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

Daniel I Chasman,Timothy Hickling,Paul M Ridker,A Katrina Loomis,Ellen Q Wang,Rebecca D Danning,Craig L Hyde,Franco Giulianini

doi:10.1038/s41598-022-07997-5

Daniel I Chasman, Timothy Hickling + Show 6 more

Open Access

https://doi.org/10.1038/s41598-022-07997-5

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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.

Highlights

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 anti-drug antibodies (ADAs) status among 8844 individuals randomized to bococizumab, which targets proprotein convertase subtilisin–kexin type 9 (PCSK9) for LDL cholesterol (LDL-C) lowering and cardiovascular protection
After up to approximately 12 months of follow-up (“Methods”), 32.4% of available SPIRE participants randomly allocated to bococizumab met the criteria for a positive ADA response, varying across sub-studies from 25.9 to 52% (Table S2)
Among 1048 available participants on treatment with a positive ADA response, 312 (29.8%) from SPIRE-HR, SPIRE-LDL, SPIRE-FH, and SPIRE-LL tested positive for presence of neutralizing antibodies (NAbs), a binary outcome variable (0/1)

Summary

Introduction

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. We explore the genetic determinants of ADAs and NAbs for bococizumab among individuals in SPIRE with European ancestry, the majority subset. In this much larger sample for pharmacogenetics of mAb therapies than has been available previously, genome-wide significant associations primarily implicated multiple variants in Scientific Reports | (2022) 12:4266

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