthetic binding protein for cancer marker |
WO1996016673A1 (en) | 1994-12-02 | 1996-06-06 | Chiron Corporation | Method of promoting an immune response with a bispecific antibody |
US5571894A (en) | 1991-02-05 | 1996-11-05 | Ciba-Geigy Corporation | Recombinant antibodies specific for a growth factor receptor |
US5587458A (en) | 1991-10-07 | 1996-12-24 | Aronex Pharmaceuticals, Inc. | Anti-erbB-2 antibodies, combinations thereof, and therapeutic and diagnostic uses thereof |
US5641870A (en) | 1995-04-20 | 1997-06-24 | Genentech, Inc. | Low pH hydrophobic interaction chromatography for antibody purification |
WO1998002463A1 (en) | 1996-07-11 | 1998-01-22 | Medarex, Inc. | THERAPEUTIC MULTISPECIFIC COMPOUNDS COMPRISED OF ANTI-FCα RECEPTOR ANTIBODIES |
US5821337A (en) | 1991-06-14 | 1998-10-13 | Genentech, Inc. | Immunoglobulin variants |
US5837234A (en) | 1995-06-07 | 1998-11-17 | Cytotherapeutics, Inc. | Bioartificial organ containing cells encapsulated in a permselective polyether suflfone membrane |
Family Cites Families (122)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6023084B2 (en) | 1979-07-11 | 1985-06-05 | 味の素株式会社 | blood substitute |
US4640835A (en) | 1981-10-30 | 1987-02-03 | Nippon Chemiphar Company, Ltd. | Plasminogen activator derivatives |
JPH0751511B2 (en) | 1982-03-15 | 1995-06-05 | 味の素株式会社 | Cancer therapeutic agent containing interleukin-2 |
US4457916A (en) | 1982-08-31 | 1984-07-03 | Asahi Kasei Kogyo Kabushiki Kaisha | Method for stabilizing Tumor Necrosis Factor and a stable aqueous solution or powder containing the same |
GB8308235D0 (en) | 1983-03-25 | 1983-05-05 | Celltech Ltd | Polypeptides |
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
US4496689A (en) | 1983-12-27 | 1985-01-29 | Miles Laboratories, Inc. | Covalently attached complex of alpha-1-proteinase inhibitor with a water soluble polymer |
AU3934085A (en) | 1984-01-30 | 1985-08-09 | Icrf Patents Ltd. | Improvements relating to growth factors |
US4843063A (en) | 1984-07-16 | 1989-06-27 | Collagen Corporation | Polypeptide cartilage-inducing factors found in bone |
EP0169016B2 (en) | 1984-07-16 | 2004-04-28 | Celtrix Pharmaceuticals, Inc. | Polypeptide cartilage-inducing factors found in bone |
EP0173484B1 (en) | 1984-08-06 | 1990-11-28 | Westinghouse Electric Corporation | Process for the separation of gadelinium isotopes |
JPS6147500A (en) | 1984-08-15 | 1986-03-07 | Res Dev Corp Of Japan | Chimera monoclonal antibody and its preparation |
JPS61134325A (en) | 1984-12-04 | 1986-06-21 | Teijin Ltd | Expression of hybrid antibody gene |
US4886747A (en) | 1985-03-22 | 1989-12-12 | Genentech, Inc. | Nucleic acid encoding TGF-β and its uses |
US5284763A (en) | 1985-03-22 | 1994-02-08 | Genentech, Inc. | Nucleic acid encoding TGF-β and its uses |
IL78197A (en) | 1985-03-22 | 1991-07-18 | Genentech Inc | Nucleic acid encoding tgf-beta and its uses |
US5262319A (en) | 1985-04-19 | 1993-11-16 | Oncogene Science, Inc. | Method for obtaining bone marrow free of tumor cells using transforming growth factor β3 |
DE3675588D1 (en) | 1985-06-19 | 1990-12-20 | Ajinomoto Kk | HAEMOGLOBIN TIED TO A POLY (ALKENYLENE OXIDE). |
US4806523A (en) | 1985-08-06 | 1989-02-21 | Collagen Corporation | Method of treating inflammation |
US4676980A (en) | 1985-09-23 | 1987-06-30 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Target specific cross-linked heteroantibodies |
US5120535A (en) | 1986-11-26 | 1992-06-09 | Oncogen | Oncostatin M and novel compositions having anti-neoplastic activity |
GB8607679D0 (en) | 1986-03-27 | 1986-04-30 | Winter G P | Recombinant dna product |
US4791192A (en) | 1986-06-26 | 1988-12-13 | Takeda Chemical Industries, Ltd. | Chemically modified protein with polyethyleneglycol |
NZ222168A (en) | 1986-10-20 | 1991-05-28 | Oncogene Science Inc | Tumour growth inhibiting protein related to tgf-#b#1 and tgf-#b#2, preparation by genetic engineering methods, antibodies and pharmaceutical compositions |
