METHODS FOR THE TREATMENT OF DISEASE USING IMMUNOGLOBULINS HAVING FC REGIONS ALTERED AFFINITIES FOR FcyRActivating and FcyRInhibiting

Abstract

The present invention relates to methods of treating or preventing cancer and other diseases using molecules, particularly polypeptides, more particularly immunoglobulins (e.g., antibodies), comprising a variant Fc region, wherein said variant Fc region comprises at least one amino acid modification relative to a wild-type Fc region, which variant Fc region binds an FcγR that activates a cellular effector (“FcγRActivating,” such as FcγRIIA or FcγRIIIA) and an FcγR that inhibits a cellular effector (“FcγInhibiting,” such as FcγRIIA) with an altered Ratio of Affinities relative to the respective binding affinities of such FcγR for the Fc region of the wild-type immunoglobulin. The methods of the invention are particularly useful in preventing, treating, or ameliorating one or more symptoms associated with a disease, disorder, or infection where either an enhanced efficacy of effector cell function mediated by FcγR is desired (e.g., cancer, infectious disease) or an inhibited effector cell response mediated by FcγR is desired (e.g., inflammation, autoimmune disease).

What is claimed is: 
     
         1 . A method for treating a disease in a subject in need thereof comprising administering to said patient a therapeutically effective amount of a polypeptide which comprises the amino acid sequence of a variant Fc region, wherein said variant Fc region exhibits an altered Ratio of Affinities to an FcγR Activating ,” and an Fcγ Inhibiting , relative to an Fc region of a wild-type immunoglobulin, wherein said variant Fc region immunospecifically binds to a target cell, and said binding ameliorates a symptom of said disease, thereby providing said treatment. 
     
     
         2 . The method of  claim 1 , wherein said FcγR Activating  is FcγRIIA and said FcγR Inhibiting  is FcγRIIB. 
     
     
         3 . The method of  claim 1 , wherein said FcγR Activating  is FcγRIIIA and said FcγR Inhibiting  is FcγRIIB. 
     
     
         4 . The method of  claim 1 , wherein the variant Fc region is a variant of a human IgG Fc region. 
     
     
         5 . The method of  claim 4 , wherein the human IgG Fc region is a human IgG1, IgG2, IgG3, or IgG4 Fc region. 
     
     
         6 . The method of  claim 1 , wherein said polypeptide is a portion of an antibody. 
     
     
         7 . The method of  claim 6 , wherein said antibody is a monoclonal antibody, a chimeric antibody, a humanized antibody, or a human antibody. 
     
     
         8 . The method of  claim 7 , wherein said antibody is a humanized antibody. 
     
     
         9 . The method of  claim 6 , wherein said antibody comprises a variable domain which binds to CD16A, CD32B, HER2/neu, A33, CD5, 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. 
     
     
         10 . The method of  claim 9 , wherein said antibody comprises a variable domain which binds to CD16A. 
     
     
         11 . The method of  claim 9 , wherein said antibody comprises a variable domain which binds to CD32B. 
     
     
         12 . The method of  claim 9 , wherein said antibody comprises a variable domain which binds to Her2/neu. 
     
     
         13 . The method of  claim 9 , wherein said antibody comprises a variable domain which binds to A33. 
     
     
         14 . The method of  claim 9 , wherein said antibody comprises a variable domain which binds to CD5. 
     
     
         15 . The method of  claim 9 , wherein said antibody comprises a variable domain which binds to CD11c. 
     
     
         16 . The method of  claim 9 , wherein said antibody comprises a variable domain which binds to CD19. 
     
     
         17 . The method of  claim 9 , wherein said antibody comprises a variable domain which binds to CD20. 
     
     
         18 . The method of  claim 9 , wherein said antibody comprises a variable domain which binds to CD22. 
     
     
         19 . The method of  claim 9 , wherein said antibody comprises a variable domain which binds to CD23. 
     
     
         20 . The method of  claim 9 , wherein said antibody comprises a variable domain which binds to CD27. 
     
     
         21 . The method of  claim 9 , wherein said antibody comprises a variable domain which binds to CD40. 
     
