Compositions comprising a combination of an anti-pd-1 antibody and another antibody

Abstract

This provides pharmaceutical compositions that comprise a combination of an anti-cancer agent which is an first antibody and a second antibody. In some embodiments, the first antibody is an anti-Programmed Death-1 (PD-1) antibody. In certain embodiments, the composition is a fixed dose formulation. In certain embodiments, the composition is administered as a flat-dose. The disclosure also provides a kit for treating a subject afflicted with a disease, the kit comprising a dosage of any composition disclosed herein and instructions for using the composition in any of the disclosed methods for treating a disease.

What is claimed is: 
     
         1 . A pharmaceutical composition comprising an X amount of a first antibody or an antigen-binding fragment thereof, which comprises an anti-PD-1 antibody or an antigen-binding fragment thereof, and a Y amount of a second antibody or an antigen-binding fragment thereof, wherein the ratio of the X amount to the Y amount is about 50:1 to about 1:50. 
     
     
         2 . The composition of  claim 1 , wherein the ratio of X to Y is about 50:1, about 40:1, about 30:1, about 20:1, about 10:1, about 5:1, about 3:1, about 1:1, about 1:3, about 1:5, about 1:10, about 1:20, about 1:30, about 1:40, or about 1:50. 
     
     
         3 . The composition of  claim 1  or  2 , wherein the anti-PD-1 antibody is nivolumab or pembrolizumab. 
     
     
         4 . The composition of  claim 3 , wherein the anti-PD-1 antibody is nivolumab. 
     
     
         5 . The composition of any one of  claims 1  to  4 , wherein the X amount of the first antibody or antigen binding fragment thereof is at least about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, or about 300 mg. 
     
     
         6 . The composition of  claim 5 , wherein the X amount of the first antibody is at least about 80 mg, about 160 mg, or about 240 mg. 
     
     
         7 . The composition of any one of  claims 1  to  6 , wherein the X amount of the first antibody or antigen-binding fragment thereof is about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, or about 300 mg. 
     
     
         8 . The composition of  claim 7 , wherein the X amount of the first antibody or antigen-binding fragment thereof is about 80 mg or about 240 mg. 
     
     
         9 . The composition of any one of  claims 1 - 8 , wherein the second antibody or antigen-binding fragment thereof is an anti-CTLA4 antibody. 
     
     
         10 . The composition of  claim 9 , wherein the ratio of X to Y is about 3:1, about 1:1, or about 1:3. 
     
     
         11 . The composition of  claim 9 , wherein (i) the X amount is about 240 mg and the Y amount is about 80 mg, (ii) the X amount is about 80 mg and the Y amount is about 80 mg; (iii) the X amount is about 160 mg and the Y amount is about 160 mg; (iv) the X amount is about 240 mg and the Y amount is about 240 mg; or (v) the X amount is about 80 mg and the Y amount is about 240 mg. 
     
     
         12 . The compositions of  claim 10  or  11 , wherein the anti-CTLA4 antibody is tremelimumab or ipilimumab. 
     
     
         13 . The composition of any one of  claims 1 - 8 , wherein the second antibody is an anti-LAG3 antibody. 
     
     
         14 . The composition of  claim 13 , wherein the ratio of X to Y is about 12:1, about 3:1, or about 1:1. 
     
     
         15 . The composition of  claim 13  or  14 , wherein the anti-LAG3 antibody is 25F7. 
     
     
         16 . The composition of any one of  claims 1 - 8 , wherein the second-antibody is an anti-CD137 antibody. 
     
     
         17 . The composition of  claim 16 , wherein the ratio of X to Y is about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:10, about 1:20, about 1:30, about 1:40, about 1:50, about 50:1, about 40:1, about 30:1, about 20:1, about 10:1, about 5:1, about 4:1 or about 2:1. 
     
     
         18 . The composition of  claim 16  or  17 , wherein the anti-CD137 antibody is urelumab. 
     
