WO2015105926A1 - Polynucléotides pour la production in vivo d'anticorps - Google Patents
Polynucléotides pour la production in vivo d'anticorps Download PDFInfo
- Publication number
- WO2015105926A1 WO2015105926A1 PCT/US2015/010547 US2015010547W WO2015105926A1 WO 2015105926 A1 WO2015105926 A1 WO 2015105926A1 US 2015010547 W US2015010547 W US 2015010547W WO 2015105926 A1 WO2015105926 A1 WO 2015105926A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- antibody
- polynucleotides
- antibodies
- fragment
- present
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/40—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against enzymes
-
- 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
-
- 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
- C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/53—DNA (RNA) vaccination
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/10—Immunoglobulins specific features characterized by their source of isolation or production
- C07K2317/14—Specific host cells or culture conditions, e.g. components, pH or temperature
Definitions
- 61/924,781 filed January 8, 2014, entitled Polynucleotides For The In Vivo Production of Antibodies
- U.S. Provisional Patent Application No. 61/924,783 filed January 8, 2014, entitled Polynucleotides For The In Vivo Production of Antibodies
- U.S. Provisional Patent Application No. 61/924,787 filed January 8, 2014, entitled Polynucleotides For The In Vivo Production of Antibodies
- 61/924,805 filed January 8, 2014, entitled Polynucleotides For The In Vivo Production of Antibodies
- U.S. Provisional Patent Application No. 61/924,807 filed January 8, 2014, entitled Polynucleotides For The In Vivo Production of Antibodies
- U.S. Provisional Patent Application No. 61/924,810 filed January 8, 2014, entitled Polynucleotides For The In Vivo Production of Antibodies
- 61/924,820 filed January 8, 2014, entitled Polynucleotides For The In Vivo Production of Antibodies
- U.S. Provisional Patent Application No. 61/924,754 filed January 8, 2014, entitled Polynucleotides For The In Vivo Production of Antibodies
- U.S. Provisional Patent Application No. 61/924,763 filed January 8, 2014, entitled Polynucleotides For The In Vivo Production of Antibodies
- 61/924,768 filed January 8, 2014, entitled Polynucleotides For The In Vivo Production of Antibodies
- U.S. Provisional Patent Application No. 61/924,775 filed January 8, 2014, entitled Polynucleotides For The In Vivo Production of Antibodies
- U.S. Provisional Patent Application No. 61/924,791 filed January 8, 2014, entitled Polynucleotides For The In Vivo Production of Antibodies
- 61/924,804 filed January 8, 2014, entitled Polynucleotides For The In Vivo Production of Antibodies
- U.S. Provisional Patent Application No. 61/924,812 filed January 8, 2014, entitled Polynucleotides For The In Vivo Production of Antibodies
- U.S. Provisional Patent Application No. 61/924,827 filed January 8, 2014, entitled Polynucleotides For The In Vivo Production of Antibodies
- 61/924,834 filed January 8, 2014, entitled Polynucleotides For The In Vivo Production of Antibodies
- U.S. Provisional Patent Application No. 61/924,841 filed January 8, 2014, entitled Polynucleotides For The In Vivo Production of Antibodies
- U.S. Provisional Patent Application No. 61/924,846 filed January 8, 2014, entitled Polynucleotides For The In Vivo Production of Antibodies and U.S. Provisional Patent Application No.
- the invention relates to compositions, methods, processes, kits and devices for the design, preparation, manufacture and/or formulation of antibodies in vivo.
- Antibodies also known as immunoglobulins, are glycoproteins produced by B cells. Using a unique and highly evolved system of recognition, antibodies can recognize a target and tag a target epitope, foreign entity or invading microbe for attack by the immune system thereby neutralizing its effect. The production of antibodies is the main function of the humoral immune system. Antibodies are secreted by a plasma cell which is a type of white blood cell.
- Antibodies occur in two physical forms, a soluble form that is secreted from the cell, and a membrane-bound form that is attached to the surface of a B cell and is referred to as the B cell receptor (BCR). Soluble antibodies are released into the blood and tissue fluids, as well as many secretions to continue to survey for invading microorganisms .
- BCR B cell receptor
- the majority of antibodies comprise two heavy chains and two light chains. There are several different types of antibody heavy chains, and several different kinds of antibodies, which are grouped into different isotypes based on which heavy chain they possess. Five different antibody isotypes isotypes (IgA, IgD, IgE, IgG and IgM) are known in mammals and trigger a different immune response for each different type of foreign object, epitope or microbe they encounter.
- IgA, IgD, IgE, IgG and IgM Five different antibody isotypes isotypes (IgA, IgD, IgE, IgG and IgM) are known in mammals and trigger a different immune response for each different type of foreign object, epitope or microbe they encounter.
- the binding of an antibody to an antigen has no direct biological effect. Rather, the significant biological effects are a consequence of secondary "effector functions" of antibodies.
- the immunoglobulins mediate a variety of these effector functions. These functions include fixation of complement, binding of phagocytic cells, lymphocytes, platelets, mast cells, and basophils which have immunoglobulin receptors. This binding can activate the cells to perform some function.
- Some antibodies or immunoglobulins also bind to receptors on placental trophoblasts, which results in transfer of the immunoglobulin across the placenta. As a result, the transferred maternal antibodies provide immunity to the fetus and newborn.
- the present invention provides such methods and compositions for the in vivo production of antibodies.
- compositions, methods, processes, kits and devices for the design, preparation, and/or manufacture of antibodies in vivo are Described herein.
- FIG. 1 is a PRIOR ART schematic of the five classes of known antibodies. The figure was taken from the URL
- FIG. 2 is a schematic comparing (A) the human IgG antibody structure to (B) a bicistronic antibody of the invention.
- FIG. 3 is a schematic of two types of antibodies of the present invention. (A) an scFv antibody and (B) a single domain IgG antibody.
- FIG. 4 is a schematic of two types of antibodies of the present invention. (A) a bispecific antibody and (B) a single domain IgA antibody.
- FIG. 5 is a schematic of certain polynucleotide constructs of the present invention illustrating (A) the modular design of the encoding polynucleotides and (B) the domains or regions of a standard antibody unit.
- RNA ribonucleic acid
- One beneficial outcome is to cause intracellular translation of the nucleic acid and production of at least one encoded peptide or polypeptide of interest.
- compositions including pharmaceutical compositions
- methods for the design, preparation, manufacture and/or formulation of antibodies where at least one component of the antibody is encoded by a polynucleotide are directed, in part, to polynucleotides, specifically IVT
- polynucleotides chimeric polynucleotides and/or circular polynucleotides encoding one or more antibodies and/or components thereof.
- polynucleotides are preferably modified in a manner as to avoid the deficiencies of or provide improvements over other antibody molecules of the art.
- antibodies or portions thereof encoded by polynucleotide(s) and antibody compositions comprising at least one polynucleotide which have been designed to produce a therapeutic outcome and optionally improve one or more of the stability and/or clearance in tissues, receptor uptake and/or kinetics, cellular access, engagement with translational machinery, m NA half-life, translation efficiency, protein production capacity, secretion efficiency (when applicable), accessibility to circulation, protein half-life and/or modulation of a cell's status, antibody target affinity and/or specificity, reduction of antibody cross reactivity, increase of antibody purity, increase or alteration of antibody effector function and/or antibody activity.
- the methods of the present invention are and can be utilized to engineer novel polynucleotides for the in vivo production of antibodies in such a manner as to provide improvements over standard antibody technology.
- the polynucleotides are designed to produce one or more antibodies, or combinations of antibodies selected from the group consisting of IgA, IgG, IgM, IgE, and IgD.
- the resultant antibodies expressed in a cell, tissue or organism from the polynucleotides of the present invention may have the following properties which mirror those of the natural isotype. They may also exhibit improved properties over the native or natural isotype.
- IgM cells B cell domain on CH4 chain
- J chain disulfide known as J chain and/or clumping
- anchoring associates with antigens
- the polynucleotides described herein may encode a human IgG construct as described in Figure 2A.
- compositions of the present invention comprise polynucleotides which encode the antibody, fragments of the antibody or variants of the antibody and are collectively referred to as "polynucleotides” “antibody polynucleotides” “constructs” or “antibody constructs.”
- compositions of the invention which comprise at least one polynucleotide are referred to as “compositions” or “antibody compositions.”
- the polypeptides encoded by the polynucleotides are collectively referred to as polypeptides, whether the polypeptides are variants, fragments or the entire antibody.
- the polynucleotides or compositions may be administered as a targeted adaptive vaccine, as disclosed in copending International application number
- the polynucleotides or compositions be administered as a neutralizing antibody.
- a tolerizing polynucleotide may be included, such as those described in copending International Application No. PCT/US2014/061104, filed October 17, 2014 (Attorney Docket No. M059), the contents of which are incorporated herein by reference in their entirety.
- nucleic acid molecules specifically polynucleotides which, in some embodiments, encode one or more peptides or polypeptides of interest.
- Such peptides or polypeptides, according to the invention are those derived from at least one of the antibodies described herein.
- nucleic acid in its broadest sense, includes any compound and/or substance that comprise a polymer of nucleotides. These polymers are often referred to as polynucleotides.
- nucleic acids or polynucleotides of the invention include, but are not limited to, ribonucleic acids (RNAs), deoxyribonucleic acids (DNAs), threose nucleic acids (TNAs), glycol nucleic acids (GNAs), peptide nucleic acids (PNAs), locked nucleic acids (LNAs, including LNA having a ⁇ - D-ribo configuration, a-LNA having an a-L- ribo configuration (a diastereomer of LNA), 2'-amino-LNA having a 2 '-amino functionalization, and 2'-amino- a-LNA having a 2'-amino functionalization), ethylene nucleic acids (ENA), cyclohexenyl nucleic acids (CeNA) or hybrids or combinations thereof.
- RNAs ribonucleic acids
- DNAs deoxyribonucleic acids
- TAAs threose nucle
- IVT polynucleotides linear polynucleotides encoding one or more antibody constructs of the present invention which are made using only in vitro transcription (IVT) enzymatic synthesis methods are referred to as "IVT polynucleotides.”
- IVT polynucleotides Methods of making IVT polynucleotides are known in the art and are described in co-pending International Publication No. WO2013151666 filed March 9, 2013 (Attorney Docket Number M300), the contents of which are incorporated herein by reference in their entirety.
- polynucleotides of the present invention which have portions or regions which differ in size and/or chemical modification pattern, chemical modification position, chemical modification percent or chemical modification population and combinations of the foregoing are known as "chimeric polynucleotides.”
- a “chimera” according to the present invention is an entity having two or more incongruous or heterogeneous parts or regions.
- a "part" or “region” of a polynucleotide is defined as any portion of the polynucleotide which is less than the entire length of the polynucleotide.
- Such constructs are taught in for example copending International Patent Application No. PCT/US2014/053907, filed September 3, 2014 (Attorney Docket Number M57), the contents of which are incorporated herein by reference in their entirety.
- the polynucleotides of the present invention that are circular are known as “circular polynucleotides” or "circP.”
- “circular polynucleotides” or “circP” means a single stranded circular polynucleotide which acts substantially like, and has the properties of, an RNA.
- the term “circular” is also meant to encompass any secondary or tertiary configuration of the circP.
- Such constructs are taught in for example copending International Application No. PCT/US2014/053904, filed September 3, 2014 (Attorney Docket Number M051) and International Application No. PCT/US2014/053907, filed September 3, 2014 (Attorney Docket Number M057), the contents of each of which are incorporated herein by reference in their entirety.
- the polynucleotide includes from about 30 to about 100,000 nucleotides (e.g., from 30 to 50, from 30 to 100, from 30 to 250, from 30 to 500, from 30 to 1,000, from 30 to 1,500, from 30 to 3,000, from 30 to 5,000, from 30 to 7,000, from 30 to 10,000, from 30 to 25,000, from 30 to 50,000, from 30 to 70,000, from 100 to 250, from 100 to 500, from 100 to 1,000, from 100 to 1,500, from 100 to 3,000, from 100 to 5,000, from 100 to 7,000, from 100 to 10,000, from 100 to 25,000, from 100 to 50,000, from 100 to 70,000, from 100 to 100,000, from 500 to 1,000, from 500 to 1,500, from 500 to 2,000, from 500 to 3,000, from 500 to 5,000, from 500 to 7,000, from 500 to 10,000, from 500 to 25,000, from 500 to 50,000, from 500 to 70,000, from 500 to 100,000, from 1,000 to 1,500, from 1,000, from 500 to 2,000, from 500 to 3,000, from 500 to 5,000
- the polynucleotides of the present invention may encode at least one peptide or polypeptide of interest.
- the polypeptide of interest comprises at least one antibody described herein, or fragments or variants thereof.
- the polynucleotides have a modular design to encode the polypeptides of interest.
- the polynucleotides have a modular design to encode at least one of the antibodies, fragments or variants thereof described hererin.
- the polynucleotide construct may encode any of the following designs: (1) the heavy chain of an antibody, (2) the light chain of an antibody, (3) the heavy and light chain of the antibody, (4) the heavy chain and light chain separated by a linker, (5) the VHl, CHI, CH2, CH3 domains, a linker and the light chain and (6) the VHl, CHI, CH2, CH3 domains, VL region, and the light chain. Any of these designs may also comprise optional linkers between any domain and/or region.
- the polynucleotides have a modular design and ecode a polypeptide of interest such as, but not limited to, an antibody, fragment or variant thereof described herein. Shown in Figure 5B are the domains or regions of a standard antibody unit.
- abciximab polynucleotides or constructs and their associated abciximab compositions are designed to produce the abciximab antibody, a variant or a portion thereof in vivo.
- Abciximab also be referred to herein as REOPRO® was originally derived from 7E3 (original monoclonal), c7E3 Fab (chimeric human-mouse Fab or F(ab')2 fragment and is provided under the brand name REOPRO®.
- Abciximab is an anticoagulant agent. It comprises an Fab fragment derived from a chimeric monoclonal IgG antibody (from human and murine origins.) Abciximab was designed based on the development of a monoclonal antibody by Barry Coller referred to as 7E3 (Coller, B.S. 1985. J Clin Invest. 76(1): 101-8.) Further studies by Coller et al demonstrated that F(ab')2 fragments of 7E3 were able to inhibit platelet aggregation in a dose-dependent manner in dogs (Coller et al, 1985. Blood. 66(6): 1456-9) and subsequent studies demonstrated a similar effect in humans (Ellis et al, 1993.
- the antibody binds the human platelet glycoprotein receptor Ilb/IIIa
- GPIIb/IIIa is an integrin adhesion receptor family member and represents the primary surface receptor responsible for platelet aggregation. Binding of Abciximab to this receptor inhibits platelet aggregation occurring through adhesive molecule binding, such as fibrinogen and von Willebrand factor, for example. Abciximab has also been shown to bind vitronectin (also known as a v p 3 integrin) receptor that is expressed by platelets as well as vascular endothelial and smooth muscle cells.
- vitronectin also known as a v p 3 integrin
- polynucleotides of the present invention may encode one or more portions of the antibody produced by hybridoma HB8832 as described by U.S. Patent Nos. 5,275,812 and 5,770,198, the contents of each of which are herein incorporated by reference in their entirety.
- Such polynucleotide-derived antibodies may comprise one or more portions of the antigen binding region of antibodies produced by hybridoma HB8832.
- antibodies encoded by polynucleotides of the present invention may comprise fragments of the antibody produced by hybridoma HB8832. Such fragments may include, but are not limited to Fab fragments or F(ab') 2 fragments, such as those described in U.S. Patent No. 5,440,020, the contents of which are herein incorporated by reference their entirety.
- Abciximab polypeptides or antibodies encoded by polynucleotides of the present invention may associate with the GPIIb/IIIa receptor. Such associations may prevent GPIIb/IIIa binding through steric hindrance as opposed to direct association with the amino acids of the receptor thought to form bonds with the GPIIb/IIIa RGD (arginine- glycine-aspartic acid) domain.
- Polynucleotide-derived antibodies disclosed herein may also bind vitronectin. Such binding may prevent activity associated with this receptor, including, but not limited to cell adhesion.
- antibodies encoded by polynucleotides of the present invention may also inhibit monocyte adhesion through association with the Mac-1 receptor of monocytes and neutrophils.
- Abciximab polynucleotides disclosed herein may be used in combination with percutaneous coronary intervention (PCI) in the prevention of complications associated with cardiac ischemic events. Such usage may be applied to subjects undergoing PCI and/or in subjects comprising unstable angina that may not be responding to typical treatment and that may be intended for PCI within about 24 hours. Further,
- polynucleotides of the present invention may be used with aspirin and/or heparin.
- Dose and regiment of the abciximab polynucleotides disclosed herein may be adjusted to achieve optimal antibody levels and/or activity as described in the REOPRO® manufacturer's administration guide and/or the FDA REOPRO® administration guide, the contents of each of which are herein incorporated by reference in their entirety.
- While contraindications associated with REOPRO® administration include internal bleeding, gastrointestinal bleeding, genitourinary bleeding, cerebrovascular accidents, bleeding diathesis, oral anticoagulants within 1 week of administration, thrombocytopenia, major surgery or trauma, intracranial neoplasm, arteriovenous malformation, aneurysm, severe uncontrolled hypertension, presumed or documented history of vasculitis, use of intravenous dextran before PCI and/or known hypersensitivity to components of the product or murine proteins, the polynucleotides on the present invention are expected to have fewer side effects and/or contraindications and as such these may be avoided by replacement with administration of polynucleotides disclosed herein.
- Abciximab antibodies encoded by polynucleotides of the present invention may remain in subjects until removal, e.g. through opsonization by way of the
- reticuloendothelial system facilitated by association with platelets.
- removal may occur due to anti-murine antibody production.
- polynucleotide-derived antibody levels may decrease rapidly, comprising a half- life of about 10 minutes or less during an initial phase, and a half-life of about 30 minutes during a second phase.
- the abciximab polynucleotides of the present invention are engineered such that they may comprise one or more coding regions.
- the coding regions of the abciximab polynucleotides may encode any of the regions or portions of the abciximab antibody. They may also further comprise coding regions not found in the original or parent abciximab antibody.
- the abciximab polynucleotides of the present invention may be engineered to produce any of the 5 standard classes of immunoglobulins as shown in Figure 1 using the abciximab antibody or any of its component parts as a starting molecule.
- the abciximab polynucleotides may also be engineered according to the present invention to produce a variant abciximab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- a variant abciximab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- adalimumab polynucleotides or constructs and their associated adalimumab compositions are designed to produce the adalimumab antibody, a variant or a portion thereof in vivo.
- Adalimumab also known as HUMIRA® was derived from clone D2E7 and developed by BASF Bioresearch Corporation and Cambridge Antibody Technology and manufactured by BASF Bioresearch Corporation, Abott Laboratories.
- Adalimumab is a fully human antibody developed using phage display technology to target tumor necrosis factor a [Kempeni, J. 1999. Ann Rheum Dis.
- Adalimumab is currently approved for treatment of a number of indications including rheumatoid arthritis, psoriasis as well as other inflammatory conditions.
- adalimumab polynucleotides of the present invention encode polypeptides (antibodies) which comprise 1330 amino acids with a molecular weight of about 148 kDa. Such antibodies may comprise Ig gamma-1 or Ig gamma-4. In some cases, adalimumab polynucleotides may encode IgG antibodies comprising two kappa light chains (approximately 24 kDa each) and two IgGl 2 ' a heavy chains
- adalimumab polynucleotides may encode any of the variable domain sequences and/or one or more of the complementarity determining regions (CDRs) disclosed in U.S. Patent No. 6,090,382, the contents of which are herein incorporated by reference in their entirety.
- CDRs complementarity determining regions
- the adalimumab antibodies of the present invention may specifically bind TNF-a. Such binding may prevent TNF-a signaling activity that typically occurs through the interaction between TNF-a and its cell surface receptors. Such receptors may include p55 and/or p75. In some cases, cells comprising surface expressed TNF-a may be subject to lysis upon treatment with mmRNA-derived antibodies disclosed herein.
- Adalimumab polynucleotides encoding antibodies of the present invention may be used to treat diseases of the immune system.
- diseases and/or conditions may include, but are not limited to rheumatoid arthritis (RA), psoriatic arthritis, ankylosing spondylitis and Crohn's disease.
- Adalimumab polynucleotide ecoded antibodies may comprise a half-life within subjects of from about 10 to about 20 days. Clearance rates for such antibodies may comprise about 12 ml/hour wherein subjects have been treated with a dose of about 0.25 mg/kg to about 10 mg/kg.
- Adalimumab antibody therapies in the art are known to be affected by interactions with other drugs. Combination with canakinumab, rilonacept and/or tofacitinib therapy may lead to increased immunosuppressive effects and/or elevated risk of infection. When combined with trastuzumab treatment, risk of neutropenia and/or anemia may be increased. During such combined therapy, subjects may be monitored for symptoms typical of adverse effects.
- the adalimumab polynucleotides of the present invention are not expected to exhibit all of the foregoing side effects or contraindications.
- the adalimumab polynucleotides of the present invention are engineered such that they may comprise one or more coding regions.
- the coding regions of the adalimumab polynucleotides may encode any of the regions or portions of the adalimumab antibody. They may also further comprise coding regions not found in the original or parent adalimumab antibody.
- the adalimumab polynucleotides of the present invention may be engineered to produce any of the 5 standard classes of immunoglobulins as shown in Figure 1 using the adalimumab antibody or any of its component parts as a starting molecule.
- the adalimumab polynucleotides may also be engineered according to the present invention to produce a variant adalimumab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- a variant adalimumab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- alemtuzumab polynucleotides or constructs and their associated alemtuzumab compositions are designed to produce the alemtuzumab antibody, a variant or a portion thereof in vivo.
- Alemtuzumab also known as CAMPATH® and Campath-1H is made by Genzyme.
- Graft-versus-host disease is a major issue facing bone marrow transplantation procedures. In the absence of treatment, such disease may prevent transplantation with marrow from unmatched donors and may affect 50%-70% of recipients receiving marrow from siblings that are fully matched.
- Alemtuzumab is a monoclonal antibody used to reduce lymphocyte populations. It functions by binding to lymphocyte surface glycoprotein CD52, leading eventually to antibody-dependent cell-mediated cytotoxicity (ADCC.) CD52 is expressed by a number of lymphocytic cells including monocytes, macrophages and granulocytes. It is not; however, expressed by erythrocytes or hematopoetic stem cells, enabling ADCC.
- alemtuzumab to selectively reduce lymphocyte numbers.
- Therapeutic uses for alemtuzumab include reducing the number of mature T lymphocytes from donor bone marrow prior to transplanting such bone marrow in a recipient (Hale, G. et al. 1983. Blood. 62(4):873-82) as well as in the treatment of B-cell chronic lymphocytic leukemia (CLL.)
- Alemtuzumab is a humanized monoclonal antibody developed by grafting complementarity determining regions (CDRs) from the rat monoclonal antibody, CAMPATH- 1G, onto a human IgGl, kappa framework and is characterized extensively by Crowe et al (Crowe, J.S. et al, 1992. Clin Exp Immunol. 87, 105-10, the contents of which are herein incorporated by reference in their entirety.) [00078] Polynucleotides of the present invention may encode campath-lH as described in Crowe, J.S. et al, 1992. Clin Exp Immunol. 87, 105-10 and/or U.S. Patent No. 6, 120,766, the contents of each of which are herein incorporated by reference in their entirety. In some cases, polynucleotides may encode one or more of the sequences listed in Table 4.
- polynucleotides of the present invention may be used to treat donor bone marrow prior to transplantation. Such treatment may lead to a reduction in the number of mature T lymphocytes, providing protection from graft- versus-host disease.
- Polynucleotide encoding antibodies of the present invention may comprise a volume of distribution of 0.18 L/kg.
- the half life of such antibodies may comprise from about 100 to about 300 hours. In some cases, the half life may comprise about 288 hours.
- Alemtuzumab treatment may lead to adverse effects when combined with other treatments.
- Combination with trastuzumab treatment may, in some cases, lead to an elevated risk for neutropenia and/or anemia.
- substitute treatment with polynucleotides of the present invention may avoid such adverse effects.
- alemtuzumab QVQLQESGPGLVRPSQTLSLTCTVSGFTFTDFYMNWVR 1 1 H-GAMMA- 1 QPPGRGLEWIGFIRDKAKGYTTEYNPSVKGRVTMLVDT (VH(1- SKNQFSLRLSSVTAADTAVYYCAREGHTAAPFDYWGQ
- the alemtuzumab polynucleotides of the present invention are engineered such that they may comprise one or more coding regions.
- the coding regions of the alemtuzumab polynucleotides may encode any of the regions or portions of the alemtuzumab antibody. They may also further comprise coding regions not found in the original or parent alemtuzumab antibody.
- the alemtuzumab polynucleotides of the present invention may be engineered to produce any of the 5 standard classes of immunoglobulins as shown in Figure 1 using the alemtuzumab antibody or any of its component parts as a starting molecule.
- the alemtuzumab polynucleotides may also be engineered according to the present invention to produce a variant alemtuzumab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- a variant alemtuzumab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- basiliximab polynucleotides or constructs and their associated basiliximab compositions are designed to produce the basiliximab antibody, a variant or a portion thereof in vivo.
- Basiliximab also known as SIMULECT® is a chimeric mouse-human anti- CD25 antibody. It is similar to another antibody, daclizumab.Basiliximab is chimeric version of RFT5, whereas daclizumab is humanized version of RFT5. The antibody is sold by Novartis Pharmaceuticals.
- Basiliximab is a chimeric monoclonal antibody (human and mouse components) that targets CD25 on T cells.
- CD25 is also known as interleukin (IL)-2 receptor alpha chain and it is expressed by activated T cells.
- Treatment with basiliximab may be carried out to prevent rejection of transplanted organs and/or tissues by reducing T cell populations in the transplanted organs and/or tissues.
- IL interleukin
- Basiliximab was developed using the variable domains of the mouse monoclonal anti-CD25 antibody, RFT5, and expressing them with human heavy and light chains, resulting in a chimeric antibody (mouse-human) as described in U.S. Patent No. 6,383,487, the contents of which are herein incorporated by reference in their entirety.
