Genome-wide pharmacogenetics of anti-drug antibody response to bococizumab highlights key residues in HLA DRB1 and DQB1
Daniel I Chasman, Craig L Hyde, Franco Giulianini, Rebecca D Danning, Ellen Q Wang, Timothy Hickling, Paul M Ridker, A Katrina Loomis, Daniel I Chasman, Craig L Hyde, Franco Giulianini, Rebecca D Danning, Ellen Q Wang, Timothy Hickling, Paul M Ridker, A Katrina Loomis
Abstract
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.
Conflict of interest statement
C. Hyde, E. Wang, and A. K. Loomis are employees of Pfizer, Inc. T. Hickling was an employee of Pfizer, Inc. during the design and implementation of the study. P. Ridker has received research grant support from Novartis, Kowa, Amarin, Pfizer, and the NHLBI; and has served as a consultant to Corvidia, Novartis, Flame, Agepha, Inflazome, AstraZeneca, Jannsen, Civi Biopharm, SOCAR, Novo Nordisk, Uptton, and Omeicos, and Boehringer-Ingelheim. D. Chasman has received funding support from Pfizer Inc. related to the genetics of bococizumab treatment. R. Danning and F. Giulianini have no disclosures.
© 2022. The Author(s).
Figures
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Source: PubMed