US 11,918,650 B2
Pharmaceutical composition comprising bispecific antibody constructs for improved storage and administration
Jeff Abel, Simi Valley, CA (US); Lingwen Cui, Thousand Oaks, CA (US); Devrishi Goswami, Thousand Oaks, CA (US); Joon Huh, Culver City, CA (US); Bharadwaj Jagannathan, Thousand Oaks, CA (US); Sekhar Kanapuram, Thousand Oaks, CA (US); Arnold McAuley, Moorpark, CA (US); Michael Schneider, Thousand Oaks, CA (US); Ananthakrishnan G. Sethuraman, Newbury Park, CA (US); Michael Treuheit, Newbury Park, CA (US); and Jun Zhang, Newbury Park, CA (US)
Assigned to AMGEN INC., Thousand Oaks, CA (US)
Filed by AMGEN INC., Thousand Oaks, CA (US)
Filed on May 7, 2018, as Appl. No. 15/972,489.
Claims priority of provisional application 62/502,578, filed on May 5, 2017.
Prior Publication US 2019/0151448 A1, May 23, 2019
Int. Cl. A61K 39/395 (2006.01); A61K 9/00 (2006.01); A61K 9/08 (2006.01); A61K 9/19 (2006.01); A61K 47/10 (2017.01); A61K 47/12 (2006.01); A61K 47/14 (2017.01); A61K 47/18 (2017.01); A61K 47/24 (2006.01); A61K 47/26 (2006.01); C07K 16/28 (2006.01); C07K 16/46 (2006.01); A61J 1/05 (2006.01); A61J 1/10 (2006.01); A61K 39/00 (2006.01)
CPC A61K 39/39591 (2013.01) [A61K 9/0019 (2013.01); A61K 9/08 (2013.01); A61K 9/19 (2013.01); A61K 39/3955 (2013.01); A61K 47/10 (2013.01); A61K 47/12 (2013.01); A61K 47/14 (2013.01); A61K 47/183 (2013.01); A61K 47/24 (2013.01); A61K 47/26 (2013.01); C07K 16/2803 (2013.01); C07K 16/2809 (2013.01); C07K 16/2863 (2013.01); C07K 16/468 (2013.01); A61J 1/05 (2013.01); A61J 1/10 (2013.01); A61K 2039/54 (2013.01); A61K 2039/545 (2013.01); A61K 2039/627 (2013.01); C07K 2317/24 (2013.01); C07K 2317/31 (2013.01); C07K 2317/41 (2013.01); C07K 2317/569 (2013.01)] 18 Claims
 
1. A method for reducing or preventing the formation of high molecular weight protein aggregates of a bispecific antibody construct in a pharmaceutical composition, the method comprising providing a pharmaceutical composition comprising
i) a bispecific antibody construct, wherein the construct binds to a target cell surface antigen via a first binding domain and to the T cell surface antigen CD3 via a second binding domain, wherein the bispecific antibody construct is present in a concentration in the range from 0.5 μg/ml to 20 mg/ml;
ii) benzyl alcohol in a concentration in the range from 0.11 to 0.9% (w/v), and
iii) a buffer comprising a salt selected from the group consisting of phosphate, acetate, citrate, succinate and tartrate, or wherein the buffer comprises histidine, glycine, TRIS glycine, Tris, or mixtures thereof,
wherein the benzyl alcohol serves to physically and microbiologically stabilize the pharmaceutical composition during storage and administration,
wherein the bispecific antibody construct shows reduction or prevention of the formation of protein aggregates (high molecular weight (HMW) species), and wherein the percentile HMW concentration is below 5%, and
wherein the composition is stored until use as a solution in a frozen state or as a lyophilisate and is then administered, after dilution or reconstitution, without requiring additional benzyl alcohol for dilution or reconstitution.