Compositions and methods relating to universal glycoforms for enhanced antibody efficacy

Abstract

The present disclosure relates to glycoproteins, particularly monoclonal antibodies, comprising a glycoengineered Fc region, wherein said Fc region comprises an optimized N-glycan having the structure of Sia2(α2-6)Gal2GlcNAc2Man3GlcNAc2. The glycoengineered Fc region binds FcγRIIA or FcγRIIIA with a greater affinity, relative to comparable monoclonal antibodies comprising the wild-type Fc region. The monoclonal antibodies of the invention are particularly useful in preventing, treating, or ameliorating one or more symptoms associated with a disease, disorder, or infection where an enhanced efficacy of effector cell function (e.g., ADCC) mediated by FcγR is desired, e.g., cancer, autoimmune, infectious disease, and in enhancing the therapeutic efficacy of therapeutic antibodies the effect of which is mediated by ADCC.

1 . A composition comprising a homogeneous population of monoclonal antibodies or antigen binding fragment thereof, wherein each glycoantibody or antigen binding fragment molecule comprising a single, uniform N-glycan on the Fc region, wherein the N-glycan has the structure of Sia 2 (α2-6)Gal 2 GlcNAc 2 Man 3 GlcNAc 2 , and wherein the N-glycan is optimized for improving effector cell function. 
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . The composition of  claim 1 , wherein the monoclonal antibodies are selected from human IgG1, IgG2, IgG3, and IgG4. 
     
     
         5 . The composition of  claim 1 , wherein the monoclonal antibodies bind to at least an antigen associated with cancers, autoimmune or inflammatory diseases, or infectious diseases. 
     
     
         6 . The composition of  claim 1 , wherein the monoclonal antibodies bind to an antigen associated with cancers. 
     
     
         7 . The composition of  claim 6 , wherein the antigen is selected from the group consisting of GD2, GD3, GM2, Globo-H, SSEA-3, SSEA-4, CD16A, CD30, CD32B, CD33, CD52, EpCAM, CEA, gpA33, HER2/neu, A33, CDS, CD11c, CD19, CD20, CD22, CD23, CD27, CD40, CD45, CD79a, CD79b, CD103, CTLA4, ErbB1, ErbB3, ErbB4, VEGF receptor, TNF-α receptor, TNF-β receptor, or TNF-γ receptor, gpA33, Mucins, TAG-72, CAIX, PSMA, Folate-binding protein, VEGF, VEGFR, Integrin αVβ3, Integrin α5β1, EGFR, ERBB2, ERBB3, MET, IGF1R, EPHA3, TRAILR1, TRAILR2, RANKL, FAP and Tenascin. 
     
     
         8 . The composition of  claim 1 , wherein the monoclonal antibodies bind to an antigen associated with an autoimmune or inflammatory disease. 
     
     
         9 . The composition of  claim 1 , wherein the antigen is selected from the group consisting of interleukin 5 and its receptor, a tumor necrosis factor and its receptor. 
     
     
         10 . The composition of  claim 1 , wherein the monoclonal antibodies bind to an antigen expressed on a virus infected cell. 
     
     
         11 . The composition of  claim 1 , wherein the antigen is selected from the group consisting of gp120, CXCR4 and Vero toxin. 
     
     
         12 . The composition of  claim 1 , wherein the composition is produced in vitro. 
     
     
         13 . A pharmaceutical formulation comprising a composition according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         14 . A method for enhancing antibody-dependent cell mediated cytotoxicity (ADCC) activity, the method comprising administering to a subject in need thereof an amount of a composition according to  claim 1 . 
     
     
         15 . A method for preventing, treating, or ameliorating one or more symptoms associated with a disease, disorder, or infection, the method comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition according to  claim 13 . 
     
     
         16 . The method of  claim 15 , wherein the disease, disorder, or infection is selected from a group consisting of cancer, autoimmune disorder, inflammatory disorder or infectious infection. 
     
     
         17 . The method of  claim 16 , wherein the cancer is selected from the group consisting of brain cancer, lung cancer, breast cancer, oral cancer, esophagus cancer, stomach cancer, liver cancer, bile duct cancer, pancreas cancer, colon cancer, kidney cancer, cervix cancer, ovary cancer and prostate cancer. In some embodiments, the cancer is brain cancer, lung cancer, breast cancer, ovarian cancer, prostate cancer, colon cancer, or pancreas cancer. 
     
     
         18 . The method of  claim 16 , wherein the cancer is selected from the group consisting of B cell lymphomas, NHL, precursor B cell lymphoblastic leukemia/lymphoma and mature B cell neoplasms, B cell chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, mantle cell lymphoma (MCL), follicular lymphoma (FL), low-grade, intermediate-grade and high-grade (FL), cutaneous follicle center lymphoma, marginal zone B cell lymphoma, MALT type marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, splenic type marginal zone B cell lymphoma, hairy cell leukemia, diffuse large B cell lymphoma, Burkitt's lymphoma, plasmacytoma, plasma cell myeloma, post-transplant lymphoproliferative disorder, Waldenstrom's macroglobulinemia, and anaplastic large-cell lymphoma (ALCL). 
     