     
         22 . The method of  claim 9 , wherein said antibody comprises a variable domain which binds to CD45. 
     
     
         23 . The method of  claim 9 , wherein said antibody comprises a variable domain which binds to CD79a. 
     
     
         24 . The method of  claim 9 , wherein said antibody comprises a variable domain which binds to CD79b. 
     
     
         25 . The method of  claim 9 , wherein said antibody comprises a variable domain which binds to CD103. 
     
     
         26 . The method of  claim 9 , wherein said antibody comprises a variable domain which binds to CTLA4. 
     
     
         27 . The method of  claim 9 , wherein said antibody comprises a variable domain which binds to ErbB1. 
     
     
         28 . The method of  claim 9 , wherein said antibody comprises a variable domain which binds to ErbB3. 
     
     
         29 . The method of  claim 9 , wherein said antibody comprises a variable domain which binds to ErbB4. 
     
     
         30 . The method of  claim 9 , wherein said antibody comprises a variable domain which binds to VEGF receptor. 
     
     
         31 . The method of  claim 9 , wherein said antibody comprises a variable domain which binds to TNF-α receptor. 
     
     
         32 . The method of  claim 9 , wherein said antibody comprises a variable domain which binds to TNF-β receptor, or TNF-γ receptor. 
     
     
         33 . The method of  claim 9 , wherein said antibody comprises a variable domain which binds to TNF-γ receptor. 
     
     
         34 . The method of  claim 9 , wherein said variable domain binds CD32B and said antibody is 2B6, 8B5, 3H7, or 1F2, or is a chimerized or humanized form of 2B6, 8B5, 3H7, or 1F2. 
     
     
         35 . The method of  claim 1 , wherein said variant Fc region possesses at least one amino acid modification relative to a wild-type Fc region at position 235, 243, 247, 255, 270, 284, 292, 300, 305, 316, 370, 392, 396, 416, 419 or 421. 
     
     
         36 . The method of  claim 35 , wherein said variant Fc region possesses at least two amino acid modifications relative to a wild-type Fc region at positions: (a) 235 and 243; (b) 243 and 292; (c) 243 and 300; (d) 243 and 305; (e) 243 and 396; (f) 247 and 270; (g) 247 and 421; (h) 255 and 270; (i) 255 and 396; (j) 270 and 316; (k) 270 and 396; (1) 270 and 416; (m) 270 and 421; (n) 292 and 300; (o) 292 and 305; (p) 292 and 396; (q) 300 and 396; (r) 305 and 396; (s) 316 and 416; (t) 392 and 270; (u) 392 and 396; (v) 419 and 270; or (w) 419 and 396. 
     
     
         37 . The method of  claim 36 , wherein said variant Fc region possesses at least amino acid modifications relative to a wild-type Fc region at positions: (a) 243, 247 and 421; (b) 243, 292 and 300; (c) 243, 292 and 305; (d) 243, 292 and 396; (e) 243 300 and 396; (f) 243, 305 and 396; (g) 247, 270 and 421; (h) 255, 270 and 396; (i) 270, 316 and 416; (j) 270, 392 and 396; (k) 270, 396 and 419; (1) 292 300 and 396; or (m) 292, 305 and 396. 
     
     
         38 . The method of  claim 37 , wherein said variant Fc region possesses at least amino acid modifications relative to a wild-type Fc region at positions: 243, 292 and 300 and at least one additional modification at position 234, 235, or 396. 
     
     
         39 . The method of  claim 38 , wherein said variant Fc region possesses at least amino acid modifications relative to a wild-type Fc region at positions: L234, F243, R292 and Y300. 
     
     
         40 . The method of  claim 39 , wherein said variant Fc region possesses at least the following amino acid modifications relative to a wild-type Fc region: L234F, F243L, R292P and Y300L. 
     
     
         41 . The method of  claim 38 , wherein said variant Fc region possesses at least amino acid modifications relative to a wild-type Fc region at positions: L235, F243, R292 and Y300. 
     
