Allelic variation in HLA‐DRB1 is associated with development of a ntidrug antibodies in cancer patients treated with atezolizumab that are neutralizing in vitro

Abstract The treatment of diseases with biologic agents can result in the formation of antidrug antibodies (ADA). Although drivers for ADA formation are unknown, a role for antigen presentation is likely, and variation in human leukocyte antigen (HLA) genes has been shown to be associated with occurrence of ADA for several biologics. Here, we performed an HLA‐wide association study in 1982 patients treated with the anti‐PD‐L1 antibody atezolizumab across eight clinical trials. On average, 29.8% of patients were ADA‐positive ( N  = 591, range of 13.5%–38.4% per study) and 14.6% of patients were positive for ADA that were neutralizing in vitro (neutralizing antibodies [NAb], N  = 278, range of 6.4%–21.9% per study). In a meta‐analysis of logistic regression coefficients, we found statistically significant associations between HLA class II alleles and ADA status. The top‐associated alleles were HLA‐DRB1*01:01 in a comparison of ADA‐positive versus ADA‐negative patients ( p  = 3.4 × 10 −5 , odds ratio [OR] 1.96, 95% confidence interval [95% CI] 1.64–2.28) and HLA‐DQA1*01:01 when comparing NAb‐positive with ADA‐negative patients ( p  = 2.8 × 10 −7 , OR 2.31, 95% CI 1.98–2.66). Both alleles occur together on a common HLA haplotype, and analyses considering only NAb‐negative, ADA‐positive patients did not yield significant results, suggesting that the genetic association is mainly driven by NAb status. In conclusion, our study showed that HLA class II genotype is associated with the risk of developing ADA, and specifically NAb, in patients treated with atezolizumab, but the effect estimates suggest that immunogenetic factors are not sufficient as clinically meaningful predictors.