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

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

Figure 1

Genome-wide associations with anti-drug antibody response to bococizumab in SPIRE. (A) Circular Manhattan plot of genome-wide associations using genome-wide genotype data imputed to the HRC reference panel. Each ring corresponds to an anti-body response phenotype ordered from the central ring toward the perimeter as ADA positive, ADA maximum titer, ADA maximum titer top 10%, NAb positive, NAb maximum titer (see “Methods”). Thin green dashed lines indicate genome-wide significance threshold (p = 5 × 10–8) for each genome-wide scan. Red dots indicate SNPs reaching genome-wide significance. See Supplementary Figure S1 for corresponding