Allelic Variation in HLA-DRB1 is Associated with Development of Anti-Drug Antibodies in Cancer Patients Treated with Atezolizumab that are Neutralizing in Vitro

The treatment of diseases with biologic agents can result in the formation of anti-drug antibodies (ADA). The occurrence of ADA were reported for atezolizumab, an anti-PD-L1 monoclonal antibody widely used as immunotherapeutic treatment in cancer patients. 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 1,982 patients treated with atezolizumab across 8 clinical trials. On average, 29.8% of patients were ADA positive (N = 591, range of 13.5% -38.4%), and 14.6% of patients were positive for ADA that were neutralizing in vitro (NAb, N = 278, range of 6.4% - 21.9%). We found statistically significant associations between HLA class II alleles and ADA status. The top-associated alleles were HLA-DRB1*01:01 for all ADA (p = 3.4*10-5, odds ratio = 1.96), and HLA-DQA1*01:01 when considering NAb only (p = 2.8 x 10-7, OR = 2.31). Both alleles occur together on a common HLA haplotype, and the ADA association was explained by the NAb subset. In conclusion, our study showed that HLA class II genotype contributes to the risk of developing ADA, and specifically NAb, in patients treated with atezolizumab, but suggests that genetic factors are not sufficient as clinically meaningful predictors.