STABLE FORMULATIONS OF ANTI-CTLA4 ANTIBODIES ALONE AND IN COMBINATION WITH PROGRAMMED DEATH RECEPTOR 1 (PD-1) ANTIBODIES AND METHODS OF USE THEREOF
The invention relates to stable formulations comprising antibodies or antigen binding fragments thereof that bind to cytotoxic T lymphocyte associated antigen 4 (CTLA4), optionally further containing an anti-human programmed death receptor 1 (PD-1) antibody or antigen binding fragment thereof. Also provided are methods of treating various cancers and chronic infections with the formulations of the invention.
1 . A co-formulation comprising:
(i) about 1 mg/ml to about 25 mg/ml of an anti-CTLA4 antibody, wherein the anti-CTLA4 antibody comprises a heavy chain variable region comprising SEQ ID NO: 88, and a light chain variable region comprising SEQ ID NO: 48.
(ii) about 1 mg/ml to about 25 mg/ml of an anti-PD1 antibody, wherein the anti-PD1 antibody is pembrolizumab;
(iii) about 10 mM of L-histidine buffer;
(iv) about 7% weight/volume (w/v) sucrose;
(v) about 0.02% w/v polysorbate 80; and
(vi) about 10 mM L-methionine, and
wherein the co-formulation has a pH between 5.0 and 6.0,
wherein the anti-CTLA4 antibody and pembrolizumab are co-formulated.
2 . The co-formulation of claim 1 , wherein the ratio of the anti-PD1 antibody to the anti-CTLA4 antibody is 1:2, 1:1, 2:1, 10:1, 1:10, 8:3, or 8:1 w/w.
3 . The co-formulation of claim 2 , wherein the ratio of the anti-PD1 antibody to the anti-CTLA4 antibody is 8:1 w/w.
4 . The co-formulation of claim 1 , wherein the concentration of the anti-CTLA4 antibody is about 1.25 mg/ml, 2.5 mg/ml, 2.9 mg/ml, 5 mg/ml, 7.9 mg/ml, 10 mg/ml, 12.5 mg/ml, 25 mg/ml.
5 . The co-formulation of claim 4 , wherein the concentration of the anti-PD1 antibody or antigen binding fragment thereof is about 25 mg/mL, 22.7 mg/mL, 2.27 mg/mL, 21.1 mg/mL or 23.5 mg/ml.
6 . The co-formulation of claim 1 , comprising about 23.5 mg/mL of the anti-PD1 antibody and about 2.9 mg/mL anti-CTLA4 antibody.
7 . The co-formulation of claim 1 , further comprising a chelator, wherein the chelator is diethylenetriaminepentaacetic acid (DTPA).
8 . The co-formulation of claim 1 , wherein the co-formulation is contained in a glass vial or an injection device.
9 . The co-formulation of claim 1 , that is a liquid co-formulation, or that is frozen to at least below −70° C., or that is a reconstituted solution from a lyophilized co-formulation.
10 . A method of treating cancer or chronic infection in a human patient in need thereof, the method comprising administering an effective amount of the co-formulation of claim 1 .