AU6934194A - Antibodies - Google Patents
AntibodiesInfo
- Publication number
- AU6934194A AU6934194A AU69341/94A AU6934194A AU6934194A AU 6934194 A AU6934194 A AU 6934194A AU 69341/94 A AU69341/94 A AU 69341/94A AU 6934194 A AU6934194 A AU 6934194A AU 6934194 A AU6934194 A AU 6934194A
- Authority
- AU
- Australia
- Prior art keywords
- antibody
- altered
- human
- complement
- binding
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2833—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against MHC-molecules, e.g. HLA-molecules
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- 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
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]
Description
ANTIBODIES
FIELD OF THE INVENTION
This invention relates to altered antibodies, to pharmaceutical, therapeutic and diagnostic compositions containing said antibodies; to processes for preparing said compositions; to methods of therapy and diagnosis using said antibodies, to a method of modulating the function of cell surface associated antigens using said antibodies; to DNA sequences coding for said antibodies; to cloning and expression vectors containing DNA sequences coding for said antibodies; to host cells transformed with said vectors and to processes for preparing said antibodies.
BACKGROUND OF THE INVENTION
In order for an antibody to be effective therapeutically it is desirable that it achieves the required physiological effect without producing any significant adverse toxic effects. Such toxic effects may be mediated, for example, via complement fixation. Antibody when bound to its cognate antigen can link to and activate the complement cascade. Complement consists of a complex series of proteins. The proteins of the complement system form two interrelated enzyme cascades, termed the classical and alternative pathways, providing two routes to the cleavage of C3, the central event in the complement system. The sequence of events comprising the classical complement pathway is recognition, enzymatic activation, and membrane attack leading to cell death. The recognition unit of the complement system is the C1 complex. The C1 complement protein complex is a unique feature of the classical complement cascade leading to C3 conversion. Complement fixation occurs when the C1q subcomponent binds directly to immunoglobulin antigen immune complex. Whether or not complement fixation occurs depends on a number of constraints. For example, only certain subclasses of immunoglobulin can fix complement even under optimal conditions. These are lgG1, lgG3 and IgM in man and lgG2a, lgG2b and IgM in mice.
The C1q molecule is potentially multivalent for attachment to the complement fixation sites of immunoglobulin. The CH2 domain of IgG and probably the CH4 domain of IgM contain binding sites for C1q. Fc bearing cells also play a role in enhancing the effect of the immune response by binding to and opsonising, phagocytosing or killing target cells coated with antibody of the relevant class. Three IgG binding receptors (FcγR) have been described for murine and human leukocytes. FcγRI has high binding affinity for monomeric IgG, while FcγRII and FcγRIII have low affinity for mono IgG and interact mainly with antigen complexed IgG. The presence of Fc receptors confers on these immune cells the ability to mediate a number of effector mechanisms important in the effector phase of the humoral response. The gamma 1 isotype of human IgG, like lgG3, binds to FcRI and, when complexed with its cognate antigen, activates complement and binds to FcRII and FcRIII. Conversely, human lgG2 and lgG4 are relatively inactive isotypes; both fail to activate the classical complement pathway and lgG4 binds weakly to FcRI [Burton, D R and Woof, J M (1992) Adv. Immunol. 51, 1. Lucisano Valim, Y M and Lachmann, P J. (1991) Clin. exp. Immunol, 84, 1].
Localisation of amino acid residues of IgG that interact with FcRI in the CH2 domain of human IgG is well established [Woof, J M et al (1986) Molec. Immunol. 23, 319. Lund, J et al (1991) J. Immunol, 147. 2657; Canfield, S M and Morrison, S L (1991), J. exp. Med. 173, 1483; Chappel, S M et al, (1991) Proc. Natl. Acad. Sci. 88i, 9036; Chappel, S M et al (1993), J. Biol. Chem 268, 25124; Alegre, M-L et al (1992) J. Immunol, 148. 3461]. Amino acid sequence comparisons of the CH2 domains of antibodies from different species and subclasses that bind well to FcRI suggested that a region at the N-terminal end of CH2 comprising residues Leu 234 - Ser 239 (using the Kabat Eu numbering system [Kabat, E A et al, (1987) Sequences of proteins of Immunological interest. US Dept. of Health and Human Services, Bethesda, MD, USA]) is critical for interaction with FcRI. The motif Leu 234, Leu 235, Gly 236, Gly 237, Pro 238, Ser 239, is present in all IgG isotypes with high affinity for FcRI [Woof, J M et al
(1986), Molec. Immunol. 23, 319]. Domain exchanges between Ig's with different Fc effector functions have demonstrated the importance of CH2 for FcRI binding [Canfield, S M and Morrison, S L (1991), J. exp. Med. 173, 1483; Chappel, S M et al, (1991) Proc. Natl. Acad. Sci. S3, 9036; Chappel, S M et al (1993), J. Biol. Chem 268, 25124] in particular the residue 235. Replacement of the Leu residue at position 235 with a Glu residue reduces the affinity of lgG3 for FcRI by 100 fold [Lund, J et al (1991) J. Immunol, 147. 2657; Canfield, S M and Morrison, S L (1991), J. exp. Med. 173, 1483]. The same Leu 235 to Glu change when performed on an lgG4 variant of OKT3 [Alegre, M-L et al (1992) J. Immunol, 148, 3461] abolished its FcRI binding and, consequently, its mitogenic properties.
Although the sequence requirements for FcRIII binding has been less extensively studied, Sarmay et al. [(1992) Molec. Immunol. 29, 633] have identified the CH2 domain residues 234 to 237 as important for lgG3 binding to all three Fc receptors. The relative importance of each residue differs with each Fc receptor with 235 and 237 being most important for FcRIII mediated cell killing. In contrast, another Fc mediated function, C1q binding and subsequent complement activation, appears to require the carboxyl terminal half of the CH2 domain [Tao, M H., Canfield, S M., and Morrison, S L(1991) J. Exp. Med. 173. 1025]. Morrison's group, following sequence analysis of polymorphisms in the CH2 domain of human IgGs also identified the importance of the C-terminal region of CH2. With a Pro to Ser change at 331 in lgG1 they abolished complement fixation and reduced C1q binding [Tao, M H et al (1993), J. Exp. Med. 178, 661]. Using inter- and intradomain switch variants of CAMPATH-1, Greenwood et al. (1993) [Eur. J. Immunol. 23, 1098] further endorsed the importance of the C-terminal end of CH2. Complement fixation could be restored to human lgG4 with just the carboxyi terminal of CH2 from residue 292 of lgG1 and not the N- terminal half or any other domain. Duncan & Winter (1988) [Nature, 332, 21] identified a motif in CH2 of Glu 318, Lys 320 and Lys 322 of the mouse lgG2b isotype. Changing any of these residues abolished C1q binding, as did the use of competitive peptides of sequences in this region. However, the C1q motif residues are also found in antibodies that do not fix
complement suggesting that these residues may well be necessary but not sufficient for complement activation.
We have found that amino acid residues necessary for C1q and FcR binding of human lgG1 are located in the N-terminal region of the CH2 domain, residues 231 to 238, using a matched set of engineered antibodies based on the anti-HLA DR antibody L243. Changing the leucine 235 in the CH2 region of lgG3 and lgG4 to glutamic acid was already known to abolish FcRI binding, we have confirmed this for lgG1 and also found a concomitant abolition of human complement fixation with retention of FcRIII mediated function. Changing the glycine at 237 to alanine of lgG1 also abolished FcRI binding and reduced complement fixation and FcRIII mediated function. Exchanging the whole region 233 to 236, with the sequence found in human lgG2 abolished FcRI binding andcomplement fixation and reduced FcRIII mediated function of lgG1. In contrast, a change in the previously described C1q binding motif, from lysine at 320 to alanine had no effect on IgG 1 -mediated complement fixation. The proposed site Leu 234 - Leu 235 - Gly 236 - Gly 237 - Pro 238 - Ser 239, is present in all IgG isotypes with high affinity for FcγRI. Recent mutagenesis experiments on lgG3 antibodies have introduced point mutations in this region and the ability of the mutants to interact with FcγRI has been examined [Lund et al (1991) J. Immunol 147, 2657-2662]. The most marked effect is seen at position 235 where replacement of the naturally occurring Leu residue with a Glu residue produces an Ig with a > 100-fold decrease in affinity for FcγRI.
Our observation of the effect of this alteration at residue 235 on the ability of the antibody to fix complement was highly surprising. Earlier protein engineering studies had introduced mutations at various positions in order to locate the C1q-binding site on IgG [Duncan & Winter (1988) Nature, 332, 738-740]. The binding site for C1q was localised to three side chains, Glu 318, Lys 320 and Lys 322 of the mouse lgG2b isotype. Residues Glu 318, Lys 320 and Lys 322 are conserved in all the human IgGs, rat lgG2b and lgG2c, mouse lgG2a, lgG2b and lgG3, guinea pig lgG1 and rabbit IgG.
Further experiments showed that the affinity of human C1q for mutant mouse lgG2b antibodies in which residue 235 was mutated was unaffected i.e. it was in the same range of values as that obtained with the wild type. Although the fact that altering residue 235 of the CH2 region of IgG is known to abolish FcγRI binding as we too observed, this concomitant substantial reduction in complement fixation has not been reported or suggested elsewhere and was completely unexpected. SUMMARY OF THE INVENTION
The invention provides a method of treating diseases in which antibody therapy leads to undesirable toxicity due to antibody mediated complement fixation comprising administering an altered antibody wherein one or more amino acid residues in the N-terminal region of the CH2 domain of said antibody are altered characterised in that the ability of said antibody to fix complement is altered as compared to unaltered antibody.
In a preferred embodiment the altered antibody binds to one or more cellular Fc receptors especially FcRIII and excluding FcRI i.e. the antibody does not bind significantly to FcRI, and more preferably binding to FcRI is abolished.
Accordingly in a further aspect the invention provides an altered antibody wherein one or more amino acid residues in the N-terminal region of the CH2 domain of said antibody are altered characterised in that the ability of said antibody to fix complement is altered, as compared to unaltered antibody.
In a further preferred embodiment the invention therefore provides an altered antibody wherein one or more amino acid residues in the N-terminal region of the CH2 domain of said antibody are altered characterised in that the ability of said antibody to fix complement is altered as compared to unaltered antibody and said altered antibody binds to one or more cellular Fc receptors especially FcRIII and does not bind significantly to FcRI.
The constant region of the antibodies to be altered according to the invention may be of animal origin and is preferably of human origin. It may also be of any isotype but is preferably human IgG and most preferably human lgG1.
In a preferred embodiment of the invention the amino acid residue(s) which is altered lies within amino acid positions 231 to 239, preferably within 234 to 239. In a particularly preferred embodiment of the invention the amino acid residue(s) which is altered lies within the motif Leu 234 Leu 235 Gly 236 Gly 237 Pro 238 Ser 239.
In a most preferred embodiment the amino acid residue(s) which is altered is either Leu 235 and/or Gly 237.
DETAILED DESCRIPTION OF THE INVENTION
As used herein the term 'altered' when used in conjunction with the ability of an antibody to fix complement most usually indicates a decrease in the ability of antibody to fix complement compared to the starting antibody. By choosing appropriate amino acids to alter it is possible to produce an antibody the ability of which to fix complement is substantially reduced such as for example by altering residue Leu 235. It is also possible to produce an antibody with an intermediate ability to fix complement by, for example altering amino acid residue Gly 237.
As used herein the phrase 'substantially reduce complement fixation' denotes that human complement fixation is preferably≤30%, more preferably≤20% and most preferably≤10% of the level seen with the starting wild type unaltered antibody.
The term 'significantly' as used with respect to FcRI binding denotes that the binding of antibody to FcRI is typically <20%, and is most preferably ≤10% of that seen with unaltered antibody.
The altered antibodies of the invention preferably bind to FcRIII as measured by their ability to mediate antibody dependent cellular cytotoxicity (ADCC) at a concentration no greater than ten times that of the wild type unaltered antibody.
The proteins encoded in the Major Histocompatibility Complex region of the genome are involved in many aspects of immunological recognition. It is known that all mammals and probably all vertebrates possess basically equivalent MHC systems and that immune response genes are linked to the MHC.
In man the major histocompatibility complex is the HLA gene cluster on chromosome 6. The main regions are D, B, C and A. The D region contains genes for class II proteins which are involved in cooperation and interaction between cells of the immune system. Many diseases have been found to be associated with the D region of the HLA gene cluster. Studies to date have shown associations with an enormous variety of diseases, including most autoimmune diseases (see for example, European Patent No. 68790). European Patent No. 68790 suggests controlling diseases associated with a particular allele of certain regions of the MHC such as the HLA-D region in humans by selectively suppressing the immune response(s) controlled by a monoclonal antibody specific for an MHC-class II antigen. We have found that by altering an MHC-class II specific antibody at position 235 in the N-terminal region of the CH2 domain it is possible to produce an antibody which fully retains its immunosuppressive properties but which has substantially reduced toxicity in vitro and is tolerated in vivo. In a further preferred embodiment the invention provides an MHC specific antibody wherein one or more amino acid residues in the N-terminal region of the CH2 domain of said antibody are altered characterised in that the ability of said antibody to fix complement is altered as compared to unaltered antibody.
In a preferred embodiment the invention provides an MHC specific monoclonal antibody characterised in that said antibody has been altered at position 235 of the N-terminal region of the CH2 domain. In some instances such as with MHC specific monoclonal antibodies it may be desfrable that the alteration in the N-terminal region of the CH2 domain of the antibody while altering the ability to fix complement additionally inhibits the binding to FcRI receptors. The antibodies are preferably specific for MHC-class II antigens and due to the alteration of one or more amino acid residues in the N-terminal region of the CH2 domain will not bind significantly to FcRI.
In a further preferred embodiment the altered antibodies of the invention or for use according to the invention are directed against an MHC class II antigen characterised in that said antibody has been altered at position 235 of the N-terminal region of the CH2 domain.
In a particularly preferred embodiment, the altered antibodies of the invention or for use according to the invention are directed against an MHC class II antigen characterised in that said antibody has been altered at position 235 of the N-terminal region of the CH2 domain and the ability of said antibody to fix complement is altered as compared to unaltered antibody and said altered antibody binds to one or more cellular Fc receptors especially FcRIII and does not bind significantly to FcRI.
In a further aspect the invention provides a method for producing an altered antibody with altered ability to fix complement comprising altering one or more amino acids in the N-terminal region of the CH2 domain of said antibody, altering the ability of said antibody to fix complement as compared with unaltered antibody.
As used herein the term 'altered antibody' is used to denote an antibody which differs from the wild type unaltered antibody at one or more amino acid residues in the N-terminal region of the CH2 domain of the Fc region of the antibody. The alteration may for example comprise the substitution
or replacement of the starting wild type antibody amino acid by another amino acid, or the deletion of an amino acid residue.
The residue numbering used herein is according to the Eu index described in Kabat et al [(1991) in: Sequences of Proteins of Immunological Interest, 5th Edition. United States Department of Health and Human Services.]
In human lgG1 and lgG3 antibodies the naturally occurring amino acid at position 235 of the N-terminal region of the CH2 domain is a leucine residue. The alterations at position 235 of replacing leucine by glutamic acid or alanine have been found particularly effective at producing a potent immuno-suppressive antibody with minimal toxicity in vitro and which is tolerated in vivo. The alteration at position 237 of replacing glycine by alanine has been found to produce an antibody with an intermediate ability to fix human complement, i.e. the complement fixation level is approximately 15-80%, preferably 20-60%, most preferably 20-40% of that seen with the starting wild type unaltered antibody.
The residue(s) could similarly be replaced using an analogous process to that described herein, by any other amino acid residue or amino acid derivative, having for example an inappropriate functionality on its side chain. This may be achieved by for example changing the charge and/or polarity of the side chain.
The altered antibodies of the invention may also be produced for example, by deleting residues such as 235, or by, for example, inserting a glycosylation site at a suitable position in the molecule. Such techniques are well known in the art, see for example the teaching of published European patent application EP-307434.
The altered antibodies of the invention may also be produced by exchanging lower hinge regions of antibodies of different isotypes. For example a G1/G2 lower hinge exchange abolished complement fixation and is a further preferred embodiment of the invention. This is described in
more detail in the accompanying examples. The G1/G2 lower hinge exchange results in an antibody with altered residues in the 231 to 238 region of the N-terminal region of the CH2 domain wherein one or more residues may be altered and/or deleted.
In a particularly preferred embodiment of the invention the antibody is a human lgG1 antibody directed against an MHC class II antigen.
In a further aspect the invention provides a method of modulating the function of cell surface associated antigens avoiding complement mediated toxicity comprising administering an altered antibody wherein one or more amino acid residues in the N-terminal region of the CH2 domain of said antibody are altered characterised in that the ability of said antibody to fix complement is altered as compared to unaltered antibody.
In a preferred embodiment of this aspect of the invention said altered antibody is able to bind to one or more cellular Fc receptors especially FcRIII while binding to FcRI is significantly reduced. Examples of such cell surface antigens include for example adhesion molecules, T-cell receptor, CD4, CD8, CD3, CD28, CD69, MHC Class I, MHC Class II and CD25.
The invention also includes therapeutic, pharmaceutical and diagnostic compositions comprising the altered antibodies according to the invention and the uses of these products and the compositions in therapy and diagnosis.
Thus in a further aspect the invention provides a therapeutic, pharmaceutical or diagnostic composition comprising an altered antibody according to the invention, in combination with a pharmaceutically acceptable excipient, diluent or carrier.
The invention also provides a process for the preparation of a therapeutic, pharmaceutical or diagnostic composition comprising admixing an altered
antibody according to the invention together with a pharmaceutically acceptable excipient, diluent or carrier.
The antibodies and compositions may be for administration in any appropriate form and amount according to the therapy in which they are employed.
The altered antibodies for use in the therapeutic, diagnostic, or pharmaceutical compositions, pr for use in the method of treatment of diseases in which antibody therapy leads to undesirable toxicity due to antibody mediated complement fixation are preferably MHC specific antibodies most preferably specific for MHC Class II antigens, and most preferably have specificity for antigen ic determinants dependent on the
DRα chain.
The therapeutic, pharmaceutical or diagnostic composition may take any suitable form for administration, and, preferably is in a form suitable for parenteral administration e.g. by injection or infusion, for example by bolus injection or continuous infusion. Where the product is for injection or infusion, it may take the form of a suspension, solution or emulsion in an oily or aqueous vehicle and it may contain formulatory agents such as suspending, preservative, stabilising and/or dispersing agents.
Alternatively, the antibody or composition may be in dry form, for reconstitution before use with an appropriate sterile liquid.
If the antibody or composition is suitable for parental administration the formulation may contain, in addition to the active ingredient, additives such as: starch - e.g. potato, maize or wheat starch or cellulose - or starch derivatives such as microcrystalline cellulose; silica; various sugars such as lactose; magnesium carbonate and/or calcium phosphate. It is desirable that, if the formulation is for parental administration it will be well tolerated by the patient's digestive system. To this end, it may be desirable to include in the formulation mucus formers and resins. It may also be desirable to improve tolerance by formulating the antibody or compositions in a capsule which is insoluble in the gastric juices. It may also be
preferable to include the antibody or composition in a controlled release formulation.
If the antibody or composition is suitable for rectal administration the formulation may contain a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other vegetable waxes or fats. The invention also provides methods of therapy and diagnosis comprising administering an effective amount of an altered antibody according to the invention to a human or animal subject.
The antibodies and compositions may be for administration in any appropriate form and amount according to the therapy in which they are employed. The dose at which the antibody is administered depends on the nature of the condition to be treated and on whether the antibody is being. used prophylactically or to treat an existing condition. The dose will also be selected according to the age and conditions of the patient. A therapeutic dose of the antibodies according to the invention may be, for example, preferably between 0.1-25mg/kg body weight per single therapeutic dose and most preferably between 0.1-10mg/kg body weight per single therapeutic dose. immunological diseases which may be treated with the antibodies of the invention include for example joint disease such as ankylosing spondylitis, juvenile rheumatoid arthritis, rheumatoid arthritis; neurological disease such as multiple sclerosis; pancreatic disease such as diabetes, juvenile onset diabetes; gastrointestinal tract disease such as chronic active hepatitis, celiac disease, ulcerative colitis, Crohns disease, pernicious anaemia; skin diseases such as psoriasis; allergic diseases such as asthma and in transplantation related conditions such as graft versus host disease, and allograft rejection. Other diseases include those described in European Patent No. 68790.
The altered antibodies of the invention may also be useful in the treatment of infectious diseases e.g. viral or bacterial infections and in cancer immunotherapy.
As used herein the term 'antibody' is used to cover natural antibodies, chimeric antibodies and CDR-grafted or humanised antibodies. Chimeric antibodies are antibodies in which an antigen binding site comprising the complete variable domains of one antibody is linked to constant domains derived from another antibody. Methods for carrying out such chimerisation procedures are described in EP 120694 (Celltech Limited), EP 125023 (Genentech Inc and City of Hope), EP 171496 (Res. Dev. Corp. Japan), EP 173494 (Stanford University) and WO 86/01533 (Celltech Ltd). CDR grafted or humanised antibodies are antibody molecules having an antigen binding site derived from an immunoglobulin from a non-human species and remaining immunoglobulin-derived parts of the molecule being derived from a human immunoglobulin. Procedures for generating CDR-grafted or humanised antibodies are described in WO 91/09967 (Celltech Ltd), WO 90/07861 (Protein Design Labs. Inc) and WO 92/11383 (Celltech Ltd).
In further aspects the invention also includes DNA sequences coding for the altered antibodies according to the invention; cloning and expression vectors containing the DNA sequences, host cells transformed with the DNA sequences and processes for producing the altered antibodies according to the invention comprising expressing the DNA sequences in the transformed host cells.
According to a further aspect of the invention there is provided a process for producing an altered antibody of the invention which process comprises: a. producing in an expression vector an operon having a DNA sequence which encodes an antibody heavy or light chain.
b. producing in an expression vector an operon having a DNA sequence which encodes a complementary antibody light or heavy chain.
c. transfecting a host cell with both operons, and
d. culturing the transfected cell line to produce the antibody molecule
wherein at least one of the expression vectors contains a DNA sequence encoding an antibody heavy chain in which one or more amino acid residues in the N-terminal region of the CH2 domain of said antibody has been altered from that in the corresponding unaltered antibody.
As will be readily apparent to one skilled in the art, the alteration in the N-terminal region of the CH2 domain may be made using techniques such as site directed mutagenesis after the whole altered antibody has been expressed. To express unaltered antibody the DNA sequences should be expressed following the teaching described above for altered antibody.
The DNA sequences preferably encode a humanised antibody; a CDR-grafted heavy and/or light chain or a chimeric antibody. The cell line may be transfected with two vectors, the first vector containing the operon encoding the light chain-derived polypeptide and the second vector containing the operon encoding the heavy chain derived polypeptide. Preferably the vectors are identical except in so far as the coding sequences and selectable markers are concerned so as to ensure as far as possible that each polypeptide chain is equally expressed.
Alternatively, a single vector may be used, the vector including a selectable marker and the operons encoding both light chain- and heavy chain-derived polypeptides.
The general methods by which the vectors may be constructed, transfection methods and culture methods are well known per se. Such methods are shown, for instance, in Maniatis et al, Molecular Cloning, Cold Spring Harbor, New York 1989 and Primrose and Old, Principles of Gene Manipulation, Blackwell, Oxford, 1980.
The altered antibody according to the invention is preferably derived from the anti-MHC antibody L243, which has been deposited at the American
Type Culture Collection, Rockville, Maryland USA under Accession number ATCC HB55, and is most preferably a chimeric or a CDR-grafted derivative
thereof. L243 was previously described by Lampson and Levy [J. Immunol. (1980) 125, 293].
The standard techniques of molecular biology may be used to prepare DNA sequences coding for the altered antibodies according to the invention. Desired DNA sequences may be synthesised completely or in part using oligonucleotide synthesis techniques. Site-directed mutagenesis and polymerase chain reaction (PCR) techniques may be used as appropriate. See for example "PCR Technology Principles and Applications for DNA Amplification" (1989), Ed. H. A. Eriich, Stockton Press, N.Y. London. For example, oligonucleotide directed synthesis as described by Jones et al [Nature, 321 , 522 (1986)] may be used. Also oligonucleotide directed mutagenesis may be used as described by Kramer et al [Nucleic Acid Res. 12 9441 (1984)].
Any suitable host cell/vector system may be used for the expression of the DNA sequences coding for the altered antibody. Bacterial e.g. E.coli and other microbial systems may be used. Eucaryotic e.g. mammalian host cell expression systems may also be used such as for example COS cells and CHO cells [Bebbington, C R (1991) Methods 2, 136-145], and myeloma or hybridoma cell lines [Bebbington, C R et al (1992) Bio/Technology 10, 169-175].
Where the altered antibody is derived from L243 CHO based expression systems are preferably used.
Assays for determining FcRIII binding indirectly via ADCC assays and for determining complement fixation and C1q binding are well known in the art, and are described in detail in the following examples.
Immune function/immunosuppression by antibodies may be assayed using techniques well known in the art including for example: Mixed Lymphocyte Responses and T-cell antigen recall responses to Tetanus Toxoid. These assays are described in detail in the following examples.
The invention is illustrated in the following non-limiting examples and with reference to the following figures in which:
Figure 1 shows: a map of plasmid pMR15.1
Figure 2 shows: a map of plasmid pMR14
Figure 3 shows: the nucieotide sequence and predicted amino acid sequence of L243 heavy chain
Figure 4 shows: the nucieotide and amino acid sequences of
(a) clone 43, (b) clone 183 (c) clone 192
Figure 5 shows: the nucieotide sequence and predicted amino acid sequence of L243 light chain
Figure 6 shows: a map of plasmid pGamma 1
Figure 7 shows: a map of plasmid pGamma 2
Figure 8 shows: the nucieotide sequence of hinge and CH2 region of human C-gamma 1
Figure 9 shows: Antigen binding potency of L243 human isotype series
Figure 10 shows: FcRI binding of L243 isotype series
Figure 11 shows: human complement fixation by L243 isotype series e
Figure 12 shows: binding of human Clq to L243 human isotype series
Figure 13 shows: human complement fixation by L243 isotype
Figure 14 shows: guinea pig complement fixation by L243 isotype
Figure 15 shows: rabbit complement fixation by L243 isotype
Figure 16 shows: FcRIII binding of L243 isotype series by ADCC
Figure 17 shows: L243 Isotype Series Inhibition of TT recall response
Figure 18 shows: L243 Isotype Series Inhibition of TT recall response
Figure 19 shows: L243 Isotype Series Inhibition of Mixed Lymphocyte
Reaction.
Figure 20 shows: L243 Isotype Series Inhibition of TT response
Figure 21 shows: L243 Isotype Series Inhibition of Mixed Lymphocyte
Reaction
Figure 22 shows: the nucieotide and amino acid sequence of VI region in
L243-gL1
Figure 23 shows: shows the nucieotide and amino acid sequence of VI region of
L243-gL2
Figure 24 shows: the nucieotide and amino acid sequence of Vh region of L243-gH
Figure 25 shows: a graph of the results of a competition assay for L243 grafts vs FITC-chimeric L243
Figure 26 shows: a graph of a Scatchard analysis for L243 gamma 4
Figure 27 shows: a graph of FcRIII binding of chimeric, grafted and
grafted [L235E] L243 as measured by ADCC
Figure 28 shows: a graph of immunosuppressive activity of CDR grafted
L243 measured by MLR
Figure 29 shows: a graph of CDR grafted L243 and grafted [L235E]
L243 TT recall response
Figure 30 shows: a graph of complement mediated cytotoxic potency of
CDR grafted L243 and CDR grafted [L235E] L243
DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION EXAMPLES
Example 1
Gene Cloning and Expression
RNA preparation from L243 hybridoma cells
Total RNA was prepared from 3 × 10exp7 L243 hybridoma cells as described below. Cells were washed in physiological saline and dissolved in RNAzol (0.2ml per 10exp6 cells). Chloroform (0.2ml per 2ml
homogenate) was added, the mixture shaken vigorously for 15 seconds and then left on ice for 15 minutes. The resulting aqueous and organic phases were separated by centrifugation for 15 minutes in an Eppendorf centrifuge and RNA precipitated from the aqueous phase by the addition of an equal volume of isopropanol. After 15 minutes on ice, the RNA was pelleted by centrifugation, washed with 70% ethanol, dried and dissolved in sterile, RNAase free water. The yield of RNA was 350 μg.
Amino acid sequence of the L243 light chain.
The sequence of the first nine amino acids of the mature L243 light chain was determined to be NH2-DIQMTQSPAS.
PCR cloning of L243 Vh and VI
The cDNA genes for the variable regions of L243 heavy and light chains were synthesised using reverse transcriptase to produce single stranded cDNA copies of the mRNA present in the total RNA, followed by Polymerase Chain Reaction (PCR) on the cDNAs with specific oligonucleotide primers. a) cDNA synthesis
cDNA was synthesised in a 20μl reaction containing the following reagents: 50mM Tris-HCI PH8.3, 75mM KCI, 10mM dithiothreitol, 3mM MgC.2, 0.5mM each deoxyribonucleoside triphosphates, 20 units RNAsin, 75ng random hexanucleotide primer, 2μg L243 RNA and 200 units Moloney Murine Leukemia Virus reverse transcriptase. After incubation at 42°C for 60 min the reaction was terminated by heating at 95°C for 5 minutes. b) PCR
Aliquots of the cDNA were subjected to PCR using combinations of primers for the heavy and light chains. The nucieotide sequences of the 5' primers for the heavy and light chains are shown in Tables 1 and 2 respectively. These sequences, ail of which contain a restriction site starting 6 nucleotides from their 5' ends, followed by the sequence GCCGCCACC to allow optimal translation of the resulting mRNAs, an initiator codon and a further 20 - 30
nucleotides, are a compilation based on the leader peptide sequences of known mouse antibodies [Kabat et al (1991 ) in Sequences of Proteins of Immunological Interest, 5th Edition - United States Department of Health and Human Services].
The 3' primers are shown in Table 3. The light chain primer spans the V - C junction of the antibody and contains a restriction site for the enzyme Spl1 to facilitate cloning of the VI PCR fragment. The heavy chain 3' primers are a mixture designed to span the J - C junction of the antibody. The first 23 nucleotides are identical to those found at the start of human C - gamma 1 , 2, 3 and 4 genes and include the Apa1 restriction site common to these human isotypes. The 3' region of the primers contain a mixed sequence based on those found in known mouse antibodies [Kabat E A, Wu, T.T.; Perry H M, Gottesman K S, and Foeller L; In: Sequences of
Proteins of Immunological Interest, 5th Edition, US Department of Health and Human Services (1991)].
The combinations of primers described above enables the PCR products for Vh and VI to be cloned directly into the appropriate expression vector (see below) to produce chimeric (mouse - human) heavy and light chains and for these genes to be expressed in mammalian cells to produce chimeric antibodies of the desired isotype.
Incubations (20 μl) for the PCR were set up as follows. Each reaction contained 10 mM Tris-HCI pH 8.3, 1.5 mM MgCtø, 50 mM KCI, 0.01% w/v gelatin, 0.25 mM each deoxyribonucleoside triphosphate, 1 - 6 pmoles 5' primer mix (Table 4), 6 pmoles 3' primer, 1 μl cDNA and 0.25 units Taq polymerase. Reactions were incubated at 95°C for 5 minutes and then cycled through 94°C for 1 minute, 55°C for 1 minute and 72°C for 1 minute. After 30 cycles, aliquots of each reaction were analysed by electrophoresis on an agarose gel. Reactions containing 5' primer mixes B1 , B2, B3 and B5 produced bands with sizes consistent with full length VI fragments while reaction B9 produced a fragment with a size
expected of a Vh gene. The band produced by the B1 primers was not followed up as previous results had shown that this band corresponds to a light chain pseudogene produced by the hybridoma cell. c) Molecular cloning of the PCR fragments
DNA fragments produced in reactions B2, B3 and B5 were digested with the enzymes BstB1 and Spl1, concentrated by ethanol precipitation, electrophoresed on a 1.4 % agarose gel and DNA bands in the range of 400 base pairs recovered. These were cloned by ligation into the vector pMR15.1 (Figure 1) that had been restricted with BstB1 and Spl1 . After ligation, mixtures were transformed into E. coli LM1035 and plasmids from the resulting bacterial colonies screened for inserts by digestion with BstB1 and Spl1. Representatives with inserts from each ligation were analysed further by nucieotide sequencing.
In a similar manner, the DNA fragments produced in reaction B9 and digested with HindIII and Apa1 were cloned into the vector pMR14 (Figure 2) that had been restricted with HindIII and Apa1.
Again, representative plasmids containing inserts were analysed by nucieotide sequencing. d) Nucleotide sequence analysis
Plasmid DNA (pE1701 and pE1702) from two isolates containing Vh inserts from reaction B9 was sequenced using the primers R1053 (which primes in the 3' region of the HCMV promoter in pMR14) and R720 (which primes in the 5' region of human C - gamma 4 and allows sequencing through the DNA insert on pMR14). The determined nucieotide sequence and predicted amino acid sequence of L243 Vh in pE1702 is given in Figure 3. The nucieotide sequence for the Vh insert in pE1701 was found to be identical to that in pE1702 except at nucieotide 20 (A in pE1701) and nucieotide 426 (A in pE1701). These two differences are in the signal peptide and J regions of Vh respectively and indicate that the two clones
examined are independent isolates arising from the use of different primers from the mixture of oligonucleotides during the PCR stage.
To analyse the light chain clones, sequence derived from priming with R1053 was examined. The nucleotide sequence and predicted amino acid sequence of the VI genes arising from reactions B2 (clone 183), B3 (clone 43 and B5 (clone 192) are shown in Figure 4. Comparison of the predicted protein sequences shows the following: i) clones 182, 183, 43 and 45 all code for a VI gene which, when the signal peptide is removed, produces a light chain whose sequence is identical to that determined by amino acid sequence analysis for L243 light chain (see above). ii) clones 182 and 183 contain a VI gene that codes for a signal peptide of 20 amino acids, while the VI gene in clones 43 and 45 results from priming with a different set of oligonucleotides and has a leader sequence of only 15 amino acids. iii) Clone 192 does not code for L243 VI. Instead, examination of the database of antibody sequences [Kabat, 1991] indicates that clone 192 contains the VI gene for MOPC21, a light chain synthesised by the NS1 myeloma fusion partner used in the production of the L243 hybridoma. iv) Clones 182 and 183 are identical except at nucleotide 26 (T in clone 182, C in clone 183). This difference can be accounted for by the use of different primers in the PCR and indicates that clones 182 and 183 are independent isolates of the same gene.