WO1988003807A2 (en) | 1986-11-17 | 1988-06-02 | Sandoz Ag | Production and use of a novel t-cell suppressor factor |
IL85035A0 (en) | 1987-01-08 | 1988-06-30 | Int Genetic Eng | Polynucleotide molecule,a chimeric antibody with specificity for human b cell surface antigen,a process for the preparation and methods utilizing the same |
JP2594793B2 (en) | 1987-08-03 | 1997-03-26 | エービー テトラパック | Manufacturing method of packaging container |
US4975278A (en) | 1988-02-26 | 1990-12-04 | Bristol-Myers Company | Antibody-enzyme conjugates in combination with prodrugs for the delivery of cytotoxic agents to tumor cells |
AU633011B2 (en) | 1988-06-28 | 1993-01-21 | La Jolla Cancer Research Foundation | Suppression of cell proliferation by decorin |
US5705609A (en) | 1988-06-28 | 1998-01-06 | La Jolla Cancer Research Foundation | Decorin fragments inhibiting cell regulatory factors |
US5654270A (en) | 1988-06-28 | 1997-08-05 | La Jolla Cancer Research Foundation | Use of fibromodulin to prevent or reduce dermal scarring |
GB8823869D0 (en) | 1988-10-12 | 1988-11-16 | Medical Res Council | Production of antibodies |
US5571714A (en) | 1988-12-22 | 1996-11-05 | Celtrix Pharmaceuticals, Inc. | Monoclonal antibodies which bind both transforming growth factors β1 and β2 and methods of use |
US5268455A (en) | 1989-05-25 | 1993-12-07 | Genentech, Inc. | Process for making biologically active polypeptides based on transforming growth factor-βsequences |
US5061786A (en) | 1989-05-25 | 1991-10-29 | Genentech, Inc. | Biologically active polypeptides based on transforming growth factor-β |
DE3920358A1 (en) | 1989-06-22 | 1991-01-17 | Behringwerke Ag | BISPECIFIC AND OLIGO-SPECIFIC, MONO- AND OLIGOVALENT ANTI-BODY CONSTRUCTS, THEIR PRODUCTION AND USE |
US5208020A (en) | 1989-10-25 | 1993-05-04 | Immunogen Inc. | Cytotoxic agents comprising maytansinoids and their therapeutic use |
US5859205A (en) | 1989-12-21 | 1999-01-12 | Celltech Limited | Humanised antibodies |
US5824297A (en) | 1990-06-25 | 1998-10-20 | Oncogene Science, Inc. | Tissue-derived tumor growth inhibitors, methods of preparation and uses thereof |
GB9015198D0 (en) | 1990-07-10 | 1990-08-29 | Brien Caroline J O | Binding substance |
GB9206318D0 (en) | 1992-03-24 | 1992-05-06 | Cambridge Antibody Tech | Binding substances |
AU665190B2 (en) | 1990-07-10 | 1995-12-21 | Cambridge Antibody Technology Limited | Methods for producing members of specific binding pairs |
US5633425A (en) | 1990-08-29 | 1997-05-27 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
US5625126A (en) | 1990-08-29 | 1997-04-29 | Genpharm International, Inc. | Transgenic non-human animals for producing heterologous antibodies |
DE69127627T2 (en) | 1990-08-29 | 1998-02-19 | Genpharm Int | Production and Use Non-human transgene heterologous antibodies for production |
US5661016A (en) | 1990-08-29 | 1997-08-26 | Genpharm International Inc. | Transgenic non-human animals capable of producing heterologous antibodies of various isotypes |
US5545806A (en) | 1990-08-29 | 1996-08-13 | Genpharm International, Inc. | Ransgenic non-human animals for producing heterologous antibodies |
US5264365A (en) | 1990-11-09 | 1993-11-23 | Board Of Regents, The University Of Texas System | Protease-deficient bacterial strains for production of proteolytically sensitive polypeptides |
US5508192A (en) | 1990-11-09 | 1996-04-16 | Board Of Regents, The University Of Texas System | Bacterial host strains for producing proteolytically sensitive polypeptides |
ATE194169T1 (en) | 1990-11-16 | 2000-07-15 | Celtrix Pharma | BETA-TYPE SIMILAR TRANSFORMING GROWTH FACTOR |
ES2113940T3 (en) | 1990-12-03 | 1998-05-16 | Genentech Inc | ENRICHMENT METHOD FOR PROTEIN VARIANTS WITH ALTERED UNION PROPERTIES. |
GB9106678D0 (en) | 1991-03-28 | 1991-05-15 | Ferguson Mark W J | Wound healing |
