Immune Complex Formation Is Associated With Loss of Tolerance and an Antibody Response to Both Drug and Target.

AMG 966 is a bi-specific, heteroimmunoglobulin molecule that binds both tumor necrosis factor alpha (TNFα) and TNF-like ligand 1A (TL1A). In a first-in-human clinical study in healthy volunteers, AMG 966 elicited anti-drug antibodies (ADA) in 53 of 54 subjects (98.1%), despite a paucity of T cell epitopes observed in T cell assays. ADA were neutralizing and bound to all domains of AMG 966. Development of ADA correlated with loss of exposure. In vitro studies demonstrated that at certain drug-to-target ratios, AMG 966 forms large immune complexes with TNFα and TL1A, partially restoring the ability of the aglycosylated Fc domain to bind FcγRIa and FcγRIIa, leading to the formation of ADA. In addition to ADA against AMG 966, antibodies to endogenous TNFα were also detected in the sera of subjects dosed with AMG 966. This suggests that the formation of immune complexes between a therapeutic and target can cause loss of tolerance and elicit an antibody response against the target.
Competing Interests: All authors were employees of Amgen during the time the study was being conducted. The authors declare this study received funding from Amgen. The funder was responsible for study design, interpretation of data, and the writing of this article. AMG 966 is disclosed in patent application WO2017/106383.
(Copyright © 2021 Kroenke, Barger, Hu, Miller, Kalenian, He, Hsu, Bartley, Chow, Teixeira dos Santos, Sullivan, Cheng, Parnes, Padaki, Kuhns and Mytych.)