     
         19 . The composition of any one of  claims 1 - 8 , wherein the second antibody is an anti-KIR antibody. 
     
     
         20 . The composition of  claim 19 , wherein the ratio of X to Y is about 30:1, about 10:1, about 3:1, about 1:1, or about 1:2. 
     
     
         21 . The composition of  claim 19  or  20 , wherein the anti-KIR antibody is 1-7F9 or lirilumab. 
     
     
         22 . The composition of any one of  claims 1 - 8 , wherein the second antibody is selected from the group consisting of: an anti-TGFβ antibody, an anti-IL-10 antibody, an anti-B7-H4 antibody, an anti-Fas ligand antibody, an anti-CXCR4 antibody, an anti-mesothelin antibody, an anti-CD27 antibody, an anti-CD27 antibody and any combination thereof. 
     
     
         23 . The composition of any one of  claims 1 - 8 , wherein the second antibody is an anti-GITR antibody. 
     
     
         24 . The composition of  claim 23 , wherein the anti-GITR antibody is MK4166 or TRX518. 
     
     
         25 . The composition of any one of  claims 1  to  8  or  22  to  24 , wherein the ratio of X:Y is about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, or about 10:1. 
     
     
         26 . The composition of any one of  claims 1  to  25 , wherein the composition is formulated in a Tris-Cl, histidine, citrate or Tris-citrate buffer. 
     
     
         27 . The composition of  claim 26 , wherein the composition is formulated in a Tris-Cl buffer, the concentration of Tris-Cl being at least about 5 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, or about 50 mM. 
     
     
         28 . The composition of  claim 27 , wherein the concentration of Tris-Cl is about 20 mM. 
     
     
         29 . The composition of  claim 26 , wherein the composition is formulated in a citrate buffer, the concentration of citrate being at least about 5 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, or about 50 mM. 
     
     
         30 . The composition of  claim 29 , wherein the citrate concentration is about 10 mM or about 20 mM. 
     
     
         31 . The composition of  claim 26 , wherein the composition is formulated in a histidine buffer, the concentration of histidine being at least about 5 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, or about 50 mM. 
     
     
         32 . The composition of  claim 31 , wherein the histidine concentration is about 20 mM. 
     
     
         33 . The composition of  claim 26 , wherein the composition is formulated in a Tris-citrate buffer, the concentration of Tris-1 being at least about 5 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, or about 50 mM, and the concentration of citrate being at least about 2 mM, about 5 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, or about 50 mM. 
     
     
         34 . The composition of  claim 33 , wherein the concentration of Tris-Cl is about 13.3 mM and the concentration of citrate is about 6.7 mM. 
     
     
         35 . The composition of any one of  claims 1 - 34 , wherein the pH of the composition is at least about 5, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, or about 8.0. 
     
     
         36 . The composition of  claim 35 , wherein the pH of the composition is at least about 6.0, about 6.2, about 6.5, about 6.6 or about 7.0 
     
     
         37 . The composition of any one of  claims 1 - 36 , wherein the composition comprises one or more additional components selected from the group consisting of: a bulking agent, a stabilizing agent, a chelating agent, a surfactant, a buffering agent, and any combination thereof. 
     
     
         38 . The composition of  claim 37 , wherein the bulking agent is selected from the group consisting of NaCl, mannitol, glycine, alanine, and any combination thereof. 
     
     
         39 . The composition of  claim 37  or  38 , wherein the stabilizing agent is selected from the group consisting of sucrose, trehalose, raffinose, arginine; or any combination thereof. 
     
     
         40 . The composition of any one of  claims 37  to  39 , wherein the chelating agent is selected from the group consisting of diethylenetriaminepentaacetic acid (DTPA), ethylenediaminetetraacetic acid, nitrilotriacetic acid, and any combination thereof. 
     
     
         41 . The composition of any one of  claims 37  to  40 , wherein the surfactant is selected from the group consisting of polysorbate 80 (PS80), polysorbate 20 (PS20), and any combination thereof. 
     