     
         42 . The method of  claim 41 , wherein said variant Fc region possesses at least the following amino acid modifications relative to a wild-type Fc region: F243L, R292P and Y300L. 
     
     
         43 . The method of  claim 42 , wherein said variant Fc region possesses L235I, L235Q, L235V or L235P. 
     
     
         44 . The method of  claim 38 , wherein said variant Fc region possesses at least amino acid modifications relative to a wild-type Fc region at positions: 235, 243, 292, 300 and 396. 
     
     
         45 . The method of  claim 44 , wherein said variant Fc region possesses at least the following amino acid modifications relative to a wild-type Fc region: F243L, R292P, Y300L and P396L. 
     
     
         46 . The method of  claim 45 , wherein said variant Fc region possesses L235V or L235P. 
     
     
         47 . The method of  claim 1 , wherein said Ratio of Affinities of said variant Fc region is less than 1, and wherein said immunospecific binding inhibits an effector function of said target cell. 
     
     
         48 . The method of  claim 47 , wherein said Ratio of Affinities reflects said variant having unchanged binding to FcγRIIIA or FcγRIIA and increased binding to FcγRIIB. 
     
     
         49 . The method of  claim 47 , wherein said Ratio of Affinities reflects said variant having increased binding to FcγRIIIA or FcγRIIA and greatly increased binding to FcγRIIB. 
     
     
         50 . The method of  claim 47 , wherein said Ratio of affinities reflects said variant having decreased binding to FcγRIIIA or FcγRIIA and increased or unchanged binding to FcγRIIB. 
     
     
         51 . The method of  claim 47 , wherein said variant Fc region possesses at least one amino acid substitution, relative to a wild-type Fc region, selected from the group consisting of: (a) P396L or (b) Y300L. 
     
     
         52 . The method of  claim 51 , wherein said variant Fc region possesses at least two amino acid substitutions, relative to a wild-type Fc region, selected from the group consisting of: (a) F243L and P396L; (b) P247L and N421K; (c) R255L and P396L; (d) R292P and V305I; (e) K392T and P396L; or (f) P396L and Q419H. 
     
     
         53 . The method of  claim 52 , wherein said variant Fc region possesses at least the three amino acid substitutions: F243L, R292P and V305I. 
     
     
         54 . The method of  claim 50 , wherein said disease is an inflammatory disorder. 
     
     
         55 . The method of  claim 54 , wherein said inflammatory disorder is an autoimmune disease. 
     
     
         56 . The method of  claim 1 , wherein said Ratio of Affinities of said variant Fc region is greater than 1, and wherein said immunospecific binding activates an effector function of an effector cell. 
     
     
         57 . The method of  claim 56 , wherein said ratio of affinities reflects said variant having increased binding to FcγRIIIA or FcγRIIA and decreased binding to FcγRIIB. 
     
     
         58 . The method of  claim 56 , wherein said ratio of affinities reflects said variant having decreased binding to FcγRIIIA or FcγRIIA and greatly decreased binding to FcγRIIB. 
     
     
         59 . The method of  claim 56 , wherein said ratio of affinities reflects said variant having increased binding to FcγRIIIA or FcγRIIA and unchanged binding to FcγRIIB. 
     
     
         60 . The method of  claim 56 , wherein said ratio of affinities reflects said variant having greatly increased binding to FcγRIIIA or FcγRIIA and increased binding to FcγRIIB. 
     
     
         61 . The method of  claim 56 , wherein said variant Fc region possesses at least one amino acid substitution, relative to a wild-type Fc region, selected from the group consisting of: (a) L234F; (b) L235I; (c) F243L; (d) D270E; (e) R292G; (f) R292P and (g) P396L. 
     
     
         62 . The method of  claim 61 , wherein said variant Fc region possesses at least two amino acid substitutions, relative to a wild-type Fc region, selected from the group consisting of: (a) F243L and R292P; (b) F243L and Y300L; (c) F243L and P396L; (d) D270E and P396L; (e) R292P and Y300L; (f) R292P and V305I; (g) R292P and P396L; (h) Y300L and P396L; and (i) P396L and Q419H. 
     
