Abstract
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.
Highlights
Over the last two decades, protein-based therapeutics targeting tumor necrosis factor alpha (TNFa) have become a foundational therapy for the treatment of inflammatory disorders
We demonstrate here that AMG 966 forms large immune complexes with target which partially restores the ability of the stable effector functionless (SEFL) Fc to bind FcgR, providing a mechanism by which these complexes drive an antibody response to both AMG 966 and endogenous TNFa
In order to assess the immunogenic risk of AMG 966 and the charge pair mutations (Supplementary Figure 1), an in silico analysis of MHC class II binding was performed using the Immune Epitope Database (IEDB) tool
Summary
Over the last two decades, protein-based therapeutics targeting tumor necrosis factor alpha (TNFa) have become a foundational therapy for the treatment of inflammatory disorders. These molecules have significantly improved patient outcomes in a number of diseases such as inflammatory bowel disease (IBD), which includes both Crohn’s disease (CD) and ulcerative colitis (UC). For CD patients, inducing and maintaining a state of deep remission is the treatment goal. Even with an armamentarium of TNFa inhibitors for physicians to choose from, most patients do not achieve this goal. For patients being treated with adalimumab, for example, only 19% of patients with moderate to severe ileocolonic CD at 52 weeks demonstrated deep remission [3]
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