Antibody Formulations and Uses Thereof

Abstract

The present application relates to formulations of anti-CD105 antibodies, antigen-binding fragments thereof, and uses thereof. Another aspect relates to pre-filled syringes of the formulations of anti-CD105 antibodies or antigen-binding fragments thereof. Another aspect relates to the use of the formulations to reduce one or more signs or symptoms of an angiogenesis-related disorder such as cancers and ophthalmologic diseases.

What is claimed is: 
     
         1 . A formulation comprising from about 1 mg/ml to about 150 mg/ml of an anti-CD105 antibody, or antigen-binding fragment thereof, up to about 100 mM buffering agent, up to about 1 M polyol, and a pH of about 4.0 to about 7.5. 
     
     
         2 . The formulation of  claim 1 , wherein at least 95% of the anti-CD105 antibody is present as a monomer following storage at about 2 to 8° C. for at least 12 months as measured by size exclusion chromatography (SEC). 
     
     
         3 . The formulation of  claim 1 , wherein at least 95% of the anti-CD105 antibody is present as a monomer following storage at about 25° C. for at least 6 months as measured by size exclusion chromatography (SEC). 
     
     
         4 . The formulation of  claim 1 , wherein at least 90% of the anti-CD105 antibody is present as a monomer following storage at about 25° C. for at least 6 months as measured by size exclusion chromatography (SEC). 
     
     
         5 . The formulation of  claim 1 , wherein said buffering agent is histidine or phosphate buffered saline. 
     
     
         6 . The formulation of  claim 1 , wherein the buffering agent is acetate and the pH is about 4. 
     
     
         7 . The formulation of  claim 1  wherein the buffering agent is histidine and the pH is about 5.5. 
     
     
         8 . The formulation of  claim 1 , wherein the anti-CD105 antibody, or antigen-binding fragment thereof, displays about 50 to 150% binding by a CD105 ELISA binding assay after storage at about 2 to 8° C. for at least 12 months. 
     
     
         9 . The formulation of  claim 1 , wherein the average isoelectric point (pI) of the anti-CD105 antibody is from about 8.7 to about 9.2 after storage at 2 to 8° C. for at least 12 months, as measured by capillary electrophoresis-isoelectric focusing. 
     
     
         10 . The formulation of  claim 1 , wherein said anti-CD105 antibody comprises a light chain variable region (V L ) having an amino acid sequence set forth as SEQ ID NO: 1; a light chain constant region (C L ) having an amino acid sequence set forth as SEQ ID NO: 2; a heavy chain variable region (V H ) having an amino acid sequence set forth as SEQ ID NO: 3; and a constant region (Fc) having an amino acid sequence set forth as SEQ ID NO: 4. 
     
     
         11 . The formulation of  claim 1 , wherein said anti-CD105 antibody comprises a V L  CDR1 having an amino acid sequence set forth as SEQ ID NO: 5; a V L  CDR2 having an amino acid sequence set forth as SEQ ID NO: 6; a V L  CDR3 having an amino acid sequence set forth as SEQ ID NO: 7; a V H  CDR1 having an amino acid sequence set forth as SEQ ID NO: 8; a V H  CDR2 having an amino acid sequence set forth as SEQ ID NO: 9; and a V H  CDR3 having an amino acid sequence set forth as SEQ ID NO: 10. 
     
     
         12 . The formulation of  claim 1 , comprising about 25 mg/ml of the anti-CD105 antibody or, antigen-binding fragment thereof. 
     
     
         13 . The formulation of  claim 1 , comprising about 50 mg/ml of the anti-CD105 antibody or, antigen-binding fragment thereof. 
     
     
         14 . The formulation of  claim 1 , comprising about 100 mg/ml of the anti-CD105 antibody or, antigen-binding fragment thereof. 
     
     
         15 . The formulation of  claim 1 , wherein said buffering agent is histidine or acetate. 
     
     
         16 . The formulation of  claim 15 , comprising about 20 mM histidine or acetate. 
     
     
         17 . The formulation of  claim 1 , wherein said formulation is formulated for intravitreal or intravenous administration. 
     
     
         18 . The formulation of  claim 1 , further comprising an acceptable carrier or excipient. 
     
     
         19 . The formulation of  claim 18 , wherein said carrier or excipient is a pharmaceutically acceptable carrier or excipient. 
     
     
         20 . The formulation of  claim 1 , which is isotonic or hypertonic. 
     
     
         21 . The formulation of  claim 1 , wherein the polyol is less than 300 mM and the formulation is made isotonic with a salt. 
     
     
         22 . The formulation of  claim 1 , wherein at least 95% of the anti-CD105 antibody is present as monomer as measured by SEC following freezing and thawing cycles of the formulation. 
     
     
         23 . The formulation of  claim 1 , wherein at least 95% of the anti-CD105 antibody is present as monomer as measured by SEC when subjected to agitation stress. 
     
     
         24 . The formulation of  claim 1 , wherein the polyol is a sugar. 
     
     
         25 . The formulation of  claim 24 , wherein said sugar is a non-reducing sugar. 
     
     
         26 . The formulation of  claim 25 , wherein the non-reducing sugar is trehalose or sucrose. 
     
     
         27 . The formulation of  claim 26 , comprising about 240 mM trehalose or sucrose. 
     
     
         28 . The formulation of  claim 24 , wherein the sugar is sorbitol. 
     
     
         29 . The formulation of  claim 28 , comprising about 240 mM sorbitol. 
     
     
         30 . The formulation of  claim 1 , further comprising a surfactant. 
     
     
         31 . The formulation of  claim 30 , wherein the surfactant is polysorbate 20, polysorbate 80 or Pluronic® F68. 
     
     
         32 . A pre-filled syringe suitable for intravenous or intravitreal administration comprising the formulation of any of the preceding claims. 
     
     
         33 . A method of treating an angiogenesis-related disease in a subject in need thereof, comprising administering to said patient a formulation comprising from about 1 mg/ml to about 150 mg/ml of an anti-CD105 antibody, or antigen-binding fragment thereof, up to about 100 mM buffering agent, up to about 1 M polyol, and a pH of about 4.0 to about 7.5. 
     
     
         34 . The method of  claim 33 , wherein said anti-CD105 antibody comprises a light chain variable region (V L ) having an amino acid sequence set forth as SEQ ID NO: 1; a light chain constant region (C L ) having an amino acid sequence set forth as SEQ ID NO: 2; a heavy chain variable region (V H ) having an amino acid sequence set forth as SEQ ID NO: 3; and a constant region (Fc) having an amino acid sequence set forth as SEQ ID NO: 4. 
     
     
         35 . The method of  claim 33 , wherein said anti-CD105 antibody comprises a V L  CDR1 having an amino acid sequence set forth as SEQ ID NO: 5; a V L  CDR2 having an amino acid sequence set forth as SEQ ID NO: 6; a V L  CDR3 having an amino acid sequence set forth as SEQ ID NO: 7; a V H  CDR1 having an amino acid sequence set forth as SEQ ID NO: 8; a V H  CDR2 having an amino acid sequence set forth as SEQ ID NO: 9; and a V H  CDR3 having an amino acid sequence set forth as SEQ ID NO: 10. 
     
     
         36 . The method of  claim 33 , comprising about 25 mg/ml anti-CD105 antibody or, antigen-binding fragment thereof. 
     
     
         37 . The method of  claim 33 , comprising about 50 mg/ml anti-CD105 antibody or, antigen-binding fragment thereof. 
     
     
         38 . The method of  claim 33 , comprising about 100 mg/ml anti-CD105 antibody or, antigen-binding fragment thereof. 
     
     
         39 . The method of  claim 33 , wherein said formulation comprises less than 300 mM polyol and the formulation is made isotonic with a salt. 
     
     
         40 . The method of  claim 33 , wherein said buffering agent is histidine or acetate. 
     
     
         41 . The method of  claim 40 , comprising about 20 mM histidine or acetate. 
     
     
         42 . The method of  claim 33 , wherein the polyol is a sugar. 
     
     
         43 . The method of  claim 42 , wherein the sugar is a non-reducing sugar. 
     
     
         44 . The method of  claim 43 , wherein the non-reducing sugar is trehalose or sucrose. 
     
     
         45 . The method of  claim 44 , comprising about 240 mM trehalose or sucrose. 
     
     
         46 . The method of  claim 42 , wherein the sugar is sorbitol. 
     
     
         47 . The method of  claim 46 , comprising about 240 mM sorbitol. 
     
     
         48 . The method of  claim 33 , wherein said formulation is administered intravitreally or intravenously. 
     
     
         49 . The method of  claim 33 , further comprising a surfactant. 
     
     
         50 . The method of  claim 49 , wherein the surfactant is polysorbate 20, polysorbate 80 or Pluronic® F68. 
     
     
         51 . The method of  claim 33 , wherein the angiogenesis-related disease is a cancer, or a metastasis. 
     
     
         52 . The method of  claim 51 , wherein the cancer is a solid tumor. 
     
     
         53 . The method of  claim 51 , wherein the cancer is an epithelial based tumor. 
     
     
         54 . The method of  claim 51 , wherein the cancer is a lung cancer, a gynecologic malignancy, a melanoma, a breast cancer, a pancreatic cancer, an ovarian cancer, a uterine cancer, a colorectal cancer, a prostate cancer, a kidney cancer, a head cancer, a pancreatic cancer, a liver cancer (hepatocellular cancer), a uterine cancer, a neck cancer, a kidney cancer (renal cell cancer), a sarcoma, a myeloma, a brain cancer, or a lymphoma. 
     
     
         55 . The method of  claim 33 , wherein said angiogenesis-related disease is an ophthalmologic condition. 
     
     
         56 . The method of  claim 55 , wherein the ophthalmologic condition is age-related macular degeneration, diabetic retinopathy, or choroidal neovascularization. 
     
     
         57 . The method of  claim 56 , wherein said age related macular degeneration (AMD) is wet AMD or dry AMD. 
     
     
         58 . The method of  claim 33 , wherein said formulation is administered to said patient one or more times. 
     
     
         59 . The method of  claim 33 , wherein said formulation is administered once per day, once per week, once per month, once bi-monthly, once every two months, once every three months, once every four months, once every 5 months, or once every 6 months. 
     
     
         60 . The method of  claim 33 , wherein said formulation is administered until one or more signs or symptoms of said angiogenesis-related disease are reduced. 
     
     
         61 . The method of  claim 60 , wherein said one or more signs or symptoms are reduced in severity or duration by about 2%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 90%, about 95%, or about 100%. 
     
     
         62 . The method of  claim 60 , wherein said one or more signs or symptoms are reduced in severity or duration by about 2-fold, about 5-fold, about 10-fold, about 15-fold, about 20-fold, about 25-fold, about 30-fold, about 35-fold, about 40-fold, about 45-fold, about 50-fold, about 55-fold, about 60-fold, about 65-fold, about 70-fold, about 75-fold, about 80-fold, about 90-fold, about 95-fold, about 100-fold or more. 
     
     
         63 . The method of  claim 60 , wherein said one or more signs or symptoms are shrinking blood vessels, inhibiting endothelial cell proliferation associated with ocular disease, clearing signs or symptoms of bleeding, treating cloudy vision, providing stasis of vision loss, improving vision, and/or preventing leakage of blood vessels. 
     
     
         64 . The method of  claim 33 , wherein treatment results in improving the patient's condition and can be assessed by determining if one or more of the following factors has occurred: decreased cell proliferation, decreased numbers of cells, increased apoptosis, or decreased survival of at least a portion of the cells comprising the cell proliferative disorder. 
     
     
         65 . The method of  claim 33 , wherein treatment results in partial or total elimination of a tumor or metastases and/or prolongation of survival of the patient. 
     
     
         66 . A method of treating an ophthalmologic condition in a patient in need thereof, comprising administering to said patient a formulation comprising from about 1 mg/ml to about 150 mg/ml of an anti-CD105 antibody, or antigen-binding fragment thereof, up to about 100 mM buffering agent, up to about 1 M polyol, a pH of about 4.0 to about 7.5, and optionally a surfactant, whereby one or more signs or symptoms of said ophthalmologic condition are ameliorated. 
     
     
         67 . The method of  claim 66 , wherein the ophthalmologic condition is age-related macular degeneration, diabetic retinopathy, or choroidal neovascularization. 
     
     
         68 . The method of  claim 67 , wherein said age-related macular degeneration (AMD) is wet AMD or dry AMD. 
     
     
         69 . The method of  claim 66 , wherein said anti-CD105 antibody comprises a light chain variable region (V L ) having an amino acid sequence set forth as SEQ ID NO: 1; a light chain constant region (C L ) having an amino acid sequence set forth as SEQ ID NO: 2; a heavy chain variable region (V H ) having an amino acid sequence set forth as SEQ ID NO: 3; and a constant region (Fc) having an amino acid sequence set forth as SEQ ID NO: 4. 
     
     
         70 . The method of  claim 66 , wherein said anti-CD105 antibody comprises a V L  CDR1 having an amino acid sequence set forth as SEQ ID NO: 5; a V L  CDR2 having an amino acid sequence set forth as SEQ ID NO: 6; a V L  CDR3 having an amino acid sequence set forth as SEQ ID NO: 7; a V H  CDR1 having an amino acid sequence set forth as SEQ ID NO: 8; a V H  CDR2 having an amino acid sequence set forth as SEQ ID NO: 9; and a V H  CDR3 having an amino acid sequence set forth as SEQ ID NO: 10. 
     
     
         71 . The method of  claim 66 , wherein said one or more signs or symptoms are shrinking blood vessels, inhibiting endothelial cell proliferation associated with ocular disease, clearing signs or symptoms of bleeding, treating cloudy vision, providing stasis of vision loss, improving vision, and/or preventing leakage of blood vessels. 
     
     
         72 . The method of  claim 66 , wherein said one or more signs or symptoms are reduced in severity or duration by about 2%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 90%, about 95%, or about 100%. 
     
     
         73 . The method of  claim 66 , wherein said one or more signs or symptoms are reduced in severity or duration by about 2-fold, about 5-fold, about 10-fold, about 15-fold, about 20-fold, about 25-fold, about 30-fold, about 35-fold, about 40-fold, about 45-fold, about 50-fold, about 55-fold, about 60-fold, about 65-fold, about 70-fold, about 75-fold, about 80-fold, about 90-fold, about 95-fold, about 100-fold or more. 
     
     
         74 . The method of  claim 66 , wherein said formulation comprises less than 300 mM polyol and the formulation is made isotonic with a salt. 
     
     
         75 . A method of preventing or treating a cancer or metastasis in a subject in need thereof, comprising administering to said patient a formulation comprising from about 1 mg/ml to about 150 mg/ml of an anti-CD105 antibody, or antigen-binding fragment thereof, up to about 100 mM buffering agent, up to about 1 M polyol, and a pH of about 4.0 to about 7.5, whereby one or more signs or symptoms of said cancer or metastasis are ameliorated. 
     
     
         76 . The method of  claim 75 , wherein said anti-CD105 antibody comprises a light chain variable region (V L ) having an amino acid sequence set forth as SEQ ID NO: 1; a light chain constant region (CO having an amino acid sequence set forth as SEQ ID NO: 2; a heavy chain variable region (V H ) having an amino acid sequence set forth as SEQ ID NO: 3; and a constant region (Fc) having an amino acid sequence set forth as SEQ ID NO: 4. 
     
     
         77 . The method of  claim 75 , wherein said anti-CD105 antibody comprises a VL CDR1 having an amino acid sequence set forth as SEQ ID NO: 5; a VL CDR2 having an amino acid sequence set forth as SEQ ID NO: 6; a VL CDR3 having an amino acid sequence set forth as SEQ ID NO: 7; a VH CDR1 having an amino acid sequence set forth as SEQ ID NO: 8; a VH CDR2 having an amino acid sequence set forth as SEQ ID NO: 9; and a VH CDR3 having an amino acid sequence set forth as SEQ ID NO: 10. 
     