- antibodies encoded by polynucleotides of the present invention are about 144 kDa.
- Such polynucleotides may encode sequences from heavy and light chain constant domains derived from human IgGl and variable domains derived from mouse anti-CD25 antibody RFT5 as disclosed in Patent No. 6,383,487, the contents of which are herein incorporated by reference in their entirety.
- polynucleotides of the present invention may encode one or more of the amino acid sequences presented in Table 5.
- Antibodies encoded by polynucleotides of the present invention may inhibit IL-2-mediated lymphocyte activation. Such inhibition may be carried out through direct binding with the CD25 alpha subunit, preventing IL-2 from binding. Such inhibition may prevent immune attack of a foreign object, including organs such as kidneys that have been transplanted.
- polynucleotides of the present invention may be used to treat kidneys prior to transplantation. Such treatment reduce or eliminate T cells from donor organs, thereby slowing or preventing immune rejection of such organs by a recipient.
- combining basiliximab treatment with other therapeutics may result in additive and/or adverse effects (see basiliximab FDA label, the contents of which is herein incorporated by reference in its entirety.)
- Combined therapy with canakinumab and/or rilonacept may increase the immunosuppressive effects of basiliximab. In some cases, this may lead to elevated risk of infection.
- Combination with trastuzumab treatment may, in some cases, may lead to an elevated risk for neutropenia and/or anemia.
- Treatment using polynucleotides of the present invention may be used in place of basiliximab treatment in order to prevent adverse effects associated with interactions between basiliximab and other treatments.
- Treatment with basiliximab can lead to a variety of side effects (see the basiliximab FDA label, the contents of which is herein incorporated by reference in its entirety.) Treatment using polynucleotides of the present invention may be used in place of basiliximab treatment in order to prevent such side effects.
- Antibodies encoded by polynucleotides of the present invention may comprise half lives that range from about 4 days to about 7 days. Clearance of such antibodies may occur at differing rates depending on subject age. For example, clearance may occur in adult and adolescent subjects at a rate of from about 30 ml/h to about 45 ml/h. In pediatric subjects, clearance may be more rapid with rates of from about 15 ml/h to about 20 ml/h.
- the basiliximab polynucleotides of the present invention are engineered such that they may comprise one or more coding regions.
- the coding regions of the basiliximab polynucleotides may encode any of the regions or portions of the basiliximab antibody. They may also further comprise coding regions not found in the original or parent basiliximab antibody.
- the basiliximab polynucleotides of the present invention may be engineered to produce any of the 5 standard classes of immunoglobulins as shown in Figure 1 using the basiliximab antibody or any of its component parts as a starting molecule.
- the basiliximab polynucleotides may also be engineered according to the present invention to produce a variant basiliximab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- a variant basiliximab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- belimumab polynucleotides or constructs and their associated belimumab compositions are designed to produce the belimumab antibody, a variant or a portion thereof in vivo.
- Belimumab also known as BENLYSTA®, LYMPHOSTAT-B® and BmAb was initially developed by Human Genome Sciences and Medlmmune and licensed to Glaxo SmithKline .
- Belimumab is a fully human antibody that has been developed to treat autoimmune disorders. Belimumab targets B-lymphocyte stimulator (BLyS,) a member of the TNF family of signaling molecules (Drugs R D 2010; 10(l):55-65.) Binding prevents maturation of B-lymphocytes into mature B-cells.
- B-lymphocyte stimulator B-lymphocyte stimulator (BLyS,) a member of the TNF family of signaling molecules (Drugs R D 2010; 10(l):55-65.) Binding prevents maturation of B-lymphocytes into mature B-cells.
- scFv single chain variable fragment
- BLyS Baker, K.P. et al., 2003. Arthritis Rheum. 48(11):3253-65.
- High affinity candidates were further optimized to develop scFvs with optimal binding.
- Lead candidates were expressed with human IgG constant domains to produce fully human antibodies that were subjected to further characterization and selection for the ability to block BLyS signaling acitivity.
- a lead candidate, LymphoStat-B was identified and used to develop belimumab.
- polynucleotides of the present invention may encode a fully human antibody capable of binding and blocking the signal transduction of BLyS such as any of the antibodies described by Baker et al (Baker, K.P. et al, 2003. Arthritis Rheum. 48(11):3253-65, the contents of which are herein incorporated by reference in their entirety.)
- polynucleotides encode one or more variable domain portions of scFvs claimed in U.S. Patent Nos. 7,138,501 and/or 7,605,236, the contents of each of which are herein incorporated by reference in their entirety.
- polynucleotides may encode one or more components of one or more antibodies disclosed in any of U.S. Patent Nos. 7,138,501, 7,605,236, 7,879,328, 8,062,906, 8,071,092, 8,101,181, 8,173,122, 8,231,873 and/or 8,303,951, the contents of each of which are herein incorporated by reference in their entirety. Further, polynucleotides of the present invention may encode one or more of any of the sequences listed in Table 6.
- Polynucleotides of the present invention may encode one or more antibodies that bind BLyS and prevent signaling activity associated with it.
- Polynucleotides of the present invention may be used in the treatment of a number of diseases and/or conditions.
- diseases and/or conditions may include, but are not limited to systemic lupus erythematosus and rheumatoid arthritis.
- Belimumab treatment may lead to adverse effects when combined with other treatments.
- combined treatment with belatacept, denosumab, fingolimod and/or hydroxyurea may lead to elevation of immunosuppressive effects.
- combination with ado-trastuzumab emtansine and/or golimumab may increase the risk of developing one or more side effects associated with belimumab treatment.
- treatment with polynucleotides of the present invention in place of belimumab treatment may prevent adverse interactions with these other treatments.
- antibodies encoded by polynucleotides of the present invention may comprise a clearance rate in serum of from about 2 ml/day/kg to about 6 ml/day/kg.
- the belimumab polynucleotides of the present invention are engineered such that they may comprise one or more coding regions.
- the coding regions of the belimumab polynucleotides may encode any of the regions or portions of the belimumab antibody. They may also further comprise coding regions not found in the original or parent belimumab antibody.
- the belimumab polynucleotides of the present invention may be engineered to produce any of the 5 standard classes of immunoglobulins as shown in Figure 1 using the belimumab antibody or any of its component parts as a starting molecule.
- the belimumab polynucleotides may also be engineered according to the present invention to produce a variant belimumab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- a variant belimumab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- bevacizumab polynucleotides or constructs and their associated bevacizumab compositions are designed to produce the bevacizumab antibody, a variant or a portion thereof in vivo.
- Bevacizumab also known as AVASTIN® is manufactured by Roche
- Bevacizumab is a 149 kDa humanized monoclonal IgGl directed against human vascular endothelial growth factor (VEGF.) While the antibody framework comprises human components, the complimentarity-determining regions (CDRs) are derived from a murine anti-VEGF antibody A.4.6.1 (Presta et al. 1997. Cancer Res. 57(20):4593-9 and FDA label.) In preclinical models, bevacizumab has been tested for the treatment of a variety of cancer types and in combination with other cancer treatments (Chen, H.X. 2004. The Oncologist. Vol. 9, Suppl 1 :27-35.)
- Polynucleotides of the present invention may encode one or more of any of the heavy chain and/or light chain amino acid sequences, one or more of any of the variable and/or constant domain amino acid sequences and/or one or more of any of the CDR amino acid sequences disclosed in U.S. Patent No. US 7,060,269 and/or
- such encoded antibodies may comprise a Kj value that does not exceed about 1 x 10 "8 M.
- antibodies comprise human antibody framework residues and murine-derived CDR residues.
- some human framework residues are also replaced with murine framework residues.
- Such antibodies may comprise amino acid sequences that correspond with humanized antibodies and/or variable light and/or heavy domains taught by Presta et al (Presta et al. 1997. Cancer Res. 57(20):4593-9.)
- polynucleotide encoded antibodies disclosed herein may bind VEGF and inhibit VEGF activity by preventing interaction between VEGF and its receptors
- Such inhibition may prevent the growth and/or proliferation of vascular endothelial cells and lead to a reduction in the formation of blood vessels and or a reduction in the number of blood vessels.
- the reduction of blood vessel number and/or formation may reduce the nutrient delivery to cancerous cells, thereby reducing the number of such cells and/or killing them.
- the polynucleotides of the present invention may be used to treat multiple forms of cancer.
- Such cancers may include, but are not limited to metastatic kidney cancer, glioblastoma, non-small cell lung cancer, colorectal cancer and HER2 -negative breast cancer.
- they may be used to treat one or more tumors demonstrated to overexpress VEGF, such tumors including any of those indicated by Herbst et al.
- the polynucleotides may be combined with one or more other therapies to improve one or more therapeutic outcome.
- Combination with chemotherapy may promote longer times to progression and/or greater survival in subjects with cancer than with chemotherapy alone.
- Contraindications may comprise combined treatment with sunitinib.
- Such combined treatment may elevate the occurrence of adverse effects associated with bevacizumab and/or sunitinib treatment including, but not limited to hypertension, anemia and/or microangiopathic hemolytic anemia. It is expected that the polynucleotides of the present invention may overcomes some or all of these contraindications.
- the bevacizumab polynucleotides of the present invention are engineered such that they may comprise one or more coding regions.
- the coding regions of the bevacizumab polynucleotides may encode any of the regions or portions of the bevacizumab antibody. They may also further comprise coding regions not found in the original or parent bevacizumab antibody.
- the bevacizumab polynucleotides of the present invention may be engineered to produce any of the 5 standard classes of immunoglobulins as shown in Figure 1 using the bevacizumab antibody or any of its component parts as a starting molecule.
- the bevacizumab polynucleotides may also be engineered according to the present invention to produce a variant bevacizumab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- a variant bevacizumab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- brentuximab vedontin polynucleotides or constructs and their associated brentuximab vedontin compositions are designed to produce the brentuximab vedontin antibody, a variant or a portion thereof in vivo.
- SGN-35 is an antineoplastic agent comprising an anti-CD30 antibody conjugated with monomethyl auristatin (MMAE) by a protease-susceptible linker. It is designed to disrupt cell cycle progression by compromising the microtubule network formation in the cytosol. This prevents cells from entering mitosis at the end of the second gap phase.
- MMAE monomethyl auristatin
- Brentuximab vedontin is able to bind tumor cells expressing CD30, leading to
- Linker cleavage allows for release of MMAE which binds to components of the microtubule network leading to disruption.
- CD30 As a marker and immunotherapy target was carried out during the 1980s and 1990s leading to the development of anti- CD30 monoclonal antibodies, mostly generated using purified CD30 as an immunogen or Hodgkin's disease (HD) cell lines (see U.S. Patent No. 7,090,843.)
- Anti-CD30 antibody AC10 first described by Bowen et al (Bowen et al, 1993, J Immunol. 151 :5896-906,) was generated using an immunogen comprising CD30 from a human cell line, YT that more closely resembled natural killer cells. AC 10 was shown to be capable of arresting growth in CD30 expressing cells leading to attempts to modify it for clinical use.
- Wahl et al created a chimeric antibody, referred to as SGN-30 or cACIO, by cloning the variable domains of AC 10 into an expression construct encoding human IgGl heavy and light chain constant domains (Wahl, A.F. et al., 2002. Cancer Res. 62(13):3736-42.) These antibodies were shown to be capable of inducing apoptosis in HD cells. Further optimization by Francisco et al led to the drug conjugated form of the antibody embodied by Bretuximab vedontin (Francisco, J.A. et al, 2003. Blood. 102: 1458-65.)
- Polynucleotides encoding antibodies of the present invention may be used for the generation of antibody-drug conjugates (ADCs.) Such ADCs may be useful for delivery of payloads, including cytotoxic payloads. They may be used to target payloads to cells expressing CD30, including, but not limited to cancerous cells. Binding of such antibodies to CD30 on cell surfaces may lead to internalization of bound antibodies with or without conjugated payloads.
- ADCs antibody-drug conjugates
- Polynucleotide encoded antibodies disclosed herein may comprise one or more components of one or more antibodies disclosed in US Patent Nos. 7,090,843 or 8,257,706 or International Publication No. WO 2005/001038, the contents of each of which are herein incorporated by reference in their entirety.
- Such components may include, but are not limited to any heavy chain, light chain, variable domain, constant domain and/or any complementarity-determining regions (CDRs.)
- Amino acid and/or nucleotide sequences for these components may include any of those listed in Table 1 of US Patent No. 7,090,843.
- Polynucleotides of the present invention may be used to treat multiple forms of cancer.
- Such forms of cancer may include, but are not limited to Hodgkin's lymphoma and anaplastic large cell lymphoma.
- Non-Hodgkin's lymphoma refers to any of a large group of cancers of lymphocytes (white blood cells). Non-Hodgkin lymphomas can occur at any age and are often marked by lymph nodes that are larger than normal, fever, and weight loss. There are many different types of non-Hodgkin lymphoma. These types can be divided into aggressive (fast-growing) and indolent (slow-growing) types, and they can be formed from either B-cells or T-cells.
- B-cell non-Hodgkin lymphomas include Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and mantle cell lymphoma.
- T-cell non-Hodgkin lymphomas include mycosis fungoides, anaplastic large cell lymphoma, and precursor T-lymphoblastic lymphoma. Lymphomas that occur after bone marrow or stem cell transplantation are usually B-cell non-Hodgkin lymphomas. Prognosis and treatment depend on the stage and type of disease.
- Polynucleotides of the present invention may avoid one or more of the contraindications, side effects or adverse drug reactions associated with brentuximab vedontin (see the FDA label for contraindications, the contents of which are herein incorporated by reference in their entirety.)
- the brentuximab vedontin polynucleotides of the present invention are engineered such that they may comprise one or more coding regions.
- the coding regions of the brentuximab vedontin polynucleotides may encode any of the regions or portions of the brentuximab vedontin antibody. They may also further comprise coding regions not found in the original or parent brentuximab vedontin antibody.
- the brentuximab vedontin polynucleotides of the present invention may be engineered to produce any of the 5 standard classes of immunoglobulins as shown in Figure 1 using the brentuximab vedontin antibody or any of its component parts as a starting molecule.
- the brentuximab vedontin polynucleotides may also be engineered according to the present invention to produce a variant brentuximab vedontin antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- a variant brentuximab vedontin antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., d
- canakinumab polynucleotides or constructs and their associated canakinumab compositions are designed to produce the canakinumab antibody, a variant or a portion thereof in vivo.
- Canakinumab also known as ILARIS® or ACZ-885 is a fully human monoclonal antibody (IgGl/ ⁇ isotype subclass) directed against interleukin (IL)-ip, and capable of blocking IL- ⁇ signal transduction without interfering with other IL-1 family member signaling (Lachmann H.J. et al. 2009. N Engl J Med. 360(23):2416-25.)
- Canakinumab was generated by immunizing mice with human IL- ⁇ (Alten H. et al. 2008. Arthritis Research & Therapy. 10:R67.) These mice were genetically engineered to comprise a portion of the human immunoglobulin repertoire.
- Hybridomas were generated from these immunized mice and clones were selected based on the production of high affinity antibodies for IL- ⁇ .
- ACZ885 produced by one of these clones was found to have an affinity for IL- ⁇ of 40 pmol/L with no cross-reactivity for human IL-l or murine IL- ⁇ ⁇ .
- Polynucleotide encoded antibodies of the present invention may comprise human heavy and light chains. Such antibodies may comprise any of the heavy and/or light chain sequences disclosed in U.S. Patent Nos. 7,446,175 and/or 8,105,587, the contents of each or which are herein incorporated by reference in their entirety. Further, polynucleotide encoded antibodies disclosed herein may comprise one or more of the CDR amino acid sequences disclosed in those patents.
- Polynucleotide encoded antibodies of the present invention may bind IL-1 ⁇ and prevent IL- ⁇ signal transduction. Such binding may comprise high affinity binding with a K D of from about 25 to about 35 pM.
- RA Rheumatoid arthritis
- RA is a chronic autoimmune disease that causes pain, stiffness, swelling and limited motion and function of many joints. While RA can affect any joint, the small joints in the hands and feet tend to be involved most often.
- Inflammation sometimes can affect organs as well, for instance, the eyes or lungs.
- One possible mechanism of RA is that the immune system of patients is abnormal and attacks the body and creates inflammation. There is no cure for RA.
- Current treatments can lessen the symptoms and slow the dysfunction of the joints (Alten H. et al. 2008. Arthritis Research & Therapy. 10:R67.)
- Polynucleotide encoded antibodies of the present invention may reduce or eliminate symptoms in subjects inflicted with RA.
- Antibody levels achieved by therapeutic treatments of the present invention as well as outcomes of therapy may comprise any of the levels and outcomes as described by Alten et al (Alten H. et al. 2008. Arthritis Research & Therapy.
- Cryopyrin is a protein thought to play a role in regulating inflammatory and apoptotic processes. Cryopyrin mutations and/or deficiencies are associated with a group of inflammatory diseases known as cryopyrin-associated periodic syndromes (CAPS.) These diseases include chronic infantile neurological cutaneous and articular (CINCA) syndrome, familial cold autoinflammatory syndrome (FCAS), neonatal-onset
- polynucleotide encoded antibodies of the present invention may neutralize all or a portion of IL- ⁇ overexpressed in one or more forms of CAPS. Some treatments may be carried out on subjects ranging in age from very young to adult age. This includes subjects that may be about 4 years old and up.
- SJIA Systemic juvenile idiopathic arthritis
- SJIA Systemic juvenile idiopathic arthritis
- Diagnosis may be difficult in many cases due to the transient nature of rashes and fever.
- Internal organs may affected.
- Polynucleotide encoded antibodies of the present invention may reduce or eliminate symptoms associated with SJIA. Some treatments may be carried out on subjects ranging in age from very young to adult age. This includes subjects that may be about two years old and up.
- COPD chronic obstructive pulmonary disease
- COPD chronic obstructive pulmonary disease
- the disease is typically progressive and may result in a variety of symptoms that include cough, shortness of breath and elevated sputum production. Smoking is the most common cause of COPD, however other genetic and environmental factors may contribute to some cases (Wells, J.M. et al., 2013. Int J Chron Obstruct Pulmon Dis. 8:509-21.)
- Polynucleotide encoded antibodies of the present invention may reduce or eliminate symptoms associated with COPD.
- canakinumab treatment including, but not limited to headache, vertigo, diarrhea, nausea, musculoskeletal pain, rhinitis, nasopharyngitis, bronchitis and increased susceptibility to influenza
- side effects associated with canakinumab treatment may be avoided by replacement therapy with the polynucleotides of the invention.
- Certain sequences encoding canakinumab fragments, domains or heavy or light chains are given in Table 9. The table is not an exhaustive list and any fragment or portion of the sequence may be encoded in the canakinumab polynucleotides of the invention.
- the canakinumab polynucleotides of the present invention are engineered such that they may comprise one or more coding regions.
- the coding regions of the canakinumab polynucleotides may encode any of the regions or portions of the canakinumab antibody. They may also further comprise coding regions not found in the original or parent canakinumab antibody.
- the canakinumab polynucleotides of the present invention may be engineered to produce any of the 5 standard classes of immunoglobulins as shown in Figure 1 using the canakinumab antibody or any of its component parts as a starting molecule.
- the canakinumab polynucleotides may also be engineered according to the present invention to produce a variant canakinumab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- a variant canakinumab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- cetuximab polynucleotides or constructs and their associated cetuximab compositions are designed to produce the cetuximab antibody, a variant or a portion thereof in vivo.
- Cetuximab is an antineoplastic agent also known as ERBITUX®.
- Cetuximab originally referred to as C225, is a chimeric antibody comprised of variable domain regions of a mouse anti-epidermal growth factor receptor (EGFr) monoclonal antibody, known as 225, and human IgGl heavy and light chain constant domains. It interacts specifically with the N-terminal portion of the receptor and blocks binding of receptor ligand.
- EGFr mouse anti-epidermal growth factor receptor
- polynucleotides of the present invention may encode antibodies comprising one or more components of cetuximab.
- Such antibodies may comprise variable domain regions from the murine antibody 225 as described in U.S. Patent No. 6,217,866 and/or in Goldstein et al, 1995. Clin Cane Res. 1 : 1311-8; the contents of each of which are herein incorporated by reference in their entirety.
- Such antibodies may comprise chimeric combinations of such variable domain regions with human IgGl components. Such combinations may comprise those found in antibody C225 as described by U.S. Patent No. 6,217,866 and/or in Goldstein et al, 1995, Clin Cane Res.
- polynucleotides described herein may encode one or more of the heavy and/or light chain anti-EGFr antibody sequences listed in Table 10.
- polynucleotides of the present invention may encode one or more components of cetuximab (see cetuximab FDA label, incorporated herein by reference in its entirety)
- Polynucleotides of the present invention may encode antibodies that specifically bind and block signaling activity of EGF receptors. Such antibodies may reduce and/or halt cell growth and/or proliferation of cells expressing or overexpressing such receptors. In some cases, this may reduce or eliminate cancerous cells and/or tumors.
- EGFR is overexpressed in about a third of epithelial-derived cancers and enhanced signaling through this receptor is associated with tumor growth and
- polynucleotides of the present invention may be used as therapeutics to ultimately block EGFR activity and reduce or eliminate the spread of cancerous cells.
- Colorectal cancer comprises cancer of the colon, rectum or appendix and can lead to death in more than half of the patients suffering from the disease due to tumor metastasis (Xiang, B. 2013. Discov Med. 15(84):301-8.)
- a number of factors increase risk for the disease including gender, diet, smoking and level of physical activity.
- polynucleotides of the present invention may be used to treat CRCs.
- polynucleotide administration according to the present invention may offer the benefits of ERBITUX® treatment in such patients without the associated side effects.
- Antibodies encoded by polynucleotides of the present invention may comprise a rate of clearance in subject of from about 0.2 L/h/m 2 to about 0.8 L/h/m 2 . In some cases, such antibodies may comprise a volume of distribution of about 2 to about 3 L/m 2 . The half life of such antibodies may comprise from about 75 hours to about 188 hours.
- the cetuximab polynucleotides of the present invention are engineered such that they may comprise one or more coding regions.
- the coding regions of the cetuximab polynucleotides may encode any of the regions or portions of the cetuximab antibody. They may also further comprise coding regions not found in the original or parent cetuximab antibody.
- the cetuximab polynucleotides of the present invention may be engineered to produce any of the 5 standard classes of immunoglobulins as shown in Figure 1 using the cetuximab antibody or any of its component parts as a starting molecule.
- cetuximab polynucleotides may also be engineered according to the present invention to produce a variant cetuximab antibody which is selected from one of
- bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- certolizumab pegol polynucleotides or constructs and their associated certolizumab pegol compositions are designed to produce the certolizumab pegol antibody, a variant or a portion thereof in vivo.
- Certolizumab pegol is an antirheumatic TNF blocker also known as
- Certolizumab pegol comprises an Fab antibody fragment that binds tumor necrosis factor (TNF)a. It is conjugated to a polyethylene glycol (PEG) moiety that is about 40 kDa in size.
- PEG polyethylene glycol
- the PEG facilitates a delay in metabolism of the fragment leading to a longer half life in subjects being treated (Chapman A.P. et al., 1999. Nature Biotech. 17:780-3.)
- Certolizumab pegol was derived humanizing a mouse anti-human TNFa antibody.
- the mouse antibody was selected based on high affinity for TNFa and the complementarity determining regions (CDRs) from that antibody were inserted into a human framework comprising an IgG Fab' fragment.
- CDRs complementarity determining regions
- several other residues were also transferred to ensure structural integrity of the antigen-binding loop structures and maintenance of high affinity (Goel, N. et al., 2010. mAbs. 2(2): 137- 47.)
- Polynucleotides of the present invention may encode an Fab' fragment, such as any of those disclosed in U.S. Patent Nos. 7,012,135, 7,186,820 and 7,402,662, the contents of each of which are herein incorporated by reference in their entirety.
- polynucleotides may encode heavy and/or light chains or fragments thereof as disclosed in U.S. Patent Nos. 7,012,135, 7,186,820 and 7,402,662 or as presented in Table 11.
- one or more antibodies produced by polynucleotides of the present invention may be conjugated to one or more PEG. Conjugation of such moieties may slow or prevent clearance of such antibodies from the circulation. PEG conjugation may comprise or be carried out according to any of the examples and/or methods described in Chapman A.P. et al., 1999. Nature Biotech. 17:780-3; the contents of which are herein incorporated by reference in their entirety.
- Polynucleotides may encode one or more antibodies capable of binding TNFa and disrupting TNFa signaling activity. Such antibodies may be conjugated to one or more PEG moiety, such as any of those described by Chapment et al (Chapman A.P. et al., 1999. Nature Biotech. 17:780-3, the contents of which are herein incorporated by reference in their entirety.) PEG moieties may enable polynucleotide-encoded antibodies of the present invention to reduce, delay or avoid metabolic clearance
- Polynucleotides of the present invention may be used according to any therapy where it is desired to reduce and/or eliminate the level of TNFa, whether it be systemic or localized.
- Such therapies may be desired in diseases and/or conditions that may include, but are not limited to septic shock, endotoxic shock, cardiovascular shock, inflammation, neurodegeneration, cancer, hepatitis, respiratory distress, arthritis, psoriasis, autoimmune diseases, Crohn's disease and transplanted tissue/organ rejection.
- Rheumatoid arthritis is a chronic autoimmune disease that causes pain, stiffness, swelling and limited motion and function of many joints. While RA can affect any joint, the small joints in the hands and feet tend to be involved most often.
- polynucleotides of the present invention may be used to treat RA and alleviate or prevent one or more symptoms associated with that condition. Polynucleotide treatment may be carried out such that expression levels of translated products are about the same as the CDP870 antibody fragments used in Choy E.H.S. et al., 2002. Rheumatology. 41 : 1133-7, the contents of which are herein incorporated by reference in their entirety.
- Psoriatic arthritis is a condition affecting as much as 30% of subjects suffering from psoriasis and is characterized by persistent inflammatory arthritis. The condition is progressive, leading to long-term tissue erosion and functional impairment in more than half of those afflicted (Mease, P.J. et al, 2013. Ann Rheum Dis. 73:48-55.)