US5858657A (en) | 1992-05-15 | 1999-01-12 | Medical Research Council | Methods for producing members of specific binding pairs |
DE69230142T2 (en) | 1991-05-15 | 2000-03-09 | Cambridge Antibody Technology Ltd. | METHOD FOR PRODUCING SPECIFIC BINDING PAIRS |
US5264586A (en) | 1991-07-17 | 1993-11-23 | The Scripps Research Institute | Analogs of calicheamicin gamma1I, method of making and using the same |
EP0861893A3 (en) | 1991-09-19 | 1999-11-10 | Genentech, Inc. | High level expression of immunoglobulin polypeptides |
WO1993006213A1 (en) | 1991-09-23 | 1993-04-01 | Medical Research Council | Production of chimeric antibodies - a combinatorial approach |
AU671606B2 (en) | 1991-10-31 | 1996-09-05 | Whitehead Institute For Biomedical Research | TGF-beta type receptor cDNAs and uses therefor |
US6008011A (en) | 1991-10-31 | 1999-12-28 | Whitehead Institute For Biomedical Research | TGF-β type II receptor cDNAs |
EP2224006A1 (en) | 1991-12-02 | 2010-09-01 | MedImmune Limited | Production of anti-self antibodies from antibody segment repertoires and displayed on phage |
US5872215A (en) | 1991-12-02 | 1999-02-16 | Medical Research Council | Specific binding members, materials and methods |
US7067637B1 (en) * | 1992-02-12 | 2006-06-27 | Biopharm Gesellschaft Zur Biotechnologischen Entwicklung Von Pharmaka Mbh | Antibody or antibody fragments specific for a protein of the TGF-β family |
US5543143A (en) | 1992-03-06 | 1996-08-06 | Corixa Corporation | Method for activating macrophages/monocytes |
GB9205800D0 (en) | 1992-03-17 | 1992-04-29 | British Tech Group | Treatment of fibrotic disorders |
EP0656941B1 (en) | 1992-03-24 | 2005-06-01 | Cambridge Antibody Technology Limited | Methods for producing members of specific binding pairs |
US5733743A (en) | 1992-03-24 | 1998-03-31 | Cambridge Antibody Technology Limited | Methods for producing members of specific binding pairs |
AU3943793A (en) | 1992-04-01 | 1993-11-08 | Whittier Institute For Diabetes And Endocrinology, The | Methods of inhibiting or enhancing scar formation in the CNS |
US5869462A (en) | 1992-09-10 | 1999-02-09 | The Board Of Trustees Of The Leland Stanford Junior University | Inhibition of proliferation of vascular smooth muscle cell |
US5821234A (en) | 1992-09-10 | 1998-10-13 | The Board Of Trustees Of The Leland Stanford Junior University | Inhibition of proliferation of vascular smooth muscle cell |
AU669256B2 (en) | 1992-10-29 | 1996-05-30 | Celtrix Pharmaceuticals, Inc. | Uses of TGF-beta receptor fragment as a therapeutic agent |
US5830847A (en) | 1992-10-30 | 1998-11-03 | Hsc Research & Development Limited Partnership | Soluble TGF-β-binding endoglin polypeptides and homodimers |
EP0672142B1 (en) | 1992-12-04 | 2001-02-28 | Medical Research Council | Multivalent and multispecific binding proteins, their manufacture and use |
EP0737071A1 (en) | 1993-06-15 | 1996-10-16 | Il- Yang Pharm. Co., Ltd. | Anti-sense oligodeoxynucleotide to fibrogenic cytokines and use thereof |
ATE186220T1 (en) | 1994-03-29 | 1999-11-15 | Univ Manchester | WOUND HEALING |
US5534615A (en) | 1994-04-25 | 1996-07-09 | Genentech, Inc. | Cardiac hypertrophy factor and uses therefor |
US5587309A (en) | 1994-04-29 | 1996-12-24 | The United States Of America As Represented By The Department Of Health And Human Services | Method of stimulating proliferation and differentiation of human fetal pancreatic cells ex vivo |
US5981483A (en) | 1994-05-04 | 1999-11-09 | Mount Sinai Hospital Corporation | Compositions comprising modulators of cytokines of the TGF-β superfamily |
US5773001A (en) | 1994-06-03 | 1998-06-30 | American Cyanamid Company | Conjugates of methyltrithio antitumor agents and intermediates for their synthesis |
US5772995A (en) | 1994-07-18 | 1998-06-30 | Sidney Kimmel Cancer Center | Compositions and methods for enhanced tumor cell immunity in vivo |