     
         63 . The method of  claim 62 , wherein said variant Fc region possesses at least three amino acid substitutions selected from the group consisting of: (a) F243L, P247L and N421K; (b) F243L, R292P andY300L; (c) F243L, R292P and Y300L; (d) F243L, R292P and V305I; (e) F243L, R292P and P396L; (f) F243L, Y300L and P396L; (g) P247L, D270E and N421K; (h) R255L, D270E and P396L; (i) D270E, G316D and R416G; (j) D270E, K392T and P396L; (k) D270E, P396L and Q419H; (1) V284M, R292L and K370N or (m) R292P, Y300L and P396L. 
     
     
         64 . The method of  claim 63 , wherein said variant Fc region possesses at least four amino acid substitutions, relative to a wild-type Fc region, selected from the group consisting of: (a) L234F, F243L, R292P and Y300L; (b) L235I, F243L, R292P and Y300L; (c) L235Q, F243L, R292P and Y300L; (d) F243L, R292P, Y300L, and P396L; (e) F243L, P247L, D270E and N421K; (f) F243L, R255L, D270E and P396L; (g) F243L, D270E, G316D and R416G; (h) F243L, D270E, K392T and P396L; (i) F243L, D270E, P396L and Q419H; (j) F243L, R292P, V305I and P396L; (k) D270E, G316D, P396L and R416G; (1) P247L, D270E, Y300L and N421K; (m) R255L, D270E, R292G and P396L; or (n) R255L, D270E, Y300L and P396L. 
     
     
         65 . The method of  claim 64 , wherein said variant Fc region possesses at least five amino acid substitutions, relative to a wild-type Fc region, selected from the group consisting of: (a) L235V, F243L, R292P, Y300L and P396L; (b) L235P, F243L, R292P, Y300L and P396L; (c) F243L, R292P, V305I, Y300L and P396L; or (d) F243L, R292P, Y300L, V305I and P396L. 
     
     
         66 . The method of  claim 56 , wherein said effector cell function is antibody-dependent cellular cytotoxicity. 
     
     
         67 . The method of  claim 56 , wherein said disease is an infectious disease. 
     
     
         68 . The method of  claim 56 , wherein said disease is cancer. 
     
     
         69 . The method of  claim 68 , wherein said polypeptide is a portion of an antibody that immunospecifically binds to a cancer antigen selected from the group consisting of: A33; B1; BAGE; beta-catenin; CA125; CD5; CD19; CD20; CD22; CD23; CD25; CD27; CD28; CD36; CD40; CD45; CD56, CD79a; CD79b; CD103, CD154; CDK4; CEA; CTLA4; EGF-R; ErbB1; ErbB3; ErbB4; GAGE-1; GAGE-2; GD2; GD3; GM2; gp100; HER-2/neu; human papillomavirus-E6; human papillomavirus-E7; KSA (17-1A); MAGE-1; MAGE-3; MART; MUC-1; MUM-1; N-acetylglucosaminyltransferase; p15; PSA; PSMA; SART; sTn; TNF-α receptor; TNF-β receptor; or TNF-γ receptor; and VEGF receptor. 
     
     
         70 . The method of  claim 68 , wherein said polypeptide is a portion of an antibody that immunospecifically binds to a breast cancer antigen, an ovarian cancer antigen, a prostate cancer antigen, a cervical cancer antigen, a pancreatic carcinoma antigen, a lung cancer antigen, a bladder cancer antigen, a colon cancer antigen, a testicular cancer antigen, a glioblastoma cancer antigen, an antigen associated with a B cell malignancy, an antigen associated with multiple myeloma, an antigen associated with non-Hodgkins lymphoma, or an antigen associated with chronic lymphocytic leukemia. 
     
     
         71 . The method of  claim 68 , further comprising the administration of one or more additional cancer therapies. 
     
     
         72 . The method of  claim 71 , wherein said additional cancer therapy is selected from the group consisting of chemotherapy, immunotherapy, radiation therapy, hormonal therapy, or surgery. 
     
     
         73 . The method of  claim 1 , wherein said subject is a human.