- polynucleotides of the present invention may be used to treat psoriatic arthritis and alleviate or prevent one or more symptoms associated with that condition.
- Crohn's Disease is a debilitating disease that frequently causes diarrhea and abdominal cramps as well as fever, bleeding, and weight loss (Baran, B. et al, 2013. ISRN Gastroenterology. 2013:208073.) It is characterized by random regions of inflammation within any area of the gastrointestinal tract.
- polynucleotides of the present invention may be used to treat Crohn's disease and alleviate or prevent one or more symptoms associated with that condition.
- primary endpoints may comprise American College of Rheumatology 20% (ACR20) response as determined at week 12 and/or modified Total Sharp Score change from baseline at the 24 th week of treatment (see Mease, P.J. et al, 2013. Ann Rheum Dis.
- Secondary endpoints may comprise Psoriatic Arthritis Response Criteria (PsARC) score, Psoriasis Area and Severity Index, Health Assessment Questionnaire Disability Index (HAQ-DI), Modified Nail Psoriasis Severity Index, Leeds Enthesitis Index and/or Leeds Dactylitis Index (Mease, P.J. et al., 2013. Ann Rheum Dis. 73:48-55.)
- PsARC Psoriatic Arthritis Response Criteria
- HAQ-DI Health Assessment Questionnaire Disability Index
- Modified Nail Psoriasis Severity Index Leeds Enthesitis Index and/or Leeds Dactylitis Index
- CIMZIA® treatment increases the risk of developing infections, with infections often developing in subjects that are also being treated with
- immunosuppressants that may include, but are not limited to methotrexate and/or corticosteroids (see CIMZIA® FDA label.) Such infections may include, but are not limited to tuberculosis (TB) infection and infections resulting from virus, fungi and/or bacterial proliferation.
- treatment with polynucleotides of the present invention may be used to avoid the elevated infection risk associated with CIMZIA® treatment.
- CIMZIA® treatment may increase the risk of developing one or more forms of cancer.
- cancers may include lymphoma.
- treatment with polynucleotides of the present invention may be used to avoid the elevated risk of developing cancer associated with CIMZIA®.
- the certolizumab pegol polynucleotides of the present invention are engineered such that they may comprise one or more coding regions.
- the coding regions of the certolizumab pegol polynucleotides may encode any of the regions or portions of the certolizumab pegol antibody. They may also further comprise coding regions not found in the original or parent certolizumab pegol antibody.
- the certolizumab pegol polynucleotides of the present invention may be engineered to produce any of the 5 standard classes of immunoglobulins as shown in Figure 1 using the certolizumab pegol antibody or any of its component parts as a starting molecule.
- the certolizumab pegol polynucleotides may also be engineered according to the present invention to produce a variant certolizumab pegol antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- a variant certolizumab pegol antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- daclizumab polynucleotides or constructs and their associated daclizumab compositions are designed to produce the daclizumab antibody, a variant or a portion thereof in vivo.
- Daclizumab also referred to as ZENAPAX, anti-Tac, anti-CD25,and anti- IL2Ralpha is an antibody developed by Protein Design Labs, Inc (3181 Porter Drive, Palo Alto, CA 94304) and subsequently acquired by Genentech and its parent company Roche.
- Daclizumab is an immunosuppressant humanized IgGl antibody used to prevent organ rejection in patients receiving a renal transplant.
- the monoclonal antibody binds to the IL2 receptor alpha subunit, also known as IL2Ralpha, CD25, or Tac.
- Daclizumab is a composite of human (90%) and murine (10%) antibody sequences.
- the human sequences were derived from the constant domains of human IgGl and the variable framework regions of the Eu myeloma antibody.
- the murine sequences were derived from the CDRs of a murine anti-Tac antibody.
- polynucleotide encoded antibodies according to the present invention may comprise one or more portions of the antibody as described by WO Patent No. 8909622 and U.S. patent Nos. 5,693,761and 7,521,054, the contents of each of which are herein incorporated by reference in their entirety.
- Such antibodies may comprise one or more portions of the variable regions, complementarity determining regions (CDR), and/or antigen binding region of antibodies as described by WO Patent No. 8909622 and U.S. patent Nos. 5,693,761and 7,521,054, the contents of each of which are herein incorporated by reference in their entirety.
- Daclizumab functions as an IL-2 receptor antagonist that inhibits IL-2 binding to the IL-2 receptor complex. Daclizumab binding is highly specific for Tac, which is expressed on activated but not resting lymphocytes. Administration of Daclizumab inhibits IL-2 -mediated activation of lymphocytes, a critical pathway in the cellular immune response involved in allograft rejection.
- the daclizumab polynucleotides of the present invention may be used as part of an immunosuppressive regimen including cyclosporine, mycophenolate mofetil, and corticosteroids. Prophylaxis of acute rejection has been demonstrated in recipients of kidney allografts when treated with daclizumab. Prophylaxis of acute rejection of other solid organs has not been demonstrated.
- daclizumab Several side effects and contraindications have been identified for daclizumab including but not limited to: gastrointestinal system (constipation, nausea, diarrhea, vomiting, abdominal pain, pyrosis, dyspepsia, abdominal distention, and epigastric pain not food-related); metabolic system (edema extremities, edema); central and peripheral nervous system (tremor, headache, dizziness); urinary system (oliguria, dysuria, renal tubular necrosis); general (posttraumatic pain, chest pain, fever, pain, fatigue); autonomic nervous system (hypertension, hypotension, aggravated hypertension); respiratory system (dyspnea, pulmonary edema, coughing); skin and appendages (impaired wound healing without infection, acne); psychiatric (insomnia); musculoskeletal system:
- the daclizumab polynucleotides of the present invention are engineered such that they may comprise one or more coding regions.
- the coding regions of the daclizumab polynucleotides may encode any of the regions or portions of the daclizumab antibody. They may also further comprise coding regions not found in the original or parent daclizumab antibody.
- the daclizumab polynucleotides of the present invention may be engineered to produce any of the 5 standard classes of immunoglobulins as shown in Figure 1 using the daclizumab antibody or any of its component parts as a starting molecule.
- the daclizumab polynucleotides may also be engineered according to the present invention to produce a variant daclizumab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- a variant daclizumab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- denosumab polynucleotides or constructs and their associated denosumab compositions are designed to produce the denosumab antibody, a variant or a portion thereof in vivo.
- Denosumab is also known as AMG 162, Prolia, Ranmark, and/or Xgeva.
- Denosumab commercial antibody was developed by Amgen, Inc. and is currently marketed under two trade names; Prolia for the treatment of post-menopausal osteoporosis and Xgena for the treatment of bone metastases from solid tumors.
- Denosumab is a fully human IgG2kappa monoclonal antibody that is used to prevent bone loss in osteopenic disorders including osteoporosis and solid tumor bone metastases.
- Bone remodeling is a homeostatic process that is balanced by the activity of osteoblasts (bone formation) and osteoclasts (bone degradation or resorption). The coupling of this system is achieved by three factors: receptor activator of nuclear factor kappa-B (RANK), receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoprotegrin (OPG).
- RANKL binding to RANK promotes osteoclast differentiation, leading to increased bone resorption.
- osteoprotegrin an inhibitor of receptor activator of nuclear factor kappa-B (RANKL) (Bekker PJ et al., 2001. J Bone Miner Res. 16(2):348-60).
- Denosumab originally referred to as AMG 162 was designed as a specific agonist inhibitor of RANKL activity.
- a Phase I safety trial conducted with AMG 162 was designed as a specific agonist inhibitor of RANKL activity.
- denosumab effectiveness of denosumab in the treatment of multiple myeloma and bone metastases associated with various cancers including, but not limited to, breast cancer (Body JJ et al, 2006. Clin Cancer Res. 15;12(4): 1221-8).
- polynucleotide encoded antibodies according to the present invention may comprise one or more portions of the antibody as described by U.S. Patent Nos. 7,364,736, 8058418 and 8409578, the contents of each of which are herein incorporated by reference in their entirety.
- nucleotide-derived antibodies may comprise one or more portions of the variable regions, complementarity determining regions (CDR), and/or antigen binding region of antibodies as described by U.S. Patent Nos. 7,364,736, 8058418 and 8409578, the contents of each of which are herein incorporated by reference in their entirety.
- Polynucleotide encoded antibodies of the present invention may directly bind to RANKL, preventing RANKL binding to RANK.
- RANKL targeting by nucleotide- derived antibodies of the present invention may inhibit osteoclast formation, function, and survival. Inhibition of osteoclast formation, function, and survival may alter bone remodeling dynamics such that bone resorption is decreased and bone formation is increased.
- the polynucleotide encoded antibodies of the present invention may be used to prevent bone resorption that leads to bone brittleness and fractures.
- Osteopenic disorders and certain cancers discussed herein are known to increase osteoclast activity and induce bone resorption.
- Breast, prostate, and multiple myeloma cancers are now known to produce factors that result in the over-expression of RANKL in the bone, and lead to increased osteoclast numbers and activity.
- Postmenopausal osteoporosis in women is a disease state of increased bone resorption resulting in brittle bones that may occur in older populations due to changes in the dynamics of bone remodeling factors.
- Osteopenic disorders may occur in conjunction with other factors and/or diseases including but not limited to adjuvant aromatase inhibitor therapy during breast cancer treatment, and men receiving androgen deprivation therapy for non-metastatic prostate cancer.
- Contraindications associated with denosumab include severe or fatal hypocalcemia; hypersensitivity reactions including hypotension, dyspnea, upper airway edema, lip swelling, rash, pruritis, urticarial, and anaphylaxis; osteonecrosis of the jaw, atypical femoral fractures, and embryo-fetal toxicity.
- polynucleotide encoded antibodies of the present invention may advantageously reduce or eliminate such contraindications.
- osteoopenic disorder refers to conditions that directly or indirectly lead to bone loss and/or brittleness and/or fracture including, but not limited to: breast, prostate, and multiple myeloma; osteoporosis, osteopenia, Paget's disease, lytic bone metastases, periodontitis, rheumatoid arthritis, and bone loss due to immobilization.
- the denosumab polynucleotides of the present invention are engineered such that they may comprise one or more coding regions.
- the coding regions of the denosumab polynucleotides may encode any of the regions or portions of the denosumab antibody. They may also further comprise coding regions not found in the original or parent denosumab antibody.
- the denosumab polynucleotides of the present invention may be engineered to produce any of the 5 standard classes of immunoglobulins as shown in Figure 1 using the denosumab antibody or any of its component parts as a starting molecule.
- the denosumab polynucleotides may also be engineered according to the present invention to produce a variant denosumab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- a variant denosumab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- Eculizumab Parent Molecule or Antibody [000224] According to the present invention, eculizumab polynucleotides or constructs and their associated eculizumab compositions are designed to produce the eculizumab antibody, a variant or a portion thereof in vivo.
- Eculizumab also known as 5G1.1 or the trade name Soliris is a commercial antibody packaged by by Alexion Parmaceuticals Inc. and Ben Venue Laboratories Inc. under the trade name Soliris for the treatment of paroxysmal nocturnal hemoglobinuria (PNH).
- PNH paroxysmal nocturnal hemoglobinuria
- Eculizumab is a recombinant humanized monoclonal IgG2/4;K antibody produced from Hybridoma 5G1.1 having ATCC designation HB-11625.
- Eculizumab contains human constant regions from human IgG2 sequences and human IgG4 sequences and murine complementarity-determining regions (CDRs) grafted onto the human framework light- and heavy-chain variable regions.
- CDRs complementarity-determining regions
- a genetic mutation in PNH patients leads to the generation of populations of abnormal red blood cells (RBCs) that are deficient in terminal complement inhibitors (CD-59), rendering PNH RBCs sensitive to persistent terminal complement-mediated destruction.
- RBCs red blood cells
- CD-59 terminal complement inhibitors
- the destruction and loss of these PNH cells results in low RBC counts (anemia) and also fatigue, difficulty in functioning, pain, dark urine, shortness of breath, and blood clots.
- Eculizumab is a monoclonal antibody that binds to the complement protein C5 specifically and with high affinity, thereby inhibiting its cleavage to C5a and C5b and subsequent generation of the terminal complement complex C5b-9. Eculizumab inhibits terminal complement mediated intravascular hemolysis in PNH patients and therefore the destruction of PNH erythrocytes that lack complement protection with CD-59.
- polynucleotide encoded antibodies according to the present invention may comprise one or more portions of the antibody as described by Patent Nos. US 6,074,642, WO1995029697, and US 6,355,245, the contents of each of which are herein incorporated by reference in their entirety.
- Such nucleotide-derived antibodies may comprise one or more portions of the variable regions, complementarity determining regions (CDR), and/or antigen binding region of antibodies as described by Patent Nos. US 6,074,642, WO1995029697, and US 6,355,245, the contents of each of which are herein incorporated by reference in their entirety.
- CDR complementarity determining regions
- the polynucleotide encoded antibodies of the present invention may directly bind to complement C5, preventing proteolytic degradation of RBCs that are deficient in terminal complement inhibitor CD-59.
- the polynucleotide encoded antibodies of the present invention may be used to reduce hemolysis in individuals with paroxysmal nocturnal hemoglobinuria (PNH). Nucleotide-derived antibodies of the present invention may also be used to inhibit complement-mediated thrombotic microangiopathy in individuals with atypical hemolytic uremic syndrome (aHUS).
- PNH paroxysmal nocturnal hemoglobinuria
- aHUS atypical hemolytic uremic syndrome
- Contraindications associated with eculizumab antibodies include unresolved serious Neisseria meningitides infection and patients who are not currently vaccinated against Neisseria meningitides.
- Other symptoms associated with eculizumab include, but are not limited to headache, nasopharyngitis, back pain, nausea, hypertension, upper respiratory tract infection, diarrhea, anemia, vomiting, urinary tract infection, and leukopenia. It is expected that the polynucleotide encoded antibodies of the present invention may overcome some or all of the contraindications or side effects associated with the eculizumab commercial antibody.
- the eculizumab polynucleotides of the present invention are engineered such that they may comprise one or more coding regions.
- the coding regions of the eculizumab polynucleotides may encode any of the regions or portions of the eculizumab antibody. They may also further comprise coding regions not found in the original or parent eculizumab antibody.
- the eculizumab polynucleotides of the present invention may be engineered to produce any of the 5 standard classes of immunoglobulins as shown in Figure 1 using the eculizumab antibody or any of its component parts as a starting molecule.
- the eculizumab polynucleotides may also be engineered according to the present invention to produce a variant eculizumab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- a variant eculizumab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- golimumab polynucleotides or constructs and their associated golimumab compositions are designed to produce the golimumab antibody, a variant or a portion thereof in vivo.
- Golimumab also known as SIMPONI®, CNT0148 and TNV148B, is a human IgGl -kappa monoclonal antibody derived from immunizing genetically engineered mice with human TNF-alpha developed by Centocor and Janessen Biotech in collaboration with Schering-Plough and Mitsubishi Tanabe Pharma.
- Golimumab is similar to the antibody Infliximab, except that is has been engineering to be fully human and it is usually given as a subcutaneous injection.
- Golimumab binds and inhibits soluble and transmembrane human TNF-alpha which is beneficial in those suffering from chronic inflammation caused by an increase in TNF-alpha.
- Golimumab was approved in 2009 by the FDA for the treatment of moderately-to-severely active rheumatoid arthritis (RA), active psoriatic arthritis (PsA), and active ankylosing spondylitis (AS) in adults.
- RA moderately-to-severely active rheumatoid arthritis
- PsA active psoriatic arthritis
- AS active ankylosing spondylitis
- Golimumab may be used as an adjunct to methotrexate treatment in subjects with RA or PsA. In 2013, Golimumab was approved by the FDA to treat adults with moderate to severe ulcerative colitis.
- the polynucleotides described herein encode a human IgGl -kappa golimumab monoclonal antibody or a fragment or variant thereof.
- These polynucleotide encoded antibodies can bind to and inhibit soluble and transmembrane human TNF-alpha.
- the inhibition of TNF-alpha can prevent the binding of TNF-alpha to its receptors which can prevent both leukocyte infiltration through prevention of cell adhesion proteins such as, but not limited to, E-selectin, ICAM-1 and VCAM-1, and proinflammatory cytokine secretion such as, but not limited to, IL-6, IL-8, G-CSF and GM- CSF.
- the polynucleotide can encode Golimumab polypeptides or a fragment or variant thereof.
- the polynucleotides described herein encode an antibody that does not bind to or neutralize other TNF superfamily ligands such as, but not limited to, lymphotoxin.
- the polynucleotide can encode Golimumab polypeptides or a fragment or variant thereof.
- the polynucleotides described herein encode a modulator of a target, such as, but not limited to, tumor necrosis factor (TNF).
- a modulator of a target such as, but not limited to, tumor necrosis factor (TNF).
- TNF tumor necrosis factor
- the polynucleotide can encode Golimumab polypeptides or a fragment or variant thereof which is known to modulate TNF-alpha in a subject.
- the polynucleotides described herein encode a tumor necrosis factor (TNF) blocker.
- TNF tumor necrosis factor
- the polynucleotides may then be used to reduce the effects of a substance in the body that can cause inflammation in a subject.
- the polynucleotide can encode Golimumab polypeptides or a fragment or variant thereof.
- a subject prior to treatment with the polynucleotides described herein a subject may be tested for infections such as, but not limited to, tuberculosis (TB).
- TB tuberculosis
- Hepatitis B infection is monitored with those undergoing treatment.
- polynucleotides described herein may encode
- Golimumab or a fragment or variant thereof may be used to treat a neurological disorder such as, but not limited to, certain forms of dementia.
- polynucleotides described herein may encode
- Golimumab or a fragment or variant thereof may be used to treat asthma.
- the polynucleotides described herein may encode may eliminate some, if not all, of the side effects associated with the commercial golimumab antibody.
- side effects include, but not limited to, body aches or pain, chills, cough, difficulty with breathing, ear congestion, fever, headache, loss of voice, muscle aches, sneezing, sore throat, stuffy or runny nose, unusual tiredness or weakness, blurred vision, feeling such as burning, crawling, itching, numbness, prickling, "pins and needles", or tingling, congestion, cough with mucus, diarrhea, dizziness, general feeling of discomfort or illness, hoarseness, joint pain, loss of appetite, muscle aches and pains, nausea, nervousness, pain or tenderness around the eyes and cheekbones, painful cold sores or blisters on the lips, pounding in the ears, shivering, shortness of breath or troubled breathing, slow or fast heartbeat, sweating, tender, swollen gland
- the polynucleotides described herein encoding golimumab polypeptide or a fragment or variant thereof are formulated for subcutaneous administration.
- the formulation may be a subcutaneous injection solution with 100 mg of drug in 1 mL of solution or 50 mg of drug in 0.5 mL of solution.
- the formulation may be stored for administration in a prefilled syringe such as, but not limited to a SMARTJECT® autoinjector.
- the polynucleotides described herein are formulated for perispinal extrathecal injection.
- polynucleotides of the invention have a half-life of at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 day or at least 14 days.
- the dose of the polynucleotides may be between 10 and 100 mg, including, but not limited to, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg and 100 mg.
- the polynucleotides described may be formulated for monthly subcutaneous injection for the treatment of ankylosing spondylitis or psoriatic arthritis.
- the amount of drug administered may be 50 mg per 0.5 mL.
- the treatment may be administered with or without methotrexate or other non- biologic Disease Modifying Antirheumatic Drugs (DMARDs).
- DMARDs non- biologic Disease Modifying Antirheumatic Drugs
- the polynucleotides described herein may be formulated for subcutaneous injections at Week 0, Week 2, Week 4 and every 4 weeks following Week 4 for the treatment of Ulcerative Colitis.
- the amount of drug administered may be 200 mg of drug at week 0, 100 mg of drug at week 2, 100 mg at Week 4 and 100 mg every 4 weeks after Week 4.
- the polynucleotides described herein are formulated for infusion administration.
- the infusion administration may be used in the treatment of moderately to severely active rheumatoid arthritis.
- the polynucleotides described herein may be formulated for intravenous infusion for the treatment of rheumatoid arthritis at Week 0, Week 4 and every 8 weeks after Week 4.
- the amount of drug administered may be 2 mg per kg administered over 30 minutes.
- the treatment may be administered with or without methotrexate.
- the polynucleotides may be administered while a subject is taking, corticosteroids, non-biologic Disease Modifying Antirheumatic Drugs (DMARDs), and/or non-steroidal anti-inflammatory drugs (NSAIDs).
- DMARDs non-biologic Disease Modifying Antirheumatic Drugs
- NSAIDs non-steroidal anti-inflammatory drugs
- the golimumab polynucleotides of the present invention are engineered such that they may comprise one or more coding regions.
- the coding regions of the golimumab polynucleotides may encode any of the regions or portions of the golimumab antibody. They may also further comprise coding regions not found in the original or parent golimumab antibody.
- the golimumab polynucleotides of the present invention may be engineered to produce any of the 5 standard classes of immunoglobulins as shown in Figure 1 using the golimumab antibody or any of its component parts as a starting molecule.
- the golimumab polynucleotides may also be engineered according to the present invention to produce a variant golimumab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- a variant golimumab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- ibritumomab polynucleotides or constructs and their associated ibritumomab compositions are designed to produce the ibritumomab antibody, a variant or a portion thereof in vivo.
- Ibritumomab also known as ZEVALIN® is a commercial monoclonal antibody that binds CD20 found on B cell surfaces. It is typically conjugated with the chelator tiuxetan, which facilitates attachment of a radioisotope such as yttrium-90 or indium- 111. It is often administered in coordination with Rituximab which also targets CD20. The two antibodies share similar VH domains. In some cases, administration is used to treat refractory non-Hodgkin's lymphoma (NHL) that develops after primary cancer treatment (Wagner, H.N. et al, 2002. J Nucl Med. 43(2):267-72.)
- NHS non-Hodgkin's lymphoma
- Ibritumomab comprises heavy and light chains of mouse origin, coming from the monoclonal antibody IDEC-Y2B8 (WHO Drug Information 14(1), 2000. List 43.) When conjugated with a radioisotope, ibritumomab is used to kill both normal and malignant B cells that express CD20, while sparing B cell precursors to allow for repopulation with healthy B cells (Hainsworth, J.D. 2000. Oncologist. 5(5):376-84.)
- Polynucleotides of the present invention may encode one or more antibodies capable of binding CD20.
- such antibodies may comprise the amino acid sequence of all or a portion of the commercial antibody, ibritumomab.
- Polynucleotides may encode heavy and/or light chain amino acid sequences of monoclonal antibody Y2B8 as described in U.S. Patent Nos. 5,736,137 and 5,776,456, the contents of each of which are herein incorporated by reference in their entirety. Some polynucleotides may encode one or more of the amino acid sequences listed in Table 16. Further,
- polynucleotides of the invention may encode one or more components of any of the antibodies described in U.S. Patent Nos. 5,736,137, 5,776,456, 6,399,061, 7,682,612, 7,744,877 and/or 8,557,244, the contents of each of which are herein incorporated by reference in their entirety.
- Antibodies produced by one or more polynucleotides disclosed herein may be conjugated with one or more chelator. Such chelators may comprise tiuxetan. In some cases chelated antibodies may be combined with one or more radioisotope. Such radioisotopes may include, but are not limited to yttrium-90 or indium- 111.
- treatment with such polynucleotides of the invention may be carried out in order to reduce or eliminate mature B lymphocyte populations.
- such treatments may be used to treat one or more forms of cancer.
- cancers may include, but are not limited to non-Hodgkin's lymphoma (NHL.)
- Non-Hodgkin's lymphoma refers to any of a large group of cancers of lymphocytes (white blood cells). Non-Hodgkin lymphomas can occur at any age and are often marked by lymph nodes that are larger than normal, fever, and weight loss. There are many different types of non-Hodgkin lymphoma. These types can be divided into aggressive (fast-growing) and indolent (slow-growing) types, and they can be formed from either B-cells or T-cells.
- B-cell non-Hodgkin lymphomas include Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and mantle cell lymphoma.
- T-cell non-Hodgkin lymphomas include mycosis fungoides, anaplastic large cell lymphoma, and precursor T-lymphoblastic lymphoma. Lymphomas that occur after bone marrow or stem cell transplantation are usually B-cell non-Hodgkin lymphomas. Prognosis and treatment depend on the stage and type of disease. Polynucleotides of the present invention may be used to treat NHL. Such treatment may comprise the expression of anti- CD20 antibodies capable of binding mature B lymphocytes, halting their growth and/or killing them.
- Adverse events associated with ibritumomab treatment may include any of those listed in Table 7 of the FDA label (herein incorporated by reference in its entirety.) In some cases, such adverse events may be avoided by replacing ibritumomab treatment with treatment with one or more polynucleotides of the present invention.
- the ibritumomab polynucleotides of the present invention are engineered such that they may comprise one or more coding regions.
- the coding regions of the ibritumomab polynucleotides may encode any of the regions or portions of the ibritumomab antibody. They may also further comprise coding regions not found in the original or parent ibritumomab antibody.
- the ibritumomab polynucleotides of the present invention may be engineered to produce any of the 5 standard classes of immunoglobulins as shown in Figure 1 using the ibritumomab antibody or any of its component parts as a starting molecule.
- the ibritumomab polynucleotides may also be engineered according to the present invention to produce a variant ibritumomab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- a variant ibritumomab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- infliximab polynucleotides or constructs and their associated infliximab compositions are designed to produce the infliximab antibody, a variant or a portion thereof in vivo.
- Infliximab also known as REMICADE® and Ig gamma- 1 chain C region, is a chimeric IgGl -kappa monoclonal antibody (composed of human constant and murine variable regions) specific for human tumor necrosis factor-alpha (TNF-alpha) developed by Centocor Pharmaceuticals.
- Infliximab is produced by a recombinant cell line cultured by continuous perfusion and is purified by a series of steps that includes measures to inactivate and remove viruses. Infliximab is similar to the commercial antibody
- Golimumab except that Golimumab has been engineering to be fully human.
- Infliximab is a monoclonal antibody that attaches to, and blocks the action of TNF-alpha by inhibiting binding of TNF-alpha with its receptors. Infliximab can also able to limit the activation of neutrophil and eosinophil functional activity, can reduce the production of tissue degrading enzymes produced by synoviocytes and/or chondrocytes and can decrease synovitis and joint erosions in collagen-induced arthritis to allows eroded joints to heal.