The nucieotide sequence and predicted amino acid sequence of the complete VI gene from clone 183 is shown in Figure 5.
Construction of human gamma 1 and gamma 2 isotypes.
The L243 Vh gene was subcloned on a HindIII - Apal fragment into pGamma 1 and pGamma 2, vectors containing the human C - gamma 1 and C - gamma 2 genes respectively (Figures 6 and 7).
Human Isotype mutants
PCR mutagenesis was used to change residue 235 in human C - gammal contained in the vector pGamma 1 from leucine to either glutamic acid or to alanine and to change residue 237 from glycine to alanine. The lower hinge region of human C-gamma 1 was also replaced by the corresponding region of human C-gamma 2. The following oligonucleotides were used to effect these changes: i) L235E change
R4911 5' GCACCTGAACTCGAGGGGGGACCGTCAGTC3'
R4910 5'CCCCCCTCGAGTTCAGGTGCTGAGGAAG3'
II) L235A change
R5081 5'GCACCTGAACTCGCAGGGGGACCGTCAGTC3'
R5082 5'GACTGACGGTCCCCCTGCGAGTTCAGGTGC3'
III) G237A change
R5088 5'GCACCTGAACTCCTGGGTGCACCGTCAGTC3'
R5087 5'GACTGACGGTGCACCCAGGAGTTCAGGTGC3'
IV) Exchange of lower hinge regions
R4909 5'GCACCTCCAGTGGCAGGACCGTCAGTCTTCCTC3' R4908 5'CGGTCCTGCCACTGGAGGTGCTGAGGAAGAG3'
Other oligonucleotides used in the PCR mutagenesis are:
R4732 5'CAGCTCGGACACCTTCTCTCCTCC3'
R4912 5'CCACCACCACGCATGTGACC3'
R4732 and R4912 prime between nucleotides 834 and 858 and between nucleotides 1156 and 1137 respectively in human C - gamma 1 (Figure 8).
The general strategy for the PCR mutagenesis was as follows. For each amino acid change, two rounds of PCR were used to generate DNA fragments containing the required substitutions. These fragments were
then restricted with the enzymes Bgl II and Sty1 and used to replace the corresponding fragments containing the wild type sequence in the pGamma 1 vector, (Figure 6). For the first round PCR, reactions (20 μl) were prepared containing the following reagents : 10 mM Tris - HCl pH 8.3, 1.5 mM MgCI2, 50 mM KCl, 0.01% gelatin, 0.25 mM each deoxyribonucleoside triphosphate, 50 ng pGamma 1 DNA, 0.4 unit Taq polymerase and 6 pmoles of each of the primer. The following combinations of primers were used:
R4911 / R4912,
R4910 / R4732,
R5081 / R4912,
R5082 / R4732,
R5088 / R4912,
R5087 / R4732,
R4909 / R4912,
R4908 / R4732. After 30 cycles through 94°C for 1 minute, 55°C for 1 minute and 72°C for 1 minute, the reactions were extracted with chloroform, the newly synthesised DNA precipitated with ethanol, dissolved in water and electrophoresed on a 1.4 % agarose gel. Gel slices containing the DNA fragments were excised from the gel, the DNA recovered from the agarose using a "Mermaid"™ kit (from Stratech Scientific Ltd., Luton, England) and eluted into 20μl sterile water.
Second round PCR was in a 100 μl reaction containing 10 mM Tris - HCl pH 8.3, 1.5 mM MgCI2, 50 mM KCI, 0.01 % gelatin, 0.25 mM each deoxyribonucleoside triphosphate, 2 units Taq polymerase, 1/20 of each pair of DNA fragments from the first round reaction and 30 pmoles of each of R4732 and R4912. After 30 cycles, see above, the reactions were extracted with phenol / chloroform (1/1) and precipitated with ethanol. Fragments were digested with Bgl11 and Sty1 , electrophoresed on a 1.4 % agarose gel and DNA bands of 250 base-pairs recovered from gel slices as previously described.
These Bgl II - Sty1 fragments were ligated in a 3 - way ligation to the 830 base-pair Sty1 - EcoRI fragment, containing the C - terminal part of the CH2 domain and the entire CH3 domain of human C - gamma 1, and the BgIII - EcoR1 vector fragment from pGammal (see Figure 6). After transformation into LM1035, plasmid minipreps from resulting colonies were screened for the presence of the Bgl II - Sty1 fragment and representatives of each taken for nucieotide sequence analysis. From this, plasmids containing the desired sequence were identified and, for future reference, named as follows : pGammal [L235E] containing glutamic acid at residue 235,
pGammal [L235A] containing alanine at residue 235,
pGammal [G237A] containing alanine at residue 237,
pGammal [g1— >g2] containing the C-gamma 2 lower hinge region.
The above plasmids were each restricted with Hind111 and Apal and the Hind111 - Apal fragment containing L243 Vh inserted to produce the following plasmids: L243Gamma1[L235E]
L243Gamma1[L235A]
L243Gamma1[G237A]
L243Gamma [g1— >g2] a) Production of chimeric L243 antibody
Antibody for biological evaluation was produced by transient expression of the appropriate heavy and light chain pairs after co-transfection into Chinese Hamster Ovary (CHO) cells using calcium phosphate precipitation.
On the day prior to transfection, semi - confluent flasks of CHO-L761 cells were trypsinised, the cells counted and T75 flasks set up each with 10exp7 cells. On the next day, the culture medium was changed 3 hours before transfection. For transfection, the calcium phosphate precipitate was
prepared by mixing 1.25 ml of 0.25M CaCI2 containing 50 μg of each of heavy and light chain expression vectors with 1.25 ml of 2×HBS (16.36 gm NaCI, 11.9 gm HEPES and 0.4 gm Na2HPO4 in 1 litre water with the pH adjusted to 7.1 with NaOH) and adding immediately into the medium on the cells. After 3 hours at 37 C in a CO2 incubator, the medium and precipitate were removed and the cells shocked by the addition of 15 ml 15 % glycerol in phosphate buffered saline (PBS) for 1 minute. The glycerol was removed, the cells washed once with PBS and incubated for 48 - 96 hours in 25 ml medium containing 10 mM sodium butyrate. Antibody was purified from the culture medium by binding to and elution from protein A - Sepharose and quantitated using an 1g ELISA (see below). b) ELISA
For the ELISA, Nunc ELISA plates were coated overnight at 4°C with a F(ab)2 fragment of a polyclonal goat anti-human Fc fragment specific antibody (Jackson Immuno-research, code 109-006-098) at 5 μg/ml in coating buffer (15mM sodium carbonate, 35mM sodium hydrogen carbonate, pH6.9). Uncoated antibody was removed by washing 5 times with distilled water. Samples and purified standards to be quantitated were diluted to approximately 1 μg/ml in conjugate buffer (0.1 M Tris-HCI pH7.0, 0.1M NaCl, 0.2% v/v Tween 20, 0,2% w/v Hammersten casein). The samples were titrated in the microtitre wells in 2-fold dilutions to give a final volume of 0.1 ml in each well and the plates incubated at room temperature for 1 hr with shaking. After the first incubation step the plates were washed 10 times with distilled water and then incubated for 1 hr as before with 0.1 ml of a mouse monoclonal anti-human kappa (clone GD12) peroxidase conjugated antibody (The Binding Site, code MP135) at a dilution of 1 in 700 in conjugate buffer. The plate was washed again and substrate solution (0.1 ml) added to each well. Substrate solution contained 150 μl N,N,N,N-tetramethylbeπzidine (10 mg/ml in DMSO), 150 μl hydrogen peroxide (30% solution) in 10 ml 0.1 M sodium acetate/sodium citrate, pH6.0. The plate was developed for 5 -10 minutes until the absorbance at 630nm was approximately 1.0 for the top standard. Absorbance at 630nm was measured using a plate reader and the concentration of the sample determined by comparing the titration curves with those of the standard.
TABLE 1
Oligonucleotide primers for the 5' region
of mouse heavy chains.
CH1 : 5'ATGAAATGCAGCTGGGTCAT(G,C)TTCTT3' CH2 : 5'ATGGGATGGAGCT(A,G)TATCAT(C,G)(C, T)TCTT3'
CH3 : 5,ATGAAG(A,T)TGTGGTTAAACTGGGTTTT3'
CH4 : 5'ATG(G,A)ACTTTGGG(T,C)TCAGCTTG(G,A)T3'
CH5 : 5'ATGGACTCCAGGCTCAATTTAGTTTT3'
CH6 : 5'ATGGCTGTC(C,T)T(G,A)G(G,C)GCT(G,A)CTCTTCTG3' CH7 : 5'ATGG(G,A)ATGGAGC(G,T) GG(G,A)TCTTT(A,C)TCTT3,
CH8 : 5'ATGAGAGTGCTGATTCTTTTGTGS'
CH9 : 5'ATGG(C,A)TTGGGTGTGGA(A,C)CTTGCTATT3'
CH10 : 5'ATGGGCAGACTTACATTCTCATTCCT3'
CH11 : 5'ATGGATTTTGGGCTGATTTTTTTTATTG3" CH12 : 5'ATGATGGTGTTAAGTCTTCTGTACCT3'
Each of the above primers has the sequence
5'GCGCGCAAGCTTGCCGCCACC3' added to its 5' end.
TABLE 2
Oligonucleotide primers for the 5' region of
mouse light chains.
CL1 : 5ΑTGAAGTTGCCTGTTAGGCTGTTGGTGCT3' CL2 : 5'ATGGAG(T,A)CAGACACACTCCTG(T,C)TATGGGT3'
CL3 : 5ΑTGAGTGTGCTCACTCAGGTCCT3'
CL4 : 5,ATGAGG(G,A)CCCCTGCTCAG(A,T)TT(C,T)TTGG3'
CL5 : 57.TGGATTT(T,A)CAGGTGCAGATT(T,A)TCAGCTT3'
CL6 : 5'ATGAGGT(T,G)C(T,C)(T,C)TG(T,C)T(G,C)AG(T,C)T(T,C)CTG
(A,G)G3'
CL7 : 5'ATGGGC(T,A)TCAAGATGGAGTCACA3'
CL8 : 5,ATGTGGGGA(T,C)CT(G,T)TTT(T,C)C(A,C)(A,C)TTTTTCA
AT3'
CL9 : 5,ATGGT(G,A)TCC(T,A)CA(G,C)CTCAGTTCCTT3, CL10 : 5'ATGTATATATGTTTGTTGTCTATTTC3' CL11 : 5'ATGGAAGCCCCAGCTCAGCTTCTCTT3'
Each of the above primers has the sequence
5'GGACTGTTCGAAGCCGCCACC3' added to its 5' end.
TABLE 3
Oligonucleotide primers for the 3' ends
of mouse Vh and VI genes.
Light chain ( CL12 ) :
5'GGATACAGTTGGTGCAGCATCCGTACGTTT3'
Heavy chain ( R2155 ):
5'GCAGATGGGCCCTTCGTTGAGGCTG(A,C)(A,G)GAGAC(G,T,A)GTGA3'
TABLE 4
5' Primer mixtures for PCR
B1 : CL2.
B2 : CL6.
B3 : CL8.
B4 : CL4, CL9.
B5 : CL1, CL3, CL5.CL7, CL10, CL11.
B6 : CH6.
B7 : CH7.
B8 : CH2, CH4.
B9 : CH1 , CH3, CH5, CH8, CH9, CH10, CH11 , CH12.
Example 2
Biological properties of engineered L243
The aim of the following experiments was to separate the immunosuppressive effects of anti-MHC-II antibodies from possible toxic consequences of their use. In the process we hope to demonstrate which Fc effector functions are necessary for immunosuppression.
ANTIGEN BINDING POTENCY BY INHIBITION ASSAY
The principle of this experiment is that antibodies that have the same binding will compete equally well with a labelled antibody for their cognate antigen. Any changes in the antigen binding potency of the engineered L243 antibodies will be revealed in this system.
Murine L243 (lgG2a) was labelled with fluorescein (FITC) using standard, techniques. All dilutions, manipulations and incubations were done in
Phosphate Buffered Saline (Gibco UK) containing 0.1% Sodium Azide
(BDH UK) and 5% Foetal Calf Serum (Sigma UK). Serial dilutions of engineered antibodies in 100μl in RB polystyrene tubes (2052 12×75mm
Falcon UK) were premixed with a constant amount in 100μl (at a previously determined optimal concentration) of the labelled antibody on 5×104 indicator cells (JY B lymphoblastoid cell line bearing high levels of HLA- DR). Cells and antibody were incubated together at 4°C for 30m in, washed twice and binding revealed using a Fluorescence Activated Cell
Scanner (FACS Becton Dickinson). After appropriate analysis, median fluorescence intensity is plotted against antibody concentration.
Results
As expected, none of the changes in the Fc portion of the molecule affected antigen binding ability (Figure 9).
ASSESSMENT OF FCγ RI BINDING.
The ability of the engineered variants of L243 to bind to FcgRI was measured. The principle of this experiment is that antibodies will bind to cells through Fc receptors and the affinity of this interaction is determined by the subclass and hence the structure of the Fc of the antibody. The
assay is based on the ability of the engineered antibodies to compete for binding with FITC labelled murine lgG2a to I FNγ stimulated U937 cells.
U937 (myelomonocytic) cells, when incubated with 500μ/ml IFNγ (Genzyme UK) for 24 hours, expresses high levels of FcgRI, as assessed by CD64 binding and monomeric lgG2a binding, low levels of FcγRII and no FcγRIII.
U937 cells are washed extensively in DMEM containing 25mM HEPES (Gibco UK), incubated for 2 hours at 37°C in RPMI 1640 (Gibco UK) and then washed again in DMEM containing 25mM HEPES (Gibco UK) to remove bovine IgG bound to Fc receptors. Serial dilutions of engineered antibodies were prepared in 50μl in Phosphate Buffered Saline (Gibco UK) containing 0.1% sodium azide in V-bottom 96 well microtitre plates' (ICN/Flow UK) and were incubated with 5x104 U937 cells in 50μl for 30min at 4°C. 50μl of FITC labelled lgG2a antibody was then added to all wells, at a previously determined optimal concentration, for a further 90min at
4°C. Cells were washed once in the microtitre tray, transferred to RB polystyrene tubes (2052 12×75mm Falcon UK) washed once again and binding was revealed using a Fluorescence Activated Cell Scanner (FACS
Becton Dickinson). After appropriate analysis, median fluorescence intensity is plotted against antibody concentration.
Results
Changes in the N-terminal region of the CH2 domain of lgG1 had profound effects on binding to FcRI (Figure 10). As expected, wild type lgG1 bound well to FcRI, lgG4 about 10 times less well and lgG2 did not bind at all. We have confirmed that the Leu 235 to Glu change in human lgG4 reduced its low FcRI binding to nothing and that the same change in lgG1 completely abolishes FcRI binding. Ala at 235 reduced (by about 100 fold) but did not ablate FcRI binding. Changing Gly 237 to Ala of lgG1 also abolished FcRI as did exchanging the whole region 233 to 236, with the sequence found in human lgG2. The G1[K320A] change had no effect on FcRI binding.
ANTIBODY DEPENDENT COMPLEMENT
MEDIATED CYTOTOXICITY.
The ability of the engineered variants of L243 to fix human complement was assessed using the technique of antibody dependent complement mediated cytotoxicity.
The principle of the experiment is that antibodies will mediate complement lysis of target cells bearing their cognate antigen if the Fc of the antibody is able to interact with the components of the (usually classical) complement cascade. The critical interaction is with the C1q molecule.
The source of complement in these experiments is human venous blood freshly drawn into endotoxin free glass bottles which is then allowed to clot at 37°C for 1 hour. The clot is detached from the glass and then incubated at 4°C for 2 hours to allow it to retract. The clot is then removed and the serum separated from the remaining red cells by centrifugation at 1000g. Once prepared, the serum can be stored for up to one month at -20°C without noticeable deterioration of potency but is best used fresh.
All manipulations, dilutions and incubations are done in RPMI 1640 medium (Gibco UK) containing 2mM Glutamine (Gibco UK) and 10% foetal calf serum (Sigma UK). Target cells (JY B lymphoblastoid cell line bearing high levels of HLA-DR) are labelled with 1mCi Na51Cr for 1 hour at room temperature, agitated every 15 min. The cells are then washed three times, to remove free radiolabel, and resuspended at 2×106/ml. Serial antibody dilutions are prepared in duplicate in V-bottom 96 well microtitre plates (ICN/Flow UK) in 25μl. Control wells containing medium only are also prepared to establish the spontaneous release of label giving the assay background. Target 51Cr labelled JY cells are added to all wells in 10μl. The same number of JY cells are also added to wells containing 2% Triton ×100 in water to establish the 100% release value. Target cells and antibody are incubated together and, after 1 hour at room temperature, 25μl serum as a source of complement is added to all wells (except the 100%) for a further 1 hour at room temperature. 100μl of EDTA saline at 4°C is then added to stop any further cell killing, the microtitre plates are
centrifuged at 200g to pellet the intact cells and 100μl supernatant is removed and counted in a gamma counter.
Percent cell lysis is calculated by subtracting the background from all values and then expressing them as a percentage of the adjusted maximum release. Replicates vary by less than 5%. Percent cell lysis is then plotted against antibody dilution.
Results
The ability of L243 to fix human complement was not affected by all the changes made in the N-terminal region of the CH2 domain, residues 233 to 237 (Figure 11). Wild type lgG1 mediated potent killing with 600ng/ml giving half maximum cell killing (64% maximum). lgG2 and lgG4 caused no cell killing even at 20μg/ml. The Gly to Ala at 237 gave an intermediate level killing (20% maximum killing at 2μg/ml). Exchanging the whole lower hinge region with the sequence found in human lgG2 failed to cause lysis even at 20μg/ml. Changes at 235 in lgG1 had unexpectedly profound effects on human complement fixation. Changing the Leu 235 to Glu abolished complement lysis (no killing at 20μg/ml). Ala at 235 permitted low levels of killing. In contrast, a change in the previously described C1q binding motif [Duncan A R and Winter G (1998), Nature, 332, 21.], from Lys to Ala at 320 effected no change from the lgG1 wild type killing (70% maximum cell killing and half the cells dead with 600ng/ml). DIRECT BINDING OF C1q
Measurement of the direct binding of human C1q to different engineered variants of L243 was established to confirm that complement mediated cytotoxicity was due to activation of the classical pathway. Purified human C1q (Sigma UK) was directly labelled with fluorescein isothiocyanate (FITC Sigma) using conventional methods. All dilutions, manipulations and incubations were done in Phosphate Buffered Saline (Gibco UK) containing 0.1% Sodium Azide (BDH UK) and 5% Foetal Calf Serum (Sigma UK). 5×104 indicator cells (JY B lymphoblastoid cell line bearing high levels of HLA-DR) were coated with the different engineered antibodies by incubating at saturating concentrations for 1 hour at 4°C in
RB polystyrene tubes (2052 12x75mm Falcon UK). After washing, serial dilutions of FITC labelled C1q in 100μl were added and were incubated together for a further 30 min at 4°C. After washing, binding of C1q was revealed using a Fluorescence Activated Cell Scanner (FACS Becton Dickinson). After appropriate analysis, median fluorescence intensity is plotted against C1q concentration.
Results
Direct binding of human C1q to the L243 human isotype series confirmed the results with complement mediated cytotoxicity (Figure 12). Labelled human C1q bound well to wild type lgG1 , when bound to JY cells, and bound poorly to lgG4. Equilibrium dissociation constants were determined essentially as described by Krause et al. [Behring Inst. Mitt. SZ 56 (1990)] and were 1.2 ×10- 7M and 1.5 ×10-8M for lgG4 and lgG1 respectively. These values compare favourably with those obtained for the mouse antibodies lgG1 and lgG2a which have similar functions [Leatherbarrow and Dwek (1984), Molec. Immunol. 21, 321]. The Leu 235 to Glu change in lgG1 reduced the binding of C1q to the same level as lgG4. In contrast, a change in the previously described C1q binding motif [Duncan A R and Winter G (1988) Nature 332, 21], from Lys to Ala at 320 had no effect on
C1q binding. The Leu 235 to Glu change in lgG4 did not alter wild type binding.
Rabbit and Guinea Pig complement
The G1[L235E] and G1[L235A] modifications behaved differently when rabbit or guinea pig serum was used as a source of complement instead of human. With rabbit C they caused the same level of lysis as the wild type G1. With guinea pig they caused 40% and 49% plateau level killing, respectively, compared with 80% killing by the lgG1 wild type. The 235 change only affects human complement binding indicating that rabbit and guinea pig complement interact differently with human lgG1 (see Figures 13-15).
ANTIBODY DEPENDENT CELL MEDIATED CYTOTOXICITY.
The ability of the engineered variants of L243 to bind to FcgRIII was assessed using antibody dependent cell mediated cytotoxicity (ADCC).
The principle of the experiment is that antibodies will mediate lysis of target cells bearing their cognate antigen if the Fc of the antibody is able to interact with Fc receptor bearing effector cells capable of cytotoxicity. The critical interaction is between antibody Fc and cellular Fc receptors.
Effector cells are prepared fresh for each experiment. Human venous blood is drawn into endotoxin free tubes containing heparin. Peripheral blood mononuclear cells (PBMC) are prepared by density gradient centrifugation according to the manufacturers instructions (Pharmacia). PBMC are adjusted to 1×107 cells/ml in RPMI 1640 medium (Gibco UK) containing 2mM Glutamine (Gibco UK) and 10% foetal calf serum (Sigma UK), in which all manipulations, dilutions and incubations are done. Target cells (JY B lymphoblastoid cell line bearing high levels of HLA-DR) are labelled with 1mCi Na51Cr for 1 hour at room temperature, agitated every 15 min. The cells are then washed three times, to remove free radiolabel, and resuspended at 2×106/ml. Serial antibody dilutions are prepared in duplicate in sterile U-bottom 96 well microtitre plates (Falcon UK) in 25μl. Control wells containing medium only are also prepared to establish the spontaneous release of label giving the assay background. Target 51Cr labelled JY cells are added to all wells in 10μl. The same number of JY cells are also added to wells containing 2% Triton x100 in water to establish the 100% release value. Target cells and antibody are incubated together and, after 30min at room temperature, 25μl effector cells are added to all wells (except the 100%) for a further 4 hours at 37°C. 100μl of EDTA saline at 4°C is then added to stop any further cell killing, the microtitre plates are centrifuged at 200g to pellet the intact cells and 100μl supernatant is removed and counted in a gamma counter.
Percent cell lysis is calculated by subtracting the background from all values and then expressing them as a percentage of the adjusted maximum release. Replicates vary by less than 5%. Percent cell lysis is then plotted against antibody dilution.
Results
Not all the changes made in the N-terminal region of the CH2 domain, residues 233 to 237, affected FcRIII mediated function (Figure 16 and Tables 5 and 7). L243 lgG2 was unable to mediate peripheral blood mononuclear cell cytotoxicity (ADCC) of HLA-DR positive JY lymphoblastoid cells at concentrations up to 100γ/ml. lgG4 caused a low level of ADCC (20% maximum killing at 1γ/ml) which could be abrogated by the Leu 235 to Glu change. Wild type lgG1 was a potent mediator of cell killing giving 50% cell death at 5ng/ml antibody. Gly to Ala at 237 reduced the igG1 wild type killing to the level seen with lgG4. Exchanging the whole lower hinge region with the sequence found in human lgG2 gave intermediate levels of killing with 500ng/ml needed for 50% cell death. In contrast, changes at 235 in lgG1 had minimal effect on ADCC. Changing the Leu 235 to Ala gave levels of killing comparable with the G1 wild type (9ng/ml for 50% cell death)) and changing the Leu 235 to Glu reduced ADCC a little (40ng/ml for 50% cell death). A change in the previously described C1q binding motif, from Lys to Ala at 320 had no effect on the ability of lgG1 to mediate ADCC.
IMMUNE FUNCTION
Ex vivo T cell function experiments were performed where an interaction between MHC-II and the T cell receptor was an obligatory requirement for T cell activation. The L243 isotype series was tested in mixed lymphocyte reactions, which measures both naive and memory T cell activation, and recall responses to tetanus toxoid which only measures a memory T cell response.
Mixed Lymphocyte Reaction.
The immunosuppressive potency of engineered variants of L243 was assessed using a mixed lymphocyte reaction.
The principle of the experiment is that when leucocytes from one individual are mixed with those of another which express different HLA alleles, they will recognise each other as foreign and will become activated. This activation is dependent, primarily, on interactions between the CD3/TcR
complex on T cells and the MHC-II molecule on antigen presenting cells. Antibodies that bind to MHC-II are known to inhibit this reaction.
Leucocytes are prepared fresh for each experiment. Human venous blood from two individuals is drawn into endotoxin free tubes containing heparin. Peripheral blood mononuclear cells (PBMC) are prepared by density gradient centrifugation according to the manufacturers instructions (Pharmacia). PBMC are adjusted to 2×106 cells/ml in RPM1 1640 medium (Gibco UK) containing 2mM Glutamine (Gibco UK), 100μ/ml/100μg/ml Penicillin/ Streptomycin (Gibco) and 10% foetal calf serum (Sigma UK), in which all manipulations, dilutions and incubations are done. PBMC from one individual are irradiated with 3000 rads. These cells will be stimulate a response from the other individual. Serial antibody dilutions are prepared in triplicate in sterile U-bottom 96 well microtitre plates (Falcon UK) in 100μl. Control wells containing medium only and optimal Cyclosporin (Sandimmun®, Sandoz) levels (100nM) are also prepared to establish the maximum response and maximum inhibition, respectively. Equal numbers of irradiated stimulators and responders are mixed together and 100μl are added to each well. Wells of stimulator alone and responders alone are also set up as controls. The experiment is incubated at 37°C in 100% humidity and 5%CO2 for 5 days. Response is measured by assessing proliferation during the last 18 hours of culture by incubation with 1μCi/well 3H-Thymidine (Amersham UK), harvesting on to glass filter mattes and counting using a beta counter.
Results are plotted as CPM against antibody concentration. Replicates vary by less than 10%. T cell Recall Response to Tetanus Toxoid
The ability of the engineered variants of L243 to suppress a secondary response was assessed using a recall response to Tetanus Toxoid.
The principle of the experiment is that T lymphocytes from an individual previously immunised with Tetanus Toxoid (TT) will respond to TT when re-exposed ex vivo. This activation is dependent on the interaction
between the CD3/TcR complex on T ceils and the MHC-II molecule on cells which process and present the antigen. Antibodies that bind to MHC-II are known to inhibit this reaction. Lymphocytes are prepared fresh for each experiment. Human venous blood is drawn into endotoxin free tubes containing heparin. Peripheral blood mononuclear cells (PBMC) are prepared by density gradient centrifugation according to the manufacturers instructions (Pharmacia). PBMC are adjusted to 2×106 cells/ml in RPMI 1640 medium (Gibco UK) containing 2mM Glutamine (Gibco UK), 100μ/ml/100μg/ml Penicillin/ Streptomycin (Gibco) and 10% foetal calf serum (Sigma UK), in which all manipulations, dilutions and incubations are done.
Serial antibody dilutions are prepared in triplicate in sterile U-bottom 96' well microtitre plates (Falcon UK) in 100μl. 50μl containing an optimal concentration of TT, previously determined by experimentation, is added to all wells. Control wells containing medium only or Cyclosporin
(Sandimmun, Sandoz) (100nM) are also prepared to establish the maximum response and maximum inhibition, respectively. 50μl PBMC are then added to each well. The experiment is incubated at 37°C in 100% humidity and 5%C02 for 7 days. Response is measured by assessing proliferation during the last 18 hours of culture by incubation with 1μCi/well
3H-Thymidine, harvesting on to glass filter mattes and counting using a beta counter.
Results are plotted as CPM against antibody concentration. Replicates vary by less than 10%.
Results (Figures 17-21)
There were no significant or qualitative differences between the effects of the L243 human isotype series between the MLR and TT response.
Maximal inhibition was achieved with G1, G1[L235E] and G1[L235A].
Approximately two orders of magnitude more of G2, G4 and G1[G237A] was required to give similar levels of inhibition. The G1/G2 L hinge exchange mutant was intermediate in immuno-suppresser potency, there was no correlation between complement fixation or FcRI binding and
immuno-suppression, G1 binding well to FcRI and fixing complement and G1[L235E] doing neither, but both giving good immunosuppression. But, there was good correlation with FcRIII binding. Human G1 and G1[L235E] interact with FcRIII and give good immunosuppression. The G1/G2 L hinge is intermediate in FcRIII binding and immuno-suppression. In contrast, the G237A mutation in human G1, in agreement with published observations, reduces FcRIII binding. This antibody gave poor immunosuppression. (Table 5). Table 6 shows a number of L243 isotype mutants.
Conclusion
We have found that amino acid residues necessary for C1q and FcR binding of human lgG1 are located in the N-terminal region of the CH2 domain, residues 231 to 238, using a matched set of engineered' antibodies based on the anti-HLA DR antibody L243. Changing the leucine 235 in the CH2 region of lgG3 and lgG4 to glutamic acid was already known to abolish FcRI binding, we have confirmed this for lgG1 and also found a concomitant abolition of human complement fixation with retention of FcRIII mediated function. Changing the giycine at 237 to alanine of lgG1 also abolished FcRI binding and reduced complement fixation and FcRIII mediated function. Exchanging the whole region 233 to 236, with the sequence found in human lgG2 abolished FcRI binding and complement fixation and reduced FcRIII mediated function of lgG1. In contrast, a change in the previously described C1q binding motif, from lysine at 320 to alanine had no effect on IgG 1 -mediated complement fixation.
The effect of these changes in lgG1 on FcRI binding are similar to published observations using lgG3 and lgG4 [Lund J et al J. Immunol. 1991. 147, 265; and Alegre M-L et al J. Immunol. 1992. 148, 3461] with changes at 235 and 237 in the lower hinge/N-terminal CH2 region markedly reducing FcRI binding. The similarities between these three isotypes strongly suggests that they interact with FcRI in a similar way. We have found residues necessary for FcRIII binding of human lgG1 within the lower hinge/N-terminal end of the CH2 region. Modification at 237 and
exchanging the lower hinge for lgG2 residues caused low and intermediate levels, respectively, of FcRIII mediated killing. These effects are similar to those reported by Sarmay et al [Molec. Immunol. 1992.29, 633] for human lgG3. In contrast to Sarmay et al using lgG3, our changes at residue 235 of lgG1 had little effect on FcRIII binding.
Greenwood et al [Eur. J. Immunol. 1993. 23, 1098], using inter and intra domain switch variants between lgG1 and lgG4, identify residues in lgG1 necessary for FcRIII binding in the C-terminal half of the CH2 domain beyond 292. This indicates that the residues we have identified within the lower hinge/N-terminal end of the CH2 region are necessary but not sufficient for FcRIII effector function mediated through binding of human lgG1. lgG1 variants with changes at 235 failed to mediate lysis with human complement and did not bind purified human C1q. We also found that an lgG1 molecule containing a change at 320 gave complement mediated killing equivalent to the lgG1 wild type. Residues, Glu 318, Lys 320 and Lys 322 were identified by protein engineering studies as necessary in mouse lgG2b for C1q binding [Duncan, A R and Winter G, Nature, 1988. 322, 21]. The same study also demonstrated that the 235 change in mouse lgG2b left unchanged its affinity for human C1q [Duncan, A R and Winter G, Nature, 1988. 322, 21]. The apparent contradiction between these observations is probably due to differences in C1q contacts between human lgG1 and mouse lgG2b.
We found that most changes in the lower hinge/N-terminal end of the CH2 domain affect C1q binding. The G1/G2 lower hinge exchange abolished complement fixation and the change at 237 also reduces it significantly. In contrast, Greenwood et al [Eur. J. Immunol. 1993. 23, 1098], found residues necessary for human complement fixation in the C-terminal half of the CH2 domain. Tao et al [J. exp. Med. 1993. 178. 661] also identify the C-terminal half of the CH2 domain as necessary for complement fixation. They are able to separate C1q binding from complement mediated lysis. lgG1 with a Pro to Ser change at 331, in the C-terminal half of the CH2 domain, is able to bind human C1q as well as the wild type but is unable to
activate complement. This predicts that the amino acids that we have identified within the lower hinge/N-terminal end of the CH2 region are necessary for C1q binding and that the C-terminal residues are necessary for the binding and activation of the antibody dependent complement cascade beyond C1q.
TABLE 5 Summary of L-243 Isotype Series
L243 RI RIII C1q MLR TT - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
G2 - - - ++ ++
G4 + - - ++ ++
G1 +++ +++ +++ ++++ ++++
G1L235E - ++± ± +++± +++± G1L235A + +++ + ++++ ++++
G1G237A + + + ++ ++
TABLE 6
Human Isotype Mutants
Gene Residue From To NAME
G1 235 L E G1[L235E]
G1 235 L A G1[L235A]
G1 237 G A G1[G237A]
G1 320 K A G1[K320A]
G4 235 L E G4[L235E]
G1 231-238 APELLGGP AP-PVAGP G1/G2L-hinge
TABLE 7
Summary of L-243 Isotype Series
L243 RIa Rlllb Complement
G2 >10 >100000 >20/0
G4 1.2 10000ex >20/0
G4[L235E] >10 > 100000 >20/0
G1 0.13 5 0.6/65
G1/G2Lh >10 500 >20/0
G1[L235E] >10 40 >20/0
G1[L235A] 5.0 9 >20/0
G1[G237A] >10 10000eX 2.0/20
G1[K320A] 0.1 10 0.6/70
a) mg/ml antibody necessary for 50% inhibition of binding of FITC- labelled mouse lgG2a antibody to U937 cells. b) ng/ml antibody necessary for half maximal cell killing in ADCC. (ex) extrapolated value. c) mg/ml antibody necessary for half maximal cell killing by human complement and percent plateau cell killing.
EXAMPLE 3
L243 is a mouse monoclonal antibody raised against human MHC Class II. The nucieotide and amino acid sequences of L243 VI and Vh are shown in Figures 5 and 3 respectively. The following examples describe the humanisation of the L243 antibody (CDR grafting).