US5968770A (en) | 1995-02-10 | 1999-10-19 | Millennium Pharmaceuticals, Inc. | Compositions and methods for the treatment and diagnosis of cardiovascular disease using rchd523 as a target |
US5824655A (en) | 1995-02-15 | 1998-10-20 | The University Of Utah | Anti-transforming growth factor-β gene therapy |
US5731168A (en) | 1995-03-01 | 1998-03-24 | Genentech, Inc. | Method for making heteromultimeric polypeptides |
US5616561A (en) | 1995-03-31 | 1997-04-01 | Regents Of The University Of California | TGF-β antagonists as mitigators of radiation-induced tissue damage |
US5780436A (en) | 1995-05-01 | 1998-07-14 | The Regents Of The University Of California | Peptide compositions with growth factor-like activity |
US5712374A (en) | 1995-06-07 | 1998-01-27 | American Cyanamid Company | Method for the preparation of substantiallly monomeric calicheamicin derivative/carrier conjugates |
US5714586A (en) | 1995-06-07 | 1998-02-03 | American Cyanamid Company | Methods for the preparation of monomeric calicheamicin derivative/carrier conjugates |
GB9601081D0 (en) | 1995-10-06 | 1996-03-20 | Cambridge Antibody Tech | Specific binding members for human transforming growth factor beta;materials and methods |
US7368111B2 (en) * | 1995-10-06 | 2008-05-06 | Cambridge Antibody Technology Limited | Human antibodies specific for TGFβ2 |
WO1997038123A1 (en) | 1996-04-05 | 1997-10-16 | Board Of Regents, The University Of Texas System | Methods for producing soluble, biologically-active disulfide bond-containing eukaryotic proteins in bacterial cells |
JPH1067674A (en) | 1996-06-19 | 1998-03-10 | Advanced Sukin Res Kenkyusho:Kk | Abnormal accumulation suppressor of extracellular matrix |
US5807708A (en) | 1996-07-30 | 1998-09-15 | Millennium Pharmaceuticals, Inc. | Conservin nucleic acid molecules and compositions |
US5948639A (en) | 1997-04-10 | 1999-09-07 | Millennium Pharmaceuticals, Inc. | TGF-β pathway genes |
JPH10295381A (en) | 1997-04-23 | 1998-11-10 | Seibutsu Bunshi Kogaku Kenkyusho:Kk | Signal transfer factor and gene encoding the same |
US6235883B1 (en) | 1997-05-05 | 2001-05-22 | Abgenix, Inc. | Human monoclonal antibodies to epidermal growth factor receptor |
US6083715A (en) | 1997-06-09 | 2000-07-04 | Board Of Regents, The University Of Texas System | Methods for producing heterologous disulfide bond-containing polypeptides in bacterial cells |
US6500920B1 (en) | 1997-06-19 | 2002-12-31 | St. Louis University | Inhibitor of transforming growth factor β and A method of inhibiting the biological effects of transforming growth factor |
US6175057B1 (en) | 1997-10-08 | 2001-01-16 | The Regents Of The University Of California | Transgenic mouse model of alzheimer's disease and cerebral amyloid angiopathy |
US6455757B1 (en) | 1997-10-08 | 2002-09-24 | The Regents Of The University Of California | Transgenic mice expressing human APP and TGF-β demonstrate cerebrovascular amyloid deposits |
US6143359A (en) | 1998-04-14 | 2000-11-07 | Lightyear Technologies (Usa), Inc. | Soluble metal hydride/transition metal dichalcogenide alloys |
WO2000034337A1 (en) * | 1998-12-10 | 2000-06-15 | Tsukuba Research Laboratory, Toagosei Co., Ltd. | Humanized monoclonal antibodies against vascular endothelial cell growth factor |
CZ303725B6 (en) * | 1999-03-25 | 2013-04-03 | Abbott Gmbh & Co. Kg | Human antibodies binding to human IL-12, and processes for preparing thereof |
US6492497B1 (en) * | 1999-04-30 | 2002-12-10 | Cambridge Antibody Technology Limited | Specific binding members for TGFbeta1 |
AU6232899A (en) | 1999-10-06 | 2001-05-10 | Campina Melkunie B.V. | Use of transforming growth factor beta and growth factors in the treatment and prevention of diseases of the intestinal mucosa |
US20010046502A1 (en) | 2000-02-04 | 2001-11-29 | The Board Of Trustees Of The University Of Illinois | Animal model for testing immunotherapies of spontaneous metastatic disease |