- the polynucleotides described herein encode a chimeric IgGl -kappa monoclonal antibody (composed of human constant and murine variable regions) or fragments or variants thereof specific for human tumor necrosis factor-alpha (TNF-alpha). These polynucleotides can bind to and inhibit soluble and transmembrane human TNF-alpha.
- TNF-alpha can prevent the binding of TNF-alpha to its receptors which can prevent both leukocyte infiltration through prevention of cell adhesion proteins such as, but not limited to, E-selectin, ICAM-1 and VCAM-1, and proinflammatory cytokine secretion such as, but not limited to, IL-6, IL-8, G-CSF and GM- CSF.
- cell adhesion proteins such as, but not limited to, E-selectin, ICAM-1 and VCAM-1
- proinflammatory cytokine secretion such as, but not limited to, IL-6, IL-8, G-CSF and GM- CSF.
- the polynucleotide can encode Infliximab or a fragment or variant thereof.
- the polynucleotides described herein encode a chimeric IgGl -kappa monoclonal antibody (composed of human constant and murine variable regions) or fragments or variants thereof specific for human tumor necrosis factor-alpha (TNF-alpha) and these polynucleotides encode an antibody that does not bind to or neutralize other TNF superfamily ligands such as, but not limited to, lymphotoxin.
- the polynucleotide can encode Infliximab or a fragment or variant thereof.
- the polynucleotides described herein encode a modulator of a target, such as, but not limited to, tumor necrosis factor (TNF).
- TNF tumor necrosis factor
- the polynucleotide can encode Infliximab or a fragment or variant thereof which is known to modulate TNF-alpha in a subject.
- the modulation of TNF-alpha may reduce the production of pro-inflammatory cytokines such as interleukin (IL) 1 and 6.
- IL interleukin
- the polynucleotides described herein may encode Infliximab or fragments or variants thereof and may be used to help reduce the symptoms of pain and inflammation associated with autoimmune diseases.
- the polynucleotides described herein may encode Infliximab or fragments or variants thereof and may be used to help manage the signs and symptoms and/or maintain clinical remission in those suffering from moderate to severe active Crohn's disease or ulcerative colitis.
- the polynucleotides described herein may encode Infliximab or fragments or variants thereof and may be used to help manage the signs and symptoms and/or maintain clinical remission in those suffering from moderate to severe active Crohn's disease or ulcerative colitis.
- the polynucleotides described herein may encode Infliximab or fragments or variants thereof and may be used to help manage the signs and symptoms and/or maintain clinical remission in those suffering from moderate to severe active Crohn's disease or ulcerative colitis.
- the polynucleotides described herein may encode Infliximab or fragments or variants thereof and may be used to help manage the signs and symptoms and/or maintain clinical remission in those suffering from moderate to severe active Crohn'
- polynucleotides may be used to treat adults with moderate to severe active Crohn's disease or ulcerative colitis.
- the polynucleotides may be used to treat children with moderate to severe active Crohn's disease or ulcerative colitis.
- the polynucleotides described herein may encode Infliximab or fragments or variants thereof and may be used to help manage the signs and symptoms in those suffering from rheumatoid arthritis, anklosing spondylitis, psoriatic arthritis and juvenile arthritis.
- the polynucleotides may be used to inhibit the progression of structural damage caused by psoriatic arthritis.
- the polynucleotides described herein may encode Infliximab or a fragment or variant thereof. These polynucleotides may be used to treat a variety of diseases and/or disorders such as but not limited to inflammatory diseases. As a non-limiting example, the polynucleotides encoding Infliximab or a fragment or variant thereof may be used as a treatment for moderate to severe active rheumatoid arthritis (RA). The use of polynucleotides encoding Infliximab as a treatment for moderate to severe active rheumatoid arthritis (RA) may be an adjunct therapy to methotrexate treatment.
- RA moderate to severe active rheumatoid arthritis
- the polynucleotides encoding Infliximab or a fragment or variant thereof may be used as a treatment for active ankylosing spondylitis (AS).
- AS active ankylosing spondylitis
- the polynucleotides encoding Infliximab or a fragment or variant thereof may be used as a treatment for moderate to severe ulcerative colitis (UC).
- UC ulcerative colitis
- the polynucleotides described herein may encode Infliximab or a fragment or variant thereof may be used in the treatment of psoriasis, sarcoidosis, Behcet's Disease, Giant Cell Arthritis, Uveitis, SAPHO syndrome, Polychondritis, Sjogren's Syndrome, Celiac Disease, Toxic Epidermal Necrolysis, Subcorneal Pustular Dermatosis, Pyoderma Gangrenosum, Pulmonary Fibrosis, Juvenile Idiopathic Arthritis, Kawasaki Disease, Crohn's Disease and Ulcerative Colitis.
- a subject prior to treatment with the polynucleotides described herein a subject may be tested for infections such as, but not limited to, tuberculosis (TB).
- TB tuberculosis
- polynucleotides described herein may encode
- Infliximab or a fragment or variant thereof may not cause moderate to severe heart failure.
- polynucleotides described herein may encode
- Infliximab or a fragment or variant thereof may not cause lymphoma or other types of cancer.
- the cancer may be hepatosplenic T-cell lymphoma (HSTCL).
- the polynucleotides described herein encoding Infliximab or a fragment or variant thereof are formulated for intravenous administration.
- the formulation may be an intravenous (IV) solution administered over 2 hours.
- the polynucleotides encoding Infliximab or a fragment or variant thereof has a half- life of at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 day or at least 14 days.
- the dose of the polynucleotides encoding Infliximab or a fragment or variant thereof may be between 1 and 50 mg/kg, including, but not limited to, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg and 50 mg/kg.
- the polynucleotides described herein encoding Infliximab or a fragment or variant thereof are administered at Week 0, at Week 2, at Week 6 and either every eight weeks after Week 6 for most therapies or every six weeks after Week 6 for arthritis of the spine.
- the polynucleotides described herein encoding Infliximab or a fragment or variant thereof may be formulated for intravenous delivery for adults with Crohn's Disease.
- the amount of drug administered may be 5 mg/kg given as an IV regimen at Week 0, Week 2 and Week 6 followed by a maintenance dose of 5 mg/kg every 8 weeks after Week 6.
- a dose of up to 10 mg/kg may be used as a maintenance dose for those who initially respond to treatment but then lose their response over time.
- the drug may be dissolved in saline (e.g., 250 mL of saline) for administration.
- the polynucleotides described herein encoding Infliximab or a fragment or variant thereof may be formulated for intravenous delivery for adults with Crohn's Disease and may be co-administered with azathioprine. Approximately 2 days before the initial administration of Infliximab a dose of oral azathioprine (e.g., 2 to 2.5 mg/kg) may be administered to the subject receiving the intravenous delivery of the drug.
- azathioprine e.g., 2 to 2.5 mg/kg
- the polynucleotides described herein encoding Infliximab or a fragment or variant thereof may be formulated for intravenous delivery for adults with Ulcerative Colitis.
- the amount of drug administered may be 5 mg/kg given as an IV regimen at Week 0, Week 2 and Week 6 followed by a maintenance dose of 5 mg/kg every 8 weeks after Week 6.
- the drug may be dissolved in saline (e.g., 250 mL of saline) for administration.
- the polynucleotides described herein encoding Infliximab or a fragment or variant thereof may be formulated for intravenous delivery for adults with Rheumatoid Arthritis.
- the amount of drug administered may be 3 mg/kg given as an IV regimen at Week 0, Week 2 and Week 6 followed by a maintenance dose of 3 mg/kg every 8 weeks after Week 6.
- a dose of up to 10 mg/kg may be used as a maintenance dose as often as every 4 weeks for those who have an incomplete response.
- the drug may be dissolved in saline (e.g., 250 mL of saline) for administration.
- combination therapy with methotrexate may also be considered.
- the polynucleotides described herein encoding Infliximab or a fragment or variant thereof may be formulated for intravenous delivery for adults with Ankylosing Spondylitis.
- the amount of drug administered may be 5 mg/kg given as an IV regimen at Week 0, Week 2 and Week 6 followed by a maintenance dose of 5 mg/kg every 6 weeks after Week 6.
- the drug may be dissolved in saline (e.g., 250 mL of saline) for administration.
- the polynucleotides described herein encoding Infliximab or a fragment or variant thereof may be formulated for intravenous delivery for adults with Psoriatic Arthritis.
- the amount of drug administered may be 5 mg/kg given as an IV regimen at Week 0, Week 2 and Week 6 followed by a maintenance dose of 3-5 mg/kg every 8 weeks after Week 6.
- the drug may be dissolved in saline (e.g., 250 mL of saline) for administration.
- combination therapy with methotrexate may also be considered.
- the polynucleotides described herein encoding Infliximab or a fragment or variant thereof may be formulated for intravenous delivery for adults with Psoriasis.
- the amount of drug administered may be 5 mg/kg given as an IV regimen at Week 0, Week 2 and Week 6 followed by a
- the drug may be dissolved in saline (e.g., 250 mL of saline) for administration.
- the polynucleotides described herein encoding Infliximab or a fragment or variant thereof may be formulated for intravenous delivery for adults with Sarcoidosis.
- the amount of drug administered may be 5 mg/kg given as an IV regimen at Week 0, Week 2 and every 4 to 8 weeks thereafter.
- the drug may be dissolved in saline (e.g., 250 mL of saline) for administration.
- the polynucleotides described herein encoding Infliximab or a fragment or variant thereof may be formulated for intravenous delivery for adults with Behcet's Disease.
- the amount of drug administered may be 5 mg/kg given over 3 hours as an IV regimen at Week 0, Week 2 and Week 6.
- the drug may be dissolved in saline (e.g., 250 mL of saline) for administration.
- the polynucleotides described herein encoding Infliximab or a fragment or variant thereof may be formulated for intravenous delivery for adults with Giant Cell Arteritis.
- the amount of drug administered may be 3 mg/kg given over 2 hours as an IV regimen at Week 0, Week 2 and Week 6.
- the drug may be dissolved in saline (e.g., 250 mL of saline) for administration.
- the polynucleotides described herein encoding Infliximab or a fragment or variant thereof may be formulated for intravenous delivery for adults with Uveitis.
- the amount of drug administered may be 5 mg/kg given as an IV regimen at Week 0, Week 2 and Week 6 followed by a
- the amount of drug administered may be a single dose of 3 mg/kg given over 3 hours as an IV.
- the drug may be dissolved in saline (e.g., 250 mL of saline) for administration.
- the polynucleotides described herein encoding Infliximab or a fragment or variant thereof may be formulated for intravenous delivery for adults with SAPHO syndrome.
- the amount of drug administered may be 3 mg/kg given as an IV regimen every 4 weeks.
- the drug may be dissolved in saline (e.g., 250 mL of saline) for administration.
- the polynucleotides described herein encoding Infliximab or a fragment or variant thereof may be formulated for intravenous delivery for adults with Polychondritis.
- the amount of drug administered may be 5 mg/kg given as an IV regimen at Week 0, Week 2, Week 6, Week 14, Week 22, Week 30 and Week 38.
- the drug may be dissolved in saline (e.g., 250 mL of saline) for administration.
- saline e.g. 250 mL of saline
- combination therapy with oral prednisone may also be considered.
- the polynucleotides described herein encoding Infliximab or a fragment or variant thereof may be formulated for intravenous delivery for adults with Sjogren's Syndrome.
- the amount of drug administered may be 3 mg/kg given as an IV regimen at Week 0, Week 2 and Week 6.
- the amount of drug administered may be 3 mg/kg given as an IV at Week 0, Week 2 and Week6 and every 12 weeks after Week 6.
- the drug may be dissolved in saline (e.g., 250 mL of saline) for administration.
- the polynucleotides described herein encoding Infliximab or a fragment or variant thereof may be formulated for intravenous delivery for adults with Celiac Disease.
- the amount of drug administered over 2 hours may be 5 mg/kg given as a single dose.
- the drug may be dissolved in saline (e.g., 250 mL of saline) for administration.
- the polynucleotides described herein encoding Infliximab or a fragment or variant thereof may be formulated for intravenous delivery for adults with Toxic Epidermal Necrolysis.
- the amount of drug administered over 2 hours may be 5 mg/kg given as a single dose.
- the drug may be dissolved in saline (e.g., 250 mL of saline) for administration.
- the polynucleotides described herein encoding Infliximab or a fragment or variant thereof may be formulated for intravenous delivery for adults with Subcorneal Pustular Dermatosis.
- the amount of drug administered over 2 hours may be 5 mg/kg given as a single dose.
- the drug may be dissolved in saline (e.g., 250 mL of saline) for administration.
- the polynucleotides described herein encoding Infliximab or a fragment or variant thereof may be formulated for intravenous delivery for adults with Pyoderma Gangrenosum.
- the amount of drug administered may be 5 mg/kg given as an IV regimen at Week 0, Week 2, Week 4, Week 8 and Week 10 and then a maintenance dose of 5 mg/kg every 6 to 8 weeks thereafter.
- the drug may be dissolved in saline (e.g., 250 mL of saline) for administration.
- the polynucleotides described herein encoding Infliximab or a fragment or variant thereof may be formulated for intravenous delivery for adults with Pulmonary Fibrosis.
- the amount of drug administered may be 3 mg/kg given as an IV regimen at Week 0, Week 2, Week 4 and Week 6 and then a maintenance dose of 3 mg/kg every other 8 weeks thereafter.
- the drug may be dissolved in saline (e.g., 250 mL of saline) for administration.
- the polynucleotides described herein encoding Infliximab or a fragment or variant thereof may be formulated for intravenous delivery for children 6 years or older with Acute Crohn's Disease.
- the amount of drug administered may be 5 mg/kg given as an IV regimen at Week 0, Week 2, and Week 6 and then a maintenance dose of 5 mg/kg every 8 weeks thereafter.
- the drug may be dissolved in saline (e.g., 250 mL of saline) for administration.
- the polynucleotides described herein encoding Infliximab or a fragment or variant thereof may be formulated for intravenous delivery for children 6 years or older with Crohn's Disease as a maintenance therapy.
- the amount of drug administered may be 5 mg/kg given as an IV regimen at Week 0, Week 2, and Week 6 and then a maintenance dose of 5 mg/kg every 8 weeks thereafter.
- the drug may be dissolved in saline (e.g., 250 mL of saline) for administration.
- the polynucleotides described herein encoding Infliximab or a fragment or variant thereof may be formulated for intravenous delivery for children 6 years or older with Ulcerative Colitis.
- the amount of drug administered may be 5 mg/kg given as an IV regimen at Week 0, Week 2, and Week 6 and then a maintenance dose of 5 mg/kg every 8 weeks thereafter.
- the drug may be dissolved in saline (e.g., 250 mL of saline) for administration.
- the polynucleotides described herein encoding Infliximab or a fragment or variant thereof may be formulated for intravenous delivery for children 10 years or older with Juvenile Idiopathic Arthritis.
- the amount of drug administered may be 3 mg/kg given as an IV regimen at Week 0, Week 2, and Week 6 and then a maintenance dose of 3 mg/kg every 8 weeks thereafter.
- the drug may be dissolved in saline (e.g., 250 mL of saline) for administration.
- the polynucleotides described herein encoding Infliximab or a fragment or variant thereof may be formulated for intravenous delivery for children 3 years or older with Kawasaki Disease.
- the amount of drug administered may be 5 mg/kg given as an IV regimen at Day 0, Day 45, Day 59 and Day 89.
- the drug may be dissolved in saline (e.g., 250 mL of saline) for administration.
- the polynucleotides described herein may encode an antibody that binds to an epitope of at least 5 amino acid residues 87-108 or both of residues 59-80 and 87-108 of hTNFc of SEQ ID NO: 1 of International Patent Application WO 1992016553 (the contents of which is herein incorporated by reference in its entirety), but which do not bind known or putative receptor binding portions of TNF, such as amino acid sequences 1-20, 11-13, 37-42, 49-57 or 155-157 of TNF of SEQ ID NO: 1 of International Patent Application WO 1992016553.
- the infliximab polynucleotides of the present invention are engineered such that they may comprise one or more coding regions.
- the coding regions of the infliximab polynucleotides may encode any of the regions or portions of the infliximab antibody. They may also further comprise coding regions not found in the original or parent infliximab antibody.
- the infliximab polynucleotides of the present invention may be engineered to produce any of the 5 standard classes of immunoglobulins as shown in Figure 1 using the infliximab antibody or any of its component parts as a starting molecule.
- the infliximab polynucleotides may also be engineered according to the present invention to produce a variant infliximab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- a variant infliximab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- ipilimumab polynucleotides or constructs and their associated ipilimumab compositions are designed to produce the ipilimumab antibody, a variant or a portion thereof in vivo.
- Ipilimumab also known as YERVOY®, Anti-cytotoxic T-lymphocyte- associated antigen-4 monoclonal antibody, MOAB CTLA-4, monoclonal antibody CTLA-4, BMS-734016, MDX-010 and MDX-CTLA-4, is a monoclonal antibody directed against cytotoxic T-lymphocyte-associated antigen-4 (CTLA4), an antigen that is expressed on activated T-cells and exhibits affinity for B7 co-stimulatory molecules that was developed by Bristol-Myers Squibb.
- CTLA4 cytotoxic T-lymphocyte-associated antigen-4
- Ipilimumab is an immunoglobulin Gl (IgGl)- kappa immunoglobulin produced in mammalian (Chinese hamster ovary) cell culture.
- Ipilimumab is a monoclonal antibody that helps the immune system recognize and kill cancer cells because by binding to CTLA4. Ipilimumab enhances T-cell activation and can block B7-1 and B7-2 T-cell co-stimulatory pathways.
- polynucleotides described herein encode a
- the monoclonal antibody directed against cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) or fragments or variants thereof.
- CTLA4 cytotoxic T-lymphocyte-associated antigen-4
- the monoclonal antibody may be a fully human immunoglobulin (IgGl -kappa) consisting of four polypeptide chains; two identical heavy chains primarily consisting of 447 amino acids each with two identical kappa light chains consisting of 215 amino acids each linked through inter-chain disulfide bonds.
- polynucleotides described herein encode a
- CTLA4 cytotoxic T-lymphocyte-associated antigen-4
- the polynucleotides can activate the immune system by targeting CTLA-4 which is found on the surface of T cells. By blocking the interaction of CTLA-4 with its ligands (e.g., CD80 and CD86) these polynucleotides can lead to the activation and spread of T cells which can infiltrate tumor and kill tumor cells.
- the polynucleotides described herein may encode at least one of the amino acid sequences, or a portion thereof, described in Table 18. In another embodiment, the polynucleotides described herein may be similar (percent homologous) to any of the nucleic acid sequences described in Table 18.
- the polynucleotides described herein encode a modulator of a target, such as, but not limited to, cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4).
- CTLA-4 cytotoxic T-lymphocyte-associated antigen-4
- the polynucleotide can encode ipilimumab or a fragment or variant thereof which is known to modulate CTLA-4 in a subject.
- the polynucleotides described herein may encode ipilimumab or fragments or variants thereof and may be used as a therapy for melanoma.
- the polynucleotides described herein may encode ipilimumab or fragments or variants thereof and may be used as a therapy for cancer such as, but not limited to, non-small cell lung carcinoma (NSCLC), small cell lung cancer (SCLC) and metastatic hormone-refractory prostate cancer.
- NSCLC non-small cell lung carcinoma
- SCLC small cell lung cancer
- metastatic hormone-refractory prostate cancer such as, but not limited to, non-small cell lung carcinoma (NSCLC), small cell lung cancer (SCLC) and metastatic hormone-refractory prostate cancer.
- a subject prior to and during treatment with the polynucleotides described herein a subject may be tested for to determine liver and thyroid function.
- ipilimumab or a fragment or variant thereof are formulated for intravenous
- the formulation may be an intravenous (IV) solution administered over 90 minutes.
- IV intravenous
- the polynucleotides encoding ipilimumab or a fragment or variant thereof has a half-life of at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 day or at least 14 days.
- the dose of the polynucleotides encoding ipilimumab or a fragment or variant thereof may be between 1 and 50 mg/kg, including, but not limited to, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg and 50 mg/kg.
- the dose of the polynucleotides encoding ipilimumab or a fragment or variant thereof is 3 mg/kg.
- the dose of the polynucleotides encoding ipilimumab or a fragment or variant thereof may be 5 mg/mL.
- the dose may be 50 mg of drug in 10 mL of solution or 200 mg of drug in 40 mL of solution.
- ipilimumab or a fragment or variant thereof are administered four times with three weeks in between each dose.
- the polynucleotides described herein encoding ipilimumab or a fragment or variant thereof are co-administered with a corticosteroid such as, but not limited to, prednisone.
- the co-administration of the corticosteroid may be used to alleviate any unwanted side-effects from administration of the polynucleotides encoding ipilimumab or a fragment or variant thereof.
- the polynucleotides described herein encoding ipilimumab or a fragment or variant thereof may be administered over 90 minutes through an IV line containing a sterile, nonpyogenic, low-protein binding inline filter. Following each administration of ipilimumab, the IV line may be flushed with 0.9% sodium chloride or 5% dextrose.
- the polynucleotides described herein encoding ipilimumab or a fragment or variant thereof may be formulated for intravenous delivery for adults with melanoma.
- the polynucleotides described herein encoding ipilimumab or a fragment or variant thereof may be formulated for intravenous delivery for adults with non-small cell lung carcinoma (NSCLC), small cell lung cancer (SCLC) or metastatic hormone-refractory prostate cancer.
- NSCLC non-small cell lung carcinoma
- SCLC small cell lung cancer
- the ipilimumab polynucleotides of the present invention are engineered such that they may comprise one or more coding regions.
- the coding regions of the ipilimumab polynucleotides may encode any of the regions or portions of the ipilimumab antibody. They may also further comprise coding regions not found in the original or parent ipilimumab antibody.
- the ipilimumab polynucleotides of the present invention may be engineered to produce any of the 5 standard classes of immunoglobulins as shown in Figure 1 using the ipilimumab antibody or any of its component parts as a starting molecule.
- the ipilimumab polynucleotides may also be engineered according to the present invention to produce a variant ipilimumab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- a variant ipilimumab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- muromonab polynucleotides or constructs and their associated muromonab compositions are designed to produce the muromonab antibody, a variant or a portion thereof in vivo.
- Muromonab-CD3 also known as ORTHOCLONE OKT3®, muromonab and AntiCD3, is a murine monoclonal antibody directed against the CD3 (T3) receptor on the surface of human T-cells (T-lymphocytes) cultured using the murine ascites method.
- Muromonab-CD3 is 93% monomeric immune globulin G type 2a (IgG2a).
- Muromonab- CD3 may be effective in the treatment of allograft rejection.
- muromonab- CD3 may act to block the function of mature T lymphocytes or it may modulate the T lymphocyte antigen receptor-CD-3 complex of circulating T lymphocytes.
- T lymphocyte antigen receptor-CD-3 complex See e.g., Hooks et al. Pharmacotherapy 1991. 11(1), 26-27; the contents of which are herein incorporated by reference in its entirety).
- the polynucleotides described herein encode a monoclonal antibody that can bind to the T-cell surface glycoprotein CD3 epsilon chain. While not wishing to be bound by theory, the binding may kill CD-3 positive cells by inducing Fc mediated apoptosis, antibody mediated cytotoxicity and complement- dependent cytotoxicity.
- the monoclonal antibody that can bind to the T-cell surface glycoprotein CD3 epsilon chain is muromonab-CD3.
- the polynucleotides described herein encode a modulator of a target, such as, but not limited to T-cell surface glycoprotein CD3 delta chain.
- the polynucleotide can encode muromonab-CD3 or a fragment or variant thereof which is known to modulate T-cell surface glycoprotein CD3 delta chain in a subject.
- the polynucleotides described herein encode a modulator of a target, such as, but not limited to T-cell surface glycoprotein CD3 epsilon chain.
- the polynucleotide can encode muromonab-CD3 or a fragment or variant thereof which is known to modulate T-cell surface glycoprotein CD3 epsilon chain in a subject.
- the polynucleotides described herein encode a modulator of a target, such as, but not limited to T-cell surface glycoprotein CD3 gamma chain.
- a modulator of a target such as, but not limited to T-cell surface glycoprotein CD3 gamma chain.
- the polynucleotide can encode muromonab-CD3 or a fragment or variant thereof which is known to modulate T-cell surface glycoprotein CD3 gamma chain in a subject.
- the polynucleotides described herein encode a modulator of a target, such as, but not limited to T-cell surface glycoprotein CD3 zeta chain.
- a modulator of a target such as, but not limited to T-cell surface glycoprotein CD3 zeta chain.
- the polynucleotide can encode muromonab-CD3 or a fragment or variant thereof which is known to modulate T-cell surface glycoprotein CD3 zeta chain in a subject.
- the polynucleotides described herein encode a modulator of a target, such as, but not limited to low affinity immunoglobulin gamma Fc region receptor III-B (FCGR3B).
- a target such as, but not limited to low affinity immunoglobulin gamma Fc region receptor III-B (FCGR3B).
- FCGR3B low affinity immunoglobulin gamma Fc region receptor III-B
- the polynucleotide can encode muromonab-CD3 or a fragment or variant thereof which is known to modulate FCGR3B in a subject.
- the polynucleotides described herein encode a modulator of a target, such as, but not limited to Complement Clr subcomponent (C1R).
- a target such as, but not limited to Complement Clr subcomponent (C1R).
- C1R Complement Clr subcomponent
- the polynucleotide can encode muromonab-CD3 or a fragment or variant thereof which is known to modulate C1R in a subject.
- the polynucleotides described herein encode a modulator of a target, such as, but not limited to Complement Clq subcomponent subunit A
- the polynucleotide can encode muromonab-CD3 or a fragment or variant thereof which is known to modulate C1QA in a subject.
- the polynucleotides described herein encode a modulator of a target, such as, but not limited to Complement Clq subcomponent subunit B (C1QB).
