Granted Patent B2

US 12,576,159 · App. 17/287,588 · Granted Mar 17, 2026

Inventors: Paul Reichert (Montville, NJ); Winifred W. Prosise (Ramsey, NJ); Xiaoyu Yang (Basking Ridge, NJ); Corey Strickland (Martinsville, NJ); Chakravarthy Nachu Narasimhan (Scotch Plains, NJ); Thierry O. Fischmann (Scotch Plains, NJ); Erika R. Walsh (Scotch Plains, NJ); Yongchao Su (Hillsborough, NJ)

Assignee: Merck Sharp & Dohme LLC

A61K47/6849A61K31/522A61K45/06A61K47/10A61P35/00C07K16/2818C30B29/58A61K2039/545C07B2200/13C07K2299/00

Abstract

Claims (16)

1 . A method for producing crystalline anti-PD-1 monoclonal antibody (mAb) comprising:

a) mixing:

i) an aqueous buffered solution comprising about 5 mg/mL to about 80 mg/mL of the anti-PD-1 mAb, wherein the anti-PD-1 mAb is pembrolizumab or a pembrolizumab variant,

ii) polyethylene glycol (PEG), and

iii) an additive comprising caffeine or theophylline;

to form a crystallization solution, wherein the crystallization solution has a pH of about 6.0 to about 8.8 and comprises between about 12% and about 15% weight per volume (w/v) PEG and about 0.1% to about 0.30% w/v additive,

wherein, when theophylline is the additive, its concentration is between about 0.15% w/v and about 0.30% w/v,

wherein, when caffeine is the additive, its concentration is between about 0.1% w/v and about 0.18% w/v;

a) incubating the crystallization solution for a period of time sufficient for crystal formation, wherein the crystallization solution is incubated a temperature between about 18° C. and about 25° C.; and

b) optionally harvesting the crystalline anti-PD-1 mAb from the solution.

2 . The method of claim 1 , wherein the aqueous buffered solution comprising the mAb further comprises histidine buffer at a pH of about 5.0 to about 6.0.

3 . The method of claim 1 , wherein the PEG and the additive are mixed together to form a precipitant solution before being mixed with the aqueous buffered solution comprising the mAb.

4 . The method of claim 1 , wherein the solution concentration of the anti-PD-1 mAb in the crystallization solution is from about 5 mg/mL to about 50 mg/mL.

5 . The method of claim 1 , wherein the crystallization solution is produced by vapor diffusion, batch crystallization or dialysis.

6 . A composition comprising an isolated crystal comprising pembrolizumab complexed with caffeine, wherein the crystal is characterized by space group P222 1 a=43.8 Å b=113.9 Å c=175.0 Å, α=β=γ=90° and a pharmaceutically acceptable carrier, further comprising about 0.01% to about 0.10% w/v non-ionic surfactant.

7 . A composition comprising an isolated crystal comprising pembrolizumab complexed with caffeine, wherein the crystal is characterized by space group P222 1 a=43.8 Å b=113.9 Å c=175.0 Å, α=β=γ=90° and a pharmaceutically acceptable carrier, further comprising a second active pharmaceutical ingredient (API).

Assignments (2)

Continuity (2)

References Cited (400)