Stable formulations of antibodies to human programmed death receptor PD-1 and related treatments

• US 9,220,776 B2
• Filed: 03/29/2012
• Issued: 12/29/2015
• Est. Priority Date: 03/31/2011
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme LLC (Merck & Co., Inc.)
• Original Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Inventors: Sharma, Manoj K., Narasimhan, Chakravarthy Nachu, Gergich, Kevin James, Kang, Soonmo Peter
• Primary Examiner(s): OUSPENSKI, ILIA I
• Application Number:
  US14/008,604
• Publication Number:
  US 20140234296A1
• Time in Patent Office: 1,370 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/39591 Stabilisation, fragmentation
• CPC Class Codes: A61K 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 16/2818 against CD28 or CD152
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered

Abstract

The present invention relates to stable formulations of antibodies against human programmed death receptor PD-1, or antigen binding fragments thereof. The present invention further provides methods for treating various cancers and chronic infections with stable formulations of antibodies against human programmed death receptor PD-1, or antigen binding fragments thereof.

Claims

1. A stable lyophilized pharmaceutical formulation of an anti-human PD-1 antibody, wherein the formulation made by lyophilizing an aqueous solution comprising:

a) 25-100 mg/mL of the anti-human PD-1 antibody;

b) about 70 mg/mL sucrose;

c) about 0.2 mg/mL polysorbate 80; and

d) about 10 mM Histidine buffer at about pH 5.0-pH 6.0, and

wherein the antibody, comprises;

i) a light chain comprising amino acid residues 20 to 237 of SEQ ID NO;

36; and

ii) a heavy chain comprising amino acid residues 20 to 466 of SEQ ID NO;

31.

2. The stable lyophilized pharmaceutical formulation of claim 1, wherein the anti-human PD-1 antibody is present at about 25 mg/mL in the aqueous solution.

3. The stable lyophilized pharmaceutical formulation of claim 1, wherein the aqueous solution has a pH of about 5.5.

4. The stable lyophilized pharmaceutical formulation of claim 1, wherein the aqueous solution comprises 25.0 mg/ml of the anti-human PD-1 antibody, 1.55 mg/ml histidine, 0.2 mg/ml polysorbate 80, 70 mg/ml sucrose, and has a pH of 5.5.

5. A stable liquid pharmaceutical formulation of an anti-human PD-1 antibody, comprising:

a) 25-100 mg/mL of the anti-human PD-1 antibody;

b) about 70 mg/mL sucrose;

c) about 0.2 mg/mL polysorbate 80; and

d) about 10 mM histidine buffer at pH 5.0-6.0,

wherein the antibody comprises;

i) a light chain comprising amino acid residues 20 to 237 of SEQ ID NO;

36; and

ii) a heavy chain comprising amino acid residues 20 to 466 of SEQ ID NO;

31, and

wherein the liquid formulation has not been previously lyophilized.

6. The stable liquid pharmaceutical formulation of claim 5, which comprises 10 mM histidine, pH 5.5, 7% sucrose, 0.02% polysorbate 80, and 25.0 mg/ml of the anti-human PD-1 antibody.

7. A method of treating cancer in a human subject in need thereof, the method comprising administering an effective amount of a pharmaceutical formulation of an anti-human PD-1 antibody comprising:

a) 25-100 mg/mL of the anti-human PD-1 antibody, or antigen binding fragment thereof;

b) about 70 mg/mL sucrose;

c) about 0.2 mg/mL polysorbate 80; and

d) about 10 mM histidine buffer at pH 5.0-6.0,

wherein the antibody comprises;

i) a light chain comprising amino acid residues 20 to 237 of SEQ ID NO;

36; and

ii) a heavy chain comprising amino acid residues 20 to 466 of SEQ ID NO;

31, and

wherein the pharmaceutical formulation is reconstituted from a stable lyophilized formulation or is a stable liquid formulation has not been previously lyophilized.

8. The method of claim 7, wherein the effective amount comprises a dose selected from the group consisting of about 1.0, 3.0, and 10 mg/kg administered at intervals of about 14 days or about 21 days throughout the course of treatment.

9. The method of claim 7, wherein the effective amount comprises a dose of 5.0 mg/kg or 10 mg/kg administered at intervals of every 2 weeks or every 3 weeks throughout the course of treatment.

10. The method of claim 7, wherein the subject has melanoma and the effective amount comprises a dose of 3.0 mg/kg administered at intervals of every 3 weeks throughout the course of treatment.

11. The method of claim 7, wherein the subject is treatment naï

ve.

12. The method of claim 7, wherein the pharmaceutical formulation is administered in a 30 minute IV infusion.

13. The method of claim 7, wherein the subject has melanoma.