WO2001057061A1 (en) | 2000-02-04 | 2001-08-09 | California Pacific Medical Center Research Institute | Novel use of ribozymes to block gene expression |
WO2001066140A1 (en) | 2000-03-09 | 2001-09-13 | Genzyme Corporation | Use of tgf-beta antagonists to treat or to prevent loss of renal function |
US6632979B2 (en) | 2000-03-16 | 2003-10-14 | Genentech, Inc. | Rodent HER2 tumor model |
US6767541B2 (en) * | 2000-03-20 | 2004-07-27 | The Regents Of The University Of California | HER-2/neu overexpression abrogates growth inhibitory pathways |
US7129084B2 (en) * | 2000-08-03 | 2006-10-31 | Therapeutic Human Polyclonals, Inc. | Production of humanized antibodies in transgenic animals |
US6509318B1 (en) | 2000-09-29 | 2003-01-21 | The Regents Of The University Of California | TGF-B inhibitors and methods |
DE10121694A1 (en) | 2001-05-02 | 2002-11-28 | Sauter Kg Feinmechanik | Spindle head for tools |
US20030125251A1 (en) * | 2001-06-21 | 2003-07-03 | Wakefield Lalage M. | Transforming growth factor beta (TGF-beta) antagonist selectively neutralizes "pathological" TGF-beta |
MXPA05000511A (en) * | 2001-07-12 | 2005-09-30 | Jefferson Foote | Super humanized antibodies. |
US20030028905A1 (en) * | 2001-07-31 | 2003-02-06 | Petra Knaus | Mutant forms of the TGF-beta type II receptor which bind all TGF-beta isoforms |
AU2002331232A1 (en) | 2001-08-14 | 2003-03-03 | Frankgen Biotechnologie Ag | An animal model exhibiting cancer, pulmonary emphysema and cardiomyopathy |
EP1798242B1 (en) * | 2002-01-18 | 2013-01-23 | Pierre Fabre Medicament | Anti-IGF-IR antibodies and their applications |
US7538195B2 (en) * | 2002-06-14 | 2009-05-26 | Immunogen Inc. | Anti-IGF-I receptor antibody |
WO2004013180A2 (en) * | 2002-08-01 | 2004-02-12 | Immunomedics, Inc. | Alpha-fetoprotein immu31 antibodies and fusion proteins and methods of use thereof |
WO2004065417A2 (en) | 2003-01-23 | 2004-08-05 | Genentech, Inc. | Methods for producing humanized antibodies and improving yield of antibodies or antigen binding fragments in cell culture |
RU2006120483A (en) * | 2003-11-13 | 2007-12-20 | Дженентек, Инк. (Us) | SCREENING ANALYSIS AND METHODS FOR TREATING TUMOR |
ES2905923T3 (en) * | 2005-02-08 | 2022-04-12 | Genzyme Corp | TGFbeta antibodies |
AU2006330542B2 (en) * | 2005-12-23 | 2012-05-24 | Eli Lilly And Company | TGF-beta binding compositions |
-
2005
- 2005-03-31 ZA ZA200608130A patent/ZA200608130B/en unknown
- 2005-03-31 CN CN2005800176135A patent/CN1961003B/en active Active
- 2005-03-31 EP EP05732737.1A patent/EP1740615B1/en active Active
- 2005-03-31 ES ES05732737.1T patent/ES2527292T3/en active Active
- 2005-03-31 KR KR1020067022715A patent/KR101245983B1/en active IP Right Grant
- 2005-03-31 BR BRPI0508761-9A patent/BRPI0508761A/en not_active Application Discontinuation
- 2005-03-31 JP JP2007506586A patent/JP5128935B2/en active Active
- 2005-03-31 US US11/096,046 patent/US7527791B2/en active Active
- 2005-03-31 CA CA2561686A patent/CA2561686C/en active Active
- 2005-03-31 MX MXPA06011199A patent/MXPA06011199A/en active IP Right Grant
- 2005-03-31 WO PCT/US2005/010994 patent/WO2005097832A2/en active Application Filing
- 2005-03-31 AU AU2005230848A patent/AU2005230848B9/en active Active
- 2005-03-31 NZ NZ550217A patent/NZ550217A/en unknown
- 2005-03-31 RU RU2006138213/13A patent/RU2386638C2/en active
-
2006
- 2006-09-28 IL IL178409A patent/IL178409A/en active IP Right Grant
-
2009
- 2009-04-14 US US12/423,664 patent/US8012482B2/en active Active
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5571894A (en) | 1991-02-05 | 1996-11-05 | Ciba-Geigy Corporation | Recombinant antibodies specific for a growth factor receptor |
US5821337A (en) | 1991-06-14 | 1998-10-13 | Genentech, Inc. | Immunoglobulin variants |
US5587458A (en) | 1991-10-07 | 1996-12-24 | Aronex Pharmaceuticals, Inc. | Anti-erbB-2 antibodies, combinations thereof, and therapeutic and diagnostic uses thereof |
WO1993016185A2 (en) | 1992-02-06 | 1993-08-19 | Creative Biomolecules, Inc. | Biosynthetic binding protein for cancer marker |
WO1996016673A1 (en) | 1994-12-02 | 1996-06-06 | Chiron Corporation | Method of promoting an immune response with a bispecific antibody |
US5641870A (en) | 1995-04-20 | 1997-06-24 | Genentech, Inc. | Low pH hydrophobic interaction chromatography for antibody purification |
US5837234A (en) | 1995-06-07 | 1998-11-17 | Cytotherapeutics, Inc. | Bioartificial organ containing cells encapsulated in a permselective polyether suflfone membrane |
WO1998002463A1 (en) | 1996-07-11 | 1998-01-22 | Medarex, Inc. | THERAPEUTIC MULTISPECIFIC COMPOUNDS COMPRISED OF ANTI-FCα RECEPTOR ANTIBODIES |
Non-Patent Citations (3)
Title |
---|
BRENNAN ET AL., SCIENCE, vol. 229, 1985, pages 81 |
CARTER ET AL., BIOLTECHNOLOTY, vol. 10, 1992, pages 163 - 167 |
MORIMOTO ET AL., JOURNAL OF BIOCHEMICAL AND BIOPHYSICAL METHODS, vol. 24, 1992, pages 107 - 117 |
Cited By (55)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8383780B2 (en) | 2005-02-08 | 2013-02-26 | Genzyme Corporation | Antibodies to TGFβ |
US10174108B2 (en) | 2005-02-08 | 2019-01-08 | Genzyme Corporation | Antibodies to TGF-beta |
US10781252B2 (en) | 2005-02-08 | 2020-09-22 | Genzyme Corporation | Antibodies to TGF-β |
US9481726B2 (en) | 2005-02-08 | 2016-11-01 | Genzyme Corporation | Antibodies to TGF-β |
US9090685B2 (en) | 2005-02-08 | 2015-07-28 | Genzyme Corporation | Antibodies to TGF-beta |
US8591901B2 (en) | 2005-02-08 | 2013-11-26 | Genzyme Corporation | Antibodies to TGF-β |
US7723486B2 (en) | 2005-02-08 | 2010-05-25 | Optein, Inc. | Antibodies to TGF-β |
US7619069B2 (en) | 2005-04-22 | 2009-11-17 | Eli Lilly And Company | Antibodies to TGF-beta 1 |
US8128927B2 (en) | 2005-04-22 | 2012-03-06 | Eli Lilly And Company | Methods of using TGF-β 1 binding compositions |
US7494651B2 (en) | 2005-12-23 | 2009-02-24 | Eli Lilly And Company | TGF-β binding antibodies |
JP2009521496A (en) * | 2005-12-23 | 2009-06-04 | イーライ リリー アンド カンパニー | TGF-β binding composition |
US7927593B2 (en) | 2005-12-23 | 2011-04-19 | Eli Lilly And Company | TGF-beta binding antibodies |
CN101346394B (en) * | 2005-12-23 | 2012-07-25 | 伊莱利利公司 | TGF-beta binding compositions |
AU2006330542B2 (en) * | 2005-12-23 | 2012-05-24 | Eli Lilly And Company | TGF-beta binding compositions |
WO2007076391A1 (en) * | 2005-12-23 | 2007-07-05 | Eli Lilly And Company | Tgf-beta binding compositions |
EP2918288A1 (en) | 2006-10-03 | 2015-09-16 | Genzyme Corporation | Use of TGF beta antagonists to treat infants at risk of developing bronchopulmonary dysplasia |
EP3254696A1 (en) | 2006-10-03 | 2017-12-13 | Genzyme Corporation | Use of tgf beta antagonists to treat infants at risk of developing bronchopulmonary dysplasia |
US8642034B2 (en) | 2006-10-03 | 2014-02-04 | Genzyme Corporation | Use of TGF-β antagonists to treat infants at risk of developing bronchopulmonary dysplasia |
WO2008063776A2 (en) | 2006-10-12 | 2008-05-29 | Genentech, Inc. | Antibodies to lymphotoxin-alpha |
JP2008237098A (en) * | 2007-03-27 | 2008-10-09 | National Institute Of Advanced Industrial & Technology | Animal model for analyzing metastasis of breast cancer to lung and/or liver |
US10633437B2 (en) | 2010-09-01 | 2020-04-28 | Genzyme Corporation | Treatment of myocardial infarction using TGF-β antagonists |
WO2013014262A1 (en) | 2011-07-27 | 2013-01-31 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for diagnosing and treating myhre syndrome |
US9468612B2 (en) | 2011-10-26 | 2016-10-18 | Seattle Children's Hospital | Cysteamine in the treatment of fibrotic disease |
US9925154B2 (en) | 2011-10-26 | 2018-03-27 | Seattle Children's Hospital | Cysteamine in the treatment of fibrotic disease |
US10035851B2 (en) | 2012-03-08 | 2018-07-31 | Ludwig Institute For Cancer Research Ltd. | TGF-β1 specific antibodies and methods and uses thereof |