CDR grafting of L243 liαht chain
Alignment of the framework regions of L243 light chain with those of the four human light chain subgroups [Kabat, E.A., Wu, T.T., Perry, H.M., Gottesman, K.S. and Foeller, C. 1991 , Sequences of Proteins of Immunological Interest, Fifth Edition] revealed that L243 was most homologous to antibodies in human light chain subgroup 1. Consequently, for constructing the CDR grafted light chain, the framework regions chosen corresponded to those of the human Group 1 consensus sequence. A' comparison of the amino acid sequences of the framework regions of L243 and the consensus human group I light chains is given below and shows that there are 21 differences (underlined) between the two sequences.
Analysis of the contribution that any of these framework differences might have on antigen binding (see published International patent application No. WO91/09967) identified 4 residues for investigation; these are at positions 45,49,70 and 71. Based on this analysis, two versions of the CDR grafted light chain were constructed. In the first of these, L243-gL1 , residues 45,49,70 and 71 are derived from the L243 light chain while in the second, L243-gL2, all residues are human consensus.
Light chain Comparisons
Kl
Construction of CDR grafted light chain L243-gL1
The construction of L243-gL1 is given below in detail. The following oligonucleotides were used in the Polymerase Chain Reactions (PCR) to introduce changes into the framework regions of the chimeric light chain: R5043 : 5 'GTAGGAGACCGGGTCACCATCACATGTCGAGCAAA3 '
R5CH4 : 5 'CTGAGGAGCTTTTCCTGGTTTCTGCTGATACCATGCTAAA3 ' R5045 : 5 'AAACCAGGAAAAGCTCCTCAGCTCCTGATCTTTGCTGCATC3 ' R5046 : 5 'CTTCTGGCTGCAGGCTGGAGATAGTTAGGGTATACTGTGTGCC3 ' R5047 : 5 'CTTCAGCCTGCAGCCAGAAGATTTTGCTACTTATTACTGTCAA3 ' R5048 : 5 'GGGCCGCTACCGTACGTTTTAGTTCCACTTTGGTGCCTTGACCGAA3 '
Three reactions, each of 20 μl, were set up each containing 10 mM Tris- HCI pH 8.3, 1.5 mM MgCI2, 50 mM KCI, 0.01% w/v gelatin, 0.25 mM each deoxyribonucleoside triphosphate, 0.1 μg chimeric L243 light chain DNA , 6 pmoles of R5043/R5044 or R5045/R5046 or R5047/R5048 and 0.25 units Taq polymerase. Reactions were cycled through 94°C for 1 minute, 55°C for 1 minute and 72°C for 1 minute. After 30 cycles, each reaction was analysed by electrophoresis on an agarose gel and the PCR fragments excised from the gel and recovered using a Mermaid Kit.
Aliquots of these were then subjected to a second round of PCR. The reaction, 100 μl, contained 10 mM Tris-HCI pH 8.3, 1.5 mM MgCI2, 50 mM KCI, 0.01% w/v gelatin, 1/10 of each of the three PCR fragments from the first set of reactions, 30 pmoles of R5043 and R5048 and 2.5 units Taq polymerase. Reaction temperatures were as above. After the PCR, the
mixture was extracted with phenol / chloroform and then with chloroform and precipitated with ethanol. The ethanol precipitate was recovered by centrifugation, dissolved in the appropriate buffer and restricted with the enzymes BstEII and Spll. The resulting product was finally electrophoresed on an agarose gel and the 270 base pair DNA fragment recovered from a gel slice and ligated into the vector pMR15.1 (Figure 1) that had previously been digested with the same enzymes.
The ligation mixture was used to transform E. coli LM1035 and resulting colonies analysed by PCR, restriction enzyme digests and nucieotide sequencing. The nucieotide and amino acid sequence of the VI region of L243-gL1 is shown in Figure 22.
Construction of CDR grafted light chain L243-gL2
L243-gL2 was constructed from L243-gL1 using PCR. The following oligonucleotides were used to introduce the amino acid changes : R1053 : 5 'GCTGACAGACTAACAGACTGTTCC3 '
R5350 :
5 'TCTAGATGGCACACCATCTGCTAAGTTTGATGCAGCATAGATCAGGAGCTTAGGA
GC3 '
R5349 :
5 'GCAGATGGTGTGCCATCTAGATTCAGTGGCAGTGGATCAGGCACAGACTTTACCC
TAAC3 '
R684 : 5 'TTCAACTGCTCATCAGAT3 '
Two reactions, each 20 μl, were set up each containing 10 mM Tris-HCI pH 8.3, 1.5 mM MgCI2, 50 mM KCI, 0.01% w/v gelatin, 0.25 mM each deoxyribonucleoside triphosphate, 0.1 μg L243-gL1, 6 pmoles of R1053/ R5350 or R5349/R684 and 0.25 units Taq polymerase. Reactions were cycled through 94°C for 1 minute, 55°C for 1 minute and 72°C for 1 minute. After 30 cycles, each reaction was analysed by electrophoresis on an agarose gel and the PCR fragments excised from the gel and recovered using a Mermaid Kit.
Aliquots of these were then subjected to a second round of PCR. The reaction, 100 μl, contained 10 mM Tris-HCI pH 8.3, 1.5 mM MgCI2, 50 mM KCI, 0.01% w/v gelatin, 1/5 of each of the PCR fragments from the first set of reactions, 30 pmoles of R1053 and R684 and 2.5 units Taq polymerase. Reaction temperatures were as above. After the PCR, the mixture was extracted with phenol / chloroform and then with chloroform and precipitated with ethanol. The ethanol precipitate was recovered by centrifugation, dissolved in the appropriate buffer and restricted with the enzymes BstEII and Spll. The resulting product was finally electrophoresed on an agarose gel and the 270 base pair DNA fragment recovered from a gel slice and ligated into the vector pMR15.1 (Figure 1) that had previously been digested with the same enzymes.
The ligation mixture was used to transform E. coli LM1035 and resulting colonies analysed by PCR, restriction enzyme digests and nucieotide sequencing. The nucleotide and amino acid sequence of the VI region of L243-gL2 is shown in Figure 23.
CDR grafting of L243 heavy chain
CDR grafting of L243 heavy chain was accomplished using the same strategy as described for the light chain. L243 heavy chain was found to be most homologous to human heavy chains belonging to subgroup 1 and therefore the consensus sequence of the human subgroup 1 frameworks was chosen to accept the L243 heavy chain CDRs.
A comparison of the framework regions of the two structures is shown below where it can be seen that L243 differs from the human consensus at 28 positions (underlined). After analysis of the contribution that any of these might make to antigen binding, only residues 27,67,69,71,72 and 75 were retained in the CDR grafted heavy chain, L243-gH.
Heavy chain comparisons
2
7
Construction of CDR grafted heavy chain. L-243 gH
L243gH was assembled by subjecting overlapping oligonucleotides to PCR in the presence of the appropriate primers. The following oligonucleotides. were used in the PCR: R3004 : 5 'GGGGGGAAGCTTGCCGCCACCATGG3 ' R3005 : 5 'CCCCCCGGGCCCTTTGTAGAAGCAG3 ' R4902 : 5 'GACAACAGGAGTGCACTCTCAGGTGCAGCTGGTGCAGTCTGGAGC
AGAGGTGAAGAAGCCTGGAGCATCTG3 ' R4903 : 5 'ACATTCACAAATTACGGAATGAATTGGGTGAGACAGGCACCTGGA
CAGGGACTCGAGTGGA3 ' R4904 : 5 ' CCTACGTACGCAGACGACTTCAAGGGAAGATTCACATTCACACTG
GAGACATCTGCATCTACAGCATACAT3 ' R4905 : 5 'CAGCAGTGTACTACTGTGCAAGAGACATTACAGCAGTGGTACCTA
CAGGATTCGACTACTGGGGACAGGGA3 ' R4897 : 5 'TGAGAGTGCACTCCTGTTGTCACAGACAGGAAGAACAGGAACACC
CAAGACCACTCCATGGTGGCGGCAAGCTTCCCCCC3 ' R4898 : 5 'CATTCCGTAATTTGTGAATGTGAATCCAGATGCCTTACAAGACAC
CTTCACAGATGCTCCAGGCTTCTTCA3 ' R4899 : 5 'GAAGTCGTCTGCGTACGTAGGCTCTCTTGTGTATGTATTAATCCA
TCCCATCCACTCGAGTCCCTGTCCAG3 '
R4900 : 5 'TTGCACAGTAGTACACTGCTGTGTCCTCAGATCTCAGAGAAGACA GCTCCATGTATGCTGTAGATGCAGAT3 ' R4901 : 5 'CCCCCCGGGCCCTTTGTAGAAGCAGAAGACACTGTCACCAGTGTT
CCCTGTCCCCAGTAGTCGAA3 '
The assembly reaction, 50 μl, contained 10 mM Tris-HCI pH 8.3, 1.5 mM MgCI2, 50 mM KCI, 0.01% w/v gelatin, 0.25 mM each deoxyribonucleoside triphosphate, 1 pmole of each Of R4897 - R4905, 10 pmoles of each of R3004 and R3005 and 2.5 units Taq polymerase. Reactions were cycled through 94 C for 1 minute, 55 C for 1 minute and 72 C for 1 minute. After 30 cycles, the reaction was extracted with phenol/chloroform (1/1), then with chloroform and precipitated with ethanol. After centrifugation, the DNA was dissolved in the appropriate restriction buffer and digested with HindIII and ApaI. The resulting fragment was isolated from an agarose gel and ligated into pMR14 (Figure 2) that had previously been digested with the same enzymes. pMR14 contains the human gamma 4 heavy chain constant region and so the heavy chain expressed from this vector will be a gamma 4 isotype. The ligation mixture was used to transform E. coli LM1035 and resulting bacterial colonies screened by restriction digest and nucieotide sequence analysis. In this way, a plasmid containing the correct sequence for L243gH was identified (Figure 24). Construction of Gamma 1 versions of chimeric and CDR grafted L243 heavy chain
Human Gamma 1 versions of L243 heavy chains were constructed by transferring the variable regions of both the murine and the CDR grafted heavy chains as HindIII to Apal fragments into the vector pGammal (Figure 6). This vector contains the human Gamma 1 heavy chain constant region.
Evaluation of activities of CDR grafted genes
The activities of the CDR grafted genes were evaluated by expressing them in mammalian cells and purifying and quantitating the newly synthesised antibodies. The methodology for this is described next,
followed by a description of the biochemical and cell based assays used for the biological characterisation of the antibodies. a) Gene Expression in CHO cells
Chimeric and CDR grafted L243 was produced for biological evaluation by transient expression of heavy and light chain pairs after co-transfection into Chinese Hamster Ovary (CHO) cells using calcium phosphate precipitation as described above for production of chimeric L243. Antibody concentration was determined using a human Ig ELISA (see below). b) ELISA
For the ELISA, Nunc ELISA plates were coated overnight at 4°C with a F(ab)2 fragment of a polyclonal goat anti-human Fc fragment specific antibody (Jackson Immuno-research, code 109-006-098) at 5 μg/ml in coating buffer (15mM sodium carbonate, 35mM sodium hydrogen carbonate, pH6.9). Uncoated antibody was removed by washing 5 times with distilled water. Samples and purified standards to be quantitated were diluted to approximately 1 μg/ml in conjugate buffer (0.1 M Tris-HCl pH7.0, 0.1M NaCI, 0.2% v/v Tween 20, 0,2% w/v Hammersten casein). The samples were titrated in the microtitre wells in 2-fold dilutions to give a final volume of 0.1 ml in each well and the plates incubated at room temperature for 1 hr with shaking. After the first incubation step the plates were washed 10 times with distilled water and then incubated for 1 hr as before with 0.1 ml of a mouse monoclonal anti-human kappa (clone GD12) peroxidase conjugated antibody (The Binding Site, code MP135) at a dilution of 1 in 700 in conjugate buffer. The plate was washed again and substrate solution (0.1 ml) added to each well. Substrate solution contained 150μl N,N,N,N-tetramethylbenzidine (10 mg/ml in DMSO), 150μl hydrogen peroxide (30% solution) in 10 ml 0.1 M sodium acetate/sodium citrate, pH6.0. The plate was developed for 5 -10 minutes until the absorbance at 630nm was approximately 1.0 for the top standard. Absorbance at 630nm was measured using a plate reader and the concentration of the sample determined by comparing the titration curves with those of the standard.
c) Competition Assay
The principle of this assay is that if the antigen binding region has been correctly transferred from the murine to human frameworks, then the CDR grafted antibody will compete equally well with a labelled chimeric antibody for binding to human MHC Class II. Any changes in the antigen binding potency will be revealed in this system.
Chimeric L243 was labelled with fluorescein (FITC) using the method of Wood et al [Wood.T., Thompson, S and Goldstein, G 1965, J. Immunol 95, 225-229 and used in the competition assay described above.
Figure 25 compares the ability of combinations of L243 heavy and light chains to compete with FITC-labelled chimeric L243 for binding to JY cells. All combinations were effective competitors although none of those containing CDR grafted heavy or light chains were as effective as the chimeric antibody itself. Thus, the combinations cH/gL1 , gH/cL and gH/gL1 were 89%, 78% and 64% respectively, as effective as chimeric L243 in this assay. d) Determination of Affinity constants by Scatchard Analysis
L243 antibodies were titrated from 10μg/ml in PBS, 5% fetal calf serum, 0.1% sodium azide in 1.5-fold dilutions (150μl each) before incubation with 5×104 JY cells per titration point for 1 hour on ice. The cells were previously counted, washed and resuspended in the same medium as the samples. After incubation, the cells were washed with 5ml of the above medium, spun down and the supernatant discarded. Bound antibody was revealed by addition of 100μl of a 1/100 dilution of FITC conjugated antihuman Fc monoclonal (The Binding Site; code MF001). The cells were then incubated for 1 hour on ice and then the excess FITC conjugate removed by washing as before. Cells were dispersed in 250μl of the same buffer and the median fluorescence intensity per cell was determined in a FACScan (Becton Dickinson) and calibrated using standard beads (Flow Cytometry standards Corporation). The number of molecules of antibody bound per cell at each antibody concentration was thus established and used to generate Scatchard plots. For the purpose of calculation, it was
assumed that the valency of binding of the FITC conjugate to L243 was 1:1 and that the F/P ratio was 3.36 (as given by the manufacturer).
A Scatchard plot comparing the affinities of chimeric L243 (cH/cL), L243-gH/L243-gL1 and L243-gH/L243-gL2 is shown in Figure 26. Chimeric L243 was found to have an apparent Kd of 4.1 nM while the CDR grafted antibodies containing gL1 and gL2 light chains had apparent Kd of 6.4nM and 9.6nM respectively. The difference in Kd values of the antibodies with the two CDR grafted light chains reflects the contribution made by residues 45,49,70 and 71 that had been retained, in L243-gL1, from the parent light chain. e) Antibody dependent cell mediated cytotoxicity
The ability of chimeric and CDR grafted L243 to mediate antibody dependent ceil cytotoxicity (ADCC) was compared as described previously. The principle of the experiment is that antibodies will mediate lysis of target cells bearing their cognate antigen if the Fc of the antibody is able to interact with Fc receptor bearing effector cells capable of cytotoxicity. A comparison of the activities of chimeric (cH/cL) and CDR grafted (gH/gL1) L243 human gamma 1 isotypes in the above assay is shown in Figure 27. Both antibodies were effective mediators of cell lysis with maximal activity being achieved at antibody concentrations of less than 100 ng/ml. There was no significant difference between the activities of the two antibodies. f) Immune function tests
Ex vivo T cell function experiments were performed where an interaction between MHC-II and the T cell receptor was an obligatory requirement for T cell activation. Chimeric and CDR grafted L243 antibodies were compared in mixed lymphocyte reactions, which measures both naive and memory T cell activation, and in recall responses to tetanus toxoid which only measures a memory T cell response.
1) Mixed Lymphocyte reaction - as described above
The principle of the experiment is that when leucocytes from one individual are mixed with those of another individual which express different HLA alleles, they will recognise each other as foreign and the lymphocytes will become activated. This activation is dependent primarily on interactions between the CD3/TcR complex on T cells and the MHC Class II molecule on antigen presenting cells. L243 is known to inhibit this reaction.
When an MLR was carried out to compare the effectiveness of the Gamma 1 isotypes of chimeric and CDR grafted L243 as inhibitors of T cell activation, no significant differences were observed between the two antibodies (Figure 28). Greater than 90% inhibition of the MLR was observed using 100 ng/ml of either antibody. 2) T cell recall response to Tetanus toxoid
The ability of chimeric and CDR grafted L243 to suppress a secondary response was assessed using a recall response to Tetanus toxin. The principle of the experiment is described above. The results of an experiment comparing the ability of human gamma 1 isotypes of chimeric and CDR grafted L243 to inhibit the response to TT is shown in Figure 29. Both antibodies were effective inhibitors of the T cell response to TT and produced titration curves that were indistinguishable. EXAMPLE 4
The ability of CDR grafted L243 with the alteration at position 235 i.e. L[235E] to mediate antibody dependent cell cytoxicity (ADCC) was measured essentially as described in the previous examples. The results are shown in Figure 27.
Similarly the CDR grafted L243 [L235E] antibody was tested in a mixed lymphocyte reaction and in recall response to tetanus toxoid essentially as described in the previous Examples. The results are provided in Figures 28 and 29.
The ability of the CDR-grafted L243 antibody [L235E] to fix human complement was assessed using the technique of antibody dependent complement mediated cytotoxicity as described in the previous Examples. The results are shown in Figure 30.
Claims (19)
1. An altered antibody wherein one or more amino acid residues in the N-terminal region of the CH2 domain of said antibody are altered characterised in that the ability of said antibody to fix complement is altered as compared to unaltered antibody.
2. An antibody according to Claim 2 which binds to one or more cellular Fc receptors and does not bind significantly to FcR1.
3. An antibody according to Claim 1 or 2 wherein the amino acid residue which is altered lies within amino acid positions 231 to 239.
4. An antibody according to any of the preceding claims which is an MHC specific antibody.
5. A method for producing an altered antibody with altered ability to fix complement as compared to unaltered antibody comprising altering one or more amino acids in the N-terminal region of the CH2 domain of said antibody altering the ability of said antibody to fix complement as compared with unaltered antibody.
6. A method of modulating the function of cell surface associated antigens avoiding complement mediated toxicity comprising administration of an altered antibody wherein one or more amino acid residues in the N-terminal region of the CH2 domain of said antibody are altered characterised in that the ability of said antibody to fix complement is altered as compared to unaltered antibody and also said antibody.
7. A method according to Claim 6 wherein said altered antibody is able to bind one or more cellular Fc receptors especially FcRIII while binding to FcRI is significantly reduced.
8. A therapeutic, diagnostic or pharmaceutical composition comprising an altered antibody according to any of the preceding claims.
9. A process for the preparation of a therapeutic, pharmaceutical or diagnostic composition comprising admixing an altered antibody according to any of the preceding claims together with a pharmaceutically acceptable excipient, diluent or carrier.
10. A method of therapy and diagnosis comprising administering an effective amount of an altered antibody according to any of the preceding claims to a human or animal subject.
11. A process for producing an altered antibody according to any of the preceding claims comprising:
a) producing in an expression vector an operon having a DNA sequence which encodes an antibody heavy or light chain
b) producing in an expression vector an operon having a DNA sequence which encodes a complementary antibody light or heavy chain
c) transfecting a host cell with both operons
and
d) culturing the transfected cell line to produce the antibody molecule.
12. A process according to Claim 11 wherein said DNA sequences encode a humanised antibody.
13. A process according to Claim 12 wherein said DNA sequences encode a CDR-grafted heavy and/or light chain, or a chimeric antibody
14. A process according to Claim 11 , 12 or 13 wherein at least one of the expression vectors contains a DNA sequence encoding an antibody heavy chain in which one or more amino acid residues in the N- terminal region of the CH2 domain has been altered from that in the corresponding unaltered antibody.
15. A process according to Claim 11 or 12 wherein the alteration in the N- terminal region of the CH2 domain is made after the unaltered antibody has been expressed.
16. An altered antibody according to any of the preceding claims derived from the anti-MHC antibody L243 (ATCC HB55).
17. An altered antibody according to any of the preceding claims wherein the lower hinge of said antibody has been exchanged with an antibody of different isotype.
18. An altered antibody according to Claim 17 wherein an lgG1 lower hinge region has been exchanged with a lgG2 lower hinge region.
19. A method of treating diseases in which antibody therapy leads to undesirable toxicity due to antibody mediated complement fixation comprising administering an altered antibody wherein one or more amino acid residues in the N-terminal region of the CH2 domain of said antibody are altered characterised in that the ability of said antibody to fix complement is altered as compared to unaltered antibody.
Applications Claiming Priority (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB939312415A GB9312415D0 (en) | 1993-06-16 | 1993-06-16 | Altered antibodies |
GB9312415 | 1993-06-16 | ||
GB9401597A GB9401597D0 (en) | 1994-01-27 | 1994-01-27 | Altered antibodies |
GB9401597 | 1994-01-27 | ||
GB9402499 | 1994-02-09 | ||
GB9402499A GB9402499D0 (en) | 1994-02-09 | 1994-02-09 | Altered abtibodies |
GB9406244A GB9406244D0 (en) | 1994-03-29 | 1994-03-29 | Altered antibodies |
GB9406244 | 1994-03-29 | ||
PCT/GB1994/001290 WO1994029351A2 (en) | 1993-06-16 | 1994-06-15 | Antibodies |
Publications (2)
Publication Number | Publication Date |
---|---|
AU6934194A true AU6934194A (en) | 1995-01-03 |
AU691811B2 AU691811B2 (en) | 1998-05-28 |
Family
ID=27451034
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU69341/94A Ceased AU691811B2 (en) | 1993-06-16 | 1994-06-15 | Antibodies |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0714409A1 (en) |
JP (1) | JPH08511420A (en) |
AU (1) | AU691811B2 (en) |
CA (1) | CA2163345A1 (en) |
WO (1) | WO1994029351A2 (en) |
Families Citing this family (1127)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4816567A (en) * | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
US5985599A (en) * | 1986-05-29 | 1999-11-16 | The Austin Research Institute | FC receptor for immunoglobulin |
US5824307A (en) | 1991-12-23 | 1998-10-20 | Medimmune, Inc. | Human-murine chimeric antibodies against respiratory syncytial virus |
CA2186455A1 (en) | 1994-03-29 | 1995-10-05 | Raymond John Owens | Antibodies against e-selectin |
US7803904B2 (en) | 1995-09-01 | 2010-09-28 | Millennium Pharmaceuticals, Inc. | Mucosal vascular addressing and uses thereof |
US7247302B1 (en) | 1996-08-02 | 2007-07-24 | Bristol-Myers Squibb Company | Method for inhibiting immunoglobulin-induced toxicity resulting from the use of immunoglobulins in therapy and in vivo diagnosis |
US7147851B1 (en) | 1996-08-15 | 2006-12-12 | Millennium Pharmaceuticals, Inc. | Humanized immunoglobulin reactive with α4β7 integrin |
US7179892B2 (en) | 2000-12-06 | 2007-02-20 | Neuralab Limited | Humanized antibodies that recognize beta amyloid peptide |
WO1999032659A1 (en) * | 1997-12-22 | 1999-07-01 | Stiftelsen Universitetsforskning Bergen (Unifob) | METHOD FOR DISEASE PROGNOSIS BASED ON Fc RECEPTOR GENOTYPING |
US6194551B1 (en) | 1998-04-02 | 2001-02-27 | Genentech, Inc. | Polypeptide variants |
US6242195B1 (en) | 1998-04-02 | 2001-06-05 | Genentech, Inc. | Methods for determining binding of an analyte to a receptor |
ATE375365T1 (en) * | 1998-04-02 | 2007-10-15 | Genentech Inc | ANTIBODIES VARIANTS AND FRAGMENTS THEREOF |
US6528624B1 (en) | 1998-04-02 | 2003-03-04 | Genentech, Inc. | Polypeptide variants |
GB9809951D0 (en) * | 1998-05-08 | 1998-07-08 | Univ Cambridge Tech | Binding molecules |
HUP0104865A3 (en) | 1999-01-15 | 2004-07-28 | Genentech Inc | Polypeptide variants with altered effector function |
US6737056B1 (en) | 1999-01-15 | 2004-05-18 | Genentech, Inc. | Polypeptide variants with altered effector function |
US7183387B1 (en) | 1999-01-15 | 2007-02-27 | Genentech, Inc. | Polypeptide variants with altered effector function |
EP1159300A2 (en) | 1999-02-12 | 2001-12-05 | Genetics Institute, Inc. | Humanized immunoglobulin reactive with b7 molecules and methods of treatment therewith |
US6972125B2 (en) | 1999-02-12 | 2005-12-06 | Genetics Institute, Llc | Humanized immunoglobulin reactive with B7-2 and methods of treatment therewith |
ES2528794T3 (en) | 2000-04-11 | 2015-02-12 | Genentech, Inc. | Multivalent antibodies and uses thereof |
AU5345901A (en) | 2000-04-13 | 2001-10-30 | Univ Rockefeller | Enhancement of antibody-mediated immune responses |
US20010046496A1 (en) | 2000-04-14 | 2001-11-29 | Brettman Lee R. | Method of administering an antibody |
AU4884001A (en) | 2000-04-21 | 2001-11-07 | Fuso Pharmaceutical Ind | Novel collectins |
DE60141463D1 (en) | 2000-06-08 | 2010-04-15 | Immune Disease Inst Inc | METHODS AND COMPOUNDS FOR INHIBITING IMMUNOGLOBULIN-MEDIATED REPERFUSION INJURIES |
EP2341060B1 (en) | 2000-12-12 | 2019-02-20 | MedImmune, LLC | Molecules with extended half-lives, compositions and uses thereof |
US7658921B2 (en) | 2000-12-12 | 2010-02-09 | Medimmune, Llc | Molecules with extended half-lives, compositions and uses thereof |
ATE382053T1 (en) | 2001-08-27 | 2008-01-15 | Genentech Inc | SYSTEM FOR ANTIBODIES EXPRESSION AND SYNTHESIS |
KR20050036852A (en) | 2001-10-15 | 2005-04-20 | 기린 비루 가부시키가이샤 | Anti-hla-dr-antibody |
US7053202B2 (en) | 2001-10-19 | 2006-05-30 | Millennium Pharmaceuticals, Inc. | Immunoglobulin DNA cassette molecules, monobody constructs, methods of production, and methods of use therefor |
US7662925B2 (en) | 2002-03-01 | 2010-02-16 | Xencor, Inc. | Optimized Fc variants and methods for their generation |
US8188231B2 (en) | 2002-09-27 | 2012-05-29 | Xencor, Inc. | Optimized FC variants |
US20040132101A1 (en) * | 2002-09-27 | 2004-07-08 | Xencor | Optimized Fc variants and methods for their generation |
US7317091B2 (en) | 2002-03-01 | 2008-01-08 | Xencor, Inc. | Optimized Fc variants |
US7132100B2 (en) | 2002-06-14 | 2006-11-07 | Medimmune, Inc. | Stabilized liquid anti-RSV antibody formulations |
US8946387B2 (en) | 2002-08-14 | 2015-02-03 | Macrogenics, Inc. | FcγRIIB specific antibodies and methods of use thereof |
US8530627B2 (en) | 2002-08-14 | 2013-09-10 | Macrogenics, Inc. | FcγRIIB specific antibodies and methods of use thereof |
US8187593B2 (en) | 2002-08-14 | 2012-05-29 | Macrogenics, Inc. | FcγRIIB specific antibodies and methods of use thereof |
US8968730B2 (en) | 2002-08-14 | 2015-03-03 | Macrogenics Inc. | FcγRIIB specific antibodies and methods of use thereof |
AU2003300829A1 (en) * | 2002-12-06 | 2004-09-09 | Diadexus, Inc. | Compositions, splice variants and methods relating to lung specific genes and proteins |
EP2368578A1 (en) | 2003-01-09 | 2011-09-28 | Macrogenics, Inc. | Identification and engineering of antibodies with variant Fc regions and methods of using same |
US7960512B2 (en) | 2003-01-09 | 2011-06-14 | Macrogenics, Inc. | Identification and engineering of antibodies with variant Fc regions and methods of using same |
US20090010920A1 (en) | 2003-03-03 | 2009-01-08 | Xencor, Inc. | Fc Variants Having Decreased Affinity for FcyRIIb |
US8084582B2 (en) | 2003-03-03 | 2011-12-27 | Xencor, Inc. | Optimized anti-CD20 monoclonal antibodies having Fc variants |
US8388955B2 (en) | 2003-03-03 | 2013-03-05 | Xencor, Inc. | Fc variants |