- C1QB Complement Clq subcomponent subunit B
- the polynucleotide can encode muromonab-CD3 or a fragment or variant thereof which is known to modulate C1QB in a subject.
- the polynucleotides described herein encode a modulator of a target, such as, but not limited to Complement Clq subcomponent subunit B
- the polynucleotide can encode muromonab-CD3 or a fragment or variant thereof which is known to modulate C1QC in a subject.
- the polynucleotides described herein encode a modulator of a target, such as, but not limited to Low affinity immunoglobulin gamma Fc region receptor III- A (FCGR3A).
- a modulator of a target such as, but not limited to Low affinity immunoglobulin gamma Fc region receptor III- A (FCGR3A).
- FCGR3A Low affinity immunoglobulin gamma Fc region receptor III- A
- the polynucleotide can encode muromonab-CD3 or a fragment or variant thereof which is known to modulate FCGR3A in a subject.
- the polynucleotides described herein encode a modulator of a target, such as, but not limited to Complement Cls subcomponent (CIS).
- a modulator of a target such as, but not limited to Complement Cls subcomponent (CIS).
- the polynucleotide can encode muromonab-CD3 or a fragment or variant thereof which is known to modulate CIS in a subject.
- the polynucleotides described herein encode a modulator of a target, such as, but not limited to High affinity immunoglobulin gamma Fc receptor I (FCGR1 A).
- a modulator of a target such as, but not limited to High affinity immunoglobulin gamma Fc receptor I (FCGR1 A).
- FCGR1 A High affinity immunoglobulin gamma Fc receptor I
- the polynucleotide can encode muromonab-CD3 or a fragment or variant thereof which is known to modulate FCGR1 A in a subject.
- the polynucleotides described herein encode a modulator of a target, such as, but not limited to Low affinity immunoglobulin gamma Fc region receptor Il-a (FCGR2A).
- a modulator of a target such as, but not limited to Low affinity immunoglobulin gamma Fc region receptor Il-a (FCGR2A).
- FCGR2A Low affinity immunoglobulin gamma Fc region receptor Il-a
- the polynucleotide can encode muromonab-CD3 or a fragment or variant thereof which is known to modulate FCGR2A in a subject.
- the polynucleotides described herein encode a modulator of a target, such as, but not limited to Low affinity immunoglobulin gamma Fc region receptor Il-b (FCGR2B).
- a modulator of a target such as, but not limited to Low affinity immunoglobulin gamma Fc region receptor Il-b (FCGR2B).
- FCGR2B Low affinity immunoglobulin gamma Fc region receptor Il-b
- the polynucleotide can encode muromonab-CD3 or a fragment or variant thereof which is known to modulate FCGR2B in a subject.
- the polynucleotides described herein encode a modulator of a target, such as, but not limited to Low affinity immunoglobulin gamma Fc region receptor II-c (FCGR2C).
- a target such as, but not limited to Low affinity immunoglobulin gamma Fc region receptor II-c (FCGR2C).
- FCGR2C Low affinity immunoglobulin gamma Fc region receptor II-c
- the polynucleotide can encode muromonab-CD3 or a fragment or variant thereof which is known to modulate FCGR2C in a subject.
- the polynucleotides described herein may encode muromonab-CD3 or fragments or variants thereof and may be used as a therapy for organ transplant recipients in order to treat and/or prevent organ rejection.
- the organ transplant may be kidney, liver, cardiac, pancreatic, bone marrow transplant (See e.g., Hooks et al. Pharmacotherapy 1991. 11(1), 26-27; the contents of which are herein incorporated by reference in its entirety).
- the polynucleotides described herein may encode muromonab-CD3 or fragments or variants thereof and may be used as an
- the polynucleotides encoding muromonab-CD3 may block the action of certain blood cells (e.g., T lymphocytes) that can cause the body to reject a transplanted organ.
- certain blood cells e.g., T lymphocytes
- the polynucleotides described herein encoding muromonab-CD3 or a fragment or variant thereof are formulated for intravenous administration.
- the formulation may be an intravenous (IV) bolus solution administered over 2 minutes.
- the dose of Muromoab-CD3 may be 5 mg administered as an IV bolus over 2 minutes daily for 10-14 days.
- the polynucleotides encoding muromonab-CD3 or a fragment or variant thereof has a half- life of at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 20 minutes, at least 25 minutes, at least 30 minutes, at least 35 minutes, at least 40 minutes, at least 45 minutes, at least 50 minutes, at least 55 minutes, at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hour, at least 11 hours, at least 12 hours, at least 13 hours, at least 14 hours, at least 15 hours, at least 16 hours, at least 17 hours, at least 18 hours, at least 19 hours, at least 20 hours, at least 21 hours, at least 22 hours, at least 23 hours, at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days or at least 7 days.
- the dose of the polynucleotides encoding muromonab- CD3 or a fragment or variant thereof may be between 1 and 50 mg/kg, including, but not limited to, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg and 50 mg/kg.
- the daily dose of polynucleotides encoding muromonab-CD3 is 5.0 mg by IV.
- the daily dose of polynucleotides encoding muromonab-CD3 is 2.5 mg by IV.
- the dose of polynucleotides encoding muromonab-CD3 produces serum levels of approximately 1000 mg/ml. According to Hooks et al. serum levels of approximately 1000 mg/ml should cause modulation of T lymphocytes in the circulation (See e.g., Hooks et al. Pharmacotherapy 1991. 11(1), 31; the contents of which are herein incorporated by reference in its entirety).
- polynucleotides encoding muromonab-CD3 methylprednisilone sodium succinate is administered by IV at a dose of 8 mg/kg. Approximately 30 minutes after the administration of the polynucleotides encoding muromonab-CD3 about 100 mg of hydrocortisone sodium succinate is administered by IV. The administration of methylprednisolone sodium succinate and/or hydrocortisone sodium succinate may help decrease the incidence and severity of a first dose reaction.
- the muromonab polynucleotides of the present invention are engineered such that they may comprise one or more coding regions.
- the coding regions of the muromonab polynucleotides may encode any of the regions or portions of the muromonab antibody. They may also further comprise coding regions not found in the original or parent muromonab antibody.
- the muromonab polynucleotides of the present invention may be engineered to produce any of the 5 standard classes of immunoglobulins as shown in Figure 1 using the muromonab antibody or any of its component parts as a starting molecule.
- the muromonab polynucleotides may also be engineered according to the present invention to produce a variant muromonab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- a variant muromonab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- natalizumab polynucleotides or constructs and their associated natalizumab compositions are designed to produce the natalizumab antibody, a variant or a portion thereof in vivo.
- Natalizumab is co-marketed, under the trade name Tysabri (formerly
- Natalizumab is a humanized monoclonal antibody that binds to alpha4- integrin that mediates adhesion and migration of immune cells through interaction with its ligand, vascular cell adhesion molecule (VCAM)-l .
- VCAM vascular cell adhesion molecule
- Natalizumab is used to prevent episodes of symptoms and slow the worsening of disability in patients with relapsing forms of multiple sclerosis (MS) (Niino M, et al., Ann Neurol, 2006, 59(5), 748-754; the content of which is herein incorporated by reference in its entirety). Natalizumab is also used to treat and prevent episodes of symptoms in people who have Crohn's disease (CD) but have not been helped by other medications or who cannot take other medications.
- MS multiple sclerosis
- natalizumab can increase the risk of developing PML, a rare brain infection that usually causes death and disability in patients, and causes other side effects in patients, particularly in those who have compromised immune system.
- Natalizumab is a recombinant humanized IgG4k monoclonal antibody produced in murine myeloma cells. Natalizumab contains human framework regions and the complementarity-determining regions (CDRs) of a murine antibody that binds to alpha4-integrin. The molecular weight of natalizumab is 149 KD.
- Natalizumab was first described in US Pat No: 5,840,299 by Bendig et al (also as described in US Pat NO: 6,033,665; and PCT patent publication NO: WO1997018838; the content of each of which are herein incorporated by reference in their entirety).
- Natalizumab is a humanized version of murine monoclonal antibody 21.6.
- the three complementary determining regions (CDRl, CDR 2 and CDR3) of humanized light chain have amino acid sequences are derived from the corresponding CDRs of the mouse immunoglobulin light chain variable regions and a variable region framework from a human kappa light chain variable framework sequence.
- the three complementary determining regions (CDRl, CDR 2 and CDR3) of humanized heavy chain have amino acid sequences from the corresponding CDRs of the mouse
- immunoglobulin heavy chain variable regions and a variable region framework from a human heavy chain variable framework sequence.
- the constant region(s) are
- Table 20 lists the amino acid sequences of heavy and light chain variable regions of natalizumab.
- Natalizumab binds to the alpha4 integrin antigen, a subunit of Very Late Antigen 4 (VLA-4) protein complex (alpha4betal integrin) which mediates adhesion and migration of immune cells (e.g. Th-1 cells) through interaction with its ligand, vascular cell adhesion molecule (VCAM)-l and mucosal addressin cellular adhesion molecule- 1 (MAdCAM-1), on the endothelial cell surface.
- VLA-4 Very Late Antigen 4
- VCAM vascular cell adhesion molecule
- MAdCAM-1 mucosal addressin cellular adhesion molecule- 1
- the alpha4beta4 integrins are expressed on the surface of most white leukocytes, including activated lymphocytes.
- Integrins are believed to play an important role in immune ceil adhesion to the endothelial cell layer on blood vessels, facilitating their subsequent migration into inflamed tissues.
- VLA-4 alpha4betal integrin heterodimers
- Natalizumab is an immunomodulator which functions by stopping activated inflammatory cells, including T-lymphocytes, of the immune system from reaching the brain (crossing the blood-brain barrier (BBB)) and spinal cord and causing damage.
- BBB blood-brain barrier
- the binding of natalizumab therefore inhibits the alpha4-mediated adhesion of leukocytes to their counter-receptor(s), an early event in many inflammatory responses, particularly those of the central nervous system, such as multiple sclerosis (MS).
- MS multiple sclerosis
- the clinical effect of natalizumab in multiple sclerosis may be a secondary result of its blockade of the molecular interaction of alpha4betal -integrin expressed by inflammatory cells with VCAM-1 on vascular endothelial cells, and with CS-1 and/or osteopontin expressed by parenchymal cells in the brain (Rice GP et al., anti-alpha4 integrin therapy for multiple sclerosis: mechanisms and rationale, Neurology, 2005, 64, 1336-1642; the content of which is herein incorporated by reference in its entirety.)
- Natalizumab is being investigated for treating inflammatory and autoimmune diseases, such as multiple Sclerosis, Crohn's Disease and Rheumatoid Arthritis.
- MS Multiple Sclerosis
- MS is a serious and disabling inflammatory and autoimmune disease of young adults, with a peak age of onset in the third decade of life. Most individuals present with the relapsing-remitting form of the disease and experience recurrent attacks, which, over time, result in accumulating permanent physical disability and cognitive decline. Almost 70% of patients will develop secondary progressive MS. Current treatments are minimally effective for secondary progressive MS.
- Crohn's Disease is a debilitating disease that frequently causes diarrhea and abdominal cramps as well as fever, bleeding, and weight loss.
- Natalizumab (Tysabri) is in clinical trial for its anti-tumor activity in patients with relapsed or refractory multiple myeloma. It could be also used in combination for the treatment of B-cell malignancies where it overcomes the resistance to rituximab (Mraz M et al., Bone marrow stromal cells protect lymphoma B-cells from rituximab-induced apoptosis and targeting integrin ⁇ -4- ⁇ - ⁇ (VLA-4) with natalizumab can overcome this resistance, British J of Hematology, 2011, 155, 53-64; the content of which is herein incorporated by reference in its entirety.). Natalizumab may also be used to treat acute myelogenous leukemia (AML) as described in US patent publication NO: 20100266587; the content of which is herein incorporated by reference in its entirety.
- AML acute myelogenous leukemia
- Natalizumab is also being investigated for treating other autoimmune diseases, active ulcerative colitis, inflammatory bowel disease, rheumatoid arthritis, intestinal inflammation (Gordon FH et al., Aliment Pharmacol Ther. 2002, 16, 699-705; US patent publication NO: US20100303780; the contents of which are herein incorporated by reference in their entirety.)
- PML is a rare infection of the central nervous system caused by a virus that can affect patients who have a compromised immune system, and usually causes death or severe disability. There is no known treatment, prevention, or cure for PML. Though the incidence of PML with natalizumab (Tysabri) remains unknown, the risk of PML when Tysabri is taken restricts its use in certain population of patients. Natalizumab is also restricted to patients who have compromised immune system (e.g. caused by HIV infection or AIDS, leukemia or lymphoma, or an organ transplant, or medicines that can weaken the immune system).
- compromised immune system e.g. caused by HIV infection or AIDS, leukemia or lymphoma, or an organ transplant, or medicines that can weaken the immune system.
- natalizumab Tysabri
- Other common side effects with natalizumab include unusual or serious infections, allergic reactions during infusion or after receiving natalizumab (Tysabri), liver damage, and other side effects.
- the polynucleotides encoding natalizumab may be used together with other antibodies specific for alpha4-intergrin or anti-VLA-4 antibodies, including, but not limited to, immunoglobulins described in US Pat. NOs. 8,226,950 assigned to Biogen plec; 8,246,958; 7,829,092; 6,602,503 and 6,551,593; and US patent publication No. 20020197233 by Relton et al; the contents of each of which are incorporated by reference in their entirety.
- VLA-4 binding monoclonal antibodies such as HP2/1, HP2/4, L25 and P4C2 are described, e.g., in U.S. Pat, No.
- the polynucleotides encoding natalizumab may be used to block the interaction between alph4-intergrin/VLA-4 and its ligand VCAM-1, therefore stopping recruiting active leukocytes in many disease conditions (e.g. MS, CD and multiple myeloma).
- Alpha 4 ⁇ integrin is a cell- surface receptor for VCAM-1, fibronectin and possibly other molecules
- the polynucleotides encoding natalizumab may be used together with other antagonists capable of binding to any integrin containing an alpha4 subunit such as VLA-4 on the surface of VLA-4 bearing cells and/or alpha4beta7 integrin on the surface of alpha4beta7 -bearing cells and/or to their respective a4 ligands such as VCAM-1 and MadCAM, respectively, or on the surface of VCAM-1 and
- the polynucleotides encoding natalizumab may be used as an immunomodulatory agent, alone or in combination with other immunomodulatory or immunosuppressive agents.
- Said agents may be selected from the group consisting of epratuzumab, adalimumab, rituximab, alemtuzumab, basiliximab, efalizumab, infliximab, muromomab veltuzumab, milatuzumab, daclizumab, basiliximab, tacrolimus, sirolimus, mycophenolate (as sodium or mofetil), Cyclosporine A, Glucocorticoids, Anti-CD3 monoclonal antibodies (OKT3), Antithymocyte globulin (ATG), Anti-CD52 monoclonal antibodies (campath 1-H), Azathioprine, Everolimus, Dactinomycin, Cyclophosphamide
- the polynucleotides encoding natalizumab may be used to treat inflammatory and autoimmune diseases, alone or in combination with other agents for treating inflammatory and autoimmune diseases, see e.g. US Pat. Nos:
- the polynucleotides encoding natalizumab may be used to treat multiple sclerosis, such as relapsing-remitting multiple sclerosis, secondary progressive multiple sclerosis, primary progressive multiple sclerosis, or clinically isolated syndrome.
- multiple sclerosis such as relapsing-remitting multiple sclerosis, secondary progressive multiple sclerosis, primary progressive multiple sclerosis, or clinically isolated syndrome.
- MS is relapsing forms of MS (see, e.g. US patent publication NOs: US20120276048; 20070207141; US20100021429; the contents of each of which are incorporated by reference in their entirety.)
- the polynucleotides encoding natalizumab may be used in combination with other agents such as a steroid (e.g. glucocorticoid), an anti- inflammatory compound, an immunosuppressive compound, and an antioxidant to treat MS (see, e.g. US Pat NOs: 8,394,763 (PPIase inhibitors for MS); US 8,344,153 PI3K inhibotors for MS; the contents of each of which are incorporated by reference in their entirety.)
- the polynucleotides encoding natalixumab may be used to treat Crohn's Disease (CD).
- the natalizumab polynucleotides of the present invention are engineered such that they may comprise one or more coding regions.
- the coding regions of the natalizumab polynucleotides may encode any of the regions or portions of the natalizumab antibody. They may also further comprise coding regions not found in the original or parent natalizumab antibody.
- the natalizumab polynucleotides of the present invention may be engineered to produce any of the 5 standard classes of immunoglobulins as shown in Figure 1 using the natalizumab antibody or any of its component parts as a starting molecule.
- the natalizumab polynucleotides may also be engineered according to the present invention to produce a variant natalizumab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- a variant natalizumab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- ofatumumab polynucleotides or constructs and their associated ofatumumab compositions are designed to produce the ofatumumab antibody, a variant or a portion thereof in vivo.
- Ofatumumab (synonym: 2F2; HuMax-CD20) is commercially available from Glaxo SmithKline and Genmab under the trade name ARZERRA.
- chlorambucil for the treatment of chronic lymphocytic leukemia (CLL) patients who have not received prior treatment and are inappropriate for fludarabine-based therapy.
- CLL chronic lymphocytic leukemia
- Ofatumumab is also being investigated clinically for treating other B-cell malignancies (e.g. follicular lymphoma diffuse large B-cell non-hodgkin's lymphoma), autoimmune diseases (e.g. rheumatoid arthritis) and infections (Jagloski SM et al, blood, 2010, 116, 3705-3714; Cang et al, J Hemat.
- this therapeutic antibody causes serious and sometimes life- threatening side effects, such as neutropenia, pneumonia and other respiratory infections.
- the administration of antibody based therapy raises a potential for
- the patient may develop serum antibodies against the therapeutic proteins.
- Ofatumumab is an anti-CD20 IgGlK human monoclonal antibody with a molecular weight of approximately 149 kDa, which binds an epitope on the CD20 antigen encompassing parts of the small and large extracellular loop (Teeling et al., J Immunology, 2006, 177, 362-371; Lin T, Pharmacogemonics and personalized medicine, 2013, 3, 51-59; the content of each of which are herein incorporated by reference in their entirety).
- the antibody was generated via transgenic mouse and hybridoma technology and is produced in a recombinant murine cell line (NS0) using standard mammalian cell cultivation and purification technologies.
- Ofatumumab is first described as 2F2 antibody in PCT patent publication WO2004035607, (also in PCT patent publication NO: WO2005103081; US patent publication NO: 20040167319; US Pat. NO: 8,529,902, the contents of each of which are herein incorporated by reference in their entirety). Sequences of human IgG heavy chain variable region and human kappa light chain variable region of ofatumumab (2F2) and the nucleic acids that encode such amino acids are listed in Table 21. The sequences of three CDR domains of heavy and light chains of ofatumumab (2F2) are also listed in Table 21.
- Ofatumumab is clinically tested for the treatment of non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), and rheumatoid arthritis (RA). See Teeling et al, Blood, 2004, 104, 1793 ; and Teeling et al, J. Immunology, 2007, 177, 362-371; Jagloski SM et al, blood, 2010, 116, 3705-3714; Cang et al, J Hemat. Onco., 2012, 5, 64; the contents of each of which are herein incorporated by reference in their entirety. Ofatumumab is also being studied for treating lymphoma, rheumatoid arthritis and multiple sclerosis. In particular, this antibody has been used (considered by the US Food and Drug Administration and the European Medicines Agency for marketing approval) as a treatment for chronic lymphocytic leukemia refractory to fludarabine and alemtuzumab in 2009.
- Ofatumumab binds specifically to both the small and large extracellular loops of the CD20 antigen (see, e.g. Teeling et al, J Immunology, 2006, 177, 362-371; Lin T, Pharmacogemonics and personalized medicine, 2013, 3, 51-59; the content of each of which are herein incorporated by reference in their entirety).
- the CD20 molecule is expressed on normal B lymphocytes (pre-B- to mature B-lymphocyte) and on B-cell CLL.
- CD20 regulates an early step(s) in the activation process for cell cycle initiation and differentiation, and possibly functions as a calcium ion channel.
- the CD20 molecule is not shed from the cell surface and is not internalized following antibody binding.
- CDC complement-dependent cytotoxicity
- ADCC antibody-dependent, cell-mediated cytotoxicity
- CLL is the most common form of leukemia in adults. Based on estimates by the American Cancer Society, CLL will account for more than 15,680 new cases and more than 4,580 deaths in the United States of America alone in 2013. At present, no curative chemotherapy is available.
- Ofatumumab is the first human monoclonal antibody approved by the US Food and Drug Administration for treating chronic lymphocytic leukemia refractory to fludarabine and alemtuzumab. Ofatumumab may be used in combination with
- chlorambucil for the treatment of patients with chronic lymphocytic leukemia (CLL) who have not received prior treatment and are inappropriate for fludarabine-based
- the ofatumumab polynucleotides of the present invention may be used for the same disorder and/or condition.
- Non-Hodgkin's lymphoma refers to any of a large group of cancers of lymphocytes (white blood cells). Non-Hodgkin lymphomas can occur at any age and are often marked by lymph nodes that are larger than normal, fever, and weight loss. Non- Hodgkin's lymphoma (NHL) may include mantle cell lymphoma, diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma(SLL), or follicular lymphoma (FL).
- DLBCL diffuse large B-cell lymphoma
- CLL chronic lymphocytic leukemia
- SLL small lymphocytic lymphoma
- FL follicular lymphoma
- Follicular lymphoma is a subgroup of Non Hodgkin's Lymphomas (NHL) and is the second most common lymphoma in the US and Europe, accounting for 11 to 35% of all NHL.
- Diffuse Large B-Cell Lymphoma is a cancer of the B-lymphocytes and represents 30% of non-Hogdkin's lymphomas in adults and is the most common lymphoid malignancy in the western world. There are an estimated 63,000 new cases of DLBCL diagnosed in the US per year. The median age at diagnosis is about 65 years.
- WM Waldenstrom's Macroglobulinemia
- NDL Non-Hodgkin's lymphoma
- the ofatumumab polynucleotides of the present invention may be used for the same disorder and/or condition.
- Pemphigus Vulgaris is a rare, chronic skin disorder in which the immune system malfunctions and produces antibodies that attack healthy cells in the skin and mucous membranes. This causes burn-like blisters and sores to appear on the skin or mucous membranes and may lead to secondary skin infections, dehydration, spread of infection through the bloodstream (sepsis) and death.
- the incidence of pemphigus vulgaris is approximately seven people per million worldwide.
- the current standard treatment for pemphigus vulgaris is systemic glucocorticoids.
- Ofatumumab may be used, in combination with other therapeutic agents, such as anti-CD22 antibodies, anti-CD47 antibodies, to treat Pemphigus Vulgaris, see, e.g. US patent publication NOs:
- WO2013085893 the content of each of which are herein incorporated by reference in their entirety.
- the ofatumumab polynucleotides of the present invention may be used for the same disorder and/or condition.
- MS Multiple Sclerosis
- RRMS relapsing remitting MS
- mAbs monoclonal antibodies
- the therapeutic efficacy of B cell depletion in MS from clinical trials of different anti-CD20 mAbs in patients with MS demonstrates the therapeutic potentials of targeting the CD20 surface antigen.
- Ofatumumab is investigated in phase II clinical trials for treating relapsing-remitting MS (RRMS), and in progressive forms of MS (Rommer P et a., Clin. Exp. Immunol, 2013, 10, el2197; Nocholas et al, J Cent. Nerv. Syst. Dis, 2012, 4, 81- 103; the contents of each of which are herein incorporated by reference in their entirety).
- the ofatumumab polynucleotides of the present invention may be used for the same disorder and/or condition.
- the polynucleotides encoding ofatumumab may be used in combination with other anti-CD-20 antibodies.
- anti-CD 20 antibodies include, but are not limited to, TRU-015, obinutuzumab (GA101), SBI-087, hA20,l 1B8, 7D8, 2C6 IgGl (as disclosed in WO2004056312), ocaratuzumab (AME-133), DXL 625, TRU-015, IMMU-106, DXL625, ocrelizumab (2H7.vl6, PRO-70769, R-1594), Bexxar® (tositumomab), Rituxan®/MabThera® (Rituximab), veltuzumab, anti-CD20 antibodies as described in US Pat NOs: 8,465,741; 8,097,713; 8,057,793; 7,879,984; and US patent publication NOs: US20130
- the polynucleotides encoding ofatumumab may be used treat any cancer (tumor) expressing CD20 (i.e. B-cell malignancies or CD20 positive cancer), including, precursor B- and T-cell neoplasms, mature B-cell neoplasms, Hodgkin's lymphoma, and immunodeficiency associated lymphoproliferative disorders, CLL and NHL, alone or in combination with other anti-cancer treatments (see, e.g. US patent publication NOs: 20110274697 and 20110189175; Cang et al, J Hematol Oncol.
- the polynucleotides encoding ofatumumab may be used with bendamustine, bortezomib, CAL-101, chlorambucil, cyclophosphamide, dexamethasone, docetaxel, doxorubicin, endostatineverolimus, etoposide, fludarabine, fostamatinib, hydroxydaunorubicin, ibritumomab, ifosphamide, lenalidomide, mesalazine, paclitaxel, pentostatin, prednisone, temsirolimus, thalidomide, tositumomab, vincristine, bruton's tyrosine kinase (BtK) inhibitors
- the polynucleotides encoding ofatumumab may be used as a B-cell depleting agent, alone or in combination with other B-cell depleting agents, to reduce the number of B-cells or treating a disease or disorder associated with aberrant B-cell activity in a subject having or suspected having the disease or disorder.
- Said other B-cell depleting agents may include, but are not limited to, a B-cell depleting anti-CD20 antibody or CD20-binding antibody fragment thereof (e.g. Rituximab, Ocrelizumab, GA101, BCX-301, Veltuzumab and DXL 625, TRU-015, SBI-087);
- Methotrexate CD37 specific binding molecules (e.g. anti-CD37antibodies, SMIP protein; see, e.g. US patent publication NO: 20100135900; the content of which is herein incorporated by reference in its entirety).
- B cell depleting agents may be used to treat chronic fatigue syndrome and optionally myalgic encephalomyelitis (see, e.g. US Pat. NO: 7,914,785; the content of which is herein incorporated by reference in its entirety).