     
         19 . The method of  claim 16 , wherein the autoimmune or inflammatory disease is selected from the group consisting of rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus (SLE), lupus nephritis, ulcerative colitis, Wegener's disease, inflammatory bowel disease, idiopathic thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), autoimmune thrombocytopenia, multiple sclerosis, psoriasis, IgA nephropathy, IgM polyneuropathies, myasthenia gravis, vasculitis, diabetes mellitus, Reynaud's syndrome, Sjorgen's syndrome and glomerulonephritis. 
     
     
         20 . The method of  claim 19 , wherein the autoimmune or inflammatory disease is rheumatoid arthritis. 
     
     
         21 . (canceled) 
     
     
         22 . The method of  claim 21 , wherein the infectious disease is caused by HIV, HCV, or a combination thereof. 
     
     
         23 . The method of  claim 15 , wherein an enhanced efficacy of effector cell function mediated by FcγR is desired for preventing, treating, or ameliorating one or more symptoms associated with the disease, disorder, or infection. 
     
     
         24 . (canceled) 
     
     
         25 . The method of  claim 15 , wherein the pharmaceutical composition is administered alone or in conjunction with a second therapeutic agent selected from a group consisting of a second antibody, a chemotherapeutic agent and an immunosuppressive agent. 
     
     
         26 . (canceled) 
     
     
         27 . (canceled) 
     
     
         28 . The composition of  claim 1 , wherein the monoclonal antibodies comprise a light chain sequence and a heavy chain sequence of Rituximab (Rituxan®). 
     
     
         29 . The composition of  claim 1 , wherein the monoclonal antibodies comprise a light chain sequence and a heavy chain sequence of Trastuzumab (Herceptin®). 
     
     
         30 . The composition of  claim 1 , wherein the monoclonal antibodies comprise a light chain sequence and a heavy chain sequence of Adalimumab (Humira). 
     
     
         31 . The composition of  claim 1 , wherein the monoclonal antibodies are F16 monoclonal antibodies. 
     
     
         32 . A method for treating a cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising an essentially homogeneous population of FDA approved monoclonal antibodies for treatment of cancer, or antigen-binding fragments thereof, wherein the FDA approved monoclonal antibodies or antigen binding fragments thereof have been glycoengineered to have a Sia 2 (α2-6)Gal 2 GlcNAc 2 Man 3 GlcNAc 2  at each Asn-297 position in the Fc region. 
     
     
         33 . The method of  claim 32 , wherein the FDA approved antibodies or antigen-binding fragments thereof are selected from the group consisting of Rituximab, Ibritumomab tiuxetan, Obinutuzumab, Ofatumumab, and Tositumomab. 
     
     
         34 . A method for treating a cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising an essentially homogeneous population of glycoengineered monoclonal glycoantibodies or antigen binding fragments thereof, wherein the glycoengineered monoclonal or antigen binding fragments thereof are selected from the group consisting of Alemtuzumab, Belimumab, Bevacizumab, Brentuximab vedotin, Canakinumab, Cetuximab, Denosumab, Ibritumomab tiuxetan, Ipilimumab, Nivolumab, Obinutuzumab, Ofatumumab, Panitumumab, Pembrolizumab, Pertuzumab, Ramucirumab, Rituximab, Siltuximab, Tocilizumab, Tositumomab and Trastuzumab, and wherein the glycoengineered monoclonal glycoantibodies or antigen binding fragments thereof have a Sia 2 (α2-6)Gal 2 GlcNAc 2 Man 3 GlcNAc 2  at each Asn-297 position in the Fc region. 
     
     
         35 . A method for treating a cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising an essentially homogeneous population of monoclonal antibodies or antigen binding fragments thereof, wherein the monoclonal antibodies or antigen binding fragments thereof are selected from the group consisting of Alemtuzumab, Belimumab, Bevacizumab, Brentuximab vedotin, Canakinumab, Cetuximab, Denosumab, Ibritumomab tiuxetan, Ipilimumab, Nivolumab, Obinutuzumab, Ofatumumab, Panitumumab, Pembrolizumab, Pertuzumab, Ramucirumab, Rituximab, Siltuximab, Tocilizumab, Tositumomab and Trastuzumab, and wherein the monoclonal antibodies or antigen binding fragments thereof have been glycoengineered to have a Sia 2 (α2-6)Gal 2 GlcNAc 2 Man 3 GlcNAc 2  at each Asn-297 position in the Fc region.