EP2184298A1 (en) | 2003-03-14 | 2010-05-12 | Wyeth a Corporation of the State of Delaware | Antibodies against human IL-21 receptor and uses therefor |
US9051373B2 (en) | 2003-05-02 | 2015-06-09 | Xencor, Inc. | Optimized Fc variants |
AU2008229860B2 (en) * | 2003-05-02 | 2012-01-12 | Xencor, Inc | Optimized Fc variants and methods for their generation |
US7700097B2 (en) | 2003-06-27 | 2010-04-20 | Biogen Idec Ma Inc. | Purification and preferential synthesis of binding molecules |
CN1871259A (en) | 2003-08-22 | 2006-11-29 | 比奥根艾迪克Ma公司 | Improved antibodies having altered effector function and methods for making the same |
US9714282B2 (en) | 2003-09-26 | 2017-07-25 | Xencor, Inc. | Optimized Fc variants and methods for their generation |
US8101720B2 (en) | 2004-10-21 | 2012-01-24 | Xencor, Inc. | Immunoglobulin insertions, deletions and substitutions |
JP2007521248A (en) | 2003-12-10 | 2007-08-02 | ミレニアム ファーマシューティカルズ, インコーポレイテッド | Humanized anti-CCR2 antibody and methods of using the antibody |
PL1691837T3 (en) | 2003-12-10 | 2012-11-30 | Squibb & Sons Llc | Ip-10 antibodies and their uses |
CA2546054C (en) | 2003-12-10 | 2014-05-13 | Medarex, Inc. | Interferon alpha antibodies and their uses |
PT1718677E (en) | 2003-12-19 | 2012-07-18 | Genentech Inc | Monovalent antibody fragments useful as therapeutics |
DE602005015542D1 (en) * | 2004-01-12 | 2009-09-03 | Applied Molecular Evolution | VARIANTS OF FC REGION |
JP5557982B2 (en) | 2004-03-01 | 2014-07-23 | イミューン ディズィーズ インスティテュート インコーポレイテッド | Natural IgM antibodies and inhibitors thereof |
CA2885854C (en) | 2004-04-13 | 2017-02-21 | F. Hoffmann-La Roche Ag | Anti-p-selectin antibodies |
AU2005244058B2 (en) | 2004-05-10 | 2011-07-28 | Macrogenics, Inc. | Humanized FcgammaRIIB specific antibodies and methods of use thereof |
CA2570823C (en) | 2004-06-21 | 2015-02-24 | Medarex, Inc. | Interferon alpha receptor 1 antibodies and their uses |
US20150010550A1 (en) | 2004-07-15 | 2015-01-08 | Xencor, Inc. | OPTIMIZED Fc VARIANTS |
EP1791563A4 (en) | 2004-07-26 | 2009-07-08 | Biogen Idec Inc | Anti-cd154 antibodies |
EA012464B1 (en) | 2004-08-04 | 2009-10-30 | Эпплайд Молекьюлар Эволюшн, Инк. | Antibody against cd20 and use thereof |
SI1773885T1 (en) | 2004-08-05 | 2010-08-31 | Genentech Inc | Humanized anti-cmet antagonists |
AU2005277567A1 (en) | 2004-08-16 | 2006-03-02 | Medimmune, Llc | Integrin antagonists with enhanced antibody dependent cell-mediated cytotoxicity activity |
RS57636B1 (en) | 2004-09-03 | 2018-11-30 | Genentech Inc | Humanized anti-beta7 antagonists and uses therefor |
US7632497B2 (en) | 2004-11-10 | 2009-12-15 | Macrogenics, Inc. | Engineering Fc Antibody regions to confer effector function |
CN102746404B (en) | 2004-11-12 | 2016-01-20 | 赞科股份有限公司 | To FcRn in conjunction with reformed Fc variant |
US8367805B2 (en) | 2004-11-12 | 2013-02-05 | Xencor, Inc. | Fc variants with altered binding to FcRn |
US8546543B2 (en) | 2004-11-12 | 2013-10-01 | Xencor, Inc. | Fc variants that extend antibody half-life |
US8802820B2 (en) | 2004-11-12 | 2014-08-12 | Xencor, Inc. | Fc variants with altered binding to FcRn |
ES2557325T5 (en) | 2004-12-28 | 2023-11-15 | Innate Pharma Sa | Monoclonal antibodies against NKG2A |
US7700099B2 (en) | 2005-02-14 | 2010-04-20 | Merck & Co., Inc. | Non-immunostimulatory antibody and compositions containing the same |
US20060233791A1 (en) | 2005-02-15 | 2006-10-19 | Duke University | Anti-CD19 antibodies and uses in oncology |
SG10201912554TA (en) | 2005-03-23 | 2020-02-27 | Genmab As | Antibodies against cd38 for treatment of multiple myeloma |
US9284375B2 (en) | 2005-04-15 | 2016-03-15 | Macrogenics, Inc. | Covalent diabodies and uses thereof |
CA2605024C (en) | 2005-04-15 | 2018-05-22 | Macrogenics, Inc. | Covalent diabodies and uses thereof |
US11254748B2 (en) | 2005-04-15 | 2022-02-22 | Macrogenics, Inc. | Covalent diabodies and uses thereof |
US9963510B2 (en) | 2005-04-15 | 2018-05-08 | Macrogenics, Inc. | Covalent diabodies and uses thereof |
CA2606102C (en) | 2005-04-26 | 2014-09-30 | Medimmune, Inc. | Modulation of antibody effector function by hinge domain engineering |
EP1885755A4 (en) | 2005-05-05 | 2009-07-29 | Univ Duke | Anti-cd19 antibody therapy for autoimmune disease |
LT2439273T (en) | 2005-05-09 | 2019-05-10 | Ono Pharmaceutical Co., Ltd. | Human monoclonal antibodies to programmed death 1(PD-1) and methods for treating cancer using anti-PD-1 antibodies alone or in combination with other immunotherapeutics |
WO2007094842A2 (en) | 2005-12-02 | 2007-08-23 | Genentech, Inc. | Binding polypeptides and uses thereof |
CN105330741B (en) | 2005-07-01 | 2023-01-31 | E.R.施贵宝&圣斯有限责任公司 | Human monoclonal antibodies to programmed death ligand 1 (PD-L1) |
AU2006265936A1 (en) | 2005-07-01 | 2007-01-11 | Medimmune, Llc | An integrated approach for generating multidomain protein therapeutics |
ES2530265T3 (en) | 2005-07-21 | 2015-02-27 | Genmab A/S | Binding potency assays of an antibody drug substance to an FC receptor |
SI2573114T1 (en) | 2005-08-10 | 2016-08-31 | Macrogenics, Inc. | Identification and engineering of antibodies with variant Fc regions and methods of using same |
EP1931709B1 (en) | 2005-10-03 | 2016-12-07 | Xencor, Inc. | Fc variants with optimized fc receptor binding properties |
CA2625998C (en) | 2005-10-06 | 2015-12-01 | Xencor, Inc. | Optimized anti-cd30 antibodies |
KR20080073293A (en) | 2005-10-14 | 2008-08-08 | 메디뮨 엘엘씨 | Cell display of antibody libraries |
EP2532679B1 (en) | 2005-10-21 | 2017-04-12 | Novartis AG | Human antibodies against il13 and therapeutic uses |
ES2577292T3 (en) | 2005-11-07 | 2016-07-14 | Genentech, Inc. | Binding polypeptides with diversified VH / VL hypervariable sequences and consensus |
CN105859886A (en) | 2005-12-02 | 2016-08-17 | 健泰科生物技术公司 | Compositions and methods associated with antibodies that bind to IL-22 and IL-22R |
PT1960434E (en) | 2005-12-08 | 2012-10-02 | Medarex Inc | Human monoclonal antibodies to fucosyl-gm1 and methods for using anti-fucosyl-gm1 |
US7763245B2 (en) | 2005-12-15 | 2010-07-27 | Genentech, Inc. | Methods and compositions for targeting polyubiquitin |
RU2450020C2 (en) | 2006-01-05 | 2012-05-10 | Дженентек, Инк. | ANTI-EphB4 ANTIBODIES AND METHODS OF USING SAID ANTIBODIES |
KR20140091765A (en) | 2006-01-12 | 2014-07-22 | 알렉시온 파마슈티칼스, 인코포레이티드 | Antibodies to ox-2/cd200 and uses thereof |
KR101617108B1 (en) | 2006-01-20 | 2016-04-29 | 제넨테크, 인크. | Anti-ephrinb2 antibodies and methods using same |
TWI417301B (en) | 2006-02-21 | 2013-12-01 | Wyeth Corp | Antibodies against human il-22 and uses therefor |
TW200744634A (en) | 2006-02-21 | 2007-12-16 | Wyeth Corp | Methods of using antibodies against human IL-22 |
EP2540741A1 (en) | 2006-03-06 | 2013-01-02 | Aeres Biomedical Limited | Humanized anti-CD22 antibodies and their use in treatment of oncology, transplantation and autoimmune disease |
AR059851A1 (en) | 2006-03-16 | 2008-04-30 | Genentech Inc | ANTIBODIES OF EGFL7 AND METHODS OF USE |
CA2648322C (en) | 2006-04-10 | 2017-11-28 | Genentech, Inc. | Disheveled pdz modulators |
WO2008105886A2 (en) | 2006-05-26 | 2008-09-04 | Macrogenics, Inc. | HUMANIZED FCγRIIB-SPECIFIC ANTIBODIES AND METHODS OF USE THEREOF |
AR060978A1 (en) | 2006-05-30 | 2008-07-23 | Genentech Inc | ANTIBODIES AND IMMUNOCATE PLAYERS AND THEIR USES |
AU2007319672B2 (en) | 2006-06-06 | 2011-06-30 | Genentech, Inc. | Anti-DLL4 antibodies and methods using same |
EP2032159B1 (en) | 2006-06-26 | 2015-01-07 | MacroGenics, Inc. | Combination of fcgammariib antibodies and cd20-specific antibodies and methods of use thereof |
LT2029173T (en) | 2006-06-26 | 2016-11-10 | Macrogenics, Inc. | Fc riib-specific antibodies and methods of use thereof |
DK2383297T5 (en) | 2006-08-14 | 2022-07-04 | Xencor Inc | Optimized antibodies directed against CD19 |
US20110182904A1 (en) | 2006-09-05 | 2011-07-28 | Deborah Zimmerman | Antibodies to bone morphogenic proteins and receptors therefor and methods for their use |
MX2009002414A (en) | 2006-09-08 | 2009-05-20 | Medimmune Llc | Humanized anti-cd19 antibodies and their use in treatment of oncology, transplantation and autoimmune disease. |
WO2008036688A2 (en) | 2006-09-18 | 2008-03-27 | Xencor, Inc. | Optimized antibodies that target hm1.24 |
SG178712A1 (en) | 2006-10-02 | 2012-03-29 | Medarex Inc | Human antibodies that bind cxcr4 and uses thereof |
WO2008060813A2 (en) | 2006-10-19 | 2008-05-22 | Merck & Co., Inc. | High affinity antibody antagonists of interleukin-13 receptor alpha 1 |
ES2388567T3 (en) | 2006-10-19 | 2012-10-16 | Csl Limited | Anti-il-13r alpha 1 antibodies and uses thereof |
SI2502938T1 (en) | 2006-10-27 | 2015-05-29 | Genentech, Inc. | Antibodies and immunoconjugates and uses therefor |
US8618248B2 (en) | 2006-10-31 | 2013-12-31 | President And Fellows Of Harvard College | Phosphopeptide compositions and anti-phosphopeptide antibody compositions and methods of detecting phosphorylated peptides |
EP2087001B1 (en) | 2006-11-02 | 2016-10-26 | Acceleron Pharma, Inc. | Alk1 receptor and ligand antagonists and uses thereof |
MX2009005189A (en) | 2006-11-15 | 2009-06-30 | Medarex Inc | Human monoclonal antibodies to btla and methods of use. |
MX2009005776A (en) | 2006-12-01 | 2009-06-10 | Medarex Inc | Human antibodies that bind cd22 and uses thereof. |
US8652466B2 (en) | 2006-12-08 | 2014-02-18 | Macrogenics, Inc. | Methods for the treatment of disease using immunoglobulins having Fc regions with altered affinities for FcγRactivating and FcγRinhibiting |
CL2007003622A1 (en) | 2006-12-13 | 2009-08-07 | Medarex Inc | Human anti-cd19 monoclonal antibody; composition comprising it; and tumor cell growth inhibition method. |
WO2008074004A2 (en) | 2006-12-14 | 2008-06-19 | Medarex, Inc. | Human antibodies that bind cd70 and uses thereof |
CA2676766A1 (en) | 2007-02-09 | 2008-08-21 | Genentech, Inc. | Anti-robo4 antibodies and uses therefor |
NZ580245A (en) | 2007-03-22 | 2012-01-12 | Biogen Idec Inc | Binding proteins, including antibodies, antibody derivatives and antibody fragments, that specifically bind cd154 and uses thereof |
US7960139B2 (en) | 2007-03-23 | 2011-06-14 | Academia Sinica | Alkynyl sugar analogs for the labeling and visualization of glycoconjugates in cells |
WO2008127656A1 (en) | 2007-04-12 | 2008-10-23 | The Brigham And Women's Hospital, Inc. | Targeting abcb5 for cancer therapy |
RU2549701C2 (en) | 2007-05-07 | 2015-04-27 | Медиммун, Ллк | Anti-icos antibodies and their application in treatment of oncological, transplantation-associated and autoimmune diseases |
EP1997830A1 (en) | 2007-06-01 | 2008-12-03 | AIMM Therapeutics B.V. | RSV specific binding molecules and means for producing them |
PE20090321A1 (en) | 2007-06-04 | 2009-04-20 | Genentech Inc | ANTI-NOTCH1 NRR ANTIBODIES, METHOD OF PREPARATION AND PHARMACEUTICAL COMPOSITION |
KR20100018040A (en) | 2007-06-06 | 2010-02-16 | 도만티스 리미티드 | Methods for selecting protease resistant polypeptides |
JP2010535032A (en) | 2007-07-31 | 2010-11-18 | メディミューン,エルエルシー | Multispecific epitope binding proteins and uses thereof |
CA2696164C (en) | 2007-08-13 | 2018-06-12 | Vasgene Therapeutics, Inc. | Cancer treatment using humanized antibodies that bind to ephb4 |
US8415455B2 (en) | 2007-09-04 | 2013-04-09 | Compugen Ltd | Polypeptides and polynucleotides, and uses thereof as a drug target for producing drugs and biologics |
CL2008002886A1 (en) | 2007-09-26 | 2009-12-04 | Chugai Pharmaceutical Co Ltd | Constant region of a human antibody; anti-interleukin-6 (yl-6) receptor antibody and pharmaceutical composition comprising it. |
AR068767A1 (en) | 2007-10-12 | 2009-12-02 | Novartis Ag | ANTIBODIES AGAINST SCLEROSTIN, COMPOSITIONS AND METHODS OF USE OF THESE ANTIBODIES TO TREAT A PATHOLOGICAL DISORDER MEDIATIONED BY SCLEROSTIN |
DK2567709T3 (en) | 2007-11-02 | 2018-03-12 | Novartis Ag | Molecules and Methods for Modulating Low-Density Lipoprotein Receptor-Related Protein 6 (LRP6) |
SI2514436T1 (en) | 2007-11-07 | 2018-04-30 | Genentech, Inc. | Il-22 for use in treating microbial disorders |
WO2015164330A1 (en) | 2014-04-21 | 2015-10-29 | Millennium Pharmaceuticals, Inc. | Anti-psyk antibody molecules and use of same for syk-targeted therapy |
AR069501A1 (en) | 2007-11-30 | 2010-01-27 | Genentech Inc | ANTI-VEGF ANTIBODIES (VASCULAR ENDOTELIAL GROWTH FACTOR) |
CN105001333B (en) | 2007-12-14 | 2019-05-17 | 诺沃—诺迪斯克有限公司 | Anti-human NKG2D antibody and application thereof |
US8795667B2 (en) | 2007-12-19 | 2014-08-05 | Macrogenics, Inc. | Compositions for the prevention and treatment of smallpox |
US8092804B2 (en) | 2007-12-21 | 2012-01-10 | Medimmune Limited | Binding members for interleukin-4 receptor alpha (IL-4Rα)-173 |
RU2490278C2 (en) | 2007-12-21 | 2013-08-20 | Медиммун Лимитед | ELEMENT BOUND WITH INTERLEUKIN-4 RECEPTOR α (IL-4Rα)-173 |
SI2808343T1 (en) | 2007-12-26 | 2019-10-30 | Xencor Inc | Fc variants with altered binding to FcRn |
CN101918555B (en) | 2008-01-11 | 2013-11-06 | 株式会社遗传科技 | Humanized anti-alpha9 integrin antibodies and the uses thereof |
US8039596B2 (en) | 2008-02-05 | 2011-10-18 | Bristol-Myers Squibb Company | Alpha 5-beta 1 antibodies and their uses |
CN101952454B (en) | 2008-02-08 | 2014-06-04 | 米迪缪尼有限公司 | Anti-IFNAR1 antibodies with reduced Fc ligand affinity |
ES2654937T3 (en) | 2008-04-02 | 2018-02-15 | Macrogenics, Inc. | Specific antibodies for the BCR complex and procedures for their use |
WO2009123894A2 (en) | 2008-04-02 | 2009-10-08 | Macrogenics, Inc. | Her2/neu-specific antibodies and methods of using same |
WO2009131256A1 (en) | 2008-04-24 | 2009-10-29 | Gene Techno Science Co., Ltd. | Humanized antibodies specific for amino acid sequence rgd of an extracellular matrix protein and the uses thereof |
TW201609138A (en) | 2008-05-02 | 2016-03-16 | 艾西利羅製藥公司 | Methods and compositions for modulating angiogenesis and pericyte composition |
JP5986745B2 (en) | 2008-07-15 | 2016-09-06 | アカデミア シニカAcademia Sinica | Glycan arrays on PTFE-like aluminum-coated glass slides and related methods |
US9182406B2 (en) | 2008-08-04 | 2015-11-10 | Biodesy, Inc. | Nonlinear optical detection of molecules comprising an unnatural amino acid possessing a hyperpolarizability |
EA027575B1 (en) | 2008-08-05 | 2017-08-31 | Новартис Аг | Antibody or antigen binding fragment thereof, binding human c5 protein, composition comprising same, nucleic acid encoding antibody or antigen binding fragment thereof, vector and host cell comprising said acid, and use of antibody or antigen binding fragment thereof |
AR072999A1 (en) | 2008-08-11 | 2010-10-06 | Medarex Inc | HUMAN ANTIBODIES THAT JOIN GEN 3 OF LYMPHOCYTARY ACTIVATION (LAG-3) AND THE USES OF THESE |
EP2927244A1 (en) | 2008-09-19 | 2015-10-07 | MedImmune, LLC | Antibodies directed to DLL4 and uses thereof |
US8298533B2 (en) | 2008-11-07 | 2012-10-30 | Medimmune Limited | Antibodies to IL-1R1 |
US20110293605A1 (en) | 2008-11-12 | 2011-12-01 | Hasige Sathish | Antibody formulation |
AU2009324037B2 (en) | 2008-12-05 | 2015-07-30 | Glaxo Group Limited | Methods for selecting protease resistant polypeptides |
AU2009325878B2 (en) | 2008-12-08 | 2014-01-16 | Compugen Ltd. | TMEM154 polypeptides and polynucleotides, and uses thereof as a drug target for producing drugs and biologics |
US8775090B2 (en) | 2008-12-12 | 2014-07-08 | Medimmune, Llc | Crystals and structure of a human IgG Fc variant with enhanced FcRn binding |
EP2379595A2 (en) | 2008-12-23 | 2011-10-26 | AstraZeneca AB | Targeted binding agents directed to 5 1 and uses thereof |
WO2010094720A2 (en) | 2009-02-19 | 2010-08-26 | Glaxo Group Limited | Improved anti-tnfr1 polypeptides, antibody variable domains & antagonists |
MX2011008843A (en) | 2009-02-23 | 2011-12-14 | Glenmark Pharmaceuticals Sa | Humanized antibodies that bind to cd19 and their uses. |
BRPI1009232B1 (en) | 2009-03-05 | 2022-05-03 | E.R. Squibb & Sons, Llc. | Isolated monoclonal antibody or an antigen-binding portion thereof, or an antibody fragment, composition comprising them, nucleic acid molecule, hybridoma and methods for preparing an anti-cadm1 antibody |
ES2572728T3 (en) | 2009-03-20 | 2016-06-02 | F. Hoffmann-La Roche Ag | Bispecific anti-HER antibodies |
CA2754163C (en) | 2009-03-25 | 2019-04-09 | Genentech, Inc. | Anti-fgfr3 antibodies and methods using same |
NZ594343A (en) | 2009-03-25 | 2013-10-25 | Genentech Inc | Novel anti-alpha5beta1 antibodies and uses thereof |
SG10201401604VA (en) | 2009-04-20 | 2014-08-28 | Oxford Biotherapeutics Ltd | Antibodies Specific To Cadherin-17 |
US9062116B2 (en) | 2009-04-23 | 2015-06-23 | Infinity Pharmaceuticals, Inc. | Anti-fatty acid amide hydrolase-2 antibodies and uses thereof |
MX2011011338A (en) | 2009-04-27 | 2012-04-19 | Novartis Ag | Composition and methods of use for therapeutic antibodies specific for the il-12 receptore betal subunit. |
JP5766179B2 (en) | 2009-04-27 | 2015-08-19 | ノバルティス アーゲー | Compositions and methods for increasing muscle growth |
EP2429582A4 (en) | 2009-05-13 | 2013-01-23 | Genzyme Corp | Anti-human cd52 immunoglobulins |
US10907209B2 (en) | 2009-05-15 | 2021-02-02 | University Health Network | Compositions and methods for treating hematological cancers targeting the SIRPα CD47 interaction |
US9676845B2 (en) | 2009-06-16 | 2017-06-13 | Hoffmann-La Roche, Inc. | Bispecific antigen binding proteins |
CA2765989C (en) | 2009-06-18 | 2016-11-29 | Pfizer Inc. | Anti notch-1 antibodies |
JP2012532619A (en) | 2009-07-16 | 2012-12-20 | グラクソ グループ リミテッド | Antagonists, uses and methods for partially inhibiting TNFR1 |
TW201106972A (en) | 2009-07-27 | 2011-03-01 | Genentech Inc | Combination treatments |
KR20120090037A (en) | 2009-07-31 | 2012-08-16 | 메다렉스, 인코포레이티드 | Fully human antibodies to btla |
WO2011021146A1 (en) | 2009-08-20 | 2011-02-24 | Pfizer Inc. | Osteopontin antibodies |
US9493578B2 (en) | 2009-09-02 | 2016-11-15 | Xencor, Inc. | Compositions and methods for simultaneous bivalent and monovalent co-engagement of antigens |
WO2011029823A1 (en) | 2009-09-09 | 2011-03-17 | Novartis Ag | Monoclonal antibody reactive with cd63 when expressed at the surface of degranulated mast cells |
US8568726B2 (en) | 2009-10-06 | 2013-10-29 | Medimmune Limited | RSV specific binding molecule |
US9096877B2 (en) | 2009-10-07 | 2015-08-04 | Macrogenics, Inc. | Fc region-containing polypeptides that exhibit improved effector function due to alterations of the extent of fucosylation, and methods for their use |
EP2470569A1 (en) | 2009-10-13 | 2012-07-04 | Oxford Biotherapeutics Ltd. | Antibodies against epha10 |
JP5889794B2 (en) | 2009-10-19 | 2016-03-22 | ジェネンテック, インコーポレイテッド | Regulation of hepatocyte growth factor activator |
NZ599337A (en) | 2009-10-22 | 2013-05-31 | Genentech Inc | Anti-hepsin antibodies and methods using same |
IN2012DN02604A (en) | 2009-10-23 | 2015-09-04 | Millennium Pharm Inc | |
WO2011056494A1 (en) | 2009-10-26 | 2011-05-12 | Genentech, Inc. | Activin receptor-like kinase-1 antagonist and vegfr3 antagonist combinations |
WO2011056502A1 (en) | 2009-10-26 | 2011-05-12 | Genentech, Inc. | Bone morphogenetic protein receptor type ii compositions and methods of use |
WO2011056497A1 (en) | 2009-10-26 | 2011-05-12 | Genentech, Inc. | Activin receptor type iib compositions and methods of use |
ES2552177T3 (en) | 2009-10-27 | 2015-11-26 | Glaxo Group Limited | Stable anti-TNFR1 polypeptides, variable domains of antibodies and antagonists |
JO3437B1 (en) | 2009-10-30 | 2019-10-20 | Esai R & D Man Co Ltd | Improved anti human Fraktalkine antibodies and uses thereof |
CN102782149B (en) | 2009-11-04 | 2014-11-12 | 默沙东公司 | Engineered anti-TSLP antibody |
RU2585488C2 (en) | 2009-11-05 | 2016-05-27 | Дженентек, Инк. | Methods and composition for secretion of heterologous polypeptides |
NZ599405A (en) | 2009-11-24 | 2014-09-26 | Medimmune Ltd | Targeted binding agents against b7-h1 |
US9428586B2 (en) | 2009-12-01 | 2016-08-30 | Compugen Ltd | Heparanase splice variant |
US10087236B2 (en) | 2009-12-02 | 2018-10-02 | Academia Sinica | Methods for modifying human antibodies by glycan engineering |
WO2011068993A1 (en) | 2009-12-02 | 2011-06-09 | Acceleron Pharma Inc. | Compositions and methods for increasing serum half-life of fc fusion proteins. |
US11377485B2 (en) | 2009-12-02 | 2022-07-05 | Academia Sinica | Methods for modifying human antibodies by glycan engineering |
TWI505836B (en) | 2009-12-11 | 2015-11-01 | Genentech Inc | Anti-vegf-c antibodies and methods using same |
CA2785139A1 (en) | 2009-12-22 | 2011-06-30 | Novartis Ag | Tetravalent cd47-antibody constant region fusion protein for use in therapy |
SI2516465T1 (en) | 2009-12-23 | 2016-08-31 | F. Hoffmann-La Roche Ag | Anti-bv8 antibodies and uses thereof |
US9023996B2 (en) * | 2009-12-23 | 2015-05-05 | Synimmune Gmbh | Anti-FLT3 antibodies |
AU2011203879A1 (en) | 2010-01-11 | 2012-08-02 | Alexion Pharmaceuticals, Inc. | Biomarkers of immunomodulatory effects in humans treated with anti-CD200 antibodies |
US8362210B2 (en) | 2010-01-19 | 2013-01-29 | Xencor, Inc. | Antibody variants with enhanced complement activity |
CN102933231B (en) | 2010-02-10 | 2015-07-29 | 伊缪诺金公司 | CD20 antibody and uses thereof |
MX2012009318A (en) | 2010-02-10 | 2012-09-07 | Novartis Ag | Methods and compounds for muscle growth. |
WO2011101328A2 (en) | 2010-02-18 | 2011-08-25 | Roche Glycart Ag | Treatment with a humanized igg class anti egfr antibody and an antibody against insulin like growth factor 1 receptor |
JP5981853B2 (en) | 2010-02-18 | 2016-08-31 | ジェネンテック, インコーポレイテッド | Neuregulin antagonists and their use in the treatment of cancer |
TW202348631A (en) | 2010-02-24 | 2023-12-16 | 美商免疫遺傳股份有限公司 | Folate receptor 1 antibodies and immunoconjugates and uses thereof |
US8802091B2 (en) | 2010-03-04 | 2014-08-12 | Macrogenics, Inc. | Antibodies reactive with B7-H3 and uses thereof |
ME03447B (en) | 2010-03-04 | 2020-01-20 | Macrogenics Inc | Antibodies reactive with b7-h3, immunologically active fragments thereof and uses thereof |
NZ602040A (en) | 2010-03-24 | 2014-12-24 | Genentech Inc | Anti-lrp6 antibodies |
US20150231215A1 (en) | 2012-06-22 | 2015-08-20 | Randolph J. Noelle | VISTA Antagonist and Methods of Use |
US10745467B2 (en) | 2010-03-26 | 2020-08-18 | The Trustees Of Dartmouth College | VISTA-Ig for treatment of autoimmune, allergic and inflammatory disorders |
US9631018B2 (en) | 2010-03-26 | 2017-04-25 | The Trustees Of Dartmouth College | Vista regulatory T cell mediator protein, vista binding agents and use thereof |
EP2371860A1 (en) | 2010-04-05 | 2011-10-05 | Fundació Privada Institut d'Investigació Oncològica de Vall d'Hebron | Antibody recognising human leukemia inhibitory factor (LIF) and use of anti-LIF antibodies in the treatment of diseases associated with unwanted cell proliferation |
WO2011130332A1 (en) | 2010-04-12 | 2011-10-20 | Academia Sinica | Glycan arrays for high throughput screening of viruses |
NZ629829A (en) | 2010-04-30 | 2015-11-27 | Alexion Pharma Inc | Anti-c5a antibodies and methods for using the antibodies |
ES2949159T3 (en) | 2010-05-06 | 2023-09-26 | Novartis Ag | Compositions and methods of use for low-density lipoprotein-related protein 6 (LRP6) therapeutic antibodies |
KR20130066631A (en) | 2010-05-06 | 2013-06-20 | 노파르티스 아게 | Compositions and methods of use for therapeutic low density lipoprotein - related protein 6 (lrp6) multivalent antibodies |
WO2011147834A1 (en) | 2010-05-26 | 2011-12-01 | Roche Glycart Ag | Antibodies against cd19 and uses thereof |
BR112012029866A2 (en) | 2010-06-03 | 2017-03-07 | Genentech Inc | method for determining the presence of a steap-1 protein |
RU2577986C2 (en) | 2010-06-18 | 2016-03-20 | Дженентек, Инк. | Antibodies against axl and their application |
WO2011161119A1 (en) | 2010-06-22 | 2011-12-29 | F. Hoffmann-La Roche Ag | Antibodies against insulin-like growth factor i receptor and uses thereof |
MX2012014975A (en) | 2010-06-22 | 2013-03-12 | Univ Colorado Regents | Antibodies to the c3d fragment of complement component 3. |
WO2011161189A1 (en) | 2010-06-24 | 2011-12-29 | F. Hoffmann-La Roche Ag | Anti-hepsin antibodies and methods of use |
NZ605449A (en) | 2010-07-09 | 2015-03-27 | Genentech Inc | Anti-neuropilin antibodies and methods of use |
WO2012010582A1 (en) | 2010-07-21 | 2012-01-26 | Roche Glycart Ag | Anti-cxcr5 antibodies and methods of use |
CA2807127C (en) | 2010-08-02 | 2019-02-12 | Leslie S. Johnson | Covalent diabodies and uses thereof |
CN103153341B (en) | 2010-08-03 | 2015-05-27 | 霍夫曼-拉罗奇有限公司 | Chronic lymphocytic leukemia (Cll) biomarkers |
CA2805564A1 (en) | 2010-08-05 | 2012-02-09 | Stefan Jenewein | Anti-mhc antibody anti-viral cytokine fusion protein |
SG187746A1 (en) | 2010-08-13 | 2013-03-28 | Roche Glycart Ag | Anti-fap antibodies and methods of use |
EP2603526A1 (en) | 2010-08-13 | 2013-06-19 | Medimmune Limited | Monomeric polypeptides comprising variant fc regions and methods of use |
BR112013002444A2 (en) | 2010-08-13 | 2016-05-24 | Roche Glycart Ag | isolated antibody, polynucleotide and polypeptide, composition, vector, host cell, antibody conjugate, pharmaceutical formulation, use of the antibody, methods of producing an antibody, treating an individual, inducing cell lysis of a tumor cell and diagnosing a disease in an individual |
WO2012022734A2 (en) | 2010-08-16 | 2012-02-23 | Medimmune Limited | Anti-icam-1 antibodies and methods of use |
CU24094B1 (en) | 2010-08-20 | 2015-04-29 | Novartis Ag | ANTIBODIES FOR THE RECEIVER 3 OF THE EPIDERMAL GROWTH FACTOR (HER3) |
CA2805054A1 (en) | 2010-08-25 | 2012-03-01 | F. Hoffmann-La Roche Ag | Antibodies against il-18r1 and uses thereof |
SG10201408229WA (en) | 2010-08-31 | 2015-02-27 | Genentech Inc | Biomarkers and methods of treatment |
WO2012035518A1 (en) | 2010-09-17 | 2012-03-22 | Compugen Ltd. | Compositions and methods for treatment of drug resistant multiple myeloma |
CN103154037A (en) | 2010-10-05 | 2013-06-12 | 诺瓦提斯公司 | Anti-IL 12 Rbeta 1 antibodies and their use in treating autoimmune and inflammatory disorders |
WO2012047968A2 (en) | 2010-10-05 | 2012-04-12 | Genentech, Inc. | Mutant smoothened and methods of using the same |
WO2012064836A1 (en) | 2010-11-10 | 2012-05-18 | Genentech, Inc. | Methods and compositions for neural disease immunotherapy |
CN103874707B (en) | 2010-11-19 | 2017-04-19 | 卫材R&D管理有限公司 | Neutralizing anti-CCL20 antibodies |
WO2012075581A1 (en) | 2010-12-06 | 2012-06-14 | Ym Biosciences Inc. | Antibodies selective for cells presenting erbb2 at high density |
KR20150088334A (en) | 2010-12-15 | 2015-07-31 | 와이어쓰 엘엘씨 | Anti-notch1 antibodies |
AU2011343570B2 (en) | 2010-12-16 | 2016-11-03 | Genentech, Inc. | Diagnosis and treatments relating to TH2 inhibition |
MX345519B (en) | 2010-12-20 | 2017-02-01 | Genentech Inc | Anti-mesothelin antibodies and immunoconjugates. |
MA34818B1 (en) | 2010-12-22 | 2014-01-02 | Genentech Inc | ANTI-PCSK9 ANTIBODIES AND METHODS OF USE |
WO2012092539A2 (en) | 2010-12-31 | 2012-07-05 | Takeda Pharmaceutical Company Limited | Antibodies to dll4 and uses thereof |
WO2012100346A1 (en) | 2011-01-24 | 2012-08-02 | Ym Biosciences Inc. | Antibodies selective for cells presenting egfr at high density |
CA2826453A1 (en) | 2011-02-03 | 2012-08-09 | Alexion Pharmaceuticals, Inc. | Use of an anti-cd200 antibody for prolonging the survival of allografts |
CN103403025B (en) | 2011-02-28 | 2016-10-12 | 弗·哈夫曼-拉罗切有限公司 | Monovalent antigen binding protein |
ES2549638T3 (en) | 2011-02-28 | 2015-10-30 | F. Hoffmann-La Roche Ag | Antigen binding proteins |
WO2012129347A1 (en) | 2011-03-21 | 2012-09-27 | Biodesy, Llc | Classification of kinase inhibitors using nonlinear optical techniques |