- the polynucleotides encoding ofatumumab may be used as a general immunotherapy antibody, for treating cancer in combination with other anti-cancer regimens.
- anti-cancer agents may include, but are not limited to, alemtuzumab, trastuzumab, gemtuzumab, gemtuzumab-ozogamicin, cetuximab, bevacizumab, zalutumumab, lintuzumab, lumiliximab, epratuzumab and pertuzumab, rituximab; antibodies against tissue factor, killer Ig-like receptors (KIR), laminin-5, EGF receptor, VEGF receptor, PDGF receptor, HER-2/neu receptor, prostate-specific antigen (PSA), prostate stem cell antigen (PSCA), carcinoembryonic antigen (CEA), cancer antigen 125 (CA125), tumor-associated calcium signal transducer antigen (
- the polynucleotides encoding ofatumumab as an antibody based therapy may be used in combination with other chemotherapy regimens, such as everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R- 763, AT-9263, a FLT-3 inhibitor, a VEGFR inhibitor, an EGFR TK inhibitor, an aurora kinase inhibitor, a PIK-1 modulator, a BcI-2 inhibitor, an HDAC inhibitor, a c-MET inhibitor, a PARP inhibitor, a Cdk inhibitor, an EG
- other chemotherapy regimens such as
- the polynucleotides encoding ofatumumab may be used to treat Chronic Obstructive Pulmonary Disease (COPD) as described in PCT patent publication NO: WO2008003319; the content of which is herein incorporated by reference in its entirety).
- COPD Chronic Obstructive Pulmonary Disease
- the polynucleotides encoding ofatumumab may be used to treat progressive multiple sclerosis (e.g. relapsing remitting multiple sclerosis), either alone or in combination with other agents such as a second anti-CD20 antibody or the polynucleotide encoding said second anti-CD20 antibody (e.g. TRU-015 or SBI-087, GA101, bA20, Rituximab) (see, e.g.
- the polynucleotides encoding ofatumumab may be used to treat autoimmune diseases, for example, rituximab refractory rheumatoid arthritis in combination with Veltuzumab, another anti-CD20 antibody; systemic lupus erythematosus (SLE) with B-lys antagonist and/or other anti-CD20 antibodies (e.g. RITUXAN®, ocrelizumab, TRU-015, and DXL625); inflammatory bowel disease (IBD) (e.g. ulcerative colitis (UC), Crohn's disease) (see, e.g. US patent publication NOs:
- the ofatumumab polynucleotides of the present invention are engineered such that they may comprise one or more coding regions.
- the coding regions of the ofatumumab polynucleotides may encode any of the regions or portions of the ofatumumab antibody. They may also further comprise coding regions not found in the original or parent ofatumumab antibody.
- the ofatumumab polynucleotides of the present invention may be engineered to produce any of the 5 standard classes of immunoglobulins as shown in Figure 1 using the ofatumumab antibody or any of its component parts as a starting molecule.
- the ofatumumab polynucleotides may also be engineered according to the present invention to produce a variant ofatumumab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- a variant ofatumumab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- omalizumab polynucleotides or constructs and their associated omalizumab compositions are designed to produce the omalizumab antibody, a variant or a portion thereof in vivo.
- Omalizumab (synonyms: anti-IgE monoclonal antibody E25; E25; humanized anti-IgE mAb; IGE 025; olizumab; RhuMa-E25) is marketed under the trade name Xolair by Roche/Genentech and Novartis.
- Omalizumab is a humanized antibody IgGl that selectively binds to human immunoglobulin E (IgE).
- IgE immunoglobulin E
- the primary use of omalizumab is for treating severe, persistent allergic asthma that does not respond to high dose of corticosteroids.
- Omalizumab (Xolair) has received approval by the Food and Drug Administration and in many other regions/countries (e.g. the Europe Union) for treating patients 12 years and older with moderate to severe allergic asthma. Clinical studies show that the efficacy of omalizumab is evident for severe asthmatics and the response rates among treated severe "allergic" asthma patients are 60-80% or higher.
- the primary benefits for the responding patients are reduced numbers of exacerbations, improved lung function, reduced numbers of emergency visits to the doctors, reduced days of hospitalization, and increased quality of life measurements.
- the other major benefit is that most responding patients can reduce or spare entirely the use of corticosteroids, which cause multiple serious side effects, when used at high doses for extended periods.
- Omalizumab's cost is high, ranging from $500 to $2,000 a month or $6,000 to $24,000 a year, limiting its availability in developing countries and leading to rationing in countries with a general healthcare system such as the UK.
- anaphylaxis a severe allergic disease happens in some patients who receive omalizumab treatment.
- Omalizumab is a recombinant DNA-derived humanized IgGl kappa monoclonal antibody that selectively binds to human immunoglobulin E (IgE).
- Omalizumab (Xolair) is produced by a Chinese hamster ovary cell suspension culture in a nutrient medium containing the antibiotic gentamicin.
- Omalizumab was originally isolated from human-mouse monoclonal E25 clone pSVIE26 gamma-chain) (see, e.g. US Pat No. 5,994,511, and PCT patent publication NO: WO1999001556, by Lowman et al, assigned to Genentech, Inc.; the contents of each of which are herein incorporated by reference in their entirety.)
- the original mouse anti-IgE clone (MaEl 1) was generated by immunizing mice with purified human IgE molecules. This murine antibody clone directed against human IgE (MaEl 1) was used to provide the CDR regions which were substituted into an IgGl
- Omalizumab selectively binds to free human immunoglobulin E (IgE) in the blood and interstitial fluid and to membrane -bound form of IgE (mlgE) on the surface of mlgE-expressing B lymphocytes.
- IgE immunoglobulin E
- mlgE membrane -bound form of IgE
- Omalizumab specifically binds to the cepsilon 3 domain of human IgE Fc region, which is the site of high-affinity IgE receptor binding.
- omalizumab does not bind to IgE that is already bound by the high affinity IgE receptor(Fc8RI) on the surface of mast cells, basophils and antigen-presenting dendritic cells (Chang et al, Anti-IgE antibodies for the treatment of IgE-mediated allergic diseases, Adv Immunol. 2007, 93, 63-119, the content of which is herein incorporated by reference in its entirety.)
- Immunoglobulin E is a member of the immunoglobulin family that is secreted by, and expressed on the surface of B-cells or B-lymphocytes. IgE mainly functions as an immune defender against parasites. IgE also plays an essential role in type I hypersensitivity, which manifests various allergic diseases, such as allergic asthma, allergic rhinitis, food allergy, and some types of chronic urticaria and atopic dermatitis. In addition, IgE plays a pivotal role in allergic conditions, such as anaphylactic reactions to certain drugs, bee stings, and antigen preparations used in specific desensitization immunotherapy. The IgE molecules (e.g.
- allergen-specific and allergen-nonspecific IgE bind to the high affinity IgE receptor (FcsRI) on the surface of mast cells and basophils.
- FcsRI high affinity IgE receptor
- the allergenic proteins bind to the allergen-specific IgE bound by FcsRI on the surface of mast cells and basophils and trigger the activation of those inflammatory cells, which release a host of inflammatory mediators, such as histamine, leukotrienes, tryptase, inflammatory cytokines, and other factors, causing various allergic symptom/diseases.
- IgE binds to B-celis (as well as to monocytes, eosinophils and platelets) through its Fc region to a low affinity IgE receptor, known as FcsRII.
- omalizumab's binding to IgE can neutralize circulating IgE by preventing IgE from binding to its high-affinity mast-cell receptor, therefore blocking IgE signaling.
- Possible mechanisms may include 1) inhibiting Erkl/2 MAPK to stimulate airway (smooth muscle) cell proliferation and remodeling; 2)
- the immune complexes formed between IgE and omalizumab in vivo are relatively small (molecular weight ⁇ 1 million) and are therefore unlikely to cause organ damage.
- Omalizumab function as an anti-IgE antagonist, blocking IgE mediated allergic reactions and other clinical conditions.
- Allergic asthma also called extrinsic asthma
- extrinsic asthma is airway obstruction and inflammation that is partially reversible with medication. It has been estimated that as high as 20 to 40% of the populations who live in economically advanced countries are affected by allergy and seek medical help. According to Asthma and Allergy Foundation of America, Allergic asthma is the most common form of asthma in USA, affecting over 50% of the 20 million asthma sufferers. Over 2.5 million children under age 18 suffer from allergic asthma. Many of the symptoms of allergic and non-allergic asthma are the same (coughing, wheezing, shortness of breath or rapid breathing, and chest tightness). However, allergic asthma is triggered by inhaled allergens such as dust mite allergen, pet dander, pollen, mold, etc. resulting in asthma symptoms.
- Immunoglobulin E is the antibody in the body that plays a major role in allergic diseases.
- the body produces the IgE antibody when it detects an allergen and causes the "allergic cascade" to begin. While allergy occurs more frequently in individuals with higher serum IgE levels, such a correlation is only statistical and not absolute. Some allergic individuals have very low serum IgE, and some people with very high IgE have no allergic problems.
- Anti-IgE antibodies have been an attractive strategy for treating allergic diseases such as asthma, (see, Thomson and Chauhuri, Clin Med Insights Circ Respir Pulm Med., 2012, 6, 27-40; the content of which is incorporated herein by reference in its entirety.)
- omalizumab treatment in patients with severe, persistent allergic asthma can reduce eosinophil numbers in the airway mucosa and the IgE bearing cells.
- Treatment of allergic subjects with omalizumab also reduces the release of Th2 cytokines from blood basophils.
- polynucleotides of the present invention may be used to treat the same or similar indications as the commercial antibody, omalizumab.
- Omalizumab is also under many clinical studies for potential treatment of allergic asthma, perennial and seasonal allergic rhinitis, food allergy (e.g. peanut), occupational allergy, pollen allergy, latex allergy, atopic dermatitis, chronic idiopathic urticaria (i.e. chronic spontaneous urticaria), mastocytosis (e.g.
- Omalizumab has also been studied in combination with allergen-based specific immunotherapy (allergy shot) for the purpose of reducing anaphylactic reactions when receiving allergen immunizations and of accelerating immunization schedule and dosing, so as to achieve therapeutic effects in shorter treatment periods and in broader patient populations.
- omalizumab Like the other protein and antibody drugs, the main adverse effect of omalizumab is anaphylaxis (a life-threatening systemic allergic reaction).
- the signs and symptoms of anaphylaxis include wheezing, shortness of breath, cough, low blood pressure, hives, swelling of the throat, etc, which may happen right after Xolair injection or hours later.
- This allergic reaction is not due to the binding of omalizumab to IgE, but because of the protein nature of the antibody drugs.
- polynucleotides of the present invention will present a profile lacking the side effects and/or adverse reactions seen with the commercial antibody.
- the polynucleotides of the present invention may be used for treating a IgE mediated disease and clinical condition, including but not limited to, asthma (e g. allergic asthma and non-allergic asthma), allergic rhinitis, conjunctivitis (hay fever), eczema, urticaria (e.g. chronic spontaneous urticarial), atopic dermatitis, food allergies (e.g. peanut) and other allergic disease (e.g. occupational allergy and pollen allergy).
- asthma e g. allergic asthma and non-allergic asthma
- allergic rhinitis hay fever
- eczema urticaria
- urticaria e.g. chronic spontaneous urticarial
- atopic dermatitis e.g. peanut
- food allergies e.g. peanut
- other allergic disease e.g. occupational allergy and pollen allergy
- polynucleotides encoding omalizumab may be used to treat allergic asthma in combination with other immunotherapeutic agents as described in US Patent application publication NOs: US 20040197326, US20070020256;
- the polynucleotide of the present invention may be used to treat other allergic disease such allergic rhinitis as described in PCT patent publication NO WO 1997033616; the content of which is herein incorporated by reference in its entirety.
- the polynucleotides encoding omalizumab may be used in combination with other anti-IgE antibodies for decreasing/inhibiting IgE signaling in a subject.
- Said other anti-IgE antibodies may include, but are not limited to, E26 and E27 as described in US Patent Nos: 5,994,511; 6,290,957; 6,682,735; 6,761,889; assigned to
- the polynucleotides of the present invention may be used to inhibit IgE signaling, in combination with other IgE signal antagonists that can inhibit the biological activity of IgE, for example, anti-IgE antibodies and variants as described herein; IgE binding factor and fragments (e.g. US Pat NO: US 4,946,788; the content of which is herein incorporated by reference in its entirety,) small molecules such as cyclic peptides that target to IgE: FceRI interaction ( Smith et al, Future Med Chem, 2013, 5, 1423-1435; the content of which is incorporated by reference in its entirety,) and anti-IgE receptor antibodies and derivatives.
- IgE signal antagonists that can inhibit the biological activity of IgE, for example, anti-IgE antibodies and variants as described herein; IgE binding factor and fragments (e.g. US Pat NO: US 4,946,788; the content of which is herein incorporated by reference in its entirety,) small molecules such as cyclic peptide
- polynucleotides of the present invention may be used for inhibiting histamine release as described in US Pat NO. 6,290,957), and reducing circulating IgE as described US Pat NO: 5,543,144; the contents of each of which are herein incorporated by reference in their entirety.
- the omalizumab polynucleotides of the present invention are engineered such that they may comprise one or more coding regions.
- the coding regions of the omalizumab polynucleotides may encode any of the regions or portions of the omalizumab antibody. They may also further comprise coding regions not found in the original or parent omalizumab antibody.
- the omalizumab polynucleotides of the present invention may be engineered to produce any of the 5 standard classes of immunoglobulins as shown in Figure 1 using the omalizumab antibody or any of its component parts as a starting molecule.
- the omalizumab polynucleotides may also be engineered according to the present invention to produce a variant omalizumab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- a variant omalizumab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- panitumumab polynucleotides or constructs and their associated panitumumab compositions are designed to produce the panitumumab antibody, a variant or a portion thereof in vivo.
- Panitumumab (synonyms: ABX-EGF; rHuMAb-EGFR, Vectibix) is a fully human monoclonal antibody that binds with high affinity to epidermal growth factor receptor (EGFR) and interferes with signals that might otherwise stimulate growth and survival of the cancer cells.
- EGFR epidermal growth factor receptor
- EGFR is a protein that plays an important role in cancer cell signaling and is over-expressed in many human cancers. The inhibition of EGFR mediated growth signal by antibody binding could inhibit the abnormal growth of EGFR expression tumor cells.
- Panitumumab received approval from the Food and Drug Administration in 2006 as a single agent for the treatment of metastatic colorectal carcinoma with disease progression on or following fluoropyrimidine, oxaliplatin, and irinotecan chemotherapy regimens. Approval is based on progression-free survival in clinical studies.
- panitumumab treatment may cause severe infusion reactions and dermatological toxicities in patients. As with other antibody based protein drugs, panitumumab treatment may raise the immunogenicity in patients.
- Panitumumab is a recombinant, human IgG2 kappa monoclonal antibody that binds specifically to the human epidermal growth factor receptor (EGFR). Panitumumab has an approximate molecular weight of 147 kDa. Panitumumab is produced in genetically engineered mammalian (Chinese Hamster Ovary) cells.
- US Pat No: 6,235,883 disclosed this fully human anti-EGFR antibody. It contains an amino acid sequence of the heavy chain variable region in which a portion of the sequence is encoded by a human V H 4-61 gene, disulfide with an amino acid sequence of the light chain variable region in which a portion of the sequence is encoded by a human VK I family gene.
- the antibody is selected from the hybridoma E7.6.3 (see, also e.g. PCT patent publication NO WO1998050433; Yang et al, Rev Oncol Hematol 2001;38: 17-25; Yang et al, Cancer Res 1999;59: 1236-1243; the contents of each of which are herein incorporated by reference in their entirety).
- panitumumab fragments, domains or heavy or light chains are given in Table 23.
- Table 23 The table is not an exhaustive list and any fragment or portion of the sequence may be encoded in the panitumumab polynucleotides of the invention.
- the EGFR is a transmembrane glycoprotein that is a member of the HER subfamily of type I receptor tyrosine kinases, including EGFR (ErbBl/HERl), HER2 (ErbB2), HER3 (ErbB3), and HER4 (ErbB4).
- EGFR is a classic membrane-bound tyrosine kinase receptors, whose activation is typically ligand dependent, with the principal ligands being EGF and TGF-a.
- EGFR is constitutively expressed in normal epithelial tissues, including the skin and hair follicle. EGFR is over-expressed in certain human cancers, including colon and rectum cancers. Interaction of EGFR with its normal ligands (eg, EGF, transforming growth factor-alpha) leads to homo- or
- EGFR activation does not initiate linear downstream pathway signaling, but rather can activate multiple pathways that cross-connect intracellularly.
- Anti-EGFR therapies include monoclonal antibodies (e.g. panitumumab) that recognize the EGFR and small molecule inhibitors of EGFR tyrosine kinase activity (TKIs).
- Panitumumab binds specifically to EGFR on both normal and tumor cells, and competitively inhibits the binding of ligands for EGFR, therefore prevents it from sending growth signals.
- Nonclinical studies show that binding of panitumumab to the EGFR prevents ligand-induced receptor autophosphorylation and activation of receptor- associated kinases, resulting in inhibition of cell growth, induction of apoptosis, decreased pro-inflammatory cytokine and vascular growth factor production, and internalization of the EGFR.
- In vitro assays and in vivo animal studies demonstrate that panitumumab inhibits the growth and survival of selected human tumor cell lines expressing EGFR.
- Panitumumab has been used in clinics to treat patients with EGFR-expressing, metastatic carcinoma of the colon or rectum (mCRC), who have progressed on or following treatment with a regimen(s) containing a fluoropyrimidine, oxaliplatin, and irinotecan.
- mCRC metastatic carcinoma of the colon or rectum
- the membrane staining intensity of EGFR in tumor cells and the percentage of tumor cells with EGFR membrane staining are decreased (see, National Cancer Institute, clinical trials,
- panitumumab has demonstrated anti-tumor activity in advanced, refractory colorectal cancer ("CRC"). Patients who received panitumumab every two weeks showed a 46 percent decrease in tumor progression rate versus those who received best supportive care alone.
- K-RAS a small serine-threonine kinase that is famesylated and inserted into the cell membrane, is an important predictor of response to anti-EGFR mAb therapy.
- Lievre et al J Clin Oncol. 2008, 26,374-379; the content of which is herein incporporated by reference in its entirety) identified a k-ras mutation in 27% of patients, with a response rate of 0% in tumors with mutated k-ras vs. 40% in tumors with wild type k-ras and a increased median overall survival.
- K-ras mutation testing may be used to guide anti- EGFR based therapeutic decisions.
- Panitumumab has also been investigated in clinical studies for treating various solid cancers, such as head and nech cancer (FINC), non-small cell lung cancer (NSCLC), metastatic gallbladder carcinoma (e.g. Markovic and Chung et al., Expert Rev Anticancer ther, 2012, 12, 1149-1159; Riley and Carloss, Oncologis, 2011, 16, 1-2; Grunwald and Hodalgo, J Natl Can Instit., 2003, 95, 851-867; the contents of each of which are herein incorporated by reference in their entirety).
- FINC head and nech cancer
- NSCLC non-small cell lung cancer
- metastatic gallbladder carcinoma e.g. Markovic and Chung et al., Expert Rev Anticancer ther, 2012, 12, 1149-1159; Riley and Carloss, Oncologis, 2011, 16, 1-2; Grunwald and Hodalgo, J Natl Can Instit., 2003, 95, 851-867; the contents of each of which are herein
- panitumumab treatment The major concerns of using panitumumab treatment include infusion reactions and dermatological toxicities. Severe infusion reactions occurred in
- panitumumab causes increased toxicities with combination chemotherapy, so it is not indicated for use in combination with chemotherapy. Severe infusion reactions included anaphylactic reactions, bronchospasm, and hypotension. Other adverse reactions may include pulmonary fibrosis,
- polynucleotides of the present invention are expected to overcome some if not all all of the side effects associated with the commercial antibody.
- the polynucleotides encoding panitumumab may further include one or more modular recognition domain(s) (MRD), generating a targeting antibody-MRD fusion molecule, as described in US Pat NO. 8,557,243, the content of which is herein incorporated by reference in its entirety.
- MRD modular recognition domain
- the nucleic acids encoding the MRD domain may be linked to the N-terminal of either heavy chain or light chain of the polynucleotide encoding panitumumab.
- the nucleic acids encoding the MRD domain may be linked to the C-terminal of either heavy chain or light chain of the polynucleotide encoding panitumumab.
- the MRD may contain in general a peptide sequence that binds to target sites of interests, for example Ang2 -binding MRD and IGF- lR-binding MRD as described in US Pat NOs: 8,557,243 and 8, 454,960; the contents of each of which are herein incorporated by reference in their entirety.
- Panitumumab as anti-EGFR therapeutic antibody, has been disclosed for the use of treating metastatic colorectal cancer (e, g. US Pat No: 8,535,670; 7,858,390; US patent publication NOs: US20060216288; and US 20100074909; Yang et al, Crit. Rev. Onco Hematol, 2001, 38, 17-32); non-small cell lung cancer (see e.g. US Pat NOs:
- the polynucleotides encoding panitumumab may be used as a targeted cancer therapy agent for treating EGFR expressing cancers, such as colorectal cancer, non-small cell lung cancer, head and neck cancer and renal carcinoma.
- cancers such as colorectal cancer, non-small cell lung cancer, head and neck cancer and renal carcinoma.
- the colorectal cancer may be a KRAS wild-type, metastatic colorectal cancer.
- the polynucleotides of the present invention may be co-administered to a cancer patient with other anti-cancer antibodies, including, but not limited to, trastuzumab, bevacizumab, rituximab, pertuzumab, cetuximab, IMC-1C11, tositumomab, ibirtumomab tiuxetan, EMD 7200, SGN-30, SGN-15, SGN-40, SGN-35, and SGN-17/19.
- other anti-cancer antibodies including, but not limited to, trastuzumab, bevacizumab, rituximab, pertuzumab, cetuximab, IMC-1C11, tositumomab, ibirtumomab tiuxetan, EMD 7200, SGN-30, SGN-15, SGN-40, SGN-35, and SGN-17/19.
- the polynucleotides of the present invention may be used in combination with other standard chemotherapeutic agents for treating tumors.
- Said chemotherapeutic agents may include folinic acid (leucovorin)-5FU-oxaliplatin
- estramustine hydroxyurea, procarbazine, mitomycin, busulfan, medroxyprogesterone, estramustine phosphate sodium, ethinyl estradiol, estradiol, megestrol acetate, methyltestosterone, diethylstilbestrol diphosphate, chlorotrianisene, testolactone, mephalen, mechlorethamine, chlorambucil, chlormethine, ifosfamide, bethamethasone sodium phosphate, dicarbazine, asparaginase, mitotane, vincristine, vinblastine, etoposide, teniposide, Topotecan, IFN-gamma, irinotecan, campto, irinotecan analogs, carmustine, fotemustine, lomustine, streptozocin, carboplatin, oxaliplatin, BBR3464, busulfan
- the polynucleotides encoding panitumumab may be used to inhibit EFGR mediating signals in a subject, alone or in combination with other an epidermal growth factor tyrosine kinase inhibitors, such as cetuximab, TheraCIM, EMD 72000, MDX447, gefitinib, lapatinib, erlotinib, PKI-166, canertinib, matuzumab, GW572016, CL-1033, EKB-569, GW2016, EKB-569 (See, e.g.
- panitumumab polynucleotides of the present invention are engineered such that they may comprise one or more coding regions.
- the coding regions of the panitumumab polynucleotides may encode any of the regions or portions of the panitumumab antibody. They may also further comprise coding regions not found in the original or parent panitumumab antibody.
- the panitumumab polynucleotides of the present invention may be engineered to produce any of the 5 standard classes of immunoglobulins as shown in Figure 1 using the panitumumab antibody or any of its component parts as a starting molecule.
- panitumumab polynucleotides may also be engineered according to the present invention to produce a variant panitumumab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- a variant panitumumab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- ranibizumab polynucleotides or constructs and their associated ranibizumab compositions are designed to produce the ranibizumab antibody, a variant or a portion thereof in vivo.
- Ranibizumab (synonyms: rhuFab V2) is marketed under the trade name Lucentis.
- Ranibizumab is a recombinant humanized IgGl kappa monoclonal antibody fragment designed for intraocular use. Ranibizumab binds to human vascular endothelial growth factor A (VEGF-A) and inhibits the biologic activity of active forms of human VEGF-A, including the cleaved form (VEGFno ) .
- VEGF-A vascular endothelial growth factor A
- VEGFno cleaved form
- Ranibizumab has been approved by the Food and Drug Administration in 2006 for treating the "wet" (i.e. neovascular) type of age related macular degeneration (AMD or ARMD), a common form of age related vision loss. It is also indicated for the treatment of patients with Macular Edema Following Retinal Vein Occlusion (RVO) and Diabetic Macular Edema (DME).
- RVO Retinal Vein Occlusion
- DME Diabetic Macular Edema
- ranibizumab The most common toxic effects of ranibizumab treatment to the eye are eye pain, vitreous floaters, increased intraocular pressure, conjunctival hemorrhage. Also arterial thromboembolic events have occurred in patients. Consequently, there is a need for improved ranibizumab molecules.
- Ranibizumab is a recombinant humanized IgGl kappa monoclonal antibody fragment (i.e. Fab fragment) derived from the same parent mouse antibody as
- bevacizumab (Avastin), much smaller than the parent full antibody but having a higher binding affinity to VEGF-A.
- Ranibizumab is specifically designed for intraocular use. The small size allows it to better penetrate the retina, and thus treat the ocular
- ranibizumab fragments, domains or heavy or light chains are given in Table 24.
- the table is not an exhaustive list and any fragment or portion of the sequence may be encoded in the ranibizumab polynucleotides of the invention.
- VEGF-A has been shown to be involved in angiogenesis and increasing vascular permeability, which is believed to contribute the progression of the neovascular form of AMD.
- Ranibizumab binds to and inhibits the biologic activity of active forms of human VEGF-A, including the biologically active, cleaved form (VEGF 110 ).
