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

doi:10.1038/s41598-022-07997-5

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

Sci Rep. 2022 Mar 11;12(1):4266. doi: 10.1038/s41598-022-07997-5.

Authors

Daniel I Chasman^{1

2}, Craig L Hyde³, Franco Giulianini⁴, Rebecca D Danning⁴, Ellen Q Wang⁵, Timothy Hickling³, Paul M Ridker^{4

6}, A Katrina Loomis³

Affiliations

¹ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA. [email protected].
² Harvard Medical School, Boston, MA, USA. [email protected].
³ Pfizer Inc., 1 Portland Street, Cambridge, MA, USA.
⁴ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁵ Pfizer Inc., New York, NY, USA.
⁶ Harvard Medical School, Boston, MA, USA.

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.

Publication types

Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Alleles
Antibodies, Monoclonal
Antibodies, Monoclonal, Humanized / therapeutic use
Antibody Formation
Gene Frequency
Genetic Predisposition to Disease
Genome-Wide Association Study*
HLA-DRB1 Chains / genetics
Haplotypes
Humans
Pharmacogenetics
Proprotein Convertase 9* / genetics

Substances

Antibodies, Monoclonal
Antibodies, Monoclonal, Humanized
HLA-DRB1 Chains
bococizumab
PCSK9 protein, human
Proprotein Convertase 9

Associated data

ClinicalTrials.gov/NCT01968967
ClinicalTrials.gov/NCT01975376
ClinicalTrials.gov/NCT01968954
ClinicalTrials.gov/NCT01968980
ClinicalTrials.gov/NCT02100514
ClinicalTrials.gov/NCT01975389