PT2691417T (en) | 2011-03-29 | 2018-10-31 | Roche Glycart Ag | Antibody fc variants |
HUE036172T2 (en) | 2011-04-01 | 2018-06-28 | Immunogen Inc | Methods for increasing efficacy of folr1 cancer therapy |
JP2014516511A (en) | 2011-04-07 | 2014-07-17 | ジェネンテック, インコーポレイテッド | Anti-FGFR4 antibody and method of use |
HUE033008T2 (en) | 2011-04-13 | 2017-11-28 | Bristol Myers Squibb Co | Fc fusion proteins comprising novel linkers or arrangements |
WO2012140627A1 (en) | 2011-04-15 | 2012-10-18 | Compugen Ltd. | Polypeptides and polynucleotides, and uses thereof for treatment of immune related disorders and cancer |
CA2833747C (en) | 2011-04-20 | 2022-10-18 | Asya Grinberg | Endoglin polypeptides and uses thereof |
WO2012146630A1 (en) | 2011-04-29 | 2012-11-01 | F. Hoffmann-La Roche Ag | N-terminal acylated polypeptides, methods for their production and uses thereof |
UA116189C2 (en) | 2011-05-02 | 2018-02-26 | Мілленніум Фармасьютікалз, Інк. | FORMULATION FOR ANTI-α4β7 ANTIBODY |
MX367097B (en) | 2011-05-02 | 2019-08-05 | Millennium Pharm Inc | FORMULATION FOR ANTI-a4ß7 ANTIBODY. |
JP5987053B2 (en) | 2011-05-12 | 2016-09-06 | ジェネンテック, インコーポレイテッド | Multiple reaction monitoring LC-MS / MS method for detecting therapeutic antibodies in animal samples using framework signature peptides |
DK2707391T3 (en) | 2011-05-13 | 2018-02-05 | Gamamabs Pharma | ANTIBODIES AGAINST HER3 |
WO2012158704A1 (en) | 2011-05-16 | 2012-11-22 | Genentech, Inc. | Fgfr1 agonists and methods of use |
KR102030531B1 (en) | 2011-05-21 | 2019-10-10 | 마크로제닉스, 인크. | Deimmunized serum-binding domains and their use for extending serum half-life |
EP2714738B1 (en) | 2011-05-24 | 2018-10-10 | Zyngenia, Inc. | Multivalent and monovalent multispecific complexes and their uses |
WO2012172495A1 (en) | 2011-06-14 | 2012-12-20 | Novartis Ag | Compositions and methods for antibodies targeting tem8 |
AR086924A1 (en) | 2011-06-15 | 2014-01-29 | Hoffmann La Roche | HUMAN EPO ANTI-RECEIVER ANTIBODIES AND THE METHODS FOR USE |
JP2014519338A (en) | 2011-06-16 | 2014-08-14 | ノバルティス アーゲー | Soluble proteins used as therapeutic agents |
EP2723376B1 (en) | 2011-06-22 | 2018-12-05 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Anti-axl antibodies and uses thereof |
CN103747803B (en) | 2011-06-22 | 2016-10-12 | 国家医疗保健研究所 | Anti-AXL antibodies and application thereof |
SG195077A1 (en) | 2011-06-22 | 2013-12-30 | Hoffmann La Roche | Removal of target cells by circulating virus-specific cytotoxic t-cells using mhc class i comprising complexes |
PE20140756A1 (en) | 2011-06-28 | 2014-07-04 | Oxford Biotherapeutics Ltd | ANTIBODIES THAT JOIN BST1 |
AU2012277376B2 (en) | 2011-06-30 | 2016-11-24 | Compugen Ltd. | Polypeptides and uses thereof for treatment of autoimmune disorders and infection |
WO2013003680A1 (en) | 2011-06-30 | 2013-01-03 | Genentech, Inc. | Anti-c-met antibody formulations |
ES2692519T3 (en) | 2011-07-01 | 2018-12-04 | Novartis Ag | Method to treat metabolic disorders |
LT2731677T (en) | 2011-07-11 | 2018-07-10 | Glenmark Pharmaceuticals S.A. | Antibodies that bind to ox40 and their uses |
WO2013010955A1 (en) | 2011-07-15 | 2013-01-24 | Morphosys Ag | Antibodies that are cross-reactive for macrophage migration inhibitory factor (mif) and d-dopachrome tautomerase (d-dt) |
MX2014001766A (en) | 2011-08-17 | 2014-05-01 | Genentech Inc | Neuregulin antibodies and uses thereof. |
US9309306B2 (en) | 2011-08-23 | 2016-04-12 | Roche Glycart Ag | Anti-MCSP antibodies |
KR20140068062A (en) | 2011-09-15 | 2014-06-05 | 제넨테크, 인크. | Methods of promoting differentiation |
MX2014002990A (en) | 2011-09-19 | 2014-05-21 | Genentech Inc | Combination treatments comprising c-met antagonists and b-raf antagonists. |
EP3628329B1 (en) | 2011-09-30 | 2022-08-10 | Dana-Farber Cancer Institute, Inc. | Therapeutic peptides comprising antibodies binding to mhc class 1 polypeptide related sequence a (mica) |
US9663573B2 (en) | 2011-10-05 | 2017-05-30 | Genentech, Inc. | Methods of treating liver conditions using Notch2 antagonists |
JP2014530816A (en) | 2011-10-14 | 2014-11-20 | ノバルティスアーゲー | Antibodies and methods for Wnt pathway related diseases |
MX2014004027A (en) | 2011-10-14 | 2014-04-30 | Genentech Inc | Zymogen activators. |
KR102102862B1 (en) | 2011-10-14 | 2020-04-22 | 제넨테크, 인크. | ANTI-HtrA1 ANTIBODIES AND METHODS OF USE |
KR20140084164A (en) | 2011-10-15 | 2014-07-04 | 제넨테크, 인크. | Scd1 antagonists for treating cancer |
WO2013059531A1 (en) | 2011-10-20 | 2013-04-25 | Genentech, Inc. | Anti-gcgr antibodies and uses thereof |
AU2012328980A1 (en) | 2011-10-28 | 2014-04-24 | Genentech, Inc. | Therapeutic combinations and methods of treating melanoma |
EP2776061B1 (en) | 2011-11-07 | 2019-08-14 | MedImmune, LLC | Multispecific and multivalent binding proteins and uses thereof |
BR112014012005A2 (en) | 2011-11-21 | 2017-12-19 | Genentech Inc | compositions, methods, pharmaceutical formulation and article |
EP2788382A2 (en) | 2011-12-05 | 2014-10-15 | Novartis AG | Antibodies for epidermal growth factor receptor 3 (her3) directed to domain ii of her3 |
CN104159924B (en) | 2011-12-05 | 2018-03-16 | 诺华股份有限公司 | The antibody of EGF-R ELISA 3 (HER3) |
EP2788024A1 (en) | 2011-12-06 | 2014-10-15 | F.Hoffmann-La Roche Ag | Antibody formulation |
WO2013101509A2 (en) | 2011-12-15 | 2013-07-04 | Alternative Innovative Technologies Llc | Hsp70 fusion protein conjugates and uses thereof |
PE20150159A1 (en) | 2011-12-21 | 2015-02-08 | Novartis Ag | COMPOSITIONS AND METHODS FOR ANTIBODIES ACTING ON THE P FACTOR |
AR089434A1 (en) | 2011-12-23 | 2014-08-20 | Genentech Inc | PROCEDURE TO PREPARE FORMULATIONS WITH HIGH CONCENTRATION OF PROTEINS |
WO2013106485A2 (en) | 2012-01-09 | 2013-07-18 | The Scripps Research Institute | Ultralong complementarity determining regions and uses thereof |
WO2013106489A1 (en) | 2012-01-09 | 2013-07-18 | The Scripps Research Institute | Humanized antibodies with ultralong cdr3s |
JP6242813B2 (en) | 2012-01-18 | 2017-12-06 | ジェネンテック, インコーポレイテッド | Anti-LRP5 antibody and method of use |
CN104168920A (en) | 2012-01-18 | 2014-11-26 | 霍夫曼-拉罗奇有限公司 | Methods of using FGF19 modulators |
AU2013216320A1 (en) | 2012-02-01 | 2014-04-03 | Compugen Ltd. | C10RF32 antibodies, and uses thereof for treatment of cancer |
BR112014019741A2 (en) | 2012-02-11 | 2020-12-22 | Genentech, Inc | USES OF AN ANTAGONIST OF THE WNT VIA, USE OF ANTI-CANCER THERAPY, METHOD OF IDENTIFICATION OF AN INDIVIDUAL WITH CANCER, METHODS FOR PREVENTING, METHOD OF INHIBITION OF A CANCER CELL PROLIFERATION, USE OF AN ANGONIST ANTAGONIST TRANSLOCATION OF ISOLATED R-SPONDINA |
JP6152120B2 (en) | 2012-02-15 | 2017-06-21 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | Affinity chromatography based on Fc receptors |
KR20140142293A (en) | 2012-03-16 | 2014-12-11 | 제넨테크, 인크. | Engineered conformationally-stabilized proteins |
US9139863B2 (en) | 2012-03-16 | 2015-09-22 | Genentech, Inc. | Engineered conformationally-stabilized proteins |
JP2015514710A (en) | 2012-03-27 | 2015-05-21 | ジェネンテック, インコーポレイテッド | Diagnosis and treatment of HER3 inhibitors |
AR090549A1 (en) | 2012-03-30 | 2014-11-19 | Genentech Inc | ANTI-LGR5 AND IMMUNOCATE PLAYERS |
MX356800B (en) | 2012-04-05 | 2018-06-13 | Ac Immune Sa | Humanized tau antibody. |
US10130714B2 (en) | 2012-04-14 | 2018-11-20 | Academia Sinica | Enhanced anti-influenza agents conjugated with anti-inflammatory activity |
CN106290917B (en) | 2012-04-25 | 2020-06-05 | 比奥德赛公司 | Method for detecting allosteric modulators of proteins |
US9156915B2 (en) | 2012-04-26 | 2015-10-13 | Thomas Jefferson University | Anti-GCC antibody molecules |
RU2014148162A (en) | 2012-05-01 | 2016-06-20 | Дженентек, Инк. | ANTI-PMEL17 ANTIBODIES AND THEIR IMMUNO CONJUGATES |
WO2013170191A1 (en) | 2012-05-11 | 2013-11-14 | Genentech, Inc. | Methods of using antagonists of nad biosynthesis from nicotinamide |
WO2013177470A1 (en) | 2012-05-23 | 2013-11-28 | Genentech, Inc. | Selection method for therapeutic agents |
ES2703540T3 (en) | 2012-06-04 | 2019-03-11 | Novartis Ag | Site-specific marking methods and molecules produced in this way |
US20130344064A1 (en) | 2012-06-08 | 2013-12-26 | Glenmark Pharmaceuticals S.A. | Anti-trka antibodies with enhanced inhibitory properties and derivatives thereof |
CN104364266A (en) | 2012-06-15 | 2015-02-18 | 霍夫曼-拉罗奇有限公司 | Anti-PCSK9 antibodies, formulations, dosing, and methods of use |
US9890215B2 (en) | 2012-06-22 | 2018-02-13 | King's College London | Vista modulators for diagnosis and treatment of cancer |
WO2014039983A1 (en) | 2012-09-07 | 2014-03-13 | The Trustees Of Dartmouth College | Vista modulators for diagnosis and treatment of cancer |
AR091649A1 (en) | 2012-07-02 | 2015-02-18 | Bristol Myers Squibb Co | OPTIMIZATION OF ANTIBODIES THAT FIX THE LYMPHOCYTE ACTIVATION GEN 3 (LAG-3) AND ITS USES |
MX353951B (en) | 2012-07-04 | 2018-02-07 | Hoffmann La Roche | Anti-theophylline antibodies and methods of use. |
ES2604012T3 (en) | 2012-07-04 | 2017-03-02 | F. Hoffmann-La Roche Ag | Covalently bound antigen-antibody conjugates |
CA2872192A1 (en) | 2012-07-04 | 2014-01-09 | F. Hoffmann-La Roche Ag | Anti-biotin antibodies and methods of use |
CN110042114A (en) | 2012-07-05 | 2019-07-23 | 弗·哈夫曼-拉罗切有限公司 | Expression and excretory system |
SG11201500087VA (en) | 2012-07-09 | 2015-02-27 | Genentech Inc | Immunoconjugates comprising anti-cd22 antibodies |
CA2874904A1 (en) | 2012-07-09 | 2014-01-16 | Genentech, Inc. | Immunoconjugates comprising anti-cd22 antibodies |
SG11201500096YA (en) | 2012-07-09 | 2015-02-27 | Genentech Inc | Immunoconjugates comprising anti - cd79b antibodies |
TW201408698A (en) | 2012-07-09 | 2014-03-01 | Genentech Inc | Anti-CD79b antibodies and immunoconjugates |
HUE056217T2 (en) | 2012-07-13 | 2022-02-28 | Roche Glycart Ag | Bispecific anti-vegf/anti-ang-2 antibodies and their use in the treatment of ocular vascular diseases |
US9334332B2 (en) | 2012-07-25 | 2016-05-10 | Kolltan Pharmaceuticals, Inc. | Anti-kit antibodies |
BR112015002263A2 (en) | 2012-08-02 | 2017-12-12 | Hoffmann La Roche | fusion polypeptide, dimeric fusion polypeptide, method for producing a soluble fc receptor, use of an immobilized fusion polypeptide and pharmaceutical composition |
AU2013306098A1 (en) | 2012-08-18 | 2015-02-12 | Academia Sinica | Cell-permeable probes for identification and imaging of sialidases |
NZ726258A (en) | 2012-08-31 | 2019-07-26 | Immunogen Inc | Antibodies and uses thereof to detect folate receptor 1 |
JOP20200308A1 (en) | 2012-09-07 | 2017-06-16 | Novartis Ag | IL-18 binding molecules |
CA2890207A1 (en) | 2012-11-05 | 2014-05-08 | Foundation Medicine, Inc. | Novel ntrk1 fusion molecules and uses thereof |
CA2884431A1 (en) | 2012-11-08 | 2014-05-15 | F. Hoffmann-La Roche Ag | Her3 antigen binding proteins binding to the beta-hairpin of her3 |
WO2014078268A2 (en) | 2012-11-13 | 2014-05-22 | Genentech, Inc. | Anti-hemagglutinin antibodies and methods of use |
EP2733153A1 (en) | 2012-11-15 | 2014-05-21 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for the preparation of immunoconjugates and uses thereof |
WO2014084859A1 (en) | 2012-11-30 | 2014-06-05 | Novartis Ag | Molecules and methods for modulating tmem16a activities |
AU2013355414B2 (en) | 2012-12-05 | 2017-02-02 | Novartis Ag | Compositions and methods for antibodies targeting EPO |
ES2780398T3 (en) | 2012-12-10 | 2020-08-25 | Biogen Ma Inc | Anti-blood dendritic cell antigen 2 antibody and use thereof |
DK3575326T3 (en) | 2012-12-17 | 2022-05-30 | Pf Argentum Ip Holdings Llc | Treatment of CD47 + disease cells with SIRP ALFA-FC fusions |
JP6475167B2 (en) | 2012-12-21 | 2019-02-27 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | Multifunctional protein containing disulfide-linked multivalent MHC class I |
PE20151289A1 (en) | 2013-01-02 | 2015-10-05 | Glenmark Pharmaceuticals Sa | ANTIBODIES THAT JOIN THE TL1A AND ITS USES |
WO2014107739A1 (en) | 2013-01-07 | 2014-07-10 | Eleven Biotherapeutics, Inc. | Antibodies against pcsk9 |
CA3150658A1 (en) | 2013-01-18 | 2014-07-24 | Foundation Medicine, Inc. | Methods of treating cholangiocarcinoma |
WO2014116749A1 (en) | 2013-01-23 | 2014-07-31 | Genentech, Inc. | Anti-hcv antibodies and methods of using thereof |
WO2014124258A2 (en) | 2013-02-08 | 2014-08-14 | Irm Llc | Specific sites for modifying antibodies to make immunoconjugates |
CN105143271A (en) | 2013-02-08 | 2015-12-09 | Irm责任有限公司 | Specific sites for modifying antibodies to make immunoconjugates |
SI2953969T1 (en) | 2013-02-08 | 2020-01-31 | Novartis Ag | Anti-il-17a antibodies and their use in treating autoimmune and inflammatory disorders |
EP2956468B1 (en) | 2013-02-12 | 2020-06-10 | Bristol-Myers Squibb Company | Tangential flow filtration based protein refolding methods |
WO2014126884A1 (en) | 2013-02-12 | 2014-08-21 | Bristol-Myers Squibb Company | High ph protein refolding methods |
JP2016509045A (en) | 2013-02-22 | 2016-03-24 | エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト | How to treat cancer and prevent drug resistance |
CA2896259A1 (en) | 2013-02-26 | 2014-09-04 | Roche Glycart Ag | Anti-mcsp antibodies |
US9487587B2 (en) | 2013-03-05 | 2016-11-08 | Macrogenics, Inc. | Bispecific molecules that are immunoreactive with immune effector cells of a companion animal that express an activating receptor and cells that express B7-H3 and uses thereof |
US9925240B2 (en) | 2013-03-06 | 2018-03-27 | Genentech, Inc. | Methods of treating and preventing cancer drug resistance |
US9498532B2 (en) | 2013-03-13 | 2016-11-22 | Novartis Ag | Antibody drug conjugates |
EP2968540A2 (en) | 2013-03-14 | 2016-01-20 | Genentech, Inc. | Combinations of a mek inhibitor compound with an her3/egfr inhibitor compound and methods of use |
CA2905070A1 (en) | 2013-03-14 | 2014-09-25 | Genentech, Inc. | Methods of treating cancer and preventing cancer drug resistance |
EP2970479B1 (en) | 2013-03-14 | 2019-04-24 | Novartis AG | Antibodies against notch 3 |
PL2968520T3 (en) | 2013-03-14 | 2022-01-03 | Macrogenics, Inc. | Bispecific molecules that are immunoreactive with immune effector cells that express an activating receptor |
WO2014159835A1 (en) | 2013-03-14 | 2014-10-02 | Genentech, Inc. | Anti-b7-h4 antibodies and immunoconjugates |
US9562099B2 (en) | 2013-03-14 | 2017-02-07 | Genentech, Inc. | Anti-B7-H4 antibodies and immunoconjugates |
AR095199A1 (en) | 2013-03-15 | 2015-09-30 | Genzyme Corp | ANTI-CD52 ANTIBODIES |
WO2014144791A2 (en) | 2013-03-15 | 2014-09-18 | Dana-Farber Cancer Institute, Inc. | Therapeutic peptides |
MX2015011899A (en) | 2013-03-15 | 2016-05-05 | Genentech Inc | Methods of treating cancer and preventing cancer drug resistance. |
CN105007950B (en) | 2013-03-15 | 2019-01-15 | 诺华股份有限公司 | Antibody drug conjugate |
BR112015021521A2 (en) | 2013-03-15 | 2017-10-10 | Genentech Inc | anti-crth2 antibodies and methods for their use |
TR201809571T4 (en) | 2013-03-15 | 2018-07-23 | Hoffmann La Roche | IL-22 polypeptides and IL-22 fc fusion proteins and methods of use. |
WO2014143739A2 (en) | 2013-03-15 | 2014-09-18 | Biogen Idec Ma Inc. | Anti-alpha v beta 6 antibodies and uses thereof |
WO2014144466A1 (en) | 2013-03-15 | 2014-09-18 | Biogen Idec Ma Inc. | Anti-alpha v beta 6 antibodies and uses thereof |
CA2903546A1 (en) | 2013-03-15 | 2014-09-25 | Biogen Ma Inc. | Treatment and prevention of acute kidney injury using anti-alpha v beta 5 antibodies |
JP6527132B2 (en) | 2013-03-15 | 2019-06-05 | ジェネンテック, インコーポレイテッド | Compositions and methods for diagnosis and treatment of liver cancer |
EA201890895A1 (en) | 2013-03-15 | 2019-02-28 | Зинджения, Инк. | MULTIVALENT AND MONOVALENT MULTIS-SPECIFIC COMPLEXES AND THEIR APPLICATION |
MX2015012872A (en) | 2013-03-15 | 2016-02-03 | Ac Immune Sa | Anti-tau antibodies and methods of use. |
EP2972373B1 (en) | 2013-03-15 | 2019-10-09 | F.Hoffmann-La Roche Ag | Biomarkers and methods of treating pd-1 and pd-l1 related conditions |
RU2687043C2 (en) | 2013-04-29 | 2019-05-06 | Ф. Хоффманн-Ля Рош Аг | Fc-RECEPTOR BINDING MODIFIED ASYMMETRIC ANTIBODIES AND METHODS OF USE |
EP2992012B1 (en) | 2013-04-29 | 2019-07-17 | F.Hoffmann-La Roche Ag | Human fcrn-binding modified antibodies and methods of use |
CN105164158A (en) | 2013-04-29 | 2015-12-16 | 豪夫迈·罗氏有限公司 | Fcrn-binding abolished ANTI-IGF-1R antibodies and their use in the treatment of vascular eye diseases |
EP2999716A2 (en) | 2013-05-20 | 2016-03-30 | F. Hoffmann-La Roche AG | Anti-transferrin receptor antibodies and methods of use |
WO2014186878A1 (en) | 2013-05-24 | 2014-11-27 | Cashman Neil R | Cell senescence markers as diagnostic and therapeutic targets |
UY35620A (en) | 2013-06-21 | 2015-01-30 | Novartis Ag | ANTIBODIES OF LEXINED OXIDATED LDL RECEIVER 1 AND METHODS OF USE |
AR096601A1 (en) | 2013-06-21 | 2016-01-20 | Novartis Ag | ANTIBODIES OF LEXINED OXIDATED LDL RECEIVER 1 AND METHODS OF USE |
US10086054B2 (en) | 2013-06-26 | 2018-10-02 | Academia Sinica | RM2 antigens and use thereof |
EP3013347B1 (en) | 2013-06-27 | 2019-12-11 | Academia Sinica | Glycan conjugates and use thereof |
EP3022224A2 (en) | 2013-07-18 | 2016-05-25 | Fabrus, Inc. | Antibodies with ultralong complementarity determining regions |
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 |
UA116479C2 (en) | 2013-08-09 | 2018-03-26 | Макродженікс, Інк. | Bi-specific monovalent fc diabodies that are capable of binding cd32b and cd79b and uses thereof |
US11384149B2 (en) | 2013-08-09 | 2022-07-12 | Macrogenics, Inc. | Bi-specific monovalent Fc diabodies that are capable of binding CD32B and CD79b and uses thereof |
CN105960414A (en) | 2013-08-14 | 2016-09-21 | 诺华股份有限公司 | Methods of treating sporadic inclusion body myositis |
CN116655801A (en) | 2013-08-22 | 2023-08-29 | 阿塞勒隆制药公司 | TGF-beta receptor type II variants and uses thereof |
EP2839842A1 (en) | 2013-08-23 | 2015-02-25 | MacroGenics, Inc. | Bi-specific monovalent diabodies that are capable of binding CD123 and CD3 and uses thereof |
EP2840091A1 (en) | 2013-08-23 | 2015-02-25 | MacroGenics, Inc. | Bi-specific diabodies that are capable of binding gpA33 and CD3 and uses thereof |
KR102585409B1 (en) | 2013-08-30 | 2023-10-05 | 이뮤노젠 아이엔씨 | Antibodies and assays for detection of folate receptor 1 |
CN105682666B (en) | 2013-09-06 | 2021-06-01 | 中央研究院 | Activation of human iNKT cells using glycolipids |
JP6623353B2 (en) | 2013-09-13 | 2019-12-25 | ベイジーン スウィッツァーランド ゲーエムベーハー | Anti-PD-1 antibodies and their use for therapy and diagnosis |
CN105518027A (en) | 2013-09-17 | 2016-04-20 | 豪夫迈·罗氏有限公司 | Methods of using anti-LGR5 antibodies |
BR112016006197B1 (en) | 2013-09-27 | 2023-04-11 | Chugai Seiyaku Kabushiki Kaisha | METHOD FOR PRODUCING A BISPECIFIC POLYPEPTIDE ANTIBODY |
KR102501920B1 (en) | 2013-10-02 | 2023-02-20 | 메디뮨 엘엘씨 | Neutralizing anti-influenza a antibodies and uses thereof |
KR20160068855A (en) | 2013-10-11 | 2016-06-15 | 제넨테크, 인크. | Nsp4 inhibitors and methods of use |
MX2016003593A (en) | 2013-10-11 | 2016-06-02 | Hoffmann La Roche | Multispecific domain exchanged common variable light chain antibodies. |
WO2015057939A1 (en) | 2013-10-18 | 2015-04-23 | Biogen Idec Ma Inc. | Anti-s1p4 antibodies and uses thereof |
MX2016004802A (en) | 2013-10-18 | 2016-07-18 | Genentech Inc | Anti-rsp02 and/or anti-rsp03 antibodies and their uses. |
RU2016119425A (en) | 2013-10-23 | 2017-11-28 | Дженентек, Инк. | METHODS FOR DIAGNOSIS AND TREATMENT OF EOSINOPHILIC DISEASES |
KR20220013459A (en) | 2013-10-25 | 2022-02-04 | 악셀레론 파마 인코포레이티드 | Endoglin peptides to treat fibrotic diseases |
CN105849125B (en) | 2013-11-07 | 2020-05-15 | 国家医疗保健研究所 | Neuregulin allosteric anti-HER 3 antibody |
CN104623637A (en) | 2013-11-07 | 2015-05-20 | 健能隆医药技术(上海)有限公司 | Application of IL-22 dimer in preparation of intravenous injection drugs |
AU2014351996B2 (en) | 2013-11-21 | 2020-01-02 | F. Hoffmann-La Roche Ag | Anti-alpha-synuclein antibodies and methods of use |
BR112016012358A2 (en) | 2013-12-06 | 2017-09-26 | Dana Farber Cancer Inst Inc | therapeutic peptides |
CN113861293A (en) | 2013-12-09 | 2021-12-31 | 爱乐科斯公司 | anti-Siglec-8 antibodies and methods of use thereof |
MA39095A1 (en) | 2013-12-13 | 2018-08-31 | Genentech Inc | Anti-cd33 antibodies and immunoconjugates |
US8980273B1 (en) | 2014-07-15 | 2015-03-17 | Kymab Limited | Method of treating atopic dermatitis or asthma using antibody to IL4RA |
CA2934028A1 (en) | 2013-12-17 | 2015-06-25 | Genentech, Inc. | Combination therapy comprising ox40 binding agonists and pd-1 axis binding antagonists |
DK3083689T3 (en) | 2013-12-17 | 2020-08-03 | Genentech Inc | Anti-CD3 antibodies and methods of use |
US8986691B1 (en) | 2014-07-15 | 2015-03-24 | Kymab Limited | Method of treating atopic dermatitis or asthma using antibody to IL4RA |
EP3083692B1 (en) | 2013-12-17 | 2020-02-19 | F.Hoffmann-La Roche Ag | Methods of treating her2-positive cancers using pd-1 axis binding antagonists and anti-her2 antibodies |
WO2015095410A1 (en) | 2013-12-17 | 2015-06-25 | Genentech, Inc. | Methods of treating cancer using pd-1 axis binding antagonists and an anti-cd20 antibody |
PL3083680T3 (en) | 2013-12-20 | 2020-06-29 | F. Hoffmann-La Roche Ag | Humanized anti-tau(ps422) antibodies and methods of use |
TWI728373B (en) | 2013-12-23 | 2021-05-21 | 美商建南德克公司 | Antibodies and methods of use |
CN106103476B (en) | 2013-12-24 | 2020-11-27 | 阿尔金克斯有限公司 | FcRn antagonists and methods of use |
US11014987B2 (en) | 2013-12-24 | 2021-05-25 | Janssen Pharmaceutics Nv | Anti-vista antibodies and fragments, uses thereof, and methods of identifying same |
PL3712174T3 (en) | 2013-12-24 | 2022-07-04 | Janssen Pharmaceutica Nv | Anti-vista antibodies and fragments |
EP3089996B1 (en) | 2014-01-03 | 2021-07-28 | 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 |
BR112016012666A2 (en) | 2014-01-03 | 2017-09-26 | Hoffmann La Roche | conjugate, antibodies, pharmaceutical formulation and uses of conjugate |
EP3092251B1 (en) | 2014-01-06 | 2021-01-20 | F. Hoffmann-La Roche AG | Monovalent blood brain barrier shuttle modules |
WO2015107026A1 (en) | 2014-01-15 | 2015-07-23 | F. Hoffmann-La Roche Ag | Fc-region variants with modified fcrn- and maintained protein a-binding properties |
US9982041B2 (en) | 2014-01-16 | 2018-05-29 | Academia Sinica | Compositions and methods for treatment and detection of cancers |
US10150818B2 (en) | 2014-01-16 | 2018-12-11 | Academia Sinica | Compositions and methods for treatment and detection of cancers |
WO2015112909A1 (en) | 2014-01-24 | 2015-07-30 | Genentech, Inc. | Methods of using anti-steap1 antibodies and immunoconjugates |
WO2015120075A2 (en) | 2014-02-04 | 2015-08-13 | Genentech, Inc. | Mutant smoothened and methods of using the same |
EP3718563A1 (en) | 2014-02-08 | 2020-10-07 | F. Hoffmann-La Roche AG | Methods of treating alzheimer's disease |
TW202239429A (en) | 2014-02-08 | 2022-10-16 | 美商建南德克公司 | Methods of treating alzheimer’s disease |
AU2015217271B2 (en) | 2014-02-12 | 2018-10-25 | Genentech, Inc. | Anti-Jagged1 antibodies and methods of use |
BR112016018980A2 (en) | 2014-02-21 | 2017-10-10 | Genentech Inc | method of treating a disorder, multispecific antibody, isolated nucleic acid, host cell, methods of producing an antibody, producing an antibody half or multispecific antibody, and producing a multispecific, immunoconjugate antibody and pharmaceutical formulation |
JP6825909B2 (en) | 2014-02-28 | 2021-02-03 | アラコス インコーポレイテッド | Methods and Compositions for Treating SIGLEC-8 Related Diseases |
NZ711451A (en) | 2014-03-07 | 2016-05-27 | Alexion Pharma Inc | Anti-c5 antibodies having improved pharmacokinetics |
KR20160125515A (en) | 2014-03-12 | 2016-10-31 | 노파르티스 아게 | Specific sites for modifying antibodies to make immunoconjugates |
EP3925973A1 (en) | 2014-03-14 | 2021-12-22 | Dana-Farber Cancer Institute, Inc. | Vaccine compositions and methods for restoring nkg2d pathway function against cancers |
MA39746A (en) | 2014-03-14 | 2021-04-28 | Hoffmann La Roche | HETEROLOGICAL POLYPEPTIDE SECRETION COMPOSITIONS AND ASSOCIATED PROCESSES |
WO2015140591A1 (en) | 2014-03-21 | 2015-09-24 | Nordlandssykehuset Hf | Anti-cd14 antibodies and uses thereof |
BR112016021383A2 (en) | 2014-03-24 | 2017-10-03 | Genentech Inc | METHOD TO IDENTIFY A PATIENT WITH CANCER WHO IS LIKE OR LESS LIKELY TO RESPOND TO TREATMENT WITH A CMET ANTAGONIST, METHOD TO IDENTIFY A PATIENT WITH PREVIOUSLY TREATED CANCER, METHOD TO DETERMINE THE EXPRESSION OF THE HGF BIOMARKER, ANTI-C-MET ANTAGONIST AND ITS USE, DIAGNOSTIC KIT AND ITS PREPARATION METHOD |
TWI687428B (en) | 2014-03-27 | 2020-03-11 | 中央研究院 | Reactive labelling compounds and uses thereof |
EP3632934A1 (en) | 2014-03-31 | 2020-04-08 | F. Hoffmann-La Roche AG | Anti-ox40 antibodies and methods of use |
WO2015153514A1 (en) | 2014-03-31 | 2015-10-08 | Genentech, Inc. | Combination therapy comprising anti-angiogenesis agents and ox40 binding agonists |
TW201622746A (en) | 2014-04-24 | 2016-07-01 | 諾華公司 | Methods of improving or accelerating physical recovery after surgery for hip fracture |
WO2015164615A1 (en) | 2014-04-24 | 2015-10-29 | University Of Oslo | Anti-gluten antibodies and uses thereof |
CA3225091A1 (en) | 2014-05-05 | 2015-11-12 | Regeneron Pharmaceuticals, Inc. | Humanized c5 and c3 animals |
MX2016015162A (en) | 2014-05-22 | 2017-03-03 | Genentech Inc | Anti-gpc3 antibodies and immunoconjugates. |
CN106661622B (en) | 2014-05-23 | 2020-08-21 | 豪夫迈·罗氏有限公司 | MIT biomarkers and methods of using the same |
US10118969B2 (en) | 2014-05-27 | 2018-11-06 | Academia Sinica | Compositions and methods relating to universal glycoforms for enhanced antibody efficacy |
EP3149161B1 (en) | 2014-05-27 | 2021-07-28 | Academia Sinica | Fucosidase from bacteroides and methods using the same |
CN106573971A (en) | 2014-05-27 | 2017-04-19 | 中央研究院 | Anti-CD20 glycoantibodies and uses thereof |
AU2015267045B2 (en) | 2014-05-27 | 2021-02-25 | Academia Sinica | Anti-HER2 glycoantibodies and uses thereof |
MA47849A (en) | 2014-05-28 | 2020-01-29 | Agenus Inc | ANTI-GITR ANTIBODIES AND THEIR METHODS OF USE |
TWI732738B (en) | 2014-05-28 | 2021-07-11 | 中央研究院 | Anti-tnf-alpha glycoantibodies and uses thereof |
EA037006B1 (en) | 2014-06-06 | 2021-01-26 | Бристол-Майерс Сквибб Компани | Antibodies against glucocorticoid-induced tumor necrosis factor receptor (gitr) and uses thereof |
JP2017526618A (en) | 2014-06-11 | 2017-09-14 | ジェネンテック, インコーポレイテッド | Anti-LgR5 antibody and use thereof |
MX2016016310A (en) | 2014-06-11 | 2017-10-20 | A Green Kathy | Use of vista agonists and antagonists to suppress or enhance humoral immunity. |
JP2017517552A (en) | 2014-06-13 | 2017-06-29 | ジェネンテック, インコーポレイテッド | Treatment and prevention of anticancer drug resistance |
EP3161001A2 (en) | 2014-06-25 | 2017-05-03 | Novartis AG | Antibodies specific for il-17a fused to hyaluronan binding peptide tags |
KR20170026362A (en) | 2014-06-26 | 2017-03-08 | 에프. 호프만-라 로슈 아게 | 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 |
JP6526189B2 (en) | 2014-07-03 | 2019-06-05 | ベイジーン リミテッド | Anti-PD-L1 antibodies and their use for therapy and diagnosis |
EP3166974A1 (en) | 2014-07-11 | 2017-05-17 | Genentech, Inc. | Anti-pd-l1 antibodies and diagnostic uses thereof |
EP3166627A1 (en) | 2014-07-11 | 2017-05-17 | Genentech, Inc. | Notch pathway inhibition |
BR112017001385B1 (en) | 2014-07-22 | 2023-12-05 | Cb Therapeutics, Inc. | ISOLATED ANTIBODY OR FRAGMENT THEREOF THAT BINDS PD-1, USE OF IT, COMPOSITION, ISOLATED POLYNUCLEOTIDE AND EXPRESSION VECTOR |
KR102476226B1 (en) | 2014-08-05 | 2022-12-12 | 아폴로믹스 인코포레이티드 | Anti-pd-l1 antibodies |
WO2016020791A1 (en) | 2014-08-05 | 2016-02-11 | Novartis Ag | Ckit antibody drug conjugates |