- Ranibizumab binds to the receptor-binding site of active forms of VEGF-A, including VEGFno, preventing the interaction of VEGF-A with its receptors (VEGFR1 and VEGFR2) on the surface of endothelial cells, therefore inhibiting cell proliferation, vascular leakage and new blood vessel formation.
- Ranibizumab can be used for the treatment of patients with macular edema after retinal vein occlusion, age-related macular degeneration (wet, neovascular), and diabetic macular edema (DME).
- AMD is a medical condition that usually affects older adults and results in a loss of vision in the center of the visual field (the macula) because of damage to the retina. It occurs in “dry” and “wet” forms. It is a major cause of blindness and visual impairment in older adults (>50 years).
- VEGF vascular endothelial growth factor
- Anti-angiogenics or anti-VEGF agents can cause regression of the abnormal blood vessels and improve vision when injected directly into the vitreous humor of the eye.
- Ranibizumab in clinical studies have been proved to be effective in treating AMD, particularly for wet AMD.
- Macular Edema occurs when fluid and protein deposits collect on or under the macula of the eye (a yellow central area of the retina) and causes it to thicken and swell (edema). The swelling may distort a person's central vision, as the macula is near the center of the retina at the back of the eyeball. Macular edema may be caused by many conditions such as Retinal vein occlusion (RVO), which is a common vascular disorder of the retina, and diabetes.
- RVO Retinal vein occlusion
- the polynucleotides encoding ranibizumab may be used as a vascular endothelial growth factor inhibitor, to neutralize VEGF activity in disease condition.
- the polynucleotides encoding ranibizumab neutralize VEGF by at least 30%, by at least 40%, by at least 50%, by at least 60%, by at least 70%, by at least 80%, by at least 90%, or by a percentage ranging between any of the values.
- the polynucleotides encoding ranibizumab are useful in the treatment of tumors in which angiogenesis plays an important role in tumor growth, including cancers and benign tumors.
- cancer to be treated herein include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia. See, e.g. US Patent publication US20100221247; US20070134244; US20120130144; and PCT patent publication NO: WO2011133668; the contents of each of which are incorporated herein be reference in their entirety.
- the present disclosure encompasses anti-angiogenic therapy, a cancer treatment strategy aimed at inhibiting the development of tumor blood vessels required for providing nutrients to support tumor growth. Because angiogenesis is involved in both primary tumor growth and metastasis, the antiangiogenic treatment provided by the disclosure is capable of inhibiting the neoplastic growth of tumor at the primary site as well as preventing metastasis of tumors at the secondary sites.
- Anti-VEGF antibodies are useful in treating eye diseases in which VEGF signal make a significant contribution to the pathogenesis, such as age related macular degeneration as described US20070134244; vascularized retinal pigment epithelial detachment as described in US20130004486; also in US20130295094; the contents of each of which are herein incorporated by reference in their entirety.
- the polynucleotides encoding ranibizumab may be used to treat an eye disease, in particular an angiogenic eye disorder.
- eye diseases may include, but are not limited to, dry and wet age related macular
- RVO retinal vein occlusion
- vPED vascularized retinal pigment epithelial detachment
- diabetic retinopathy central retinal vein occlusion and corneal neovascularization.
- the polynucleotides encoding ranibizumab may be used with one or more other VEGF antagonists.
- VEGF antagonists include molecules which interfere with the interaction between VEGF and a natural VEGF receptor, e.g. molecules which bind to VEGF or a VEGF receptor and prevent or otherwise hinder the interaction between VEGF and a VEGF receptor.
- Specific exemplary VEGF antagonists include anti-VEGF antibodies, anti-VEGF receptor antibodies, and VEGF receptor-based chimeric molecules (also referred to herein as "VEGF-Traps").
- ranibizumab polynucleotides of the present invention are engineered such that they may comprise one or more coding regions.
- the coding regions of the ranibizumab polynucleotides may encode any of the regions or portions of the ranibizumab antibody. They may also further comprise coding regions not found in the original or parent ranibizumab antibody.
- ranibizumab polynucleotides of the present invention may be engineered to produce any of the 5 standard classes of immunoglobulins as shown in Figure 1 using the ranibizumab antibody or any of its component parts as a starting molecule.
- ranibizumab polynucleotides may also be engineered according to the present invention to produce a variant ranibizumab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- a variant ranibizumab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- rituximab polynucleotides or constructs and their associated rituximab compositions are designed to produce the rituximab antibody, a variant or a portion thereof in vivo.
- Rituximab (synonym: anti-CD20) is a chimeric human-mouse monoclonal antibody recognizing the CD 20 antigen expressed on B-lymphocytes.
- Rituximab is a type I anti-CD20 antibody, which is potent in inducing complement mediated cytotoxicity (CDC) and antigen dependent cell-mediated cytotoxicity (ADCC).
- Rituximab is approved by the Food and Drug Administration (FDA) for treating CD-20 positive non-hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), rheumatoid arthritis (RA) and other diseases.
- FDA Food and Drug Administration
- Rituximab may cause serious and sometimes life-threatening side effects in patients, such as cardiac arrhythmias.
- the intravenous infusion reactions during and/or after the treatment are the most common adverse reactions.
- Extremely high level of immunotherapeutic antibody is required to deplete circulating tumor cells, which is beyond the tolerable toxicity caused by administrating antibodies into a patient.
- Rituximab is a genetically engineered chimeric human-murine monoclonal antibody directly against the CD20 antigen found on the surface of normal and malignant B-lymphocytes. This antibody is an IgGl kappa immunoglobulin containing murine light-and heavy chain variable region sequences and human gamma I heavy-chain and kappa light-chain constant region sequences.
- Rituximab is a dimer, composed of two heavy chains of 451 amino acids and two light chains of 213 amino acids and has an approximate molecular weight of 145 kD. The sequences of both heavy and light chain are listed in Table 25.
- Rituximab was genetically engineered using the murine 2B8 antibody, as disclosed in US Pat NO. 5,736,137 (Andersen, et. al.) issued on April 17, 1998, assigned to IDEC Pharmaceuticals Corporation, and US Pat NO: 7,422,739, assigned to Biogen pout, the contents of each of which are herein incorporated by reference in their entirety.
- This antibody may be further modified for increased binding affinity and effector function, e.g. as described in US patent publication NOs: US20050123546, US20070071745; PCT publication NOs: WO 2005/044859 and WO2007/031875, the contents of each of which are herein incorporated by reference in their entirety.
- Rituximab binds to the CD20 antigen, which is predominantly expressed on pre-B and mature B cells, and on >90% of B-cell non-Hodgkin's lympohomas (NHL), but not found on hematopoietic stem cells, pro-B cells, normal plasma cells or other normal tissues.
- CD20 regulates an early step(s) in the activation process for cell cycle initiation and differentiation, and possibly functions as a calcium ion channel. It is also known that CD20 is not shed from the cell surface and does not internalize upon antibody binding.
- the antibody Rituximab tends to stick to one side of cancerous B cells, forming a cap and drawing proteins over to that side, leading to selective killing of B-cells by natural killer cells (NK).
- NK natural killer cells
- the Fab regions of rituximab bind to the CD20 antigen on B lymphocytes, while the Fc domain recruits antibodies and complements to mediate antibody dependent cellular cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC), inducing cell lysis (Reft ME, et. al, Blood, 1994, 83, 435-445, the content of which is herein incorporated by reference in its entirety).
- Rituximab binds to amino acid residues 170-173 and 182-185 on CD20, which are physically close to each other as a result of a disulfide bond between residues 167 and 183 (e.g. Binder et al, Blood, 2006, 108, 1975-1978; the content of which is herein incorporated by reference in its entirety).
- Rituximab affects the interferon (IFN) I response genes as described by Verweij CL et al, Discov Med, 2011, 12, 229-236; the content of which is herein incorporated by reference in its entirety.
- IFN interferon
- Rituximab is approved for the treatment of patients with B cell lymphomas, rheumatoid arthritis and other diseases.
- Non-Hodgkin's lymphoma refers to any of a large group of cancers of lymphocytes (white blood cells). Non-Hodgkin lymphomas can occur at any age and are often marked by lymph nodes that are larger than normal, fever, and weight loss.
- Non- Hodgkin's lymphoma may include mantle cell lymphoma, diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma(SLL), or follicular lymphoma (FL).
- Rituximab is used to treat relapsed or refractory low-grade or follicular, CD20-positive, B-cell NHL as a single agent; or to treat previously untreated follicular, CD20-positive, B-cell NHL in combination with first line chemotherapy, or to treat previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens.
- Rituximab may also be used for patients achieving a complete or partial response to rituximab in combination with chemotherapy, as single-agent maintenance therapy; or for patients with nonprogressing (including stable disease), low-grad, CD20-positive, B-cell NHL as a single agent after first-line CVP chemotherapy.
- CLL/SLL Chronic lymphocytic leukemia/small lymphocytic lymphoma
- Rituximab is indicated for untreated and previously treated CD20-positive CLL; combined therapy with fludarabine and cyclophosphamide (FC).
- Rheumatoid arthritis is a chronic autoimmune disease that causes pain, stiffness, swelling and limited motion and function of many joints. While RA can affect any joint, the small joints in the hands and feet tend to be involved most often.
- Inflammation sometimes can affect organs as well, for instance, the eyes or lungs.
- One possible mechanism of RA is that the immune system of patients is abnormal and attacks the body and creates inflammation. There is no cure for RA. Current treatments can lessen the symptoms and slow the dysfunction of the joints.
- Rituximab is approved by the Food and Drug Administration to treat active rheumatoid arthritis unresponsive to DMARDs (Disease-Modifying Antirheumatic Drugs) and anti-TNF-alpha agents.
- Rituximab is used to treat rheumatoid arthritis in combination with methotrexate (MTX) (e.g. Mease PJ et al., J RheomatoL, 2010, 37, 917-927; also reviewed by Rosman et al, BMC Medcine, 2013, 11, 88; the contents of each of which are herein incorporated by reference in their entirety).
- MTX methotrexate
- Rituximab is beneficial for other off-label indications in patients with other autoimmune diseases (such as systemic lupus erythematosus (SLE)), Castleman's disease, Granulomatosis with polyangiitis (GP) (previously Wegener Granulomatosis), and Microscopic Polyangiitis.
- SLE systemic lupus erythematosus
- GP Granulomatosis with polyangiitis
- Microscopic Polyangiitis may also be used to treat Immune
- Thrombocytopenic Purpura IPP
- refractory autoimmune hemolytic anemia Castleman's disease
- thrombocytopenia arthritis-related SLE
- systemic sclerosis(SyS) and
- corticosteroid refractory pemphigus vulgaris e.g. Cianchini G et al., J Am Acad
- polynucleotides of the present invention may be used to treat any of the disorders or diseases taught herein.
- Rituximab may be used to treat B- cell lymphomas, including relapsed indolent lymphoma (McLaughlin P et al., J Clin Oncol. 1998, 16, 2825-33, the content of which is incorporated herein by reference in its entirety), non-hodgkin's lymphoma and chronic lymphocytic leukemia (see, e.g.
- Rituximab may also be used to treat rheumatoid arthritis (Edwards JC et al., N Engl J Med. 2004,350,2572-81 , the content of which is incorporated herein by reference in its entirety), with methotrexate, to reduce the signs and symptoms of moderate to severe active RA in adults, after treatment with at least one other medicine such as a Tumor Necrosis Factor (TNF) antagonist has been used and did not work well enough; or Granulomatosis with Polyangiitis (GPA) (previously Wegener's Granulomatosis) and Microscopic Polyangiitis (MP A), with glucocorticoids.
- TNF Tumor Necrosis Factor
- the polynucleotides of the present invention may be used to treat hematological cancer (e.g. non-hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL)), autoimmune disease (e.g. Rheumatoid arthritis); anti- rejection after organ transplant and other B cell related diseases and conditions.
- hematological cancer e.g. non-hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL)
- NHL non-hodgkin lymphoma
- CLL chronic lymphocytic leukemia
- autoimmune disease e.g. Rheumatoid arthritis
- the polynucleotides of the present invention may be used in combination with other anti-CD20 antibodies to treat CD20 positive cancers and/or other clinical conditions.
- the anti-CD 20 antibodies include, but are not limited to, ocrelizuman (2H7.vl6, PRO-70769, R-1594), DXL 625, ocaratuzumab (AME-133), TRU-015, ofatumumab (2F2), tositumomab, 11B8 (as disclosed in WO 2004035607), AT80 (as disclosed in WO2009030368), humanized B-Lyl antibody (a chimeric humanized antibody as disclosed in WO2005044859), obinutuzumab (GA101), HI47 Ig G3 (ECACC, hybridoma), 2C6 IgGl (as disclosed in WO2004056312), 2F2 IgGl (HuMax-CD20) (as disclosed in WO2004035607 and WO2005
- anti-CD20 antibodies comprising the polynucleotides of the present invention may also be used to treat Other disease such as inflammatory bowel disease (IBD), Sjogren's syndrome, polychondritis or mononeuritis multiplex (e.g. US patent publication NOs:
- anti-CD20 antibodies may be encode by the amino acids
- nuclei acid sequence may be modified and codon optimized using the known nucleic acid sequences, for example those described in US Pat NO: 8,097,713, the content of which is incorporated herein by reference in its entirety.
- the polynucleotides encoding Rituximab may be used, in combination with other B-cells depleting antibodies, to deplete B cells for treating a clinical conditions such as B cell malignancies (e.g. chronic lymphocytic leukemia), autoimmune diseases, organ transplantation and serious infections.
- B cell depleting antibodies may include, but are not limited to, antibodies against CD 19, CD22, CD23, CD27, CD37, CD40, CD53, CD72, CD73, CD74, CDro78, CD79a, CD79b, CD80, CD81, CD82, CD83, CDw84, CD85 and CD86 (e.g. US Pat No: 6,896,885; 7,718,425; US patent publication NOs: US20130309224; 20130295005; US20130266561,
- the polynucleotides encoding Rituximab may be used for treating hematological cancer in combination with other anti-tumor monoclonal antibodies.
- said anti-tumor monoclonal antibodies may be trastuzumab (anti-Her-2), cetuximab (anti-Her-1), bevacizumab, edrecolomab, panitumumab or alemtuzumab, anti-CD22 antibodies as described in US Pat. NO:
- said other monoclonal antibodies may be encoded by the polynucleotides similar to the
- the polynucleotides of the present invention may be used to treat hematological cancers/malignancies, in combination with other cytotoxic, chemotherapeutic and/or anti-cancer agents (e.g. US patent publication NO:
- the anti-cancer agents may be cytokine IL-15 (e.g. PCT patent publication WO2013076183); CHOP (cyclophosphamide,
- the polynucleotides of the present invention may be used to treat autoimmune diseases alone or in combination with other therapeutic agents (see, e.g. US Pat NO: 7,074,403; US patent publication NOs: US20090214561;
- the polynucleotides encoding Rituximab may be used for treating vasculitis with human glucocorticosteroid (e.g. US Pat. NO: 8,545,843); rheumatoid arthritis with anti-IL-6R antibodies or methotrexate (e.g.
- autoimmune diseases selected from the group consisting of acute idiopathic thrombocytopenic purpura, chronic idiopathic thrombocytopenic purpura, myasthenia gravis, lupus erythematosus, Sjogren's syndrome and rheumatoid arthritis
- sphingomyelin e.g. US Pat NO: 7,683,044
- autoimmune and immune dysfunction diseases with anti-CD-74 antibodies e.g. US patent publication 20130295005
- multiple sclerosis e.g.
- lupus with hormone steroids e.g. methylprednisolone, prednisone, mycophenolate mofetil, methotrexate, hydroxychloroquine, chloroquine, quinacrine, azathiprine, or 6- mercaptopurine
- steroids e.g. methylprednisolone, prednisone, mycophenolate mofetil, methotrexate, hydroxychloroquine, chloroquine, quinacrine, azathiprine, or 6- mercaptopurine
- the polynucleotides of the present invention may be used to treat infections such as viral infections.
- Rituximab antibodies generated by the polynucleotides of the present invention may be used to treat viral infections in combination with other B-cell depleting antibodies such as anti- CD 10, CD19, CD21, CD22, CD23, CD24, CD37, CD53, CD72, CD73, CD74, CDw75, CDw76, CD77, CDw78, CD79a, CD79b, CD80, CD81, CD82, CD83, CDw84, CD85 and CD86 (see, e.g. US Pat NOs: 7,718,425; 6,306,393; 6,183,744; US patent publication NOs: 20110008250; US20080233128; the contents of each of which are incorporated herein by reference in their entirety).
- Rituximab antibodies generated by the polynucleotides of the present invention may be used to treat other diseases such as inflammatory bowel disease (IBD) (e.g. US patent publication NO: US20060233797), Sjogren's syndrome (e.g. US patent publication NO: US20060062787); and polychondritis or mononeuritis multiplex (e.g. US patent publication NO: US20060002930); the contents of each of which are incorporated herein by reference in their entirety.
- IBD inflammatory bowel disease
- Sjogren's syndrome e.g. US patent publication NO: US20060062787
- polychondritis or mononeuritis multiplex e.g. US patent publication NO: US20060002930
- the polynucleotides of the present invention may be used to reduce the risk of relapse of a B-cell-related disease in a patient receiving a bone marrow or peripheral blood stem cell transplant (e.g. US patent publication NO:
- the rituximab polynucleotides of the present invention are engineered such that they may comprise one or more coding regions.
- the coding regions of the rituximab polynucleotides may encode any of the regions or portions of the rituximab antibody. They may also further comprise coding regions not found in the original or parent rituximab antibody.
- the rituximab polynucleotides of the present invention may be engineered to produce any of the 5 standard classes of immunoglobulins as shown in Figure 1 using the rituximab antibody or any of its component parts as a starting molecule.
- the rituximab polynucleotides may also be engineered according to the present invention to produce a variant rituximab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- a variant rituximab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- tocilizumab polynucleotides or constructs and their associated tocilizumab compositions are designed to produce the tocilizumab antibody, a variant or a portion thereof in vivo.
- Tocilizumab (synonyms: atlizumab) is a recombinant, humanized monoclonal antibody against human interleukine 6 receptor (IL-6R). Tocilizumab is an
- immunosuppressive drug mainly for the treatment of rheumatoid arthritis (RA) and systemic juvenile idiopathic arthritis, a severe form of RA in children.
- Tocilizumab is a recombinant, humanized, anti-human interleukin 6 (IL-6) receptor monoclonal antibody.
- the light chain is made up of 214 amino acids.
- the heavy chain is made up of 448 amino acids.
- the four polypeptide chains are linked intra- and inter-molecularly by disulfide bonds.
- this chimeric antibody to human interleukin 6 receptor has light chains each having a human light chain constant Kc and an light chain variable region (V region) of a mouse monoclonal antibody to human IL- 6R; and heavy chains (H chains) each having a human H chain constant r ⁇ -lC region, and H chain V region of a mouse monoclonal antibody to human IL-6R (also in US Pat NOs: 5,795,965; and 5,817,790; the contents of each of which are herein incorporated by reference in their entirety.)
- the partial amino acid sequences of heavy and light chain are listed in Table 26.
- variants and/or derivatives from the same parent antibodies are also encompassed in the present invention such as the subtypes of humanized anti-IL-6R antibodies described in US Pat NO: 8,398,980 (also in US20130209456), and mutated tocilizumab with a high affinity as described in US Pat. NO: 8,562,991; the contents of each of which are herein incorporated by reference in its entirety.
- Interleukin (IL)-6 a cytokine
- IL-6 a cytokine
- RA chronic inflammatory autoimmune diseases
- systemic onset juvenile idiopathic arthritis (soJIA) Crohn's disease
- CD Crohn's disease
- SLE systemic lupus erythematosus
- IL-6 activities can explain many symptoms of these diseases. More importantly, serum levels of IL-6 are correlated with disease activity.
- IL-6 signal is mainly mediated by binding the IL-6 receptor.
- IL-6 binds to either membrane-bound or soluble IL-6R, and this complex in turn binds to the 130 gp signal transducer. This process enhances the inflammatory cascade, inducing
- angiogenesis and amplifying the activity of adhesion molecules and the activation of osteoclasts.
- Tocilizumab binds specifically to soluble as well as membrane-bound IL-6 receptors (sIL-6R and mIL-6R), and has been shown to inhibit IL-6-mediated signaling through these receptors.
- Tocilizumab is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response to one or more Disease-Modifying Anti-Rheumatic Drugs (DMARDs). It is also indicated for the treatment of active polyarticular juvenile idiopathic arthritis (PJIA) and active systemic juvenile idiopathic arthritis (S JIA) in patients 2 years of age and older.
- RA rheumatoid arthritis
- DMARDs Disease-Modifying Anti-Rheumatic Drugs
- tocilizumab is also approved for the treatment of castleman's disease, a rare benign B cell tumor.
- tocilizumab The most common side effects of tocilizumab include upper respiratory tract infections, nasopharyngitis, headache, hypertension and increased ALT.
- the polynucleotides of the present invention may be used as IL-6 antagonist, inhibiting IL-6 mediated biological activities.
- it may be used together with other IL-6 antagonist such as Remicade, Zenapx, sirukumab, Elsilimomab, an anti-IL-6 monoclonal antibody.
- the polynucleotides of the present invention may be used to treat an IL-6R associated diseases.
- IL-6 associated diseases may include, but are not limited to, acute chronic inflammatory diseases and autoimmune diseases: nephritis, mesangial proliferative nephritis, Crohn's disease, ulcerative colitis, pancreatitis, juvenile idiopathic arthritis or systemic juvenile idiopathic arthritis, vasculitis, Kawasaki disease, rheumatoid arthritis, systemic erythematosus, psoriasis, Sjogren syndrome, adult Still's disease;neoplasmic diseases: multiple myeloma, Castleman's disease, malignant lymphoma, renal cancer; infectious diseases: infection with HIV, infection with EBV; and cachexia: cachexia.
- the polynucleotides of the present invention may be used as monotherapy or in combination with conventional DMARDs in adult patients with moderate to severe rheumatoid arthritis. In some aspects, it may be used to treat juvenile idiopathic arthritis and systemic idiopathic arthritis.
- the tocilizumab polynucleotides of the present invention are engineered such that they may comprise one or more coding regions.
- the coding regions of the tocilizumab polynucleotides may encode any of the regions or portions of the tocilizumab antibody. They may also further comprise coding regions not found in the original or parent tocilizumab antibody.
- the tocilizumab polynucleotides of the present invention may be engineered to produce any of the 5 standard classes of immunoglobulins as shown in Figure 1 using the tocilizumab antibody or any of its component parts as a starting molecule.
- the tocilizumab polynucleotides may also be engineered according to the present invention to produce a variant tocilizumab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- a variant tocilizumab antibody which is selected from one of (a) an intrabody, (b) a bicistronic or pseudobicistronic antibody, (c) a single domain antibody, either VHH or dAb, (d) a single chain variable fragment (scFv) antibody, and (e) a bispecific antibody which may comprise any two regions from two different antibodies, e.g., dAb or VHH.
- tositumomab polynucleotides or constructs and their associated tositumomab compositions are designed to produce the tositumomab antibody, a variant or a portion thereof in vivo.
- Tositumomab (synonyms: Ig gamma- 1 chain C region; anti-Bl antibody) is a cell specific anti-CD20 antibody, mainly used to treat non-Hodgkin's lymphoma and lymphocytic leukemia, in particular, for the treatment of CD20 antigen expressing relapsed or refractory, low grade, follicular, or transformed non-Hodgkin's lymphoma, including patients with rituximab-refractory non-Hodgkin s lymphoma.
- Tositumomab is usually applied with a sequential infusion followed by iodine tositumomab, which is the same antibody covalently bound to the radionuclide iodine-131.
- the tositumomab/iodine- 131 tositumomab regimen (also called the Bexxar therapeutic regimen), as an
- antineoplastic radioimmunotherapeutic monoclonal antibody-based regimen has established the efficacy in treating relapsed or chemotherapy/rituxan refractory follicular lymphoma in patients.
- Tositumomab is a human-murine chimeric IgG2a lambda ( ⁇ ) antibody against human antigen CD20, which is a transmembrane phosphoprotein expressed on pre-B- lymphocytes and mature B lymphocytes.
- Tositumomab is a dimer, containing 2 heavy chains of 451 residues and 2 mouse monoclonal BlRlgammer2a-chain, disulfide with mouse monoclonal B1R1 ⁇ chain with 220 residues.
- Tositumomab was humanized from the mouse antibody anti-Bl (obtained from the Hall 299-15 ceil line) by Kaminski and Wahl et al (see, e.g. US Pat. NOs:
- This chimeric antibody comprises the Bl antigen-binding domain (CD20 binding) and a human Fc and hinge region.
- the amino acid sequences of chimeric heavy chain and light chain are listed in 26.
- Tositumomab binds to the CD20 antigen, which is predominantly expressed on mature B cells and on >90% of B-cell non-Hodgkin's lympohomas.
- the antibody leads to selective killing of B-cells.
- the Bexxar regimen composing of tositumomab/iodine-131 tositumomab can delivers radiation, which enhances the killing effect of the antibody. Normal B cells then will recover in 6-9 months because the parent B-cells do not express the CD20 anti gen.