     
         78 . The method of  claim 75 , wherein administration of the formulation prolongs the life of the subject. 
     
     
         79 . The method of  claim 75 , wherein said cancer is a primary tumor or a metastatic tumor. 
     
     
         80 . The method of  claim 75 , wherein said cancer is a solid tumor. 
     
     
         81 . The method of  claim 80 , wherein said solid tumor is of a tissue or organ selected from among skin, melanoma, lung, pancreas, breast, ovary, colon, rectum, stomach, thyroid, laryngeal, ovarian, prostate, colorectal, head, neck, eye, mouth, throat, esophagus, chest, bone, testicular, lymphoid, marrow, bone, sarcoma, renal, sweat gland, liver, kidney, brain (e.g. glioblastoma multiforme, glioma), and the like. 
     
     
         82 . The method of  claim 81 , wherein said solid tumor is a colon tumor, a breast tumor, a kidney tumor, a lung tumor, a prostate tumor, an ovarian tumor, or a metastasis of any of such tumors. 
     
     
         83 . The method of  claim 75 , wherein treatment results in improving the subject's condition and can be assessed by determining if one or more of the following factors has occurred: decreased cell proliferation, decreased numbers of cells, increased apoptosis, or decreased survival of at least a portion of the cells comprising the cell proliferative disorder. 
     
     
         84 . The method of  claim 75 , wherein treatment results in partial or total elimination of a tumor or metastases and/or prolongation of survival of the patient. 
     
     
         85 . The method of  claim 75 , wherein said one or more signs or symptoms are reduced in severity or duration by about 2%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 90%, about 95%, or about 100%. 
     
     
         86 . The method of  claim 75 , wherein said one or more signs or symptoms are reduced in severity or duration by about 2-fold, about 5-fold, about 10-fold, about 15-fold, about 20-fold, about 25-fold, about 30-fold, about 35-fold, about 40-fold, about 45-fold, about 50-fold, about 55-fold, about 60-fold, about 65-fold, about 70-fold, about 75-fold, about 80-fold, about 90-fold, about 95-fold, about 100-fold or more. 
     
     
         87 . The method of  claim 75 , comprising about 25 mg/ml anti-CD105 antibody or, antigen-binding fragment thereof. 
     
     
         88 . The method of  claim 75 , comprising about 50 mg/ml anti-CD105 antibody or, antigen-binding fragment thereof. 
     
     
         89 . The method of  claim 75 , comprising about 100 mg/ml anti-CD105 antibody or, antigen-binding fragment thereof. 
     
     
         90 . The method of  claim 75 , wherein said buffering agent is histidine or acetate. 
     
     
         91 . The method of  claim 90 , comprising about 20 mM histidine or acetate. 
     
     
         92 . The method of  claim 75 , wherein the polyol is a sugar. 
     
     
         93 . The method of  claim 92 , wherein said sugar is a non-reducing sugar. 
     
     
         94 . The method of  claim 93 , wherein the non-reducing sugar is trehalose or sucrose. 
     
     
         95 . The method of  claim 94 , comprising about 240 mM trehalose or sucrose. 
     
     
         96 . The method of  claim 92 , wherein said sugar is sorbitol. 
     
     
         97 . The method of  claim 96 , comprising about 240 mM sorbitol. 
     
     
         98 . The method of  claim 75 , wherein said formulation comprises less than 300 mM polyol and the formulation is made isotonic with a salt. 
     
     
         99 . The method of  claim 75 , further comprising a surfactant. 
     
     
         100 . The method of  claim 99 , wherein the surfactant is polysorbate 20, polysorbate 80 or Pluronic® F68. 
     
     
         101 . The method of  claim 75 , wherein said formulation is administered intravenously. 
     
     
         102 . A formulation comprising any one of the formulations 1-39 of Table 1. 
     
     
         103 . A pre-filled syringe comprising a formulation of  claim 102 . 
     
     
         104 . Use of a formulation of  claim 102  for the treatment of an angiogenesis-related disease. 
     
     
         105 . Use of a formulation of  claim 102  in the manufacture of a medicament for the treatment of an angiogenesis-related disease.