EP3194437B1 (en) | 2014-08-07 | 2021-01-20 | Novartis AG | Angiopoietin-like 4 (angptl4) antibodies and methods of use |
CN107148428B (en) | 2014-08-07 | 2021-03-09 | 诺华股份有限公司 | Angiopoietin-like protein 4 antibodies and methods of use |
TN2016000577A1 (en) | 2014-08-12 | 2018-04-04 | Novartis Ag | Anti-cdh6 antibody drug conjugates |
IL250583B (en) | 2014-08-19 | 2022-07-01 | Merck Sharp & Dohme | Anti-tigit antibodies |
JO3663B1 (en) | 2014-08-19 | 2020-08-27 | Merck Sharp & Dohme | Anti-lag3 antibodies and antigen-binding fragments |
AU2015308818B2 (en) | 2014-08-28 | 2021-02-25 | Bioatla Llc | Conditionally active chimeric antigen receptors for modified T-cells |
WO2016040369A2 (en) | 2014-09-08 | 2016-03-17 | Academia Sinica | HUMAN iNKT CELL ACTIVATION USING GLYCOLIPIDS |
US9751946B2 (en) | 2014-09-12 | 2017-09-05 | Genentech, Inc. | Anti-CLL-1 antibodies and immunoconjugates |
CA2957354A1 (en) | 2014-09-12 | 2016-03-17 | Genentech, Inc. | Cysteine engineered antibodies and conjugates |
EA201790545A1 (en) | 2014-09-12 | 2017-07-31 | Дженентек, Инк. | ANTIBODIES AND IMMUNOCONJUGATES AGAINST HER2 |
EP3191518B1 (en) | 2014-09-12 | 2020-01-15 | Genentech, Inc. | Anti-b7-h4 antibodies and immunoconjugates |
JP6730261B2 (en) | 2014-09-17 | 2020-07-29 | ジェネンテック, インコーポレイテッド | Immune complex containing anti-HER2 antibody |
PL3262071T3 (en) | 2014-09-23 | 2020-08-10 | F. Hoffmann-La Roche Ag | Method of using anti-cd79b immunoconjugates |
CN107108721B (en) | 2014-09-29 | 2021-09-07 | 杜克大学 | Bispecific molecules comprising an HIV-1 envelope targeting arm |
MA41044A (en) | 2014-10-08 | 2017-08-15 | Novartis Ag | COMPOSITIONS AND METHODS OF USE FOR INCREASED IMMUNE RESPONSE AND CANCER TREATMENT |
WO2016061389A2 (en) | 2014-10-16 | 2016-04-21 | Genentech, Inc. | Anti-alpha-synuclein antibodies and methods of use |
MA41480A (en) | 2014-10-17 | 2017-12-19 | Glenmark Pharmaceuticals Sa | ANTIBODIES BOUND TO CCR6 AND THEIR USES |
CA2966523A1 (en) | 2014-11-03 | 2016-05-12 | Genentech, Inc. | Assays for detecting t cell immune subsets and methods of use thereof |
CN114381521A (en) | 2014-11-03 | 2022-04-22 | 豪夫迈·罗氏有限公司 | Methods and biomarkers for efficacy prediction and assessment of OX40 agonist treatment |
CA2966558C (en) | 2014-11-05 | 2024-03-12 | Genentech, Inc. | Methods of producing two chain proteins in bacteria |
CA2961439A1 (en) | 2014-11-05 | 2016-05-12 | Genentech, Inc. | Anti-fgfr2/3 antibodies and methods using same |
RU2020141422A (en) | 2014-11-05 | 2021-01-13 | Дженентек, Инк. | METHODS FOR OBTAINING TWO-STRAIN PROTEINS IN BACTERIA |
RU2017119428A (en) | 2014-11-06 | 2018-12-06 | Дженентек, Инк. | COMBINED THERAPY, INCLUDING THE USE OF OX40-CONNECTING AGONISTS AND TIGIT INHIBITORS |
WO2016073157A1 (en) | 2014-11-06 | 2016-05-12 | Genentech, Inc. | Anti-ang2 antibodies and methods of use thereof |
CA2960797A1 (en) | 2014-11-06 | 2016-05-12 | F. Hoffmann-La Roche Ag | Fc-region variants with modified fcrn-binding and methods of use |
AR102522A1 (en) | 2014-11-06 | 2017-03-08 | Hoffmann La Roche | FC REGION VARIATIONS WITH MODIFIED PROPERTIES OF UNION TO FCRN AND PROTEIN A |
CR20170240A (en) | 2014-11-10 | 2018-04-03 | Genentech Inc | ANTI-INTERLEUCINA-33 ANTIBODIES AND THEIR USES |
EP3552488A1 (en) | 2014-11-10 | 2019-10-16 | F. Hoffmann-La Roche AG | Animal model for nephropathy and agents for treating the same |
JP6831783B2 (en) | 2014-11-14 | 2021-02-17 | ノバルティス アーゲー | Antibody drug conjugate |
WO2016081384A1 (en) | 2014-11-17 | 2016-05-26 | 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 |
US11008403B2 (en) | 2014-11-19 | 2021-05-18 | Genentech, Inc. | Anti-transferrin receptor / anti-BACE1 multispecific antibodies and methods of use |
WO2016081639A1 (en) | 2014-11-19 | 2016-05-26 | Genentech, Inc. | Antibodies against bace1 and use thereof for neural disease immunotherapy |
RS60631B1 (en) | 2014-11-21 | 2020-09-30 | Bristol Myers Squibb Co | Antibodies against cd73 and uses thereof |
EP3221346B1 (en) | 2014-11-21 | 2020-09-02 | Bristol-Myers Squibb Company | Antibodies comprising modified heavy constant regions |
US20170327584A1 (en) | 2014-11-26 | 2017-11-16 | Millennium Pharmaceuticals, Inc. | Vedolizumab for the Treatment of Fistulizing Crohn's Disease |
EP3227332B1 (en) | 2014-12-03 | 2019-11-06 | F.Hoffmann-La Roche Ag | Multispecific antibodies |
EP3226900A4 (en) | 2014-12-05 | 2018-09-19 | Immunext, Inc. | Identification of vsig8 as the putative vista receptor and its use thereof to produce vista/vsig8 modulators |
US9975949B2 (en) | 2014-12-05 | 2018-05-22 | Genentech, Inc. | Anti-CD79b antibodies and methods of use |
ES2764299T3 (en) | 2014-12-09 | 2020-06-02 | Inst Nat Sante Rech Med | Human monoclonal antibodies against AXL |
RU2017120039A (en) | 2014-12-10 | 2019-01-10 | Дженентек, Инк. | ANTIBODIES TO HEMATOENCEPHALIC BARRIER RECEPTORS AND METHODS OF APPLICATION |
PT3233912T (en) | 2014-12-19 | 2021-08-09 | Regenesance B V | Antibodies that bind human c6 and uses thereof |
RU2746356C2 (en) | 2014-12-19 | 2021-04-12 | Чугаи Сейяку Кабусики Кайся | C5 antibodies and their application methods |
UY36449A (en) | 2014-12-19 | 2016-07-29 | Novartis Ag | COMPOSITIONS AND METHODS FOR ANTIBODIES DIRECTED TO BMP6 |
TWI708786B (en) | 2014-12-23 | 2020-11-01 | 美商必治妥美雅史谷比公司 | Antibodies to tigit |
EP3237906B8 (en) | 2014-12-23 | 2020-10-28 | Bluelight Therapeutics, Inc. | Attachment of proteins to interfaces for use in nonlinear optical detection |
CA2973978A1 (en) | 2015-01-14 | 2016-07-21 | The Brigham And Women's Hospital, Inc. | Treatment of cancer with anti-lap monoclonal antibodies |
US10495645B2 (en) | 2015-01-16 | 2019-12-03 | Academia Sinica | Cancer markers and methods of use thereof |
US9975965B2 (en) | 2015-01-16 | 2018-05-22 | Academia Sinica | Compositions and methods for treatment and detection of cancers |
WO2016117346A1 (en) | 2015-01-22 | 2016-07-28 | Chugai Seiyaku Kabushiki Kaisha | A combination of two or more anti-c5 antibodies and methods of use |
EP3248005B1 (en) | 2015-01-24 | 2020-12-09 | Academia Sinica | Novel glycan conjugates and methods of use thereof |
WO2016118961A1 (en) | 2015-01-24 | 2016-07-28 | Academia Sinica | Cancer markers and methods of use thereof |
KR20170110129A (en) | 2015-02-05 | 2017-10-10 | 추가이 세이야쿠 가부시키가이샤 | Antibodies comprising ionic concentration dependent antigen binding domains, Fc region variants, antibodies that bind to IL-8, and their use |
US10550173B2 (en) | 2015-02-19 | 2020-02-04 | Compugen, Ltd. | PVRIG polypeptides and methods of treatment |
CN107580500B (en) | 2015-02-19 | 2023-05-30 | 康姆普根有限公司 | anti-PVRIG antibodies and methods of use |
WO2016135041A1 (en) | 2015-02-26 | 2016-09-01 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Fusion proteins and antibodies comprising thereof for promoting apoptosis |
MA41636A (en) | 2015-03-06 | 2018-01-09 | Millennium Pharm Inc | METHOD OF TREATMENT OF PRIMITIVE SCLEROSANT CHOLANGITIS |
JP2018509413A (en) | 2015-03-09 | 2018-04-05 | アルゲン−エックス ビーブイビーエー | Methods for reducing serum levels of Fc-containing agents using FcRn antagonists |
MX2017011486A (en) | 2015-03-16 | 2018-06-15 | 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 |
JP6903587B2 (en) | 2015-04-03 | 2021-07-14 | ユーリカ セラピューティックス, インコーポレイテッド | Constructs targeting AFP peptide / MHC complexes and their use |
CN107969128A (en) | 2015-04-17 | 2018-04-27 | 高山免疫科学股份有限公司 | Immune modulator with adjustable affinity |
JP7044553B2 (en) | 2015-04-24 | 2022-03-30 | ジェネンテック, インコーポレイテッド | How to identify bacteria containing bound 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 |
SG11201708804WA (en) | 2015-05-07 | 2017-11-29 | Agenus Inc | Anti-ox40 antibodies and methods of use thereof |
EP4238994A3 (en) | 2015-05-11 | 2024-02-07 | F. Hoffmann-La Roche AG | Compositions and methods of treating lupus nephritis |
ES2835866T3 (en) | 2015-05-12 | 2021-06-23 | Hoffmann La Roche | Therapeutic and diagnostic procedures for cancer |
WO2016188911A1 (en) | 2015-05-22 | 2016-12-01 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Human monoclonal antibodies fragments inhibiting both the cath-d catalytic activity and its binding to the lrp1 receptor |
EP3302563A1 (en) | 2015-05-29 | 2018-04-11 | H. Hoffnabb-La Roche Ag | Humanized anti-ebola virus glycoprotein antibodies and methods of use |
CA2987410A1 (en) | 2015-05-29 | 2016-12-08 | Bristol-Myers Squibb Company | Antibodies against ox40 and uses thereof |
KR20180012753A (en) | 2015-05-29 | 2018-02-06 | 제넨테크, 인크. | Treatment and Diagnosis Methods for Cancer |
CN107810012A (en) | 2015-06-02 | 2018-03-16 | 豪夫迈·罗氏有限公司 | Use the composition and method of the anti-Antybody therapy sacred diseases of IL 34 |
CN107849124B (en) | 2015-06-05 | 2021-09-24 | 基因泰克公司 | anti-TAU antibodies and methods of use |
PE20180041A1 (en) | 2015-06-05 | 2018-01-09 | Novartis Ag | ANTIBODIES TARGETING BONE MORPHOGENETIC PROTEIN (BMP9) AND METHODS FROM THESE |
EP3303399A1 (en) | 2015-06-08 | 2018-04-11 | H. Hoffnabb-La Roche Ag | Methods of treating cancer using anti-ox40 antibodies |
CA2988420A1 (en) | 2015-06-08 | 2016-12-15 | Genentech, Inc. | Methods of treating cancer using anti-ox40 antibodies and pd-1 axis binding antagonists |
JP2018524295A (en) | 2015-06-15 | 2018-08-30 | ジェネンテック, インコーポレイテッド | Antibodies and immune complexes |
WO2016204966A1 (en) | 2015-06-16 | 2016-12-22 | Genentech, Inc. | Anti-cd3 antibodies and methods of use |
CN107847568B (en) | 2015-06-16 | 2022-12-20 | 豪夫迈·罗氏有限公司 | anti-CLL-1 antibodies and methods of use |
TWI731861B (en) | 2015-06-16 | 2021-07-01 | 美商建南德克公司 | HUMANIZED AND AFFINITY MATURED ANTIBODIES TO FcRH5 AND METHODS OF USE |
MX2017016353A (en) | 2015-06-17 | 2018-05-02 | Genentech Inc | Methods of treating locally advanced or metastatic breast cancers using pd-1 axis binding antagonists and taxanes. |
WO2016203432A1 (en) | 2015-06-17 | 2016-12-22 | Novartis Ag | Antibody drug conjugates |
JP6846362B2 (en) | 2015-06-17 | 2021-03-24 | アラコス インコーポレイテッド | Methods and Compositions for Treating Fibrous Diseases |
JP2018524312A (en) | 2015-06-17 | 2018-08-30 | ジェネンテック, インコーポレイテッド | Anti-HER2 antibody and method of use |
JP7026509B2 (en) | 2015-06-24 | 2022-02-28 | ヤンセン ファーマシューティカ エヌブイ | Anti-VISTA antibody and fragment |
EP3313877B1 (en) | 2015-06-24 | 2020-06-03 | H. Hoffnabb-La Roche Ag | Humanized anti-tau(ps422) antibodies and methods of use |
DK3313879T3 (en) | 2015-06-24 | 2022-03-14 | Hoffmann La Roche | Anti-transferrin receptor antibodies with adapted affinity |
JOP20200312A1 (en) | 2015-06-26 | 2017-06-16 | Novartis Ag | Factor xi antibodies and methods of use |
JP2018520153A (en) | 2015-06-29 | 2018-07-26 | ジェネンテック, インコーポレイテッド | Type II anti-CD20 antibody for use in organ transplantation |
ES2898065T3 (en) | 2015-06-29 | 2022-03-03 | Ventana Med Syst Inc | Materials and Procedures for Performing Histochemical Assays for Human Proepiregulin and Amphiregulin |
CA2991980A1 (en) | 2015-07-13 | 2017-01-19 | Compugen Ltd. | Hide1 compositions and methods |
KR20180035852A (en) | 2015-08-03 | 2018-04-06 | 노파르티스 아게 | Methods for treating FGF21-associated disorders |
WO2017024171A1 (en) | 2015-08-04 | 2017-02-09 | 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 |
EP3341415B1 (en) | 2015-08-28 | 2021-03-24 | H. Hoffnabb-La Roche Ag | Anti-hypusine antibodies and uses thereof |
EA201890630A1 (en) | 2015-09-01 | 2018-10-31 | Эйдженус Инк. | ANTIBODIES AGAINST PD-1 AND METHODS OF THEIR APPLICATION |
RU2731644C2 (en) | 2015-09-09 | 2020-09-07 | Новартис Аг | Molecules binding to thymic stromal lymphopoietin (tslp), and methods of using such molecules |
US10000561B2 (en) | 2015-09-09 | 2018-06-19 | Novartis Ag | Thymic stromal lymphopoietin (TSLP)-binding molecules and methods of using the molecules |
US9862760B2 (en) | 2015-09-16 | 2018-01-09 | Novartis Ag | Polyomavirus neutralizing antibodies |
EP3349796A4 (en) | 2015-09-17 | 2019-05-29 | ImmunoGen, Inc. | Therapeutic combinations comprising anti-folr1 immunoconjugates |
CR20180217A (en) | 2015-09-18 | 2018-05-03 | Chugai Pharmaceutical Co Ltd | ANTIBODIES THAT JOIN INTERLEUCINE 8 (IL-8) AND ITS USES |
CA2999369C (en) | 2015-09-22 | 2023-11-07 | Spring Bioscience Corporation | Anti-ox40 antibodies and diagnostic uses thereof |
WO2017053807A2 (en) | 2015-09-23 | 2017-03-30 | Genentech, Inc. | Optimized variants of anti-vegf antibodies |
WO2017053906A1 (en) | 2015-09-24 | 2017-03-30 | Abvitro Llc | Hiv antibody compositions and methods of use |
AR106188A1 (en) | 2015-10-01 | 2017-12-20 | Hoffmann La Roche | ANTI-CD19 HUMANIZED HUMAN ANTIBODIES AND METHODS OF USE |
KR102146319B1 (en) | 2015-10-02 | 2020-08-25 | 에프. 호프만-라 로슈 아게 | Bispecific antibodies specific for PD1 and TIM3 |
AU2016329251B2 (en) | 2015-10-02 | 2023-02-02 | F. Hoffmann-La Roche Ag | Anti-PD1 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 |
CN114014936A (en) | 2015-10-02 | 2022-02-08 | 豪夫迈·罗氏有限公司 | Bispecific anti-human CD 20/human transferrin receptor antibodies and methods of use |
BR112018002570A2 (en) | 2015-10-02 | 2018-10-16 | Hoffmann La Roche | bispecific antigen binding molecule, bispecific antibody, polynucleotides, ox40-specific binding antibody, pharmaceutical composition and method for inhibiting tumor cell growth in an individual |
MA43345A (en) | 2015-10-02 | 2018-08-08 | Hoffmann La Roche | PYRROLOBENZODIAZEPINE ANTIBODY-DRUG CONJUGATES AND METHODS OF USE |
EP3150636A1 (en) | 2015-10-02 | 2017-04-05 | F. Hoffmann-La Roche AG | Tetravalent multispecific antibodies |
AU2016334623A1 (en) | 2015-10-07 | 2018-02-15 | F. Hoffmann-La Roche Ag | Bispecific antibodies with tetravalency for a costimulatory TNF receptor |
MA43354A (en) | 2015-10-16 | 2018-08-22 | Genentech Inc | CONJUGATE DRUG CONJUGATES WITH CLOUDY DISULPHIDE |
WO2017066714A1 (en) | 2015-10-16 | 2017-04-20 | Compugen Ltd. | Anti-vsig1 antibodies and drug conjugates |
MA45326A (en) | 2015-10-20 | 2018-08-29 | Genentech Inc | CALICHEAMICIN-ANTIBODY-DRUG CONJUGATES AND METHODS OF USE |
US10604577B2 (en) | 2015-10-22 | 2020-03-31 | Allakos Inc. | Methods and compositions for treating systemic mastocytosis |
JO3555B1 (en) | 2015-10-29 | 2020-07-05 | Merck Sharp & Dohme | Antibody neutralizing human respiratory syncytial virus |
MA44334A (en) | 2015-10-29 | 2018-09-05 | Novartis Ag | ANTIBODY CONJUGATES INCLUDING A TOLL-TYPE RECEPTOR AGONIST |
CN114891102A (en) | 2015-10-29 | 2022-08-12 | 豪夫迈·罗氏有限公司 | 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 |
EP3368074A2 (en) | 2015-10-30 | 2018-09-05 | Hoffmann-La Roche AG | Anti-factor d antibodies and conjugates |
HUE054093T2 (en) | 2015-10-30 | 2021-08-30 | Hoffmann La Roche | Anti-htra1 antibodies and methods of use thereof |
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 |
AU2016356780A1 (en) | 2015-11-19 | 2018-06-28 | Bristol-Myers Squibb Company | Antibodies against glucocorticoid-induced tumor necrosis factor receptor (GITR) and uses thereof |
WO2017095875A1 (en) | 2015-11-30 | 2017-06-08 | Bristol-Myers Squibb Company | Anti human ip-10 antibodies and their uses |
CN108883173B (en) | 2015-12-02 | 2022-09-06 | 阿吉纳斯公司 | Antibodies and methods of use thereof |
CA3006477A1 (en) | 2015-12-04 | 2017-06-08 | Novartis Ag | Antibody cytokine engrafted compositions and methods of use for immunoregulation |
WO2017106129A1 (en) | 2015-12-16 | 2017-06-22 | Merck Sharp & Dohme Corp. | Anti-lag3 antibodies and antigen-binding fragments |
CA3008102A1 (en) | 2015-12-18 | 2017-06-22 | Novartis Ag | Antibodies targeting cd32b and methods of use thereof |
PL3390442T3 (en) | 2015-12-18 | 2024-03-18 | Chugai Seiyaku Kabushiki Kaisha | Anti-c5 antibodies and methods of use |
EP3405478A4 (en) | 2015-12-23 | 2019-10-30 | Moonshot Pharma LLC | Methods for inducing an immune response by inhibition of nonsense mediated decay |
MX2018008347A (en) | 2016-01-08 | 2018-12-06 | Hoffmann La Roche | Methods of treating cea-positive cancers using pd-1 axis binding antagonists and anti-cea/anti-cd3 bispecific antibodies. |
WO2017127764A1 (en) | 2016-01-20 | 2017-07-27 | Genentech, Inc. | High dose treatments for alzheimer's disease |
CA3019952A1 (en) | 2016-02-04 | 2017-08-10 | Curis, Inc. | Mutant smoothened and methods of using the same |
CN116920085A (en) | 2016-02-12 | 2023-10-24 | 詹森药业有限公司 | anti-VISTA (B7H 5) antibodies |
CN109196121B (en) | 2016-02-29 | 2022-01-04 | 基因泰克公司 | Methods for treatment and diagnosis of cancer |
EA201891983A8 (en) | 2016-03-04 | 2020-05-28 | Бристол-Майерс Сквибб Компани | COMBINED THERAPY BY ANTIBODIES TO CD73 |
TW201808978A (en) | 2016-03-08 | 2018-03-16 | 中央研究院 | Methods for modular synthesis of N-glycans and arrays thereof |
AU2017234009A1 (en) | 2016-03-14 | 2018-09-27 | Millennium Pharmaceuticals, Inc. | Method of preventing graft versus host disease |
BR112018068625A2 (en) | 2016-03-14 | 2019-07-30 | Millennium Pharm Inc | methods of treating or preventing graft versus host disease |
TW202248213A (en) | 2016-03-15 | 2022-12-16 | 日商中外製藥股份有限公司 | Methods of treating cancers using pd-1 axis binding antagonists and anti-gpc3 antibodies |
EP3430034A1 (en) | 2016-03-16 | 2019-01-23 | Merrimack Pharmaceuticals, Inc. | Engineered trail for cancer therapy |
KR102640157B1 (en) | 2016-03-22 | 2024-02-27 | 인쎄름 (엥스띠뛰 나씨오날 드 라 쌍떼 에 드 라 흐쉐르슈 메디깔) | Humanized anti-claudin-1 antibodies and uses thereof |
TW201735949A (en) | 2016-03-24 | 2017-10-16 | 千禧製藥公司 | Methods of treating gastrointestinal immune-related adverse events in anti-CTLA4 anti-PD-1 combination treatments |
US11760803B2 (en) | 2016-03-24 | 2023-09-19 | Takeda Pharmaceutical Company Limited | Methods of treating gastrointestinal immune-related adverse events in immune oncology treatments |
JP6943872B2 (en) | 2016-03-25 | 2021-10-06 | ジェネンテック, インコーポレイテッド | Multiple whole antibody and antibody complex drug quantification assay |
WO2017180864A1 (en) | 2016-04-14 | 2017-10-19 | Genentech, Inc. | Anti-rspo3 antibodies and methods of use |
CN109328069B (en) | 2016-04-15 | 2023-09-01 | 亿一生物医药开发(上海)有限公司 | Use of IL-22 in the treatment of necrotizing enterocolitis |
ES2850428T3 (en) | 2016-04-15 | 2021-08-30 | Hoffmann La Roche | Cancer monitoring and treatment procedures |
KR20190006495A (en) | 2016-04-15 | 2019-01-18 | 알파인 이뮨 사이언시즈, 인코포레이티드 | CD80 variant immunoregulatory proteins and uses thereof |
KR20230051602A (en) | 2016-04-15 | 2023-04-18 | 알파인 이뮨 사이언시즈, 인코포레이티드 | Icos ligand variant immunomodulatory proteins and uses thereof |
JP2019515670A (en) | 2016-04-15 | 2019-06-13 | ジェネンテック, インコーポレイテッド | Methods for monitoring and treating cancer |
MY198114A (en) | 2016-04-15 | 2023-08-04 | Macrogenics Inc | Novel b7-h3-binding molecules, antibody drug conjugates thereof and methods of use thereof |
CA3021086C (en) | 2016-04-15 | 2023-10-17 | Bioatla, Llc | Anti-axl antibodies, antibody fragments and their immunoconjugates and uses thereof |
RU2021111187A (en) | 2016-04-15 | 2021-04-29 | Янссен Фармасьютикалз, Инк. | ANTIBODIES AGAINST HUMAN VISTA AND THEIR APPLICATION |
US11312766B2 (en) | 2016-04-27 | 2022-04-26 | Novartis Ag | Antibodies against growth differentiation factor 15 and uses thereof |
UA123323C2 (en) | 2016-05-02 | 2021-03-17 | Ф. Хоффманн-Ля Рош Аг | The contorsbody - a single chain target binder |
EP3455256A1 (en) | 2016-05-09 | 2019-03-20 | Bristol-Myers Squibb Company | Tl1a antibodies and uses thereof |
EP3455252B1 (en) | 2016-05-11 | 2022-02-23 | F. Hoffmann-La Roche AG | Modified anti-tenascin antibodies and methods of use |
SI3455261T1 (en) | 2016-05-13 | 2023-01-31 | 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 |
TW201802121A (en) | 2016-05-25 | 2018-01-16 | 諾華公司 | Reversal binding agents for anti-factor XI/XIa antibodies and uses thereof |
MX2018014387A (en) | 2016-05-27 | 2019-03-14 | Agenus Inc | Anti-tim-3 antibodies and methods of use thereof. |
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 |
EP3464280B1 (en) | 2016-06-06 | 2021-10-06 | F. Hoffmann-La Roche AG | Silvestrol antibody-drug conjugates and methods of use |
WO2017218434A1 (en) | 2016-06-12 | 2017-12-21 | Millennium Pharmaceuticals, Inc. | Method of treating inflammatory bowel disease |
WO2017216724A1 (en) | 2016-06-15 | 2017-12-21 | Novartis Ag | Methods for treating disease using inhibitors of bone morphogenetic protein 6 (bmp6) |
CN109563160B (en) | 2016-06-24 | 2023-02-28 | 豪夫迈·罗氏有限公司 | Anti-polyubiquitin multispecific antibodies |
WO2018007314A1 (en) | 2016-07-04 | 2018-01-11 | F. Hoffmann-La Roche Ag | Novel antibody format |
CN109475536B (en) | 2016-07-05 | 2022-05-27 | 百济神州有限公司 | Combination of a PD-l antagonist and a RAF inhibitor for the treatment of cancer |
JP7027401B2 (en) | 2016-07-14 | 2022-03-01 | ブリストル-マイヤーズ スクイブ カンパニー | Antibodies to TIM3 and its use |
WO2018014260A1 (en) | 2016-07-20 | 2018-01-25 | Nanjing Legend Biotech Co., Ltd. | Multispecific antigen binding proteins and methods of use thereof |
US20190330318A1 (en) | 2016-07-25 | 2019-10-31 | Biogen Ma Inc. | Anti-hspa5 (grp78) antibodies and uses thereof |
WO2018022945A1 (en) | 2016-07-28 | 2018-02-01 | Alpine Immune Sciences, Inc. | Cd112 variant immunomodulatory proteins and uses thereof |
US11471488B2 (en) | 2016-07-28 | 2022-10-18 | Alpine Immune Sciences, Inc. | CD155 variant immunomodulatory proteins and uses thereof |
CN110088127A (en) | 2016-07-28 | 2019-08-02 | 高山免疫科学股份有限公司 | CD155 variant immune modulator and application thereof |
NL2017267B1 (en) | 2016-07-29 | 2018-02-01 | Aduro Biotech Holdings Europe B V | Anti-pd-1 antibodies |
RU2019104730A (en) | 2016-07-29 | 2020-08-28 | Чугаи Сейяку Кабусики Кайся | BISPECIFIC ANTIBODY WITH INCREASED ACTIVITY, ALTERNATIVE FUNCTION OF COFACTOR FVIII |
NL2017270B1 (en) | 2016-08-02 | 2018-02-09 | Aduro Biotech Holdings Europe B V | New anti-hCTLA-4 antibodies |
CN109790223A (en) | 2016-08-05 | 2019-05-21 | 阿拉科斯有限责任公司 | Anti- SIGLEC-7 antibody for treating cancer |
CN116251182A (en) | 2016-08-05 | 2023-06-13 | 中外制药株式会社 | Compositions for preventing or treating IL-8 related diseases |
JP7250674B2 (en) | 2016-08-08 | 2023-04-03 | エフ・ホフマン-ラ・ロシュ・アクチェンゲゼルシャフト | CANCER TREATMENT AND DIAGNOSTIC METHOD |
WO2018031662A1 (en) | 2016-08-11 | 2018-02-15 | Genentech, Inc. | Pyrrolobenzodiazepine prodrugs and antibody conjugates thereof |
AU2017313085A1 (en) | 2016-08-19 | 2019-03-14 | Beigene Switzerland Gmbh | Use of a combination comprising a Btk inhibitor for treating cancers |
JP7213549B2 (en) | 2016-08-22 | 2023-01-27 | シーエイチオー ファーマ インコーポレイテッド | Antibodies, Binding Fragments, and Methods of Use |
WO2018044970A1 (en) | 2016-08-31 | 2018-03-08 | University Of Rochester | Human monoclonal antibodies to human endogenous retrovirus k envelope (herv-k) and uses thereof |
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 |
CN109689682B (en) | 2016-09-19 | 2022-11-29 | 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 |
JOP20190055A1 (en) | 2016-09-26 | 2019-03-24 | Merck Sharp & Dohme | Anti-cd27 antibodies |
CN110139674B (en) | 2016-10-05 | 2023-05-16 | 豪夫迈·罗氏有限公司 | Method for preparing antibody drug conjugates |
AU2017339517B2 (en) | 2016-10-06 | 2024-03-14 | Foundation Medicine, Inc. | Therapeutic and diagnostic methods for cancer |
TW202246349A (en) | 2016-10-11 | 2022-12-01 | 美商艾吉納斯公司 | Anti-lag-3 antibodies and methods of use thereof |
WO2018068201A1 (en) | 2016-10-11 | 2018-04-19 | Nanjing Legend Biotech Co., Ltd. | Single-domain antibodies and variants thereof against ctla-4 |
EP3532091A2 (en) | 2016-10-29 | 2019-09-04 | H. Hoffnabb-La Roche Ag | Anti-mic antibidies and methods of use |
CA3041340A1 (en) | 2016-11-09 | 2018-05-17 | Agenus Inc. | Anti-ox40 antibodies, anti-gitr antibodies, and methods of use thereof |
CN109996809A (en) | 2016-11-14 | 2019-07-09 | 诺华股份有限公司 | Composition relevant to fusogenic protein MINION, method and therapeutical uses |
AU2017361081A1 (en) | 2016-11-15 | 2019-05-23 | Genentech, Inc. | Dosing 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 |
JOP20190100A1 (en) | 2016-11-19 | 2019-05-01 | Potenza Therapeutics Inc | Anti-gitr antigen-binding proteins and methods of use thereof |
AU2017361887B2 (en) | 2016-11-21 | 2019-08-15 | Cureab Gmbh | Anti-GP73 antibodies and immunoconjugates |
JP7227146B2 (en) | 2016-11-23 | 2023-02-21 | バイオベラティブ セラピューティクス インコーポレイテッド | A bispecific antibody that binds to coagulation factor IX and coagulation factor X |
MX2019006340A (en) | 2016-12-07 | 2019-11-07 | Agenus Inc | Anti-ctla-4 antibodies and methods of use thereof. |
CA3046082A1 (en) | 2016-12-07 | 2018-06-14 | Agenus Inc. | Antibodies and methods of use thereof |
CR20230163A (en) | 2016-12-07 | 2023-07-06 | Genentech Inc | Anti-tau antibodies and methods of use |
AU2017373884A1 (en) | 2016-12-07 | 2019-05-30 | Ac Immune Sa | Anti-tau antibodies and methods of their use |
EP3551663A1 (en) | 2016-12-12 | 2019-10-16 | H. Hoffnabb-La Roche Ag | Methods of treating cancer using anti-pd-l1 antibodies and antiandrogens |
US10583191B2 (en) | 2016-12-19 | 2020-03-10 | Mosaic Biomedicals Slu | Antibodies against LIF and uses thereof |
BR112019012691A2 (en) | 2016-12-19 | 2019-11-19 | Fundacio Privada Inst Catalana De Recerca I Estudis Avancats | antibodies against lif and its uses |
EP3559034B1 (en) | 2016-12-20 | 2020-12-02 | H. Hoffnabb-La Roche Ag | Combination therapy of anti-cd20/anti-cd3 bispecific antibodies and 4-1bb (cd137) agonists |
JOP20190134A1 (en) | 2016-12-23 | 2019-06-02 | Potenza Therapeutics Inc | Anti-neuropilin antigen-binding proteins and methods of use thereof |
EP3559047A1 (en) | 2016-12-23 | 2019-10-30 | Novartis AG | Factor xi antibodies and methods of use |
BR112019013189A2 (en) | 2017-01-03 | 2019-12-10 | Hoffmann La Roche | bispecific antigen binding molecules, polynucleotide, host cell, bispecific antigen binding molecule production method, pharmaceutical composition, use, methods for inhibiting tumor cell growth in an individual and for treating cancer or an infectious disease |
TW201825515A (en) | 2017-01-04 | 2018-07-16 | 美商伊繆諾金公司 | Met antibodies and immunoconjugates and uses thereof |
US20180244785A1 (en) | 2017-01-09 | 2018-08-30 | Merrimack Pharmaceuticals, Inc. | Anti-fgfr antibodies and methods of use |
TW201831517A (en) | 2017-01-12 | 2018-09-01 | 美商優瑞科生物技術公司 | Constructs targeting histone h3 peptide/mhc complexes and uses thereof |
CN110461847B (en) | 2017-01-25 | 2022-06-07 | 百济神州有限公司 | Crystalline forms of (S) -7- (1- (but-2-alkynoyl) piperidin-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide, preparation and use thereof |
EP4223774A3 (en) | 2017-01-31 | 2023-09-27 | Chugai Seiyaku Kabushiki Kaisha | A pharmaceutical composition for use in the treatment or prevention of a c5-related disease and a method for treating or preventing a c5-related disease |
JOP20190187A1 (en) | 2017-02-03 | 2019-08-01 | Novartis Ag | Anti-ccr7 antibody drug conjugates |
CA3052911A1 (en) | 2017-02-08 | 2018-08-16 | Novartis Ag | Fgf21 mimetic antibodies and uses thereof |
AR110873A1 (en) | 2017-02-10 | 2019-05-08 | Genentech Inc | ANTIBODIES AGAINST TRIPTASE, COMPOSITIONS OF THESE AND USES OF THESE |
EP3583124A1 (en) | 2017-02-17 | 2019-12-25 | Bristol-Myers Squibb Company | Antibodies to alpha-synuclein and uses thereof |
AU2018225745B2 (en) | 2017-02-27 | 2023-12-07 | Regeneron Pharmaceuticals, Inc. | Humanized model of kidney and liver disorders |
TW201837467A (en) | 2017-03-01 | 2018-10-16 | 美商建南德克公司 | Diagnostic and therapeutic methods for cancer |
WO2018158398A1 (en) | 2017-03-02 | 2018-09-07 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Antibodies having specificity to nectin-4 and uses thereof |
US11732022B2 (en) | 2017-03-16 | 2023-08-22 | Alpine Immune Sciences, Inc. | PD-L2 variant immunomodulatory proteins and uses thereof |