US9518112B2 (en) | 2012-03-08 | 2016-12-13 | Ludwig Institute For Cancer Research Ltd | TGF-β1 specific antibodies and methods and uses thereof |
US10947303B2 (en) | 2012-03-08 | 2021-03-16 | Ludwig Institute For Cancer Research, Ltd. | TGF-ß1 specific antibodies and methods and uses thereof |
US11253546B2 (en) | 2014-12-15 | 2022-02-22 | The Regents Of The University Of California | Bispecific OR-gate chimeric antigen receptor responsive to CD19 and CD20 |
US11384350B2 (en) | 2014-12-15 | 2022-07-12 | The Regents Of The University Of California | Cytotoxic molecules responsive to intracellular ligands for selective T cell mediated killing |
US11976112B2 (en) | 2015-03-04 | 2024-05-07 | Genzyme Coporation | scFv-Fc dimers that bind transforming growth factor-β1 with high affinity, avidity and specificity |
US11325971B2 (en) | 2015-03-04 | 2022-05-10 | Genzyme Corporation | scFv-Fc dimers that bind transforming growth factor-β1 with high affinity, avidity and specificity |
US11325970B2 (en) | 2015-03-04 | 2022-05-10 | Genzyme Corporation | Modified-IgG antibodies that bind transforming growth factor-β1 with high affinity, avidity and specificity |
US11834495B2 (en) | 2015-03-04 | 2023-12-05 | Genzyme Corporation | Modified-IgG antibodies that bind transforming growth factor-BETA1 with high affinity, avidity and specificity |
WO2016201282A2 (en) | 2015-06-12 | 2016-12-15 | Ludwig Institute For Cancer Research Ltd | TGF-β3 SPECIFIC ANTIBODIES AND METHODS AND USES THEREOF |
US11485780B2 (en) | 2015-06-12 | 2022-11-01 | Ludwig Institute For Cancer Research, Ltd. | TGF-β3 specific antibodies and methods and uses thereof |
US10723793B2 (en) | 2015-06-12 | 2020-07-28 | Ludwig Institute For Cancer Research, Ltd. | TGF-β3 specific antibodies and methods and uses thereof |
EP4169945A1 (en) * | 2015-10-30 | 2023-04-26 | The Regents of the University of California | Transforming growth factor-beta-responsive polypeptides and their methods for use |
US11014980B2 (en) | 2015-10-30 | 2021-05-25 | The Regents Of The University Of California | Transforming growth factor-beta-responsive polypeptides and their methods for use |
EP3368571A4 (en) * | 2015-10-30 | 2019-11-06 | The Regents of The University of California | Transforming growth factor-beta-responsive polypeptides and their methods for use |
WO2017075433A1 (en) | 2015-10-30 | 2017-05-04 | The Regents Of The University Of California | Transforming growth factor-beta-responsive polypeptides and their methods for use |
WO2017201036A1 (en) | 2016-05-17 | 2017-11-23 | Genentech, Inc. | Stromal gene signatures for diagnosis and use in immunotherapy |
US11518803B2 (en) | 2016-06-08 | 2022-12-06 | UCB Biopharma SRL | Antagonist antibodies that bind to human TGFB1, TGFB2 and to TGFB3 and their use for the treatment of lung fibrosis |
US12049496B2 (en) | 2017-01-20 | 2024-07-30 | Sanofi | Anti-TGF-beta antibodies and their use |
US10844115B2 (en) | 2017-01-20 | 2020-11-24 | Genzyme Corporation | Bone-targeting antibodies |
US11242384B2 (en) | 2017-01-20 | 2022-02-08 | Sanofi | Anti-TGF-beta antibodies and their use |
US10766955B2 (en) | 2017-01-20 | 2020-09-08 | Sanofi | Anti-TGF-β antibodies and their use |
WO2019090263A1 (en) | 2017-11-06 | 2019-05-09 | Genentech, Inc. | Diagnostic and therapeutic methods for cancer |
WO2020095104A1 (en) | 2018-11-05 | 2020-05-14 | Ludwig Institute For Cancer Research Ltd. | HUMANIZED AND VARIANT TGF-β3 SPECIFIC ANTIBODIES AND METHODS AND USES THEREOF |
WO2020095113A1 (en) | 2018-11-05 | 2020-05-14 | Ludwig Institute For Cancer Research Ltd | Humanized and variant tgf-beta1 specific antibodies and methods and uses thereof |
WO2020201362A2 (en) | 2019-04-02 | 2020-10-08 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods of predicting and preventing cancer in patients having premalignant lesions |
WO2022115611A1 (en) | 2020-11-25 | 2022-06-02 | Catamaran Bio, Inc. | Cellular therapeutics engineered with signal modulators and methods of use thereof |