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Immunology (AREA)
- General Health & Medical Sciences (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Life Sciences & Earth Sciences (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
L'invention concerne des compositions et des procédés de préparation, de fabrication et d'utilisation thérapeutique de polynucléotides codant pour un anticorps, un variant ou un fragment.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP15735068.7A EP3092250A4 (fr) | 2014-01-08 | 2015-01-08 | Polynucléotides pour la production in vivo d'anticorps |
US15/106,000 US20170002060A1 (en) | 2014-01-08 | 2015-01-08 | Polynucleotides for the in vivo production of antibodies |
Applications Claiming Priority (64)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201461924812P | 2014-01-08 | 2014-01-08 | |
US201461924817P | 2014-01-08 | 2014-01-08 | |
US201461924802P | 2014-01-08 | 2014-01-08 | |
US201461924781P | 2014-01-08 | 2014-01-08 | |
US201461924811P | 2014-01-08 | 2014-01-08 | |
US201461924810P | 2014-01-08 | 2014-01-08 | |
US201461924841P | 2014-01-08 | 2014-01-08 | |
US201461924783P | 2014-01-08 | 2014-01-08 | |
US201461924754P | 2014-01-08 | 2014-01-08 | |
US201461924787P | 2014-01-08 | 2014-01-08 | |
US201461924850P | 2014-01-08 | 2014-01-08 | |
US201461924773P | 2014-01-08 | 2014-01-08 | |
US201461924799P | 2014-01-08 | 2014-01-08 | |
US201461924827P | 2014-01-08 | 2014-01-08 | |
US201461924819P | 2014-01-08 | 2014-01-08 | |
US201461924774P | 2014-01-08 | 2014-01-08 | |
US201461924791P | 2014-01-08 | 2014-01-08 | |
US201461924804P | 2014-01-08 | 2014-01-08 | |
US201461924770P | 2014-01-08 | 2014-01-08 | |
US201461924805P | 2014-01-08 | 2014-01-08 | |
US201461924846P | 2014-01-08 | 2014-01-08 | |
US201461924807P | 2014-01-08 | 2014-01-08 | |
US201461924768P | 2014-01-08 | 2014-01-08 | |
US201461924820P | 2014-01-08 | 2014-01-08 | |
US201461924775P | 2014-01-08 | 2014-01-08 | |
US201461924779P | 2014-01-08 | 2014-01-08 | |
US201461924763P | 2014-01-08 | 2014-01-08 | |
US201461924776P | 2014-01-08 | 2014-01-08 | |
US201461924795P | 2014-01-08 | 2014-01-08 | |
US201461924834P | 2014-01-08 | 2014-01-08 | |
US201461924767P | 2014-01-08 | 2014-01-08 | |
US61/924,804 | 2014-01-08 | ||
US61/924,774 | 2014-01-08 | ||
US61/924,767 | 2014-01-08 | ||
US61/924,768 | 2014-01-08 | ||
US61/924,795 | 2014-01-08 | ||
US61/924,807 | 2014-01-08 | ||
US61/924,802 | 2014-01-08 | ||
US61/924,846 | 2014-01-08 | ||
US61/924,773 | 2014-01-08 | ||
US61/924,817 | 2014-01-08 | ||
US61/924,775 | 2014-01-08 | ||
US61/924,783 | 2014-01-08 | ||
US61/924,776 | 2014-01-08 | ||
US61/924,811 | 2014-01-08 | ||
US61/924,820 | 2014-01-08 | ||
US61/924,781 | 2014-01-08 | ||
US61/924,827 | 2014-01-08 | ||
US61/924,810 | 2014-01-08 | ||
US61/924,754 | 2014-01-08 | ||
US61/924,834 | 2014-01-08 | ||
US61/924,805 | 2014-01-08 | ||
US61/924,791 | 2014-01-08 | ||
US61/924,799 | 2014-01-08 | ||
US61/924,812 | 2014-01-08 | ||
US61/924,841 | 2014-01-08 | ||
US61/924,787 | 2014-01-08 | ||
US61/924,850 | 2014-01-08 | ||
US61/924,779 | 2014-01-08 | ||
US61/924,763 | 2014-01-08 | ||
US61/924,770 | 2014-01-08 | ||
US61/924,819 | 2014-01-08 | ||
US201461993715P | 2014-05-15 | 2014-05-15 | |
US61/993,715 | 2014-05-15 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2015105926A1 true WO2015105926A1 (fr) | 2015-07-16 |
Family
ID=53524318
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2015/010547 WO2015105926A1 (fr) | 2014-01-08 | 2015-01-08 | Polynucléotides pour la production in vivo d'anticorps |
Country Status (2)
Country | Link |
---|---|
EP (1) | EP3092250A4 (fr) |
WO (1) | WO2015105926A1 (fr) |
Cited By (45)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9186372B2 (en) | 2011-12-16 | 2015-11-17 | Moderna Therapeutics, Inc. | Split dose administration |
WO2016014846A1 (fr) * | 2014-07-23 | 2016-01-28 | Moderna Therapeutics, Inc. | Polynucléotides modifiés destinés à la production d'anticorps intracellulaires |
US9254311B2 (en) | 2012-04-02 | 2016-02-09 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of proteins |
US9283287B2 (en) | 2012-04-02 | 2016-03-15 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of nuclear proteins |
US9301993B2 (en) | 2012-04-02 | 2016-04-05 | Moderna Therapeutics, Inc. | Modified polynucleotides encoding apoptosis inducing factor 1 |
US9447164B2 (en) | 2010-08-06 | 2016-09-20 | Moderna Therapeutics, Inc. | Engineered nucleic acids and methods of use thereof |
US9533047B2 (en) | 2011-03-31 | 2017-01-03 | Modernatx, Inc. | Delivery and formulation of engineered nucleic acids |
US9572897B2 (en) | 2012-04-02 | 2017-02-21 | Modernatx, Inc. | Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins |
WO2017117218A1 (fr) * | 2015-12-30 | 2017-07-06 | Momenta Pharmaceuticals, Inc. | Méthodes associées à des produits biologiques |
US9701965B2 (en) | 2010-10-01 | 2017-07-11 | Modernatx, Inc. | Engineered nucleic acids and methods of use thereof |
WO2017200787A1 (fr) * | 2016-05-18 | 2017-11-23 | Arizona Board Of Regents On Behalf Of Arizona State University | Chimères peptide-adn pour le traitement des cancers à surexpression de her |
WO2018009838A1 (fr) | 2016-07-07 | 2018-01-11 | Rubius Therapeutics, Inc. | Compositions et procédés associés à des systèmes cellulaires thérapeutiques exprimant de l'arn exogène |
WO2018094059A1 (fr) * | 2016-11-16 | 2018-05-24 | University Of Maryland, Baltimore | Procédés de traitement de troubles liés aux os |
US10023626B2 (en) | 2013-09-30 | 2018-07-17 | Modernatx, Inc. | Polynucleotides encoding immune modulating polypeptides |
US10077439B2 (en) | 2013-03-15 | 2018-09-18 | Modernatx, Inc. | Removal of DNA fragments in mRNA production process |
US10138507B2 (en) | 2013-03-15 | 2018-11-27 | Modernatx, Inc. | Manufacturing methods for production of RNA transcripts |
WO2019008335A1 (fr) | 2017-07-07 | 2019-01-10 | Avacta Life Sciences Limited | Protéines d'échafaudage |
US10258698B2 (en) | 2013-03-14 | 2019-04-16 | Modernatx, Inc. | Formulation and delivery of modified nucleoside, nucleotide, and nucleic acid compositions |
US10286086B2 (en) | 2014-06-19 | 2019-05-14 | Modernatx, Inc. | Alternative nucleic acid molecules and uses thereof |
US10385088B2 (en) | 2013-10-02 | 2019-08-20 | Modernatx, Inc. | Polynucleotide molecules and uses thereof |
US10407683B2 (en) | 2014-07-16 | 2019-09-10 | Modernatx, Inc. | Circular polynucleotides |
EP3492105A4 (fr) * | 2016-07-26 | 2020-02-26 | Nihon University | Agent thérapeutique pour la parodontite. |
US10590161B2 (en) | 2013-03-15 | 2020-03-17 | Modernatx, Inc. | Ion exchange purification of mRNA |
US10849920B2 (en) | 2015-10-05 | 2020-12-01 | Modernatx, Inc. | Methods for therapeutic administration of messenger ribonucleic acid drugs |
WO2021074695A1 (fr) | 2019-10-16 | 2021-04-22 | Avacta Life Sciences Limited | FRACTIONS DE MÉDICAMENTS BISPÉCIFIQUES DE L'INHIBITEUR DE PD-L1 ET DE L'INHIBITEUR DE TGFβ |
US11027025B2 (en) | 2013-07-11 | 2021-06-08 | Modernatx, Inc. | Compositions comprising synthetic polynucleotides encoding CRISPR related proteins and synthetic sgRNAs and methods of use |
WO2021249786A1 (fr) | 2020-06-09 | 2021-12-16 | Avacta Life Sciences Limited | Polypeptides et procédés de diagnostic du sars-cov2 |
WO2022023559A1 (fr) * | 2020-07-31 | 2022-02-03 | Curevac Ag | Mélanges d'anticorps codés par des acides nucléiques |
US11377470B2 (en) | 2013-03-15 | 2022-07-05 | Modernatx, Inc. | Ribonucleic acid purification |
WO2022155404A1 (fr) * | 2021-01-14 | 2022-07-21 | Translate Bio, Inc. | Méthodes et compositions pour administrer des anticorps codés par arnm |
US11421038B2 (en) | 2007-01-09 | 2022-08-23 | Curevac Ag | RNA-coded antibody |
US11434486B2 (en) | 2015-09-17 | 2022-09-06 | Modernatx, Inc. | Polynucleotides containing a morpholino linker |
WO2022234003A1 (fr) | 2021-05-07 | 2022-11-10 | Avacta Life Sciences Limited | Polypeptides se liant à cd33 avec protéine stefin a |
US20230065040A1 (en) * | 2016-11-10 | 2023-03-02 | Translate Bio, Inc. | Subcutaneous delivery of messenger rna |
WO2023031394A1 (fr) | 2021-09-03 | 2023-03-09 | CureVac SE | Nouvelles nanoparticules lipidiques pour l'administration d'acides nucléiques |
US11603399B2 (en) | 2013-03-13 | 2023-03-14 | Modernatx, Inc. | Long-lived polynucleotide molecules |
WO2023057946A1 (fr) | 2021-10-07 | 2023-04-13 | Avacta Life Sciences Limited | Polypeptides sériques de liaison pd-l1 prolongés à demi-vie |
WO2023057567A1 (fr) | 2021-10-07 | 2023-04-13 | Avacta Life Sciences Limited | Affimers de liaison à pd-l1 |
WO2023073228A1 (fr) | 2021-10-29 | 2023-05-04 | CureVac SE | Arn circulaire amélioré pour exprimer des protéines thérapeutiques |
WO2023144330A1 (fr) | 2022-01-28 | 2023-08-03 | CureVac SE | Inhibiteurs de facteurs de transcription codés par un acide nucleique |
US11802146B2 (en) | 2018-01-05 | 2023-10-31 | Modernatx, Inc. | Polynucleotides encoding anti-chikungunya virus antibodies |
WO2023218243A1 (fr) | 2022-05-12 | 2023-11-16 | Avacta Life Sciences Limited | Protéines de fusion de liaison lag-3/pd-l1 |
WO2023227608A1 (fr) | 2022-05-25 | 2023-11-30 | Glaxosmithkline Biologicals Sa | Vaccin à base d'acide nucléique codant pour un polypeptide antigénique fimh d'escherichia coli |
DE202023106198U1 (de) | 2022-10-28 | 2024-03-21 | CureVac SE | Impfstoff auf Nukleinsäurebasis |
RU2818678C2 (ru) * | 2019-05-23 | 2024-05-03 | Новартис Аг | Способы лечения хронической спонтанной крапивницы с применением ингибитора тирозинкиназы брутона |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20110033389A1 (en) * | 2009-04-29 | 2011-02-10 | Zhifeng Chen | Modified antibodies for passive immunotherapy |
US20130195867A1 (en) * | 2007-01-09 | 2013-08-01 | Curevac Gmbh | Rna-coded antibody |
US20130196377A1 (en) * | 2011-12-26 | 2013-08-01 | Samsung Electronics Co., Ltd. | Protein complex and method of preparing same |
WO2013151666A2 (fr) * | 2012-04-02 | 2013-10-10 | modeRNA Therapeutics | Polynucléotides modifiés destinés à la production de produits biologiques et de protéines associées à une maladie humaine |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080187954A1 (en) * | 2004-03-10 | 2008-08-07 | Lonza Ltd. | Method For Producing Antibodies |
EP2859102A4 (fr) * | 2012-06-08 | 2016-05-11 | Shire Human Genetic Therapies | Polynucléotides résistant à la nucléase et leurs utilisations |
ES2882110T3 (es) * | 2013-03-14 | 2021-12-01 | Translate Bio Inc | Métodos y composiciones para administrar anticuerpos codificados con ARNm |
-
2015
- 2015-01-08 WO PCT/US2015/010547 patent/WO2015105926A1/fr active Application Filing
- 2015-01-08 EP EP15735068.7A patent/EP3092250A4/fr not_active Withdrawn
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20130195867A1 (en) * | 2007-01-09 | 2013-08-01 | Curevac Gmbh | Rna-coded antibody |
US20110033389A1 (en) * | 2009-04-29 | 2011-02-10 | Zhifeng Chen | Modified antibodies for passive immunotherapy |
US20130196377A1 (en) * | 2011-12-26 | 2013-08-01 | Samsung Electronics Co., Ltd. | Protein complex and method of preparing same |
WO2013151666A2 (fr) * | 2012-04-02 | 2013-10-10 | modeRNA Therapeutics | Polynucléotides modifiés destinés à la production de produits biologiques et de protéines associées à une maladie humaine |
Non-Patent Citations (1)
Title |
---|
See also references of EP3092250A1 * |
Cited By (71)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11421038B2 (en) | 2007-01-09 | 2022-08-23 | Curevac Ag | RNA-coded antibody |
US9937233B2 (en) | 2010-08-06 | 2018-04-10 | Modernatx, Inc. | Engineered nucleic acids and methods of use thereof |
US9447164B2 (en) | 2010-08-06 | 2016-09-20 | Moderna Therapeutics, Inc. | Engineered nucleic acids and methods of use thereof |
US9701965B2 (en) | 2010-10-01 | 2017-07-11 | Modernatx, Inc. | Engineered nucleic acids and methods of use thereof |
US11911474B2 (en) | 2011-03-31 | 2024-02-27 | Modernatx, Inc. | Delivery and formulation of engineered nucleic acids |
US10898574B2 (en) | 2011-03-31 | 2021-01-26 | Modernatx, Inc. | Delivery and formulation of engineered nucleic acids |
US9950068B2 (en) | 2011-03-31 | 2018-04-24 | Modernatx, Inc. | Delivery and formulation of engineered nucleic acids |
US9533047B2 (en) | 2011-03-31 | 2017-01-03 | Modernatx, Inc. | Delivery and formulation of engineered nucleic acids |
US9271996B2 (en) | 2011-12-16 | 2016-03-01 | Moderna Therapeutics, Inc. | Formulation and delivery of PLGA microspheres |
US9295689B2 (en) | 2011-12-16 | 2016-03-29 | Moderna Therapeutics, Inc. | Formulation and delivery of PLGA microspheres |
US9186372B2 (en) | 2011-12-16 | 2015-11-17 | Moderna Therapeutics, Inc. | Split dose administration |
US9675668B2 (en) | 2012-04-02 | 2017-06-13 | Moderna Therapeutics, Inc. | Modified polynucleotides encoding hepatitis A virus cellular receptor 2 |
US9827332B2 (en) | 2012-04-02 | 2017-11-28 | Modernatx, Inc. | Modified polynucleotides for the production of proteins |
US9587003B2 (en) | 2012-04-02 | 2017-03-07 | Modernatx, Inc. | Modified polynucleotides for the production of oncology-related proteins and peptides |
US10385106B2 (en) | 2012-04-02 | 2019-08-20 | Modernatx, Inc. | Modified polynucleotides for the production of secreted proteins |
US10577403B2 (en) | 2012-04-02 | 2020-03-03 | Modernatx, Inc. | Modified polynucleotides for the production of secreted proteins |
US9572897B2 (en) | 2012-04-02 | 2017-02-21 | Modernatx, Inc. | Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins |
US9782462B2 (en) | 2012-04-02 | 2017-10-10 | Modernatx, Inc. | Modified polynucleotides for the production of proteins associated with human disease |
US9814760B2 (en) | 2012-04-02 | 2017-11-14 | Modernatx, Inc. | Modified polynucleotides for the production of biologics and proteins associated with human disease |
US9303079B2 (en) | 2012-04-02 | 2016-04-05 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins |
US9572896B2 (en) | 2012-04-02 | 2017-02-21 | Modernatx, Inc. | In vivo production of proteins |
US9828416B2 (en) | 2012-04-02 | 2017-11-28 | Modernatx, Inc. | Modified polynucleotides for the production of secreted proteins |
US9301993B2 (en) | 2012-04-02 | 2016-04-05 | Moderna Therapeutics, Inc. | Modified polynucleotides encoding apoptosis inducing factor 1 |
US9878056B2 (en) | 2012-04-02 | 2018-01-30 | Modernatx, Inc. | Modified polynucleotides for the production of cosmetic proteins and peptides |
US9283287B2 (en) | 2012-04-02 | 2016-03-15 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of nuclear proteins |
US9255129B2 (en) | 2012-04-02 | 2016-02-09 | Moderna Therapeutics, Inc. | Modified polynucleotides encoding SIAH E3 ubiquitin protein ligase 1 |
US9254311B2 (en) | 2012-04-02 | 2016-02-09 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of proteins |
US10772975B2 (en) | 2012-04-02 | 2020-09-15 | Modernatx, Inc. | Modified Polynucleotides for the production of biologics and proteins associated with human disease |
US10703789B2 (en) | 2012-04-02 | 2020-07-07 | Modernatx, Inc. | Modified polynucleotides for the production of secreted proteins |
US11603399B2 (en) | 2013-03-13 | 2023-03-14 | Modernatx, Inc. | Long-lived polynucleotide molecules |
US10258698B2 (en) | 2013-03-14 | 2019-04-16 | Modernatx, Inc. | Formulation and delivery of modified nucleoside, nucleotide, and nucleic acid compositions |
US11377470B2 (en) | 2013-03-15 | 2022-07-05 | Modernatx, Inc. | Ribonucleic acid purification |
US10858647B2 (en) | 2013-03-15 | 2020-12-08 | Modernatx, Inc. | Removal of DNA fragments in mRNA production process |
US10077439B2 (en) | 2013-03-15 | 2018-09-18 | Modernatx, Inc. | Removal of DNA fragments in mRNA production process |
US10590161B2 (en) | 2013-03-15 | 2020-03-17 | Modernatx, Inc. | Ion exchange purification of mRNA |
US10138507B2 (en) | 2013-03-15 | 2018-11-27 | Modernatx, Inc. | Manufacturing methods for production of RNA transcripts |
US11845772B2 (en) | 2013-03-15 | 2023-12-19 | Modernatx, Inc. | Ribonucleic acid purification |
US11027025B2 (en) | 2013-07-11 | 2021-06-08 | Modernatx, Inc. | Compositions comprising synthetic polynucleotides encoding CRISPR related proteins and synthetic sgRNAs and methods of use |
US10023626B2 (en) | 2013-09-30 | 2018-07-17 | Modernatx, Inc. | Polynucleotides encoding immune modulating polypeptides |
US10815291B2 (en) | 2013-09-30 | 2020-10-27 | Modernatx, Inc. | Polynucleotides encoding immune modulating polypeptides |
US10385088B2 (en) | 2013-10-02 | 2019-08-20 | Modernatx, Inc. | Polynucleotide molecules and uses thereof |
US10286086B2 (en) | 2014-06-19 | 2019-05-14 | Modernatx, Inc. | Alternative nucleic acid molecules and uses thereof |
US10407683B2 (en) | 2014-07-16 | 2019-09-10 | Modernatx, Inc. | Circular polynucleotides |
WO2016014846A1 (fr) * | 2014-07-23 | 2016-01-28 | Moderna Therapeutics, Inc. | Polynucléotides modifiés destinés à la production d'anticorps intracellulaires |
US11434486B2 (en) | 2015-09-17 | 2022-09-06 | Modernatx, Inc. | Polynucleotides containing a morpholino linker |
US10849920B2 (en) | 2015-10-05 | 2020-12-01 | Modernatx, Inc. | Methods for therapeutic administration of messenger ribonucleic acid drugs |
US11590157B2 (en) | 2015-10-05 | 2023-02-28 | Modernatx, Inc. | Methods for therapeutic administration of messenger ribonucleic acid drugs |
WO2017117218A1 (fr) * | 2015-12-30 | 2017-07-06 | Momenta Pharmaceuticals, Inc. | Méthodes associées à des produits biologiques |
US11719704B2 (en) | 2015-12-30 | 2023-08-08 | Momenta Pharmaceuticals, Inc. | Methods related to biologics |
WO2017200787A1 (fr) * | 2016-05-18 | 2017-11-23 | Arizona Board Of Regents On Behalf Of Arizona State University | Chimères peptide-adn pour le traitement des cancers à surexpression de her |
US10532109B2 (en) | 2016-05-18 | 2020-01-14 | Arizona Board Of Regents On Behalf Of Arizona State University | Peptide-DNA chimeras for treatment of HER overexpressing cancers |
WO2018009838A1 (fr) | 2016-07-07 | 2018-01-11 | Rubius Therapeutics, Inc. | Compositions et procédés associés à des systèmes cellulaires thérapeutiques exprimant de l'arn exogène |
EP3492105A4 (fr) * | 2016-07-26 | 2020-02-26 | Nihon University | Agent thérapeutique pour la parodontite. |
US20230065040A1 (en) * | 2016-11-10 | 2023-03-02 | Translate Bio, Inc. | Subcutaneous delivery of messenger rna |
WO2018094059A1 (fr) * | 2016-11-16 | 2018-05-24 | University Of Maryland, Baltimore | Procédés de traitement de troubles liés aux os |
WO2019008335A1 (fr) | 2017-07-07 | 2019-01-10 | Avacta Life Sciences Limited | Protéines d'échafaudage |
US11802146B2 (en) | 2018-01-05 | 2023-10-31 | Modernatx, Inc. | Polynucleotides encoding anti-chikungunya virus antibodies |
RU2818678C2 (ru) * | 2019-05-23 | 2024-05-03 | Новартис Аг | Способы лечения хронической спонтанной крапивницы с применением ингибитора тирозинкиназы брутона |
WO2021074695A1 (fr) | 2019-10-16 | 2021-04-22 | Avacta Life Sciences Limited | FRACTIONS DE MÉDICAMENTS BISPÉCIFIQUES DE L'INHIBITEUR DE PD-L1 ET DE L'INHIBITEUR DE TGFβ |
WO2021249786A1 (fr) | 2020-06-09 | 2021-12-16 | Avacta Life Sciences Limited | Polypeptides et procédés de diagnostic du sars-cov2 |
WO2022023559A1 (fr) * | 2020-07-31 | 2022-02-03 | Curevac Ag | Mélanges d'anticorps codés par des acides nucléiques |
WO2022155404A1 (fr) * | 2021-01-14 | 2022-07-21 | Translate Bio, Inc. | Méthodes et compositions pour administrer des anticorps codés par arnm |
WO2022234003A1 (fr) | 2021-05-07 | 2022-11-10 | Avacta Life Sciences Limited | Polypeptides se liant à cd33 avec protéine stefin a |
WO2023031394A1 (fr) | 2021-09-03 | 2023-03-09 | CureVac SE | Nouvelles nanoparticules lipidiques pour l'administration d'acides nucléiques |
WO2023057567A1 (fr) | 2021-10-07 | 2023-04-13 | Avacta Life Sciences Limited | Affimers de liaison à pd-l1 |
WO2023057946A1 (fr) | 2021-10-07 | 2023-04-13 | Avacta Life Sciences Limited | Polypeptides sériques de liaison pd-l1 prolongés à demi-vie |
WO2023073228A1 (fr) | 2021-10-29 | 2023-05-04 | CureVac SE | Arn circulaire amélioré pour exprimer des protéines thérapeutiques |
WO2023144330A1 (fr) | 2022-01-28 | 2023-08-03 | CureVac SE | Inhibiteurs de facteurs de transcription codés par un acide nucleique |
WO2023218243A1 (fr) | 2022-05-12 | 2023-11-16 | Avacta Life Sciences Limited | Protéines de fusion de liaison lag-3/pd-l1 |
WO2023227608A1 (fr) | 2022-05-25 | 2023-11-30 | Glaxosmithkline Biologicals Sa | Vaccin à base d'acide nucléique codant pour un polypeptide antigénique fimh d'escherichia coli |
DE202023106198U1 (de) | 2022-10-28 | 2024-03-21 | CureVac SE | Impfstoff auf Nukleinsäurebasis |
Also Published As
Publication number | Publication date |
---|---|
EP3092250A1 (fr) | 2016-11-16 |
EP3092250A4 (fr) | 2017-05-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20170002060A1 (en) | Polynucleotides for the in vivo production of antibodies | |
WO2015105926A1 (fr) | Polynucléotides pour la production in vivo d'anticorps | |
US10973917B2 (en) | MRNA combination therapy for the treatment of cancer | |
US11596609B2 (en) | Combinations of mRNAs encoding immune modulating polypeptides and uses thereof | |
US11873327B2 (en) | Polynucleotides encoding tethered interleukin-12 (IL12) polypeptides and uses thereof | |
US20190192653A1 (en) | Compositions and methods for tolerizing cellular systems | |
ES2667522T3 (es) | Anticuerpo monoclonal humano para CD134 (OX40) humana y procedimientos de preparación y utilización del mismo | |
AU2019293600A1 (en) | Compositions and methods for modulating monocyte and macrophage inflammatory phenotypes and immunotherapy uses thereof | |
EP3966227A1 (fr) | Compositions et méthodes d'augmentation vectorisée de la destruction, de l'expression et/ou de la régulation de protéines | |
JP2022062277A (ja) | 増加した免疫活性において使用するためのactriiアンタゴニスト | |
US20190241658A1 (en) | Therapeutic mRNAs encoding anti CTLA-4 antibodies | |
EP3532489A1 (fr) | Anticorps monoclonaux neutralisants anti-tl1a | |
EP3252077A1 (fr) | Efficacité supérieure d'anticorps cd37 dans des échantillons sanguins cll | |
JP2020511493A (ja) | セマフォリン−4d抗体とエピジェネティック調節剤の組み合わせを用いたがんの処置方法 | |
TW202031687A (zh) | 一種融合蛋白及其用途 | |
US20220048948A1 (en) | Cd40 targeted peptides and uses thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 15735068 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 15106000 Country of ref document: US |
|
REEP | Request for entry into the european phase |
Ref document number: 2015735068 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2015735068 Country of ref document: EP |
|
NENP | Non-entry into the national phase |
Ref country code: DE |