EP3596116B1 (en) | 2017-03-16 | 2023-09-06 | Alpine Immune Sciences, Inc. | Pd-l1 variant immunomodulatory proteins and uses thereof |
AU2018235838B2 (en) | 2017-03-16 | 2023-12-14 | Alpine Immune Sciences, Inc. | CD80 variant immunomodulatory proteins and uses thereof |
MX2019011141A (en) | 2017-03-22 | 2019-11-05 | Genentech Inc | Optimized antibody compositions for treatment of ocular disorders. |
AU2018240117A1 (en) | 2017-03-24 | 2019-09-19 | Beth Israel Deaconess Medical Center, Inc. | Methods for preventing and treating heart disease |
TW202400231A (en) | 2017-03-28 | 2024-01-01 | 美商建南德克公司 | Methods of treating neurodegenerative diseases |
CN110382542B (en) | 2017-03-29 | 2023-06-09 | 豪夫迈·罗氏有限公司 | Bispecific antigen binding molecules to costimulatory TNF receptors |
CN110573528B (en) | 2017-03-29 | 2023-06-09 | 豪夫迈·罗氏有限公司 | Bispecific antigen binding molecules to costimulatory TNF receptors |
JOP20190203A1 (en) | 2017-03-30 | 2019-09-03 | Potenza Therapeutics Inc | Anti-tigit antigen-binding proteins and methods of use thereof |
WO2018185618A1 (en) | 2017-04-03 | 2018-10-11 | Novartis Ag | Anti-cdh6 antibody drug conjugates and anti-gitr antibody combinations and methods of treatment |
BR112019017753A2 (en) | 2017-04-04 | 2020-04-07 | Hoffmann La Roche | bispecific molecule, polynucleotide, vector, cell, methods for the production of a molecule and for the treatment of an individual, composition and use of the bispecific molecule |
KR102346336B1 (en) | 2017-04-05 | 2022-01-04 | 에프. 호프만-라 로슈 아게 | Bispecific antibodies that specifically bind to PD1 and LAG3 |
MX2019011916A (en) | 2017-04-05 | 2020-01-09 | Hoffmann La Roche | Anti-lag3 antibodies. |
TWI796329B (en) | 2017-04-07 | 2023-03-21 | 美商默沙東有限責任公司 | Anti-ilt4 antibodies and antigen-binding fragments |
AU2018252546A1 (en) | 2017-04-13 | 2019-10-10 | Sairopa B.V. | Anti-SIRPα antibodies |
BR112019017241A2 (en) | 2017-04-13 | 2020-04-14 | Agenus Inc | anti-cd137 antibodies and methods of using them |
MX2019012192A (en) | 2017-04-14 | 2020-01-21 | Genentech Inc | Diagnostic and therapeutic methods for cancer. |
JP7248588B2 (en) | 2017-04-21 | 2023-03-29 | ジェネンテック, インコーポレイテッド | Use of KLK5 antagonists for the treatment of disease |
WO2018200586A1 (en) | 2017-04-26 | 2018-11-01 | Eureka Therapeutics, Inc. | Constructs specifically recognizing glypican 3 and uses thereof |
US20220135670A1 (en) | 2017-04-27 | 2022-05-05 | Tesaro, Inc. | Antibody agents directed against lymphocyte activation gene-3 (lag-3) and uses thereof |
AR111651A1 (en) | 2017-04-28 | 2019-08-07 | Novartis Ag | CONJUGATES OF ANTIBODIES THAT INCLUDE TOLL TYPE RECEIVER AGONISTS AND COMBINATION THERAPIES |
BR112019022268A2 (en) | 2017-04-28 | 2020-05-19 | Millennium Pharm Inc | method for the treatment of pediatric disorders |
EP3618863B1 (en) | 2017-05-01 | 2023-07-26 | Agenus Inc. | Anti-tigit antibodies and methods of use thereof |
WO2018204594A1 (en) | 2017-05-04 | 2018-11-08 | Acceleron Pharma Inc. | Tgf-beta receptor type ii fusion proteins and uses thereof |
MX2019013137A (en) | 2017-05-05 | 2020-07-14 | Allakos Inc | Methods and compositions for treating allergic ocular diseases. |
CN111094335B (en) | 2017-05-15 | 2022-08-23 | 罗切斯特大学 | Broadly neutralizing anti-influenza monoclonal antibodies and uses thereof |
JOP20190271A1 (en) | 2017-05-24 | 2019-11-21 | Novartis Ag | Antibody-cytokine engrafted proteins and methods of use for immune related disorders |
US20200270334A1 (en) | 2017-05-24 | 2020-08-27 | Novartis Ag | Antibody-cytokine engrafted proteins and methods of use in the treatment of cancer |
US20200362058A1 (en) | 2017-05-24 | 2020-11-19 | Novartis Ag | Antibody-cytokine engrafted proteins and methods of use |
WO2018215937A1 (en) | 2017-05-24 | 2018-11-29 | Novartis Ag | Interleukin-7 antibody cytokine engrafted proteins and methods of use in the treatment of cancer |
KR20220167342A (en) | 2017-05-25 | 2022-12-20 | 브리스톨-마이어스 스큅 컴퍼니 | Antibodies comprising modified heavy constant regions |
US11225523B2 (en) | 2017-06-01 | 2022-01-18 | Compugen Ltd. | Triple combination antibody therapies |
UY37758A (en) | 2017-06-12 | 2019-01-31 | Novartis Ag | METHOD OF MANUFACTURING OF BIESPECTIFIC ANTIBODIES, BISPECTIFIC ANTIBODIES AND THERAPEUTIC USE OF SUCH ANTIBODIES |
WO2018229715A1 (en) | 2017-06-16 | 2018-12-20 | Novartis Ag | Compositions comprising anti-cd32b antibodies and methods of use thereof |
WO2018229706A1 (en) | 2017-06-16 | 2018-12-20 | Novartis Ag | Combination therapy for the treatment of cancer |
WO2018236904A1 (en) | 2017-06-19 | 2018-12-27 | Surface Oncology, Inc. | Combination of anti-cd47 antibodies and cell death-inducing agents, and uses thereof |
BR112019024410A2 (en) | 2017-06-20 | 2020-07-14 | Amgen Inc. | method of treating or improving metabolic disorders using gastric inhibitory peptide receptor (gipr) binding proteins in combination with glp 1 agonists |
JP2020525434A (en) | 2017-06-22 | 2020-08-27 | ムーンショット ファーマ エルエルシー | Method of treating cancer with a composition comprising amlexanox and an immunomodulator |
CN111587124B (en) | 2017-06-23 | 2024-01-12 | 维洛斯生物股份有限公司 | ROR1 antibody immunoconjugates |
CA3066518A1 (en) | 2017-06-26 | 2019-01-03 | Beigene, Ltd. | Immunotherapy for hepatocellular carcinoma |
CN110785433A (en) | 2017-06-28 | 2020-02-11 | 诺华股份有限公司 | Method for preventing and treating urinary incontinence |
MX2020000342A (en) | 2017-07-11 | 2020-08-17 | Compass Therapeutics Llc | Agonist antibodies that bind human cd137 and uses thereof. |
JP2020527351A (en) | 2017-07-21 | 2020-09-10 | ジェネンテック, インコーポレイテッド | Cancer treatment and diagnosis |
EP3658589B1 (en) | 2017-07-26 | 2023-09-27 | Forty Seven, Inc. | Anti-sirp-alpha antibodies and related methods |
SG11202000759XA (en) | 2017-07-27 | 2020-02-27 | Daiichi Sankyo Co Ltd | Anti-cd147 antibody |
WO2019033043A2 (en) | 2017-08-11 | 2019-02-14 | Genentech, Inc. | Anti-cd8 antibodies and uses thereof |
EP3684811A2 (en) | 2017-08-17 | 2020-07-29 | Massachusetts Institute of Technology | Multiple specificity binders of cxc chemokines and uses thereof |
WO2019040780A1 (en) | 2017-08-25 | 2019-02-28 | Five Prime Therapeutics Inc. | B7-h4 antibodies and methods of use thereof |
EP3684413A1 (en) | 2017-09-20 | 2020-07-29 | Chugai Seiyaku Kabushiki Kaisha | Dosage regimen for combination therapy using pd-1 axis binding antagonists and gpc3 targeting agent |
MX2020002710A (en) | 2017-09-29 | 2020-07-20 | Chugai Pharmaceutical Co Ltd | Multispecific antigen-binding molecule having blood coagulation factor viii (fviii) cofactor function-substituting activity, and pharmaceutical formulation containing said molecule as active ingredient. |
CN111164208B (en) | 2017-09-29 | 2023-08-04 | 第一三共株式会社 | Antibody-pyrrolobenzodiazepine derivative conjugates |
EP3694870A1 (en) | 2017-10-10 | 2020-08-19 | Alpine Immune Sciences, Inc. | Ctla-4 variant immunomodulatory proteins and uses thereof |
WO2019075090A1 (en) | 2017-10-10 | 2019-04-18 | Tilos Therapeutics, Inc. | Anti-lap antibodies and uses thereof |
CN111372950A (en) | 2017-10-12 | 2020-07-03 | 免疫苏醒公司 | VEGFR-antibody light chain fusion proteins |
EA202090974A1 (en) | 2017-10-18 | 2020-08-05 | Элпайн Иммьюн Сайенсиз, Инк. | VARIANT IMMUNOMODULATING PROTEINS OF ICOS LIGAND AND ACCOMPANYING COMPOSITIONS AND METHODS |
EP3697441B1 (en) | 2017-10-20 | 2023-06-07 | F. Hoffmann-La Roche AG | Method for generating multispecific antibodies from monospecific antibodies |
WO2019081983A1 (en) | 2017-10-25 | 2019-05-02 | Novartis Ag | Antibodies targeting cd32b and methods of use thereof |
CA3078676A1 (en) | 2017-10-30 | 2019-05-09 | F. Hoffmann-La Roche Ag | Method for in vivo generation of multispecific antibodies from monospecific antibodies |
WO2019089753A2 (en) | 2017-10-31 | 2019-05-09 | Compass Therapeutics Llc | Cd137 antibodies and pd-1 antagonists and uses thereof |
JP2021502066A (en) | 2017-11-06 | 2021-01-28 | ジェネンテック, インコーポレイテッド | Cancer diagnosis and therapy |
WO2019100052A2 (en) | 2017-11-20 | 2019-05-23 | Compass Therapeutics Llc | Cd137 antibodies and tumor antigen-targeting antibodies and uses thereof |
EP3713965A1 (en) | 2017-11-22 | 2020-09-30 | Novartis AG | Reversal binding agents for anti-factor xi/xia antibodies and uses thereof |
WO2019108795A1 (en) | 2017-11-29 | 2019-06-06 | Beigene Switzerland Gmbh | Treatment of indolent or aggressive b-cell lymphomas using a combination comprising btk inhibitors |
CA3083363A1 (en) | 2017-12-01 | 2019-06-06 | Novartis Ag | Polyomavirus neutralizing antibodies |
MX2020005981A (en) | 2017-12-08 | 2020-08-24 | Argenx Bvba | Use of fcrn antagonists for treatment of generalized myasthenia gravis. |
WO2019126133A1 (en) | 2017-12-20 | 2019-06-27 | Alexion Pharmaceuticals, Inc. | Liquid formulations of anti-cd200 antibodies |
US11802154B2 (en) | 2017-12-20 | 2023-10-31 | Alexion Pharmaceuticals, Inc. | Humanized anti-CD200 antibodies and uses thereof |
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 |
EP3728321A1 (en) | 2017-12-22 | 2020-10-28 | F. Hoffmann-La Roche AG | Use of pilra binding agents for treatment of a disease |
KR20200104886A (en) | 2017-12-28 | 2020-09-04 | 난징 레전드 바이오테크 씨오., 엘티디. | Antibodies and variants against PD-L1 |
KR20200104333A (en) | 2017-12-28 | 2020-09-03 | 난징 레전드 바이오테크 씨오., 엘티디. | Single-domain antibodies to TIGIT and variants thereof |
CN111479588A (en) | 2017-12-29 | 2020-07-31 | 豪夫迈·罗氏有限公司 | Methods for improving VEGF receptor blocking selectivity of anti-VEGF antibodies |
SG11202006148UA (en) | 2018-01-03 | 2020-07-29 | Alpine Immune Sciences Inc | Multi-domain immunomodulatory proteins and methods of use thereof |
EP3735422A1 (en) | 2018-01-05 | 2020-11-11 | AC Immune SA | Misfolded tdp-43 binding molecules |
JP7358361B2 (en) | 2018-01-12 | 2023-10-10 | ブリストル-マイヤーズ スクイブ カンパニー | Antibodies against TIM3 and their uses |
US11713353B2 (en) | 2018-01-15 | 2023-08-01 | Nanjing Legend Biotech Co., Ltd. | 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 |
PT3743088T (en) | 2018-01-26 | 2022-12-05 | Hoffmann La Roche | Compositions and methods of use |
MA51676A (en) | 2018-01-26 | 2021-05-05 | Hoffmann La Roche | IL-22 FC FUSION PROTEINS AND METHODS OF USE |
WO2019148412A1 (en) | 2018-02-01 | 2019-08-08 | Merck Sharp & Dohme Corp. | Anti-pd-1/lag3 bispecific antibodies |
AU2019218959A1 (en) | 2018-02-08 | 2020-09-03 | Genentech, Inc. | Bispecific antigen-binding molecules and methods of use |
SG11202007564VA (en) | 2018-02-09 | 2020-09-29 | Genentech Inc | Therapeutic and diagnostic methods for mast cell-mediated inflammatory diseases |
CN111757894A (en) | 2018-02-14 | 2020-10-09 | Abba 疗法股份公司 | Anti-human PD-L2 antibody |
MX2020008502A (en) | 2018-02-21 | 2020-09-25 | Genentech Inc | DOSING FOR TREATMENT WITH IL-22 Fc FUSION PROTEINS. |
WO2019165434A1 (en) | 2018-02-26 | 2019-08-29 | Genentech, Inc. | Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies |
BR112020017925A2 (en) | 2018-03-02 | 2020-12-22 | Five Prime Therapeutics, Inc. | ANTIBODIES AGAINST B7-H4 AND METHODS OF USE OF THE SAME |
NL2020520B1 (en) | 2018-03-02 | 2019-09-12 | Labo Bio Medical Invest B V | Multispecific binding molecules for the prevention, treatment and diagnosis of neurodegenerative disorders |
US11859006B2 (en) | 2018-03-05 | 2024-01-02 | Saitama Medical University | Method of treating ectopic ossification or diffuse intrinsic pontine glioma in a subject by administering an anti-ALK2 antibody |
WO2019175071A1 (en) | 2018-03-13 | 2019-09-19 | F. Hoffmann-La Roche Ag | Therapeutic combination of 4-1 bb agonists with anti-cd20 antibodies |
KR102411489B1 (en) | 2018-03-14 | 2022-06-23 | 서피스 온콜로지, 인크. | Antibodies that bind to CD39 and uses thereof |
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 |
EP3768720A4 (en) | 2018-03-20 | 2022-01-05 | Wuxi Biologics Ireland Limited | Novel anti-lag-3 antibody polypeptide |
TW201945393A (en) | 2018-03-21 | 2019-12-01 | 美商戊瑞治療有限公司 | Antibodies binding to VISTA at acidic pH |
US11332524B2 (en) | 2018-03-22 | 2022-05-17 | Surface Oncology, Inc. | Anti-IL-27 antibodies and uses thereof |
TW202003565A (en) | 2018-03-23 | 2020-01-16 | 美商必治妥美雅史谷比公司 | Antibodies against MICA and/or MICB and uses thereof |
AU2019245243A1 (en) | 2018-03-29 | 2020-09-03 | Genentech, Inc | Modulating lactogenic activity in mammalian cells |
EP3774917A4 (en) | 2018-03-30 | 2022-01-19 | Nanjing Legend Biotech Co., Ltd. | Single-domain antibodies against lag-3 and uses thereof |
US11155618B2 (en) | 2018-04-02 | 2021-10-26 | Bristol-Myers Squibb Company | Anti-TREM-1 antibodies and uses 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 |
MA52231A (en) | 2018-04-12 | 2021-02-17 | Fundacio Privada Inst Catalana De Recerca I Estudis Avancats | COMBINATION OF LIF INHIBITORS AND PD-1 AXIS INHIBITORS FOR USE IN THE TREATMENT OF CANCER |
WO2019200357A1 (en) | 2018-04-12 | 2019-10-17 | Surface Oncology, Inc. | Biomarker for cd47 targeting therapeutics and uses therefor |
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 |
CA3096703A1 (en) | 2018-05-03 | 2019-11-07 | University Of Rochester | Anti-influenza neuraminidase monoclonal antibodies and uses thereof |
CN110464842B (en) | 2018-05-11 | 2022-10-14 | 信达生物制药(苏州)有限公司 | Formulations comprising anti-PCSK 9 antibodies and uses thereof |
JP2021524756A (en) | 2018-05-14 | 2021-09-16 | ウェアウルフ セラピューティクス, インコーポレイテッド | Activateable cytokine polypeptides and how to use them |
ES2955511T3 (en) | 2018-05-14 | 2023-12-04 | Werewolf Therapeutics Inc | Activatable interleukin 2 polypeptides and methods of use thereof |
AU2019269131B2 (en) | 2018-05-14 | 2024-02-22 | Fundació Privada Institució Catalana De Recerca I Estudis Avançats | Antibodies against LIF and dosage forms thereof |
TW202015726A (en) | 2018-05-30 | 2020-05-01 | 瑞士商諾華公司 | Entpd2 antibodies, combination therapies, and methods of using the antibodies and combination therapies |
EP3801766A1 (en) | 2018-05-31 | 2021-04-14 | Novartis AG | Hepatitis b antibodies |
AU2019277029C1 (en) | 2018-06-01 | 2024-01-04 | Novartis Ag | Binding molecules against BCMA and uses thereof |
WO2019235426A1 (en) | 2018-06-04 | 2019-12-12 | 中外製薬株式会社 | Antigen-binding molecule showing changed half-life in cytoplasm |
WO2019241758A1 (en) | 2018-06-15 | 2019-12-19 | Alpine Immune Sciences, Inc. | Pd-1 variant immunomodulatory proteins and uses thereof |
CA3103369A1 (en) | 2018-06-18 | 2019-12-26 | Medimmune Limited | Combination of lif inhibitors and platinum-based antineoplastic agents for use in treating cancer |
WO2019246557A1 (en) | 2018-06-23 | 2019-12-26 | Genentech, Inc. | Methods of treating lung cancer with a pd-1 axis binding antagonist, a platinum agent, and a topoisomerase ii inhibitor |
EP3818082A1 (en) | 2018-07-04 | 2021-05-12 | F. Hoffmann-La Roche AG | Novel bispecific agonistic 4-1bb antigen binding molecules |
PE20211604A1 (en) | 2018-07-09 | 2021-08-23 | Five Prime Therapeutics Inc | ILT4 UNION ANTIBODIES |
WO2020013170A1 (en) | 2018-07-10 | 2020-01-16 | 国立大学法人神戸大学 | ANTI-SIRPα ANTIBODY |
WO2020014306A1 (en) | 2018-07-10 | 2020-01-16 | Immunogen, Inc. | Met antibodies and immunoconjugates and uses thereof |
TW202028235A (en) | 2018-07-11 | 2020-08-01 | 美商戊瑞治療有限公司 | Antibodies binding to vista at acidic ph |
CA3104147A1 (en) | 2018-07-18 | 2020-01-23 | Genentech, Inc. | Methods of treating lung cancer with a pd-1 axis binding antagonist, an antimetabolite, and a platinum agent |
AU2019306628A1 (en) | 2018-07-20 | 2021-02-11 | Surface Oncology, Inc. | Anti-CD112R compositions and methods |
KR20210038697A (en) | 2018-08-01 | 2021-04-07 | 추가이 세이야쿠 가부시키가이샤 | A pharmaceutical composition for use in the treatment or prevention of a c5-related disease and a method for treating or preventing a c5-related disease |
BR112021001776A2 (en) | 2018-08-01 | 2021-05-04 | Imcheck Therapeutics Sas | anti-btn3a antibodies and their use in the treatment of cancer or infectious disorders |
WO2020027330A1 (en) | 2018-08-03 | 2020-02-06 | 中外製薬株式会社 | Antigen-binding molecule containing two antigen-binding domains that are linked to each other |
WO2020033926A2 (en) | 2018-08-09 | 2020-02-13 | Compass Therapeutics Llc | Antibodies that bind cd277 and uses thereof |
CA3051549A1 (en) | 2018-08-09 | 2020-02-09 | Regeneron Pharmaceuticals, Inc. | Methods for assessing binding affinity of an antibody variant to the neonatal fc receptor |
US20210388089A1 (en) | 2018-08-09 | 2021-12-16 | Compass Therapeutics Llc | Antigen binding agents that bind cd277 and uses thereof |
WO2020033925A2 (en) | 2018-08-09 | 2020-02-13 | Compass Therapeutics Llc | Antibodies that bind cd277 and uses thereof |
WO2020032230A1 (en) | 2018-08-10 | 2020-02-13 | 中外製薬株式会社 | Anti-cd137 antigen-binding molecule and utilization 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 |
GB201814281D0 (en) | 2018-09-03 | 2018-10-17 | Femtogenix Ltd | Cytotoxic agents |
BR112021003472A2 (en) | 2018-09-06 | 2021-05-18 | Daiichi Sankyo Company, Limited | cyclic dinucleotide derivative and antibody-drug conjugate thereof |
WO2020053742A2 (en) | 2018-09-10 | 2020-03-19 | Novartis Ag | Anti-hla-hbv peptide antibodies |
JP2022500084A (en) | 2018-09-13 | 2022-01-04 | ザ ボード オブ リージェンツ オブ ザ ユニバーシティー オブ テキサス システム | New LILRB4 antibody and its use |
WO2020061376A2 (en) | 2018-09-19 | 2020-03-26 | Alpine Immune Sciences, Inc. | Methods and uses of variant cd80 fusion proteins and related constructs |
AU2019342099A1 (en) | 2018-09-19 | 2021-04-08 | Genentech, Inc. | Therapeutic and diagnostic methods for bladder cancer |
EP4249917A3 (en) | 2018-09-21 | 2023-11-08 | F. Hoffmann-La Roche AG | Diagnostic methods for triple-negative breast cancer |
JP2022502088A (en) | 2018-09-27 | 2022-01-11 | エクシリオ デベロップメント, インコーポレイテッド | Masked cytokine polypeptide |
JP7221379B2 (en) | 2018-10-01 | 2023-02-13 | エフ・ホフマン-ラ・ロシュ・アクチェンゲゼルシャフト | Bispecific antigen-binding molecule comprising anti-FAP clone 212 |
EP3861025A1 (en) | 2018-10-01 | 2021-08-11 | F. Hoffmann-La Roche AG | Bispecific antigen binding molecules with trivalent binding to cd40 |
JP2022504839A (en) | 2018-10-10 | 2022-01-13 | ティロス・セラピューティクス・インコーポレイテッド | Anti-LAP antibody mutants and their use |
UY38407A (en) | 2018-10-15 | 2020-05-29 | Novartis Ag | TREM2 STABILIZING ANTIBODIES |
WO2020081493A1 (en) | 2018-10-16 | 2020-04-23 | Molecular Templates, Inc. | Pd-l1 binding proteins |
MX2021004348A (en) | 2018-10-18 | 2021-05-28 | Genentech Inc | Diagnostic and therapeutic methods for sarcomatoid kidney cancer. |
EP3873532A1 (en) | 2018-10-31 | 2021-09-08 | Novartis AG | Dc-sign antibody drug conjugates |
AU2019375413A1 (en) | 2018-11-05 | 2021-05-27 | Genentech, Inc. | Methods of producing two chain proteins in prokaryotic host cells |
BR112021008908A2 (en) | 2018-11-07 | 2021-08-17 | Daiichi Sankyo Company, Limited | method for improving blood peptide kinetics |
EP3880714A4 (en) | 2018-11-16 | 2022-07-20 | Memorial Sloan Kettering Cancer Center | Antibodies to mucin-16 and methods of use thereof |
KR20210096559A (en) | 2018-11-27 | 2021-08-05 | 이노벤트 바이오로직스 (쑤저우) 컴퍼니, 리미티드 | Anti-IL-23p19 antibodies and uses thereof |
JP2022513653A (en) | 2018-11-28 | 2022-02-09 | ブリストル-マイヤーズ スクイブ カンパニー | Antibodies containing modified heavy chain constant regions |
JP2022510276A (en) | 2018-11-30 | 2022-01-26 | アルパイン イミューン サイエンシズ インコーポレイテッド | CD86 variant immunomodulatory protein and its use |
KR20210100656A (en) | 2018-12-05 | 2021-08-17 | 제넨테크, 인크. | Diagnostic methods and compositions for cancer immunotherapy |
WO2020118011A1 (en) | 2018-12-06 | 2020-06-11 | Alexion Pharmaceuticals, Inc. | Anti-alk2 antibodies and uses thereof |
MX2021006573A (en) | 2018-12-06 | 2021-07-15 | Genentech Inc | Combination therapy of diffuse large b-cell lymphoma comprising an anti-cd79b immunoconjugates, an alkylating agent and an anti-cd20 antibody. |
CN113227119A (en) | 2018-12-10 | 2021-08-06 | 基因泰克公司 | Photocrosslinked peptides for site-specific conjugation to Fc-containing proteins |
MA54472A (en) | 2018-12-14 | 2022-03-23 | Boehringer Ingelheim Io Canada Inc | ANTI-PERIOSTIN ANTIBODIES AND THEIR USES |
WO2020128863A1 (en) | 2018-12-19 | 2020-06-25 | Novartis Ag | Anti-tnf-alpha antibodies |
AR117327A1 (en) | 2018-12-20 | 2021-07-28 | 23Andme Inc | ANTI-CD96 ANTIBODIES AND METHODS OF USE OF THEM |
EP3898667A2 (en) | 2018-12-20 | 2021-10-27 | F. Hoffmann-La Roche AG | Modified antibody fcs and methods of use |
CN113631714A (en) | 2018-12-21 | 2021-11-09 | 豪夫迈·罗氏有限公司 | Methods of producing polypeptides using apoptosis-resistant cell lines |
JP2022514950A (en) | 2018-12-21 | 2022-02-16 | 23アンドミー・インコーポレイテッド | Anti-IL-36 antibody and how to use it |
AU2019406712A1 (en) | 2018-12-21 | 2021-06-17 | F. Hoffmann-La Roche Ag | Antibody that binds to VEGF and IL-1beta and methods of use |
BR112021011900A2 (en) | 2018-12-21 | 2021-09-08 | Novartis Ag | ANTIBODIES TO PMEL17 AND CONJUGATES THEREOF |
EP3902833A2 (en) | 2018-12-26 | 2021-11-03 | City of Hope | Activatable masked anti-ctla4 binding proteins |
CN113272327A (en) | 2018-12-30 | 2021-08-17 | 豪夫迈·罗氏有限公司 | Anti-rabbit CD19 antibodies and methods of use thereof |
AU2020208193A1 (en) | 2019-01-14 | 2021-07-29 | BioNTech SE | Methods of treating cancer with a PD-1 axis binding antagonist and an RNA vaccine |
WO2020148207A1 (en) | 2019-01-14 | 2020-07-23 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Human monoclonal antibodies binding to hla-a2 |
CN113474371A (en) | 2019-01-16 | 2021-10-01 | 指南针制药有限责任公司 | Formulations of antibodies that bind to human CD137 and uses thereof |
CA3127236A1 (en) | 2019-01-22 | 2020-07-30 | Bristol-Myers Squibb Company | Antibodies against il-7r alpha subunit and uses thereof |
WO2020154405A2 (en) | 2019-01-22 | 2020-07-30 | Genentech, Inc. | Immunoglobulin a antibodies and methods of production and use |
EP3914615A1 (en) | 2019-01-23 | 2021-12-01 | F. Hoffmann-La Roche AG | Methods of producing multimeric proteins in eukaryotic host cells |
JPWO2020153467A1 (en) | 2019-01-24 | 2021-12-02 | 中外製薬株式会社 | New cancer antigens and antibodies against those antigens |
GB201901197D0 (en) | 2019-01-29 | 2019-03-20 | Femtogenix Ltd | G-A Crosslinking cytotoxic agents |
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 |
MX2021010565A (en) | 2019-03-08 | 2021-10-13 | Genentech Inc | Methods for detecting and quantifying membrane-associated proteins on extracellular vesicles. |
MA55296A (en) | 2019-03-14 | 2022-03-23 | Hoffmann La Roche | CANCER TREATMENT WITH BISPECIFIC ANTIBODIES TO HER2XCD3 IN COMBINATION WITH AN ANTI-HER2 MAB |
WO2020196474A1 (en) | 2019-03-25 | 2020-10-01 | 第一三共株式会社 | Antibody-pyrrolobenzodiazepine derivative conjugate |
TW202102226A (en) | 2019-03-27 | 2021-01-16 | 日商第一三共股份有限公司 | Combination of antibody-pyrrolobenzodiazepine derivative conjugate and PARP inhibitor |
MX2021012160A (en) | 2019-04-08 | 2022-01-06 | Biogen Ma Inc | Anti-integrin antibodies and uses thereof. |
GB2589049C (en) | 2019-04-11 | 2024-02-21 | argenx BV | Anti-IgE antibodies |
MX2021012607A (en) | 2019-04-17 | 2022-03-11 | Alpine Immune Sciences Inc | Methods and uses of variant icos ligand (icosl) fusion proteins. |
CN114364703A (en) | 2019-04-19 | 2022-04-15 | 豪夫迈·罗氏有限公司 | Anti-merk antibodies and methods of use thereof |
TW202106876A (en) | 2019-04-19 | 2021-02-16 | 日商中外製藥股份有限公司 | Chimeric receptor recognizing modification site of antibody |
AU2020270376A1 (en) | 2019-05-03 | 2021-10-07 | Genentech, Inc. | Methods of treating cancer with an anti-PD-L1 antibody |
JP2022532217A (en) | 2019-05-14 | 2022-07-13 | ウェアウルフ セラピューティクス, インコーポレイテッド | Separation part and how to use it |
JP2022536602A (en) | 2019-05-14 | 2022-08-18 | ジェネンテック, インコーポレイテッド | Methods of using anti-CD79B immunoconjugates to treat follicular lymphoma |
CA3140063A1 (en) | 2019-05-20 | 2020-11-26 | Novartis Ag | Antibody drug conjugates having linkers comprising hydrophilic groups |
JP2022532918A (en) | 2019-05-20 | 2022-07-20 | ノバルティス アーゲー | MCL-1 Inhibitor Antibody-Drug Conjugate and Usage |
US20230071196A1 (en) | 2019-05-21 | 2023-03-09 | Novartis Ag | Variant cd58 domains and uses thereof |
KR20220010743A (en) | 2019-05-21 | 2022-01-26 | 노파르티스 아게 | Trispecific binding molecules to BCMA and uses thereof |
TW202100559A (en) | 2019-05-21 | 2021-01-01 | 瑞士商諾華公司 | Cd19 binding molecules and uses thereof |
SG11202112453TA (en) | 2019-05-23 | 2021-12-30 | Ac Immune Sa | Anti-tdp-43 binding molecules and uses thereof |
MA56102A (en) | 2019-06-07 | 2022-04-13 | Argenx Bvba | PHARMACEUTICAL FORMULATIONS OF FCRN INHIBITORS SUITABLE FOR SUBCUTANEOUS ADMINISTRATION |
BR112021024938A2 (en) | 2019-06-12 | 2022-01-25 | Novartis Ag | Natriuretic peptide receptor 1 antibodies and methods of use |
EP3990476A1 (en) | 2019-06-25 | 2022-05-04 | Gilead Sciences, Inc. | Flt3l-fc fusion proteins and methods of use |
WO2020260326A1 (en) | 2019-06-27 | 2020-12-30 | F. Hoffmann-La Roche Ag | Novel icos antibodies and tumor-targeted antigen binding molecules comprising them |
AR119382A1 (en) | 2019-07-12 | 2021-12-15 | Hoffmann La Roche | PRE-TARGETING ANTIBODIES AND METHODS OF USE |
JPWO2021010326A1 (en) | 2019-07-12 | 2021-01-21 | ||
WO2021011681A1 (en) | 2019-07-15 | 2021-01-21 | Bristol-Myers Squibb Company | Antibodies against human trem-1 and uses thereof |
EP3999543A1 (en) | 2019-07-15 | 2022-05-25 | Bristol-Myers Squibb Company | Anti-trem-1 antibodies and uses thereof |
WO2021009263A1 (en) | 2019-07-16 | 2021-01-21 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Antibodies having specificity for cd38 and uses thereof |
JP2022542863A (en) | 2019-07-24 | 2022-10-07 | ハー・ルンドベック・アクチエゼルスカベット | Anti-mGluR5 antibody and uses thereof |
JPWO2021020282A1 (en) | 2019-07-26 | 2021-02-04 | ||
KR20220041881A (en) | 2019-07-29 | 2022-04-01 | 컴퓨젠 엘티디. | Anti-PVRIG antibody formulations and uses thereof |
MX2022001153A (en) | 2019-07-31 | 2022-02-22 | Hoffmann La Roche | Dosage and administration regimen for the treatment or prevention of c5-related diseases by the use of the anti-c5 antibody crovalimab. |
US20220275070A1 (en) | 2019-07-31 | 2022-09-01 | Hoffmann-La Roche Inc. | Dosage and administration regimen for the treatment or prevention of c5-related diseases by the use of the anti-c5 antibody crovalimab |
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 |
US20220242962A1 (en) | 2019-08-12 | 2022-08-04 | Aptevo Research And Development Llc | 4-1bb and ox40 binding proteins and related compositions and methods, antibodies against 4-1bb, antibodies against ox40 |
US11680098B2 (en) | 2019-08-30 | 2023-06-20 | Agenus Inc. | Antibodies that specifically bind human CD96 |
KR20220062304A (en) | 2019-09-12 | 2022-05-16 | 제넨테크, 인크. | Compositions and methods for treating lupus nephritis |
WO2021055329A1 (en) | 2019-09-16 | 2021-03-25 | Surface Oncology, Inc. | Anti-cd39 antibody compositions and methods |
TW202124446A (en) | 2019-09-18 | 2021-07-01 | 瑞士商諾華公司 | Combination therapies with entpd2 antibodies |
JP2022548881A (en) | 2019-09-18 | 2022-11-22 | ノバルティス アーゲー | ENTPD2 Antibodies, Combination Therapy and Methods of Using Antibodies and Combination Therapy |
US20210130492A1 (en) | 2019-09-18 | 2021-05-06 | Genentech, Inc. | Anti-klk7 antibodies, anti-klk5 antibodies, multispecific anti-klk5/klk7 antibodies, and methods of use |
CA3149719A1 (en) | 2019-09-19 | 2021-03-25 | Bristol-Myers Squibb Company | Antibodies binding to vista at acidic ph |
KR20220066295A (en) | 2019-09-20 | 2022-05-24 | 제넨테크, 인크. | Dosing of Anti-Tryptase Antibodies |
AU2020353672A1 (en) | 2019-09-25 | 2022-03-31 | Surface Oncology, LLC | Anti-IL-27 antibodies and uses thereof |
CR20220127A (en) | 2019-09-27 | 2022-05-27 | Genentech Inc | Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies |
WO2021070181A1 (en) | 2019-10-08 | 2021-04-15 | Nectin Therapeutics Ltd. | Antibodies against the poliovirus receptor (pvr) and uses thereof |
JP7413519B2 (en) | 2019-10-18 | 2024-01-15 | ジェネンテック, インコーポレイテッド | Methods of using anti-CD79B immunoconjugates to treat diffuse large B-cell lymphoma |
US11459389B2 (en) | 2019-10-24 | 2022-10-04 | Massachusetts Institute Of Technology | Monoclonal antibodies that bind human CD161 |
CA3160162A1 (en) | 2019-11-04 | 2021-05-14 | Compugen Ltd. | Combination therapy with anti-pvrig antibodies formulations and anti-pd-1 antibodies |
US20220389103A1 (en) | 2019-11-06 | 2022-12-08 | Genentech, Inc. | Diagnostic and therapeutic methods for treatment of hematologic cancers |
CN114929741A (en) | 2019-12-04 | 2022-08-19 | 免疫医疗有限公司 | Antibodies against LIF and uses thereof |
WO2021116119A1 (en) | 2019-12-09 | 2021-06-17 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Antibodies having specificity to her4 and uses thereof |
PE20221511A1 (en) | 2019-12-13 | 2022-10-04 | Genentech Inc | ANTI-LY6G6D ANTIBODIES AND METHODS OF USE |
CN113045655A (en) | 2019-12-27 | 2021-06-29 | 高诚生物医药(香港)有限公司 | anti-OX 40 antibodies and uses thereof |
US20230058982A1 (en) | 2019-12-27 | 2023-02-23 | Chugai Seiyaku Kabushiki Kaisha | Anti-ctla-4 antibody and use thereof |
CA3160204A1 (en) | 2020-01-06 | 2021-07-15 | Vaccinex, Inc. | Anti-ccr8 antibodies and uses thereof |
CA3163172A1 (en) | 2020-01-08 | 2021-07-15 | Peter Verheesen | Methods for treating pemphigus disorders |
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 |
TW202142257A (en) | 2020-01-31 | 2021-11-16 | 美商建南德克公司 | Methods of inducing neoepitope-specific t cells with a pd-1 axis binding antagonist and an rna vaccine |
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 |
WO2021173844A1 (en) | 2020-02-26 | 2021-09-02 | Biograph 55, Inc. | C19 c38 bispecific antibodies |
WO2021170067A1 (en) | 2020-02-28 | 2021-09-02 | 上海复宏汉霖生物技术股份有限公司 | Anti-cd137 construct and use thereof |
CN115151573A (en) | 2020-02-28 | 2022-10-04 | 上海复宏汉霖生物技术股份有限公司 | anti-CD 137 constructs, multispecific antibodies, and uses thereof |
WO2021175954A1 (en) | 2020-03-04 | 2021-09-10 | Imcheck Therapeutics Sas | Antibodies having specificity for btnl8 and uses thereof |
IL295979A (en) | 2020-03-06 | 2022-10-01 | Ona Therapeutics S L | Anti-cd36 antibodies and their use to treat cancer |
CN115209921A (en) | 2020-03-06 | 2022-10-18 | 第一三共株式会社 | Antibody drug conjugates comprising novel cyclic dinucleotide derivatives |
IL296241A (en) | 2020-03-10 | 2022-11-01 | Massachusetts Inst Technology | Compositions and methods for immunotherapy of npm1c-positive cancer |
WO2021183849A1 (en) | 2020-03-13 | 2021-09-16 | Genentech, Inc. | Anti-interleukin-33 antibodies and uses thereof |
US20240043530A1 (en) | 2020-03-13 | 2024-02-08 | Jiangsu Hengrui Pharmaceuticals Co., Ltd. | PVRIG Binding Protein And Its Medical Uses |
EP4121163A1 (en) | 2020-03-19 | 2023-01-25 | Genentech, Inc. | Isoform-selective anti-tgf-beta antibodies and methods of use |
US11365239B2 (en) | 2020-03-20 | 2022-06-21 | Tsb Therapeutics (Beijing) Co., Ltd. | Anti-SARS-COV-2 antibodies and uses thereof |
CA3169967A1 (en) | 2020-03-24 | 2021-09-30 | Genentech, Inc. | Tie2-binding agents and methods of use |
JP2023518841A (en) | 2020-03-26 | 2023-05-08 | ジェネンテック, インコーポレイテッド | Modified mammalian cells with reduced host cell proteins |
WO2021195513A1 (en) | 2020-03-27 | 2021-09-30 | Novartis Ag | Bispecific combination therapy for treating proliferative diseases and autoimmune disorders |
CN115397850A (en) | 2020-03-30 | 2022-11-25 | 豪夫迈·罗氏有限公司 | Antibodies that bind to VEGF and PDGF-B and methods of use thereof |
AR121706A1 (en) | 2020-04-01 | 2022-06-29 | Hoffmann La Roche | OX40 AND FAP-TARGETED BSPECIFIC ANTIGEN-BINDING MOLECULES |
CA3170570A1 (en) | 2020-04-01 | 2021-10-07 | James J. KOBIE | Monoclonal antibodies against the hemagglutinin (ha) and neuraminidase (na) of influenza h3n2 viruses |
CN115698717A (en) | 2020-04-03 | 2023-02-03 | 基因泰克公司 | Methods of treatment and diagnosis of cancer |
US20230272056A1 (en) | 2020-04-09 | 2023-08-31 | Merck Sharp & Dohme Llc | Affinity matured anti-lap antibodies and uses thereof |
WO2021207662A1 (en) | 2020-04-10 | 2021-10-14 | Genentech, Inc. | Use of il-22fc for the treatment or prevention of pneumonia, acute respiratory distress syndrome, or cytokine release syndrome |
MX2022013173A (en) | 2020-04-24 | 2022-11-30 | Hoffmann La Roche | Enzyme and pathway modulation with sulfhydryl compounds and their derivatives. |
TW202206111A (en) | 2020-04-24 | 2022-02-16 | 美商建南德克公司 | Methods of using anti-cd79b immunoconjugates |
EP4143345A1 (en) | 2020-04-28 | 2023-03-08 | Genentech, Inc. | Methods and compositions for non-small cell lung cancer immunotherapy |
US11634477B2 (en) | 2020-04-28 | 2023-04-25 | The Rockefeller University | Neutralizing anti-SARS-CoV-2 antibodies and methods of use thereof |
US20230181756A1 (en) | 2020-04-30 | 2023-06-15 | Novartis Ag | Ccr7 antibody drug conjugates for treating cancer |
BR112022022045A2 (en) | 2020-04-30 | 2023-01-10 | Sairopa B V | ANTIGEN-BINDING ANTIBODY OR FRAGMENT OF THE SAME WHICH BINDS HUMAN CD103, ONE OR MORE NUCLEIC ACIDS, EXPRESSION SYSTEM, HOST CELL, COMPOSITION, METHODS OF PRODUCTION OF AN ANTIBODY OR ANTIGEN-BINDING FRAGMENT, TO DETECT THE PRESENCE OF CD103 IN A BIOLOGICAL SAMPLE, TO TREAT OR PREVENT A CONDITION MEDIATED BY CD103 SIGNALING IN AN INDIVIDUAL IN NEED, TO INHIBIT CD103 SIGNALING IN A CELL, TO INHIBIT THE BINDING OF CD103 TO E-CADHERIN PRESENT IN A CELL, TO REMOVE THE CD103-EXPRESSING CELLS IN AN INDIVIDUAL, TO TREAT OR PREVENT A DISEASE AND IMAGING AGENT |
TW202200212A (en) | 2020-05-03 | 2022-01-01 | 中國大陸商聯寧(蘇州)生物製藥有限公司 | Antibody-drug conjugates comprising an anti-trop-2 antibody |
EP4146684A2 (en) | 2020-05-08 | 2023-03-15 | Alpine Immune Sciences, Inc. | April and baff inhibitory immunomodulatory proteins with and without a t cell inhibitory protein and methods of use thereof |
EP4149558A1 (en) | 2020-05-12 | 2023-03-22 | INSERM (Institut National de la Santé et de la Recherche Médicale) | New method to treat cutaneous t-cell lymphomas and tfh derived lymphomas |
JP2023528235A (en) | 2020-05-17 | 2023-07-04 | アストラゼネカ・ユーケイ・リミテッド | SARS-CoV-2 Antibodies and Methods of Selecting and Using The Same |
JP2023526540A (en) | 2020-05-22 | 2023-06-21 | フォーマイコン アーゲー | ACE2 fusion proteins and methods of use thereof |
CN113993900B (en) | 2020-05-27 | 2023-08-04 | 舒泰神(北京)生物制药股份有限公司 | Antibodies specifically recognizing nerve growth factor and uses thereof |
BR112022024339A2 (en) | 2020-05-29 | 2022-12-27 | 23Andme Inc | ANTI CD200R1 ANTIBODIES AND METHODS OF THEIR USE |
EP4157462A1 (en) | 2020-06-02 | 2023-04-05 | Dynamicure Biotechnology LLC | Anti-cd93 constructs and uses 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 |
US20230340081A1 (en) | 2020-06-08 | 2023-10-26 | Hoffmann-La Roche Inc. | Anti-hbv antibodies and methods of use |
EP4165415A1 (en) | 2020-06-12 | 2023-04-19 | Genentech, Inc. | Methods and compositions for cancer immunotherapy |
KR20230025691A (en) | 2020-06-16 | 2023-02-22 | 제넨테크, 인크. | Methods and compositions for treating triple negative breast cancer |
EP4168118A1 (en) | 2020-06-18 | 2023-04-26 | Genentech, Inc. | Treatment with anti-tigit antibodies and pd-1 axis binding antagonists |
CN116234824A (en) | 2020-06-22 | 2023-06-06 | 阿尔米雷尔有限公司 | anti-IL-36 antibodies and methods of use thereof |
JP2023532234A (en) | 2020-06-22 | 2023-07-27 | イノベント バイオロジクス(スーチョウ)カンパニー,リミティド | Anti-CD73 antibody and its use |
WO2021262783A1 (en) | 2020-06-24 | 2021-12-30 | Genentech, Inc. | Apoptosis resistant cell lines |
AR122721A1 (en) | 2020-06-25 | 2022-09-28 | Merck Sharp & Dohme | HIGH-AFFINITY ANTIBODIES DIRECTED TO TAU PHOSPHORYLATED AT SERINE 413 |
CR20230076A (en) | 2020-07-10 | 2023-03-13 | Hoffmann La Roche | Antibodies which bind to cancer cells and target radionuclides to said cells |
AU2021308653A1 (en) | 2020-07-17 | 2023-02-16 | Genentech, Inc. | Anti-Notch2 antibodies and methods of use |
GB2597532A (en) | 2020-07-28 | 2022-02-02 | Femtogenix Ltd | Cytotoxic compounds |
US20230322935A1 (en) | 2020-07-29 | 2023-10-12 | Dynamicure Biotechnology Llc | Anti-cd93 constructs and uses thereof |
JP2023536602A (en) | 2020-08-03 | 2023-08-28 | ジェネンテック, インコーポレイテッド | Diagnostic and therapeutic methods for lymphoma |
WO2022031978A1 (en) | 2020-08-06 | 2022-02-10 | Bioverativ Usa Inc. | Inflammatory cytokines and fatigue in subject with a complement mediated disease |
US20220041694A1 (en) | 2020-08-10 | 2022-02-10 | Astrazeneca Uk Limited | Sars-cov-2 antibodies for treatment and prevention of covid-19 |
KR20230054456A (en) | 2020-08-25 | 2023-04-24 | 길리애드 사이언시즈, 인코포레이티드 | Multispecific Antigen Binding Molecules Targeting HIV and Methods of Using The Same |
EP4204448A2 (en) | 2020-08-27 | 2023-07-05 | cureab GmbH | Anti-golph2 antibodies for macrophage and dendritic cell differentiation |
KR20230056766A (en) | 2020-08-28 | 2023-04-27 | 제넨테크, 인크. | CRISPR/Cas9 multiple knockout of host cell proteins |
KR20230061458A (en) | 2020-09-04 | 2023-05-08 | 에프. 호프만-라 로슈 아게 | Antibodies that bind to VEGF-A and ANG2 and methods of use |
MX2023002901A (en) | 2020-09-14 | 2023-06-01 | Ichnos Sciences SA | Antibodies that bind to il1rap and uses thereof. |
CN116406291A (en) | 2020-10-05 | 2023-07-07 | 基因泰克公司 | Administration of treatment with anti-FCRH 5/anti-CD 3 bispecific antibodies |
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 |
TWI815194B (en) | 2020-10-22 | 2023-09-11 | 美商基利科學股份有限公司 | INTERLEUKIN-2-Fc FUSION PROTEINS AND METHODS OF USE |
WO2022090801A2 (en) | 2020-10-26 | 2022-05-05 | Compugen Ltd. | Pvrl2 and/or pvrig as biomarkers for treatment |
WO2022093981A1 (en) | 2020-10-28 | 2022-05-05 | Genentech, Inc. | Combination therapy comprising ptpn22 inhibitors and pd-l1 binding antagonists |
AU2021367988A1 (en) | 2020-10-29 | 2023-05-11 | Formycon Ag | Ace2 fusion proteins and uses thereof |
EP4240766A2 (en) | 2020-11-04 | 2023-09-13 | Genentech, Inc. | Subcutaneous dosing of anti-cd20/anti-cd3 bispecific antibodies |
JP2023548064A (en) | 2020-11-04 | 2023-11-15 | ジェネンテック, インコーポレイテッド | Administration for treatment with anti-CD20/anti-CD3 bispecific antibody and anti-CD79B antibody drug conjugate |
AR123997A1 (en) | 2020-11-04 | 2023-02-01 | Univ Rockefeller | NEUTRALIZING ANTIBODIES AGAINST SARS-CoV-2 |
US20220162329A1 (en) | 2020-11-04 | 2022-05-26 | Genentech, Inc. | Dosing for treatment with anti-cd20/anti-cd3 bispecific antibodies |
EP4240765A2 (en) | 2020-11-06 | 2023-09-13 | Novartis AG | Antibody fc variants |
WO2022097060A1 (en) | 2020-11-06 | 2022-05-12 | Novartis Ag | Cd19 binding molecules and uses thereof |
EP4240494A1 (en) | 2020-11-06 | 2023-09-13 | Novartis AG | Anti-cd19 agent and b cell targeting agent combination therapy for treating b cell malignancies |
AU2021378152A1 (en) | 2020-11-11 | 2023-06-22 | Daiichi Sankyo Company, Limited | COMBINATION OF AN ANTIBODY-DRUG CONJUGATE WITH ANTI-SIRPα ANTIBODY |
JP2023553808A (en) | 2020-11-24 | 2023-12-26 | ノバルティス アーゲー | MCL-1 inhibitor antibody-drug conjugates and methods of use |
EP4251648A2 (en) | 2020-11-24 | 2023-10-04 | Novartis AG | Anti-cd48 antibodies, antibody drug conjugates, and uses thereof |
MX2023006426A (en) | 2020-12-01 | 2023-07-17 | Aptevo Res And Development Llc | Heterodimeric psma and cd3-binding bispecific antibodies. |
WO2022130182A1 (en) | 2020-12-14 | 2022-06-23 | Novartis Ag | Reversal binding agents for anti-natriuretic peptide receptor 1 (npr1) antibodies and uses thereof |
KR20230120665A (en) | 2020-12-17 | 2023-08-17 | 에프. 호프만-라 로슈 아게 | Anti-HLA-G Antibodies and Uses Thereof |
AU2021399453A1 (en) | 2020-12-18 | 2023-07-27 | Zhuhai Trinomab Pharmaceutical Co., Ltd. | Respiratory syncytial virus-specific binding molecule |
WO2022140797A1 (en) | 2020-12-23 | 2022-06-30 | Immunowake Inc. | Immunocytokines and uses thereof |
CA3203257A1 (en) | 2020-12-23 | 2022-06-30 | Li Li | Anti-b7-h3 antibody and uses thereof |
MX2023007846A (en) | 2021-01-06 | 2023-07-07 | F Hoffmann La Roche Ag | Combination therapy employing a pd1-lag3 bispecific antibody and a cd20 t cell bispecific antibody. |
AU2022207615A1 (en) | 2021-01-12 | 2023-07-13 | F. Hoffmann-La Roche Ag | Split antibodies which bind to cancer cells and target radionuclides to said cells |
EP4277668A1 (en) | 2021-01-13 | 2023-11-22 | F. Hoffmann-La Roche AG | Combination therapy |
US20220227844A1 (en) | 2021-01-15 | 2022-07-21 | The Rockefeller University | Neutralizing anti-sars-cov-2 antibodies |
WO2022165275A2 (en) | 2021-01-28 | 2022-08-04 | Compugen Ltd. | Combination therapy with anti-pvrig antibodies formulations and anti-pd-1-antibodies |
WO2022165266A1 (en) | 2021-01-28 | 2022-08-04 | Compugen Ltd. | Anti-pvrig antibodies formulations and uses thereof |
TW202241454A (en) | 2021-02-01 | 2022-11-01 | 日商第一三共股份有限公司 | Novel method for producing antibody-immunostimulator conjugate |
JP2024509695A (en) | 2021-02-03 | 2024-03-05 | ジェネンテック, インコーポレイテッド | Multispecific binding proteolysis platform and methods of use |
CA3208060A1 (en) | 2021-02-17 | 2022-08-25 | Jessie-Farah Fecteau | Anti-cd30l antibodies and uses thereof |
TW202317612A (en) | 2021-03-01 | 2023-05-01 | 美商艾希利歐發展股份有限公司 | Combination of ctla4 and pd1/pdl1 antibodies for treating cancer |
EP4301781A1 (en) | 2021-03-01 | 2024-01-10 | Xilio Development, Inc. | Combination of masked ctla4 and pd1/pdl1 antibodies for treating cancer |
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 |
WO2022184854A2 (en) | 2021-03-03 | 2022-09-09 | Formycon Ag | Formulations of ace2 fc fusion proteins |
TW202302646A (en) | 2021-03-05 | 2023-01-16 | 美商當康生物科技有限公司 | Anti-vista constructs and uses thereof |
IL305758A (en) | 2021-03-10 | 2023-11-01 | Immunowake Inc | Immunomodulatory molecules and uses thereof |
AR125074A1 (en) | 2021-03-12 | 2023-06-07 | Genentech Inc | ANTI-KLK7 ANTIBODIES, ANTI-KLK5 ANTIBODIES, ANTI-KLK5/KLK7 MULTI-SPECIFIC ANTIBODIES AND METHODS OF USE |
IL305283A (en) | 2021-03-15 | 2023-10-01 | Genentech Inc | Compositions and methods of treating lupus nephritis |
WO2022197877A1 (en) | 2021-03-19 | 2022-09-22 | Genentech, Inc. | Methods and compositions for time delayed bio-orthogonal release of cytotoxic agents |
JP2024511424A (en) | 2021-03-25 | 2024-03-13 | ダイナミキュア バイオテクノロジー エルエルシー | Anti-IGFBP7 construct and its use |
EP4313296A1 (en) | 2021-03-31 | 2024-02-07 | Bioverativ USA Inc. | Reducing surgery-associated hemolysis in cold agglutinin disease patients |
EP4314068A1 (en) | 2021-04-02 | 2024-02-07 | The Regents Of The University Of California | Antibodies against cleaved cdcp1 and uses thereof |
WO2022221720A1 (en) | 2021-04-16 | 2022-10-20 | Novartis Ag | Antibody drug conjugates and methods for making thereof |
TW202305122A (en) | 2021-04-19 | 2023-02-01 | 美商建南德克公司 | Modified mammalian cells |
WO2022235867A2 (en) | 2021-05-06 | 2022-11-10 | The Rockefeller University | Neutralizing anti-sars- cov-2 antibodies and methods of use thereof |
AU2022269139A1 (en) | 2021-05-07 | 2023-11-16 | Alpine Immune Sciences, Inc. | Methods of dosing and treatment with a taci-fc fusion immunomodulatory protein |
JP2024516970A (en) | 2021-05-07 | 2024-04-18 | サーフィス オンコロジー, エルエルシー | Anti-IL-27 antibodies and uses thereof |
IL308351A (en) | 2021-05-12 | 2024-01-01 | Genentech Inc | Methods of using anti-cd79b immunoconjugates to treat diffuse large b-cell lymphoma |
BR112023023777A2 (en) | 2021-05-14 | 2024-01-30 | Genentech Inc | ISOLATED ANTIBODIES, PHARMACEUTICAL COMPOSITION, ISOLATED NUCLEIC ACID, ISOLATED VECTOR, ISOLATED HOST CELL, METHOD FOR PRODUCING AN ANTIBODY, METHOD FOR TREATING A CONDITION ASSOCIATED WITH LOSS OF TREM2 FUNCTION, METHOD FOR REDUCING STREM2 LEVELS AND USE OF AN ANTIBODY |
TW202313094A (en) | 2021-05-18 | 2023-04-01 | 美商基利科學股份有限公司 | Methods of using flt3l-fc fusion proteins |
WO2022243261A1 (en) | 2021-05-19 | 2022-11-24 | F. Hoffmann-La Roche Ag | Agonistic cd40 antigen binding molecules targeting cea |
KR20240010469A (en) | 2021-05-21 | 2024-01-23 | 제넨테크, 인크. | Modified cells for production of recombinant products of interest |
TW202306994A (en) | 2021-06-04 | 2023-02-16 | 日商中外製藥股份有限公司 | Anti-ddr2 antibodies and uses thereof |
IL309349A (en) | 2021-06-14 | 2024-02-01 | argenx BV | Anti-il-9 antibodies and methods of use thereof |
WO2022266660A1 (en) | 2021-06-17 | 2022-12-22 | Amberstone Biosciences, Inc. | Anti-cd3 constructs and uses thereof |
JP2023535884A (en) | 2021-06-22 | 2023-08-22 | ノバルティス アーゲー | Bispecific antibody for use in treating hidradenitis suppurativa |
JP7472405B2 (en) | 2021-06-25 | 2024-04-22 | 中外製薬株式会社 | Anti-CTLA-4 antibody |
WO2022270612A1 (en) | 2021-06-25 | 2022-12-29 | 中外製薬株式会社 | Use of anti-ctla-4 antibody |
WO2023275621A1 (en) | 2021-07-01 | 2023-01-05 | Compugen Ltd. | Anti-tigit and anti-pvrig in monotherapy and combination treatments |
BR112023026966A2 (en) | 2021-07-02 | 2024-03-12 | Hoffmann La Roche | METHODS FOR TREATING AN INDIVIDUAL WITH MELANOMA, FOR ACHIEVING A CLINICAL RESPONSE, FOR TREATING AN INDIVIDUAL WITH NON-HODGKIN LYMPHOMA, FOR TREATING A POPULATION OF INDIVIDUALS WITH NON-HODGKIN LYMPHOMA, AND FOR TREATING AN INDIVIDUAL WITH METASTATIC COLORECTAL CANCER |
WO2023283611A1 (en) | 2021-07-08 | 2023-01-12 | Staidson Biopharma Inc. | Antibodies specifically recognizing tnfr2 and uses thereof |
TW202306985A (en) | 2021-07-12 | 2023-02-16 | 美商建南德克公司 | Structures for reducing antibody-lipase binding |
CN115812082A (en) | 2021-07-14 | 2023-03-17 | 舒泰神(北京)生物制药股份有限公司 | Antibody specifically recognizing CD40 and application thereof |
TW202309097A (en) | 2021-07-14 | 2023-03-01 | 美商建南德克公司 | Anti-c-c motif chemokine receptor 8 (ccr8) antibodies and methods of use |
WO2023004386A1 (en) | 2021-07-22 | 2023-01-26 | Genentech, Inc. | Brain targeting compositions and methods of use thereof |
WO2023001884A1 (en) | 2021-07-22 | 2023-01-26 | F. Hoffmann-La Roche Ag | Heterodimeric fc domain antibodies |
AU2022317820A1 (en) | 2021-07-28 | 2023-12-14 | F. Hoffmann-La Roche Ag | Methods and compositions for treating cancer |
WO2023007472A1 (en) | 2021-07-30 | 2023-02-02 | ONA Therapeutics S.L. | Anti-cd36 antibodies and their use to treat cancer |
CN117897404A (en) | 2021-08-02 | 2024-04-16 | 信达生物制药(苏州)有限公司 | anti-CD 79b×CD3 bispecific antibodies and uses thereof |
WO2023012147A1 (en) | 2021-08-03 | 2023-02-09 | F. Hoffmann-La Roche Ag | Bispecific antibodies and methods of use |
WO2023019092A1 (en) | 2021-08-07 | 2023-02-16 | Genentech, Inc. | Methods of using anti-cd79b immunoconjugates to treat diffuse large b-cell lymphoma |
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 |
WO2023028591A1 (en) | 2021-08-27 | 2023-03-02 | Genentech, Inc. | Methods of treating tau pathologies |
TW202325727A (en) | 2021-08-30 | 2023-07-01 | 美商建南德克公司 | Anti-polyubiquitin multispecific antibodies |
CA3232806A1 (en) | 2021-09-30 | 2023-04-06 | Seagen Inc. | B7-h4 antibody-drug conjugates for the treatment of cancer |
WO2023052541A1 (en) | 2021-09-30 | 2023-04-06 | Imcheck Therapeutics | Combination of an anti-btn3a activating antibody and an il-2 agonist for use in therapy |
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 |
WO2023064958A1 (en) | 2021-10-15 | 2023-04-20 | Compugen Ltd. | Combination therapy with anti-pvrig antibodies formulations, anti-tigit antibodies, and anti-pd-1 antibodies |
WO2023081818A1 (en) | 2021-11-05 | 2023-05-11 | American Diagnostics & Therapy, Llc (Adxrx) | Monoclonal antibodies against carcinoembryonic antigens, and their uses |
TW202342095A (en) | 2021-11-05 | 2023-11-01 | 英商阿斯特捷利康英國股份有限公司 | Composition for treatment and prevention of covid-19 |
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 |
AR127692A1 (en) | 2021-11-16 | 2024-02-21 | Ac Immune Sa | ANTI-ASC ANTIBODIES FOR USE IN ANTI-INFLAMMATORY TREATMENTS |
CA3235096A1 (en) | 2021-11-17 | 2023-05-25 | Disc Medicine, Inc. | Methods for treating anemia of kidney disease |
WO2023094507A1 (en) | 2021-11-24 | 2023-06-01 | Formycon Ag | Improved ace2 fusion proteins |
WO2023094571A1 (en) | 2021-11-25 | 2023-06-01 | Formycon Ag | Stabilization of ace2 fusion proteins |
TW202330582A (en) | 2021-12-15 | 2023-08-01 | 美商建南德克公司 | Stabilized il-18 polypeptides and uses thereof |
AR128031A1 (en) | 2021-12-20 | 2024-03-20 | Hoffmann La Roche | ANTI-LTBR AGONIST ANTIBODIES AND BISPECIFIC ANTIBODIES THAT COMPRISE THEM |
WO2023131901A1 (en) | 2022-01-07 | 2023-07-13 | Johnson & Johnson Enterprise Innovation Inc. | Materials and methods of il-1beta binding proteins |
WO2023139107A1 (en) | 2022-01-18 | 2023-07-27 | argenx BV | Galectin-10 antibodies |
US20230322958A1 (en) | 2022-01-19 | 2023-10-12 | Genentech, Inc. | Anti-Notch2 Antibodies and Conjugates and Methods of Use |
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 |
WO2023168352A1 (en) | 2022-03-03 | 2023-09-07 | Yale University | Humanized 3e10 antibodies, variants, and antigen binding fragments thereof |
WO2023172883A1 (en) | 2022-03-07 | 2023-09-14 | Alpine Immune Sciences, Inc. | Immunomodulatory proteins of variant cd80 polypeptides, cell therapies thereof and related methods and uses |
WO2023173026A1 (en) | 2022-03-10 | 2023-09-14 | Sorrento Therapeutics, Inc. | Antibody-drug conjugates and uses thereof |
WO2023178192A1 (en) | 2022-03-15 | 2023-09-21 | Compugen Ltd. | Il-18bp antagonist antibodies and their use in monotherapy and combination therapy in the treatment of cancer |
US20240103010A1 (en) | 2022-03-18 | 2024-03-28 | Compugen Ltd. | Pvrl2 and/or pvrig as biomarkers for treatment |
WO2023178357A1 (en) | 2022-03-18 | 2023-09-21 | Evolveimmune Therapeutics, Inc. | Bispecific antibody fusion molecules and methods of use thereof |
WO2023186756A1 (en) | 2022-03-28 | 2023-10-05 | F. Hoffmann-La Roche Ag | Interferon gamma variants and antigen binding molecules comprising these |
WO2023187657A1 (en) | 2022-03-30 | 2023-10-05 | Novartis Ag | Methods of treating disorders using anti-natriuretic peptide receptor 1 (npr1) antibodies |
WO2023191816A1 (en) | 2022-04-01 | 2023-10-05 | Genentech, Inc. | Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies |
US20230406930A1 (en) | 2022-04-13 | 2023-12-21 | Genentech, Inc. | Pharmaceutical compositions of therapeutic proteins and methods of use |
WO2023209177A1 (en) | 2022-04-29 | 2023-11-02 | Astrazeneca Uk Limited | Sars-cov-2 antibodies and methods of using the same |
WO2023215737A1 (en) | 2022-05-03 | 2023-11-09 | Genentech, Inc. | Anti-ly6e antibodies, immunoconjugates, and uses thereof |
TW202400638A (en) | 2022-05-10 | 2024-01-01 | 法商感應檢查療法公司 | Anti-btn3a antibodies for use in methods of treating gastro-intestinal inflammatory disorders |
WO2023219613A1 (en) | 2022-05-11 | 2023-11-16 | Genentech, Inc. | Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies |
WO2023217933A1 (en) | 2022-05-11 | 2023-11-16 | F. Hoffmann-La Roche Ag | Antibody that binds to vegf-a and il6 and methods of use |
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 |
WO2023237928A2 (en) | 2022-06-10 | 2023-12-14 | Horizon Therapeutics Ireland Dac | Igf1r antibodies |
WO2023242372A1 (en) | 2022-06-15 | 2023-12-21 | argenx BV | Fcrn/hsa binding molecules and methods of use |
WO2023245048A1 (en) | 2022-06-15 | 2023-12-21 | Bioverativ Usa Inc. | Anti-complement c1s antibody formulation |
WO2023250507A1 (en) | 2022-06-24 | 2023-12-28 | Bioverativ Usa Inc. | Methods for treating complement-mediated diseases |
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 |
WO2024020407A1 (en) | 2022-07-19 | 2024-01-25 | Staidson Biopharma Inc. | Antibodies specifically recognizing b- and t-lymphocyte attenuator (btla) and uses thereof |
WO2024020579A1 (en) | 2022-07-22 | 2024-01-25 | Bristol-Myers Squibb Company | Antibodies binding to human pad4 and uses thereof |
WO2024020564A1 (en) | 2022-07-22 | 2024-01-25 | Genentech, Inc. | Anti-steap1 antigen-binding molecules and uses thereof |
WO2024026496A1 (en) | 2022-07-28 | 2024-02-01 | Compugen Ltd. | Combination therapy with anti-pvrig antibodies formulations and anti-pd-1 antibodies |
WO2024028731A1 (en) | 2022-08-05 | 2024-02-08 | Janssen Biotech, Inc. | Transferrin receptor binding proteins for treating brain tumors |
WO2024028732A1 (en) | 2022-08-05 | 2024-02-08 | Janssen Biotech, Inc. | Cd98 binding constructs for treating brain tumors |
WO2024037633A2 (en) | 2022-08-19 | 2024-02-22 | Evive Biotechnology (Shanghai) Ltd | Formulations comprising g-csf and uses thereof |
WO2024044675A1 (en) | 2022-08-25 | 2024-02-29 | Beigene, Ltd. | Methods of cancer treatment using anti-pd1 antibodies in combination with anti-tim3 antibodies |
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 |
WO2024052503A1 (en) | 2022-09-08 | 2024-03-14 | Institut National de la Santé et de la Recherche Médicale | Antibodies having specificity to ltbp2 and uses thereof |
WO2024077018A2 (en) | 2022-10-04 | 2024-04-11 | Alpine Immune Sciences, Inc. | Methods and uses of taci-fc fusion immunomodulatory protein |
WO2024074498A1 (en) | 2022-10-04 | 2024-04-11 | Imcheck Therapeutics | Combination of a btn3a activating antibody, a bcl2 inhibitor and hypomethylating agent for use in treating cancer |
WO2024077239A1 (en) | 2022-10-07 | 2024-04-11 | Genentech, Inc. | Methods of treating cancer with anti-c-c motif chemokine receptor 8 (ccr8) antibodies |
-
1994
- 1994-06-15 JP JP7501518A patent/JPH08511420A/en active Pending
- 1994-06-15 WO PCT/GB1994/001290 patent/WO1994029351A2/en not_active Application Discontinuation
- 1994-06-15 AU AU69341/94A patent/AU691811B2/en not_active Ceased
- 1994-06-15 EP EP94917750A patent/EP0714409A1/en not_active Withdrawn
- 1994-06-15 CA CA 2163345 patent/CA2163345A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
WO1994029351A3 (en) | 1994-12-22 |
EP0714409A1 (en) | 1996-06-05 |
AU691811B2 (en) | 1998-05-28 |
WO1994029351A2 (en) | 1994-12-22 |
CA2163345A1 (en) | 1994-12-22 |
JPH08511420A (en) | 1996-12-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU691811B2 (en) | Antibodies | |
EP0715653B1 (en) | Humanised antibodies | |
AU2004283135B2 (en) | Antibodies having a mutated amino acid residue at position 268 (CH2 region) in constant regions | |
US5834597A (en) | Mutated nonactivating IgG2 domains and anti CD3 antibodies incorporating the same | |
CA2212750C (en) | Humanized antibodies against cd3 | |
CN116333133A (en) | anti-GPRC 5D antibodies, bispecific antigen binding molecules binding GPRC5D and CD3 and uses thereof | |
US20020032312A1 (en) | Therapeutic compounds comprised of anti-fc receptor antibodies | |
EP1362868A2 (en) | Humanized and chimeric monoclonal antibodies that bind epidermal growth factor receptor (EGF-R) | |
PL180157B1 (en) | Humanised antibodies and their application | |
JP2004000249A (en) | Preparation of antibody | |
AU2004245038A1 (en) | De-immunized anti-CD3 antibody | |
CA2295604C (en) | Lo-cd2a antibody and uses thereof for inhibiting t cell activation and proliferation | |
US5730979A (en) | LO-CD2a antibody and uses thereof for inhibiting T cell activation and proliferation | |
KR20040020866A (en) | Silenced anti-CD28 antibodies and use therof | |
JP2001521374A (en) | LO-CD2a antibody inhibiting T cell activation and proliferation and use thereof | |
JP4808841B2 (en) | LO-CD2a antibodies that inhibit T cell activation and proliferation and methods of use thereof | |
AU778551B2 (en) | Novel peptide and screening method by using the same | |
JP2024508048A (en) | Preparation of Siglec-15 binding protein and its use |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |