ANTI-NERVE GROWTH FACTOR (NGF) ANTIBODY COMPOSITIONS
The present invention relates to stable compositions of anti-NGF antibodies, and antigen-binding fragments thereof, and their uses in the prevention and/or treatment of various diseases and disorders in which NGF activity is detrimental, e.g., pain disorders.
1 . A pharmaceutical composition comprising:
(a) an anti-nerve growth factor (NGF) antibody, or antigen binding fragment thereof;
(b) a histidine buffer at a concentration of about 5 to about 60 mM; and
(c) polysorbate 80 at a concentration of about 0.01% to about 0.1%;
wherein the pH of the composition is about 5.0 to about 6.0.
2 . The pharmaceutical composition of claim 1 , wherein the composition further comprises about 1 to about 100 mg/mL of a polyol.
3 . The pharmaceutical composition of claim 1 , wherein the composition further comprises about 10 to about 100 mg/mL of a sugar.
4 . The pharmaceutical composition of claim 1 , wherein the concentration of the antibody, or antigen-binding portion thereof, is about 1 to about 240 mg/mL.
5 . The pharmaceutical composition of claim 2 or 3 , wherein the molar ratio of (a) anti-NGF antibody, or antigen binding fragment thereof, to (b) polyol, sugar, or combination thereof, is greater than 1:1400.
6 . The pharmaceutical composition of claim 1 , wherein said composition comprises:
(a) about 20 mg/mL of the antibody, or antigen-binding portion thereof;
(b) about 15 mM histidine; and
(c) about 0.01% polysorbate 80;
wherein the pH of the formulation is about 5.5.
7 . The pharmaceutical composition of claim 1 , wherein said composition comprises:
(a) about 60 mg/mL of the antibody, or antigen-binding portion thereof;
(b) about 30 mM histidine; and
(c) about 0.02% polysorbate 80;
wherein the pH of the formulation is about 5.5.
8 . The pharmaceutical composition of claim 1 , wherein the composition is lyophilized.
9 . The lyophilized pharmaceutical composition of claim 8 , comprising:
(a) about 1 to about 120 mg of an anti-NGF antibody, or antigen binding fragment thereof;
(b) about 1 to about 10 mg of histidine; and
(c) about 0.1 to about 0.4 mg of polysorbate 80.
10 . The lyophilized pharmaceutical composition of claim 9 , further comprising about 1 to about 100 mg of a polyol.
11 . The lyophilized pharmaceutical composition of claim 9 , further comprising about 1 to about 100 mg of a sugar.
12 . The pharmaceutical composition of claim 1 , wherein the anti-NGF antibody, or antigen-binding portion thereof, binds to human NGF.
13 . The pharmaceutical composition of claim 12 , wherein the anti-NGF antibody, or antigen-binding portion thereof, comprises a human IgG4 constant region.
14 . The pharmaceutical composition of claim 13 , wherein the anti-NGF antibody, or antigen-binding portion comprises a hinge region mutation.
15 . The pharmaceutical composition of claim 14 , wherein the hinge region mutation comprises a mutation of a serine at amino acid position 108 of SEQ ID NO: 9.
16 . The pharmaceutical composition of claim 14 , wherein the human IgG4 constant region comprises the amino acid sequence of SEQ ID NO: 10.
17 . The pharmaceutical composition of claim 12 , wherein the antibody, or antigen-binding portion thereof, has one or more of the following functional properties:
a) binds to human NGF but does not bind to human brain-derived neurotrophic factor (BDNF), human neurotrophin 3 (NT-3) or human neurotrophin 4 (NT-4);
b) binds to human or rat NGF with a K D of 100 pM or less;
c) inhibits binding of NGF to TrkA or p75 NTR ;
d) inhibits NGF-dependent proliferation of TF-1 cells;
e) inhibits NGF-dependent chick dorsal root ganglion survival; and
f) inhibits NGF-dependent PC12 cell neurite outgrowth.
18 . The pharmaceutical composition of claim 12 , wherein the antibody, or antigen-binding portion thereof, does not exhibit a rebound effect when administered to a subject.
19 . The pharmaceutical composition of claim 1 , wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising CDRs 1, 2 and 3, having the amino acid sequences of SEQ ID NOs: 3, 4 and 5, respectively.
20 . The pharmaceutical composition of claim 1 , wherein the antibody, or antigen-binding portion thereof, comprises a light chain variable region comprising CDRs 1, 2 and 3, having the amino acid sequences of SEQ ID NOs: 6, 7 and 8, respectively.
21 . The pharmaceutical composition of claim 1 , wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1.
22 . The pharmaceutical composition of claim 1 , wherein the antibody, or antigen-binding portion thereof, comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 2.
23 . The pharmaceutical composition of claim 1 , wherein the antibody, or antigen-binding portion thereof, competes for binding to NGF with an antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 2.
24 . The pharmaceutical composition of claim 1 , wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 13.
25 . The pharmaceutical composition of claim 1 , wherein the antibody, or antigen binding portion thereof, comprises a light chain comprising the amino acid sequence of SEQ ID NO: 16.
26 . A pharmaceutical composition comprising:
(a) an anti-nerve growth factor (NGF) antibody comprising a human IgG4 constant region, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO:13 and a light chain having the amino acid sequence of SEQ ID NO:16, wherein the concentration of the antibody, or antigen binding fragment thereof, is about 10 to about 50 mg/mL;
(b) a histidine buffer at a concentration of about 10 to about 30 mM histidine; and
(c) polysorbate 80 at a concentration of about 0.01% to 0.02%;
wherein the pH of the composition is about 5.0 to about 6.0.
27 . The pharmaceutical composition of claim 26 , further comprising about 10 to about 50 mg/mL mannitol.
28 . The pharmaceutical composition of claim 26 , further comprising about 5 to about 70 mg/mL sucrose.
29 . The pharmaceutical composition of claim 26 , consisting essentially of:
(a) about 10 to 30 mg/mL of the antibody or antigen-binding fragment thereof;
(b) about 15 mM histidine buffer; and
(c) about 0.01% polysorbate 80;
wherein the pH of the composition is about 5.5.
30 . The pharmaceutical composition of claim 27 , consisting essentially of:
(a) about 10 to 30 mg/mL of the antibody or antigen-binding fragment thereof;
(b) about 15 mM histidine buffer;
(c) about 0.01% polysorbate 80; and
(d) about 10 to 30 mg/mL mannitol;
wherein the pH of the composition is about 5.5.
31 . The pharmaceutical composition of claim 28 , consisting essentially of:
(a) about 10 to 30 mg/mL of the antibody or antigen-binding fragment thereof;
(b) about 15 mM histidine buffer;
(c) about 0.01% polysorbate 80; and
(d) about 40 to 70 mg/mL sucrose;
wherein the pH of the composition is about 5.5.
32 . The pharmaceutical composition of claim 28 , consisting essentially of:
(a) about 10 to 30 mg/mL of the antibody or antigen-binding fragment thereof;
(b) about 15 mM histidine buffer;
(c) about 0.01% polysorbate 80;
(d) about 10 to 30 mg/mL mannitol; and
(e) about 5 to 10 mg/mL sucrose;
wherein the pH of the composition is about 5.5.
33 . The pharmaceutical composition of any one of claim 27 or 28 , wherein the ratio of (a) antibody, or antigen binding fragment thereof, to (b) polyol, sugar, or combination thereof, is greater than 1:1400.
34 . The pharmaceutical composition of claim 26 , wherein the pharmaceutical composition is lyophilized.
35 . The pharmaceutical composition of claim 1 , wherein the antibody, or antigen-binding portion thereof, is selected from the group consisting of a monoclonal antibody, a human antibody, a humanized antibody, a chimerical antibody, a CDR-grafted antibody, a Fab, a Fab′, a F(ab′)2, a Fv, a disulfide linked Fv, a scFv, a single domain antibody, a diabody, a multispecific antibody, a dual specific antibody, and a bispecific antibody.
36 . The pharmaceutical composition of claim 1 , wherein the formulation is stable in a liquid form for at least about 3 months at 2-25° C.
37 . The pharmaceutical composition of claim 1 , wherein the formulation is stable for at least 6 months in frozen or lyophilized form.
38 . The pharmaceutical composition of claim 37 , wherein the formulation is stored frozen at −80° C.
39 . The pharmaceutical composition of claim 37 , wherein the formulation is stored in lyophilized form at 2-25° C.
40 . The pharmaceutical composition of claim 36 or 37 , wherein there is less than about 10% aggregation of the antibody.
41 . The pharmaceutical composition of claim 1 , wherein the formulation is suitable for intravenous, subcutaneous and/or intramuscular administration.
42 . A device comprising the pharmaceutical composition of any claim 1 .
43 . The device of claim 42 , wherein the device is selected from the group consisting of a syringe, a pen, an implant, a needle-free injection device, an inhalation device, and a patch.
44 . A kit comprising the pharmaceutical composition of claim 1 or device of claim
45 . A method of attenuating or inhibiting an NGF mediated disease or condition in a subject, the method comprising administering to the subject the pharmaceutical composition of claim 1 .
46 . The method of claim 45 , wherein the NGF mediated disease or condition is pain.
47 . The method of claim 45 , wherein the pharmaceutical composition is suitable for administration intravenously, subcutaneously or intra-articularly.
48 . The method of claim 45 , wherein the pharmaceutical composition is suitable for administration with a second pharmaceutical agent.