title: Viscosity-Lowering Effect of Amino Acids and Salts on Highly Concentrated Solutions of Two IgG1 Monoclonal Antibodies.
abstract: Monoclonal antibodies display complicated solution properties in highly concentrated (>100 mg/mL) formulations, such as high viscosity, high aggregation propensity, and low stability, among others, originating from protein-protein interactions within the colloidal protein solution. These properties severely hinder the successful development of high-concentration mAb solution for subcutaneous injection. We hereby investigated the effects of several small-molecule excipients with diverse biophysical-chemical properties on the viscosity, aggregation propensity, and stability on two model IgG1 (JM1 and JM2) mAb formulations. These excipients include nine amino acids or their salt forms (Ala, Pro, Val, Gly, Ser, HisHCl, LysHCl, ArgHCl, and NaGlu), four representative salts (NaCl, NaAc, Na2SO4, and NH4Cl), and two chaotropic reagents (urea and GdnHCl). With only salts or amino acids in their salt-forms, significant decrease in viscosity was observed for JM1 (by up to 30-40%) and JM2 (by up to 50-80%) formulations, suggesting charge-charge interaction between the mAbs dictates the high viscosity of these mAbs formulations. Most of these viscosity-lowering excipients did not induce substantial protein aggregation or changes in the secondary structure of the mAbs, as evidenced by HPLC-SEC, DSC, and FT-IR analysis, even in the absence of common protein stabilizers such as sugars and surfactants. Therefore, amino acids in their salt-forms and several common salts, such as ArgHCl, HisHCl, LysHCl, NaCl, Na2SO4, and NaAc, could potentially serve as viscosity-lowering excipients during high-concentration mAb formulation development.
authors.affiliation: School of Pharmaceutical Sciences and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University , Beijing 100084, China.
authors.forename: Shujing
authors.initials: S
authors.lastname: Wang
authors.affiliation: China R&D and Scientific Affair, Shanghai Discovery Center, Janssen Research & Development, Johnson & Johnson, Shanghai 200030, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.affiliation: China R&D and Scientific Affair, Shanghai Discovery Center, Janssen Research & Development, Johnson & Johnson, Shanghai 200030, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Hu
authors.affiliation: Janssen Research & Development, Johnson & Johnson, Malvern, Pennsylvania 19355, United States.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Dai
authors.affiliation: China R&D and Scientific Affair, Shanghai Discovery Center, Janssen Research & Development, Johnson & Johnson, Shanghai 200030, China.
authors.forename: Xiuying
authors.initials: X
authors.lastname: Feng
authors.affiliation: School of Pharmaceutical Sciences and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University , Beijing 100084, China.
authors.forename: Xinyi
authors.initials: X
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Sciences and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University , Beijing 100084, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Qian
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D005079:Excipients / Q000737:chemistry; D007074:Immunoglobulin G / Q000737:chemistry*; D019999:Pharmaceutical Solutions / Q000737:chemistry*; D012492:Salts / Q000737:chemistry*; D014783:Viscosity
chemical_list: D000596:Amino Acids; D000911:Antibodies, Monoclonal; D005079:Excipients; D007074:Immunoglobulin G; D019999:Pharmaceutical Solutions; D012492:Salts
keywords: amino acids; mAb stability; monoclonal antibody; protein−protein interaction; subcutaneous injection; viscosity