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In this largest to-date genetic analysis of anti-drug antibody (ADA) response to a therapeutic monoclonal antibody (MAb), genome-wide association was performed for five measures of ADA status among 8844 individuals randomized to bococizumab, which targets PCSK9 for LDL-C lowering and cardiovascular protection. Index associations prioritized specific amino acid substitutions at the  DRB1  and  DQB1  MHC class II genes rather than canonical haplotypes. Two clusters of missense variants at  DRB1  were associated with general ADA measures (residues 9, 11, 13; and 96, 112, 120, 180) and a third cluster of missense variants in  DQB1  was associated with ADA measures including neutralizing antibody (NAb) titers (residues 66, 67, 71, 74, 75). The structural disposition of the missense substitutions implicates peptide antigen binding and CD4 effector function, mechanisms that are potentially generalizable to other therapeutic mAbs.   Clinicaltrials.gov : NCT01968954, NCT01968967, NCT01968980, NCT01975376, NCT01975389, NCT02100514.

Genome-wide pharmacogenetics of anti-drug antibody response to bococizumab highlights key residues in HLA DRB1 and DQB1