Adalimumab Immunogenicity Is Negatively Correlated with Anti-Hinge Antibody Levels in Patients with Rheumatoid Arthritis

Abstract

Patients with rheumatoid arthritis (RA) are frequently treated with anti-TNF immunoglobulin therapy but develop neutralizing antibodies against these drugs, necessitating therapeutic monitoring of drug concentrations and anti-drug antibodies. Patients with RA have multiple factors related to their autoimmune disposition that interfere with conventionally used methods to detect anti-drug antibodies. Currently deployed analytical methods have significant limitations that hinder clinical interpretation and/or routine use, and no method can detect immunogenicity and drug levels simultaneously to provide clinically meaningful recommendations. Given these limitations, the objective of this study was to identify sources of and associations with assay interference in patients with RA. We designed a modular, immunogenicity and drug concentration detection technology to identify the factors that interfere with the detection of adalimumab and anti-adalimumab antibodies in a cohort of 206 patients with RA. Patients were included from the University of Pittsburgh Rheumatoid Arthritis Comparative Effectiveness Research (RACER) registry. In this cohort, we analyzed clinical and plasma factors associated with anti-adalimumab and anti-hinge antibodies. A novel flow cytometry-based assay was developed and validated that simultaneously measures adalimumab and anti-adalimumab antibody concentrations, overcoming many of the interference factors that are limitations of conventional assays, including anti-Fc and anti-hinge antibodies. C-reactive protein (p=0.035), DAS28 score (p=0.002), and disease activity category (p=0.009) were significantly associated with anti-adalimumab antibodies, but not with anti-hinge antibodies (p>0.05). Anti-hinge antibodies were inversely associated with drug neutralizing antibodies (p=0.002). In patients with RA, anti-hinge antibodies may have a potential protective effect against the development of anti-adalimumab antibodies.

Synthetically mannosylated antigens induce antigen-specific humoral tolerance and reduce anti-drug antibody responses to immunogenic biologics

“…This technology has the potential to be applied in combination as a pre-treatment to a number of immunogenic biologics in which ADA responses can limit therapeutic efficacy. Examples of immunogenic therapeutics with efficacy-limiting ADA responses include chronically administered monoclonal antibody therapies such as adalimumab, 63 enzyme replacement therapies such as phenylalanine ammonia lyase for the treatment of phenylketonuria, 64 and factor VIII replacement for hemophilia A. 65 With further validation, it may be used in combination with adeno-associated viral vectors to prevent ADAs and allow re-dosing.…”

Synthetically mannosylated antigens induce antigen-specific humoral tolerance and reduce anti-drug antibody responses to immunogenic biologics

“…This technology has the potential to be applied in combination as a pretreatment to a number of immunogenic biologics in which ADA responses can limit therapeutic efficacy. Examples of potential use cases include preventing ADAs to chronically administered monoclonal antibody therapies such as adalimumab 62 , enzyme replacement therapies such as phenylalanine ammonia lyase for the treatment of phenylketonuria 63 and factor VIII replacement for hemophilia A 64 .…”

Genetic polymorphisms of FcGR2B and adalimumab effectiveness in Colombian patients with rheumatoid arthritis. Cases-controls study

“…In a study evaluating ADAs and adalimumab it was shown that at least 98% had speci c ADAs against adalimumab with a neutralizing effect at 2 weeks after the start of drug initiation (22). However, it has been seen that anti-hinge antibodies had less neutralization of adalimumab (23). In one study, it was shown that patients with high levels of anti-adalimumab antibodies had increased Rheumatoid Factor values and positive association with increased C-Reactive Protein and DAS28 (24).…”