     
         42 . The composition of  claim 37 , wherein the composition comprises NaCl at a concentration of at least about 5 mM, at least about 10 mM, at least about 15 mM, at least about 20 mM, at least about 25 mM, at least about 30 mM, at least about 35 mM, at least about 40 mM, at least about 45 mM, at least about 50 mM, at least about 60 mM, at least about 70 mM, at least about 75 mM, at least about 80 mM, at least about 90 mM, at least about 100 mM, at least about 110 mM, at least about 120 mM, at least about 130 mM, at least about 140 mM, at least about 150 mM, at least about 175 mM, at least about 200 mM, at least about 225 mM, at least about 250 mM, at least about 275 mM, at least about 300 mM, at least about 350 mM, at least about 400 mM, at least about 450 mM or at least about 450 mM. 
     
     
         43 . The composition of  claim 42 , wherein the concentration of NaCl is about 100 mM, about 96.15 mM, about 83.3 mM, about 78.57 mM or about 50 mM. 
     
     
         44 . The composition of  claim 37 , wherein the composition comprises mannitol (% w/v) USP at a concentration of at least about 0.25%, at least about 0.5%, at least about 0.75%, at least about 1%, at least about 1.5%, at least about 2%, at least about 2.5%, at least about 3%, at least about 3.5%, at least about 4%, at least about 4.5%, at least about 5%, at least about 7.5% or at least about 10%. 
     
     
         45 . The composition of  claim 44 , wherein the concentration of mannitol is about 1%, about 1.15%, about 1.67%, about 1.86%, or about 3%. 
     
     
         46 . The composition of  claim 37 , wherein the composition comprises DTPA, USP at a concentration of at least about 5 μM, at least about 10 μM, at least about 15 μM, at least about 20 μM, at least about 25 μM, at least about 30 μM, at least about 40 μM, at least about 50 μM, at least about 60 μM, at least about 70 μM, at least about 75 μM, at least about 80 μM, at least about 90 μM, at least about 100 μM, at least about 110 μM, at least about 120 μM, at least about 130 μM, at least about 140 μM, at least about 150 μM, at least about 175 μM, or at least about 200 μM. 
     
     
         47 . The composition of  claim 46 , wherein the concentration of DTPA is about 20 μM, about 50 μM, about 65.71 μM, about 73.3 μM, about 93.85 μM, or 100 μM. 
     
     
         48 . The composition of  claim 37 , wherein the composition comprises PS80 (% w/v) at a concentration of at least about 0.005%, at least about 0.01%, at least about 0.015%, at least about 0.02%, at least about 0.03%, at least about 0.04%, at least about 0.05%, at least about 0.06%, at least about 0.07%, at least about 0.08%, at least about 0.09%, or at least about 0.1%. 
     
     
         49 . The composition of  claim 48 , wherein the concentration of PS80 is about 0.01%, about 0.012%, about 0.013%, about 0.02%, about 0.23%, about 0.04%, or about 0.05%. 
     
     
         50 . The composition of  claim 37 , wherein the composition comprises sucrose (% w/v) at a concentration of at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 4.5%, at least about 5%, at least about 5.5%, at least about 6%, at least about 6.5%, at least about 7%, at least about 7.5%, at least about 8%, at least about 8.5%, at least about 9%, at least about 9.5%, at least about 10%, at least about 12% or at least about 15%. 
     
     
         51 . The composition of  claim 50 , wherein the concentration of sucrose is about 6% or about 8.5%. 
     
     
         52 . A pharmaceutical composition comprising a 1:1 ratio of nivolumab to ipilimumab in a buffer comprising about 13.3 mM Tris, about 6.7 mM citrate, about 1.67% mannitol, about 83.3 mM NaCl, about 73.3 μM DTPA and about 0.013% PS80 at a pH of about 6.2. 
     
