Treatment- and population-specific genetic risk factors for anti-drug antibodies against interferon-beta: a GWAS

Abstract

Background Upon treatment with biopharmaceuticals, the immune system may produce anti-drug antibodies (ADA) that inhibit the therapy. Up to 40% of multiple sclerosis patients treated with interferon β (IFNβ) develop ADA, for which a genetic predisposition exists. Here, we present a genome-wide association study on ADA and predict the occurrence of antibodies in multiple sclerosis patients treated with different interferon β preparations. Methods We analyzed a large sample of 2757 genotyped and imputed patients from two cohorts (Sweden and Germany), split between a discovery and a replication dataset. Binding ADA (bADA) levels were measured by capture-ELISA, neutralizing ADA (nADA) titers using a bioassay. Genome-wide association analyses were conducted stratified by cohort and treatment preparation, followed by fixed-effects meta-analysis. Results Binding ADA levels and nADA titers were correlated and showed a significant heritability (47% and 50%, respectively). The risk factors differed strongly by treatment preparation: The top-associated and replicated variants for nADA presence were the HLA-associated variants rs77278603 in IFNβ-1a s.c.- (odds ratio (OR) = 3.55 (95% confidence interval = 2.81–4.48), p = 2.1 × 10−26) and rs28366299 in IFNβ-1b s.c.-treated patients (OR = 3.56 (2.69–4.72), p = 6.6 × 10−19). The rs77278603-correlated HLA haplotype DR15-DQ6 conferred risk specifically for IFNβ-1a s.c. (OR = 2.88 (2.29–3.61), p = 7.4 × 10−20) while DR3-DQ2 was protective (OR = 0.37 (0.27–0.52), p = 3.7 × 10−09). The haplotype DR4-DQ3 was the major risk haplotype for IFNβ-1b s.c. (OR = 7.35 (4.33–12.47), p = 1.5 × 10−13). These haplotypes exhibit large population-specific frequency differences. The best prediction models were achieved for ADA in IFNβ-1a s.c.-treated patients. Here, the prediction in the Swedish cohort showed AUC = 0.91 (0.85–0.95), sensitivity = 0.78, and specificity = 0.90; patients with the top 30% of genetic risk had, compared to patients in the bottom 30%, an OR = 73.9 (11.8–463.6, p = 4.4 × 10−6) of developing nADA. In the German cohort, the AUC of the same model was 0.83 (0.71–0.92), sensitivity = 0.80, specificity = 0.76, with an OR = 13.8 (3.0–63.3, p = 7.5 × 10−4). Conclusions We identified several HLA-associated genetic risk factors for ADA against interferon β, which were specific for treatment preparations and population backgrounds. Genetic prediction models could robustly identify patients at risk for developing ADA and might be used for personalized therapy recommendations and stratified ADA screening in clinical practice. These analyses serve as a roadmap for genetic characterizations of ADA against other biopharmaceutical compounds.

Polyethylene Glycol Immunogenicity: Theoretical, Clinical, and Practical Aspects of Anti-Polyethylene Glycol Antibodies

“…This is consistent with few reports of immunogenicity for most pegylated human proteins. It should be noted, however, that antibodies can be generated against proteins that differ from a bona fide human protein by only a single or few amino acids, as well as by differences in glycosylation and other post-translational modifications. , Manufacturing, purification, and formulation conditions can also affect the immunogenicity of recombinant human proteins. , As more generic forms of pegylated medicines come on the market, additional scrutiny of possible immunogenicity due to subtle differences in manufacturing processes may be warranted …”

“…Non-human foreign proteins typically induce strong anti-PEG antibody responses. Individual differences in each component of the immune system, especially expression of specific major histocompatibility complex alleles, can influence how immunogenic a particular protein appears to an individual patient. ,, …”

“…Individual differences in each component of the immune system, especially expression of specific major histocompatibility complex alleles, can influence how immunogenic a particular protein appears to an individual patient. 83,105,106 LIPOSOMES AND NANOPARTICLES Pegylated liposomes and nanoparticles can cross-link BCRs on PEG-specific B cells to induce production of anti-PEG IgM antibodies via a TI-2 response. 107,108 The thymus-independent nature of the response is shown by induction of anti-PEG antibodies in BALB/c nude mice which lack T cells.…”

MOTS-c Functionally Prevents Metabolic Disorders

“…The most common side effects of peptide-based drugs that have been reported include the production of antidrug antibodies, off-target effects, and gastrointestinal side effects. For example, anti-drug antibodies can develop in up to 40% of multiple sclerosis patients treated with IFN-β [ 75 ]. Although dipeptidyl peptidase 4 inhibitors have been approved for treating of T2D, their non-incretin substrates cause off-target effects such as heart failure [ 76 ].…”

Harnessing Type I IFN Immunity Against SARS-CoV-2 with Early Administration of IFN-β

“…In addition, long-term treatment with either molecule may illicit neutralizing anti-drug antibodies that can adversely affect treatment, as first reported in a patient receiving IFN-β for nasopharyngeal carcinoma [ 123 – 126 ]. These idiosyncratic reactions may be polygenically driven [ 127 ]. In all, short-term IFN-α or IFN-β treatment appears safe with little side effects and has proven efficient in the treatment of certain viral infections.…”