Antibody responses in mice to particles formed from adsorption of a murine monoclonal antibody onto glass microparticles.
Immunogenicity of therapeutic monoclonal antibodies (mAbs) is a concern because of the effects of anti-drug antibodies (ADAs) on therapeutic efficacy. Particulate matter has been suggested as a potential contributing factor to immunogenicity. In this study, we investigated ADA levels in mice in response to administration of a murine immunoglobulin G (IgG)2c/κ mAb (mAb1) that was generated in C57BL/6J mice. Particles of mAb1 were formed by adsorbing the protein to glass microparticles. Formulations containing microparticles were administered subcutaneously to mice of either the syngeneic strain, C57Bl/6J, or the allogeneic strain, BALB/c. ADA levels were measured using an isotype-specific enzyme-linked immunosorbent assay method. Whereas BALB/c mice showed strong IgG1 and IgG2b responses against both the particulate and native mAb1 samples, adsorption of mAb1 to particles rendered it slightly more immunogenic than its native, soluble form. In BALB/c mice, immunoglobulin M (IgM) was produced after the first week of injections and then faded gradually. In contrast, C57BL/6J mice showed moderate IgM, IgG1, IgG2b, and IgG3 responses to injections of glass particle-adsorbed mAb1. ADA responses were higher in the allogeneic BALB/c mice, which do not produce mAbs of the IgG2c/κ isotype. Thus, the presence of both foreign epitopes and particles may be important in inducing ADA responses.
Department of Chemical and Biological Engineering, Center for Pharmaceutical Biotechnology, University of Colorado, Boulder, Colorado, 80303.
Maliheh
M
Shomali
Angelika
A
Freitag
Julia
J
Engert
Michael
M
Siedler
Zehra
Z
Kaymakcalan
Gerhard
G
Winter
John F
JF
Carpenter
Theodore W
TW
Randolph
D000327:Adsorption / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000917:Antibody Formation / Q000276:immunology*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D005260:Female; D007074:Immunoglobulin G / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL
D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G
ELISA assay; adjuvant effect; adsorption; aggregates; anti-drug antibody (ADA); immunogenicity; infrared spectroscopy; microparticles; monoclonal antibody (mAb); protein