     
         53 . A pharmaceutical composition comprising a 3:1 ratio of nivolumab to ipilimumab in a Tris-citrate buffer comprising about 1.15% mannitol, about 96.15 mM NaCl, about 93.85 μM DTPA and about 0.012% PS80 at a pH of about 6.6. 
     
     
         54 . A pharmaceutical composition comprising a 1:3 ratio of nivolumab to ipilimumab in a Tris-citrate buffer comprising about 1.86% mannitol, about 78.57 mM NaCl, about 65.71 μM DTPA and about 0.023% PS80 at a pH of about 6.0. 
     
     
         55 . A pharmaceutical composition comprising a 3:1 ratio of nivolumab to ipilimumab in a 20 mM histidine buffer comprising about 50 mM NaCl, about 50 μM DTPA, about 6% sucrose, and about 0.05% PS80 at about pH 6. 
     
     
         56 . A pharmaceutical composition comprising a 3:1 ratio of nivolumab to ipilimumab in a about 20 mM histidine buffer comprising about 50 mM NaCl, about 50 μM DTPA, about 6% sucrose, and about 0.05% PS80 at about pH 7. 
     
     
         57 . A pharmaceutical composition comprising a 3:1 ratio of nivolumab to ipilimumab in an about 20 mM histidine buffer comprising about 50 μM DTPA, about 8.5% sucrose, and about 0.05% PS80 at about pH 6. 
     
     
         58 . A pharmaceutical composition comprising comprises a 3:1 ratio of nivolumab to ipilimumab in an about 20 mM citrate buffer comprising about 50 mM NaCl, about 50 μM DTPA, about 6% sucrose, and about 0.05% PS80 at about pH 6. 
     
     
         59 . A pharmaceutical composition comprising a 3:1 ratio of nivolumab to ipilimumab in an about 20 mM citrate buffer comprising about 50 mM NaCl, about 20 μM DTPA, about 3% mannitol, and about 0.04% PS80 at about pH 6. 
     
     
         60 . A pharmaceutical composition comprising a 1:1 ratio of nivolumab to ipilimumab in an about 20 mM citrate buffer comprising about 50 mM NaCl, about 100 μM DTPA, about 3% mannitol, and about 0.02% PS80 at about pH 6. 
     
     
         61 . A pharmaceutical composition comprising a 1:1 ratio of nivolumab to ipilimumab in an about 20 mM citrate buffer comprising about 50 mM NaCl, about 100 μM DTPA, about 3% mannitol, and about 0.02% PS80 at about pH 6.5. 
     
     
         62 . A pharmaceutical composition comprising a 1:1 ratio of nivolumab to ipilimumab in an about 20 mM citrate buffer comprising about 100 mM NaCl, about 100 μM DTPA, about 1.0% mannitol, and about 0.02% PS80 at about pH 6.5. 
     
     
         63 . A pharmaceutical composition comprising a 1:1 ratio of nivolumab to ipilimumab in an about 20 mM citrate buffer comprising about 50 mM NaCl, about 100 μM DTPA, about 6% sucrose, and about 0.02% PS80 at about pH 6.0. 
     
     
         64 . A pharmaceutical composition comprising a 1:3 ratio of nivolumab to ipilimumab comprising about 4.62 mg/ml nivolumab, about 1.54 mg/ml ipilimumab, about 18.5 mM Tris Hydrochloride, about 1.5 mM Sodium Citrate Dihydrate, about 96.2 mM NaCl, about 1.2% Mannitol, about 93.9 μM Pentetic Acid, about 0.012% PS80 at about pH 6.0. 
     
     
         65 . A pharmaceutical composition comprising a 1:3 ratio of nivolumab to ipilimumab comprising about 4.61 mg/ml nivolumab, about 1.54 mg/ml ipilimumab, about 18.46 mM Tris Hydrochloride, about 1.54 mM Sodium Citrate Dihydrate, about 96.15 mM NaCl, about 1.15% Mannitol, about 93.85 μM Pentetic Acid, about 0.012% PS80 at about pH 6.3. 
     