WO2023020592A1 (en) * | 2021-08-18 | 2023-02-23 | 丹生医药技术(上海)有限公司 | TGF-β/VEGF BI-FUNCTIONAL ANTIBODY FUSION PROTEIN |
WO2023080900A1 (en) | 2021-11-05 | 2023-05-11 | Genentech, Inc. | Methods and compositions for classifying and treating kidney cancer |
WO2024077166A1 (en) | 2022-10-05 | 2024-04-11 | Genentech, Inc. | Methods and compositions for classifying and treating lung cancer |
WO2024077095A1 (en) | 2022-10-05 | 2024-04-11 | Genentech, Inc. | Methods and compositions for classifying and treating bladder cancer |
Also Published As
Publication number | Publication date |
---|---|
CA2561686A1 (en) | 2005-10-20 |
US7527791B2 (en) | 2009-05-05 |
BRPI0508761A (en) | 2007-08-14 |
CN1961003A (en) | 2007-05-09 |
AU2005230848A1 (en) | 2005-10-20 |
EP1740615A2 (en) | 2007-01-10 |
NZ550217A (en) | 2009-11-27 |
IL178409A0 (en) | 2007-02-11 |
ES2527292T3 (en) | 2015-01-22 |
CN1961003B (en) | 2013-03-27 |
JP5128935B2 (en) | 2013-01-23 |
AU2005230848B9 (en) | 2011-06-02 |
ZA200608130B (en) | 2008-12-31 |
AU2005230848B2 (en) | 2010-09-09 |
IL178409A (en) | 2015-02-26 |
MXPA06011199A (en) | 2007-04-16 |
US20090285810A1 (en) | 2009-11-19 |
US20050276802A1 (en) | 2005-12-15 |
JP2008505610A (en) | 2008-02-28 |
EP1740615B1 (en) | 2014-11-05 |
US8012482B2 (en) | 2011-09-06 |
CA2561686C (en) | 2014-12-02 |
RU2386638C2 (en) | 2010-04-20 |
KR20060133604A (en) | 2006-12-26 |
WO2005097832A3 (en) | 2005-12-01 |
RU2006138213A (en) | 2008-05-10 |
KR101245983B1 (en) | 2013-06-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8012482B2 (en) | Humanized anti-TGF-beta antibodies | |
JP7301106B2 (en) | Monoclonal antibody against fibroblast growth factor receptor 2 | |
US9926371B2 (en) | M-CSF specific monoclonal antibody and uses thereof | |
RU2639506C2 (en) | Antibodies against vascular endothelial growth factor (vegf) | |
JP5457671B2 (en) | M-CSF specific monoclonal antibody and use thereof | |
US8455623B2 (en) | Compositions and methods for diagnosing and treating cancer | |
US11767362B1 (en) | Methods of treating cancers using PD-1 axis binding antagonists and anti-GPC3 antibodies | |
CN111868089A (en) | B7-H4 antibody dosing regimen | |
US20240026006A1 (en) | Methods of treating cancers using pd-1 axis binding antagonists and anti-gpc3 antibodies |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2005230848 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2561686 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 178409 Country of ref document: IL Ref document number: PA/a/2006/011199 Country of ref document: MX |
|
WWE | Wipo information: entry into national phase |
Ref document number: 200608130 Country of ref document: ZA Ref document number: 550217 Country of ref document: NZ |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2007506586 Country of ref document: JP |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: DE |
|
ENP | Entry into the national phase |
Ref document number: 2005230848 Country of ref document: AU Date of ref document: 20050331 Kind code of ref document: A |
|
WWP | Wipo information: published in national office |
Ref document number: 2005230848 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1020067022715 Country of ref document: KR Ref document number: 2005732737 Country of ref document: EP Ref document number: 6381/DELNP/2006 Country of ref document: IN |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2006138213 Country of ref document: RU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 200580017613.5 Country of ref document: CN |
|
WWP | Wipo information: published in national office |
Ref document number: 1020067022715 Country of ref document: KR |
|
WWP | Wipo information: published in national office |
Ref document number: 2005732737 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: PI0508761 Country of ref document: BR |