     
         66 . The composition of any one of  claims 1 - 65 , wherein the composition is stable at about 5° C. for at least about 1 week, at least about 2 weeks, at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, at least about 9 months, at least about 1 year, at least about 2 years or at least about 5 years. 
     
     
         67 . The composition of any one of  claims 1 - 66 , wherein the composition is stable at about 40° C. for at least about 1 week, at least about 2 weeks, at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, at least about 9 months, at least about 1 year, at least about 2 years or at least about 5 years. 
     
     
         68 . The composition of any one of  claims 1 - 67 , wherein the composition is stable at about 25° C. for at least about 1 week, at least about 2 weeks, at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, at least about 9 months, at least about 1 year, at least about 2 years or at least about 5 years. 
     
     
         69 . The composition of any one of  claims 1  to  68 , which exhibits a change of an acidic peak that is less than about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, or about 1% after being stored for about 6 months or about 3 months at about 5° C. 
     
     
         70 . The composition of any one of  claims 1  to  68 , which exhibits a change of an acidic peak that is less than about 15%, about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2% or about 1% after being stored for about 3 months at about 25° C. 
     
     
         71 . The composition of any one of  claims 1  to  68 , which exhibits a change of an acidic peak that is less than about 15%, about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2% or about 1% after being stored for about 3 months at about 40° C. 
     
     
         72 . The composition of any one of  claims 1  to  72 , which exhibits a change of a high molecular weight peak that is less than about 5%, about 4%, about 3%, about 2%, about 1.5%, about 1.4%, about 1.3%, about 1.2%, about 1.1%, about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1% after being stored for about 3 months at about 4° C. 
     
     
         73 . The composition of any one of  claims 1  to  71 , which exhibits a change of a high molecular weight peak that is less than about 5%, about 4%, about 3%, about 2%, about 1.5%, about 1.4%, about 1.3%, about 1.2%, about 1.1%, about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1% after being stored for about 2 months or about 3 months at about 25° C. 
     
     
         74 . The composition of any one of  claims 1  to  71 , which exhibits a change of a high molecular weight peak that is less than about 5%, about 4%, about 3%, about 2%, about 1.5%, about 1.4%, about 1.3%, about 1.2%, about 1.1%, about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1% after being stored for about 2 months or about 3 months at about 40° C. 
     
     
         75 . The composition of any one of  claims 1 - 74 , which exhibits a change of a main peak of Capillary Isoelectric Focusing (cIEF) analysis that is less than about 5%, about 4%, about 3%, about 2%, about 1.5%, about 1.4%, about 1.3%, about 1.2%, about 1.1%, about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1% after being stored for about 1 month at about 4° C. 
     
     
         76 . The composition of any one of  claims 1 - 74 , which exhibits a change of a main peak of Capillary Isoelectric Focusing (cIEF) analysis that is less than about 5%, about 4%, about 3%, about 2%, about 1.5%, about 1.4%, about 1.3%, about 1.2%, about 1.1%, about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1% after being stored for about 1 month at about 25° C. 
     
     
         77 . The composition of any one of  claims 1 - 74 , which exhibits a change of a main peak of Capillary Isoelectric Focusing (cIEF) analysis that is less than about 5%, about 4%, about 3%, about 2%, about 1.5%, about 1.4%, about 1.3%, about 1.2%, about 1.1%, about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1% after being stored for about 1 month at about 40° C. 
     
     
         78 . The composition of any one of  claims 1 - 77 , which exhibits a change of a low molecular weight peak that is less than about 5%, about 4%, about 3%, about 2%, about 1.5%, about 1.4%, about 1.3%, about 1.2%, about 1.1%, about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1% after being stored for about 2 months at about 40° C. 
     
     
         79 . The composition of any one of  claims 1 - 77 , which exhibits a change of a low molecular weight peak that is less than about 5%, about 4%, about 3%, about 2%, about 1.5%, about 1.4%, about 1.3%, about 1.2%, about 1.1%, about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1% after being stored for about 2 months at about 25° C. 
     
     
         80 . The composition of any one of  claims 1 - 77 , which exhibits a change of a low molecular weight peak that is less than about 5%, about 4%, about 3%, about 2%, about 1.5%, about 1.4%, about 1.3%, about 1.2%, about 1.1%, about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1% after being stored for about 2 months at about 4° C. 
     
     
         81 . The composition of any one of  claims 1 - 80 , wherein the composition is diluted prior to use. 
     
     
         82 . The composition of  claim 81 , wherein the composition is diluted with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP prior to use. 
     
     
         83 . The composition of  claim 61  or  82  wherein the composition is diluted to obtain a desired concentration of first and second antibody. 
     
     
         84 . A kit comprising the composition of any one of  claims 1 - 83 . 
     
     
         85 . A method of making the composition of any one of  claims 1 - 83 . 
     
     
         86 . The method of  claim 85 , wherein a formulation comprising the anti-PD-1 antibody drug product is mixed with a formulation comprising the second antibody drug product to obtain the desired ratio in a final drug product with no buffer changes. 
     
     
         87 . The method of  claim 85 , wherein a formulation comprising the anti-PD-1 antibody drug substance and a formulation comprising the second antibody drug substance is subject to buffer exchanges and/or concentration before being mixed to obtain the desired ratio in a final drug product. 
     
     
         88 . A method of modulating an immune response to a patient in need thereof comprising administering the composition of any one of  claims 1 - 83  to the patient. 
     
     
         89 . A method of administering two antibodies at the same time to a patient in need thereof comprising administering to the patient the composition of any one of  claims 1  to  83 , wherein the antibodies are capable of treating at least one disease or condition. 
     
     
         90 . A method of treating a disease or condition comprising administering the composition of any one of  claims 1 - 83  to a patient. 
     
     
         91 . The method of  claim 89  or  90 , wherein the disease or condition is an infectious disease. 
     
     
         92 . The method of  claim 89  or  90 , wherein the disease is cancer. 
     
     
         93 . The method of  claim 92 , wherein the cancer is melanoma cancer, renal cancer, prostate cancer, breast cancer, colon cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors of childhood, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, environmentally induced cancers including those induced by asbestos, and any combinations thereof. 
     
     
         94 . The method of  claim 92  or  93 , wherein the composition is administered intravenously. 
     
     
         95 . The method of any one of  claims 88  to  94  wherein the composition is diluted prior to administration. 
     
     
         96 . The method of any one of  claims 84  to  95 , wherein the composition is administered at a flat dose. 
     
     
         97 . The method of  claim 96 , wherein the amount of the first antibody and the amount of the second antibody administered to the patient at a single dose are identical the X amount and the Y amount, respectively. 
     
     
         98 . The method of any one of  claims 88  to  95 , wherein the composition is administered at a weight-based dose. 
     
     
         99 . The composition of  claim 98 , wherein the amount of the first antibody administered to the patient is at least about 0.5 mg/kg, about 1 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 3 mg/kg or about 5 mg/kg. 
     
     
         100 . The composition of  claim 98 , wherein the X amount of the first antibody administered to the patient at least about 1 mg/kg. 
     
     
         101 . The method of any one of  claims 88 - 100 , wherein the composition is administered at least about weekly, at least about twice weekly, at least about every two weeks, at least about every three weeks, or at least about monthly. 
     
     
         102 . The method of any one of  claims 88 - 101 , wherein the administering lasts for at least about 8 weeks, at least about 12 weeks, at least about 3 months, at least about 6 months, at least about 9 months, at least about 1 year, at least about 18 months, at least about 2 years or greater than 2 years. 
     
     
         103 . The method of any one of  claims 88 - 102 , wherein the patient is also treated with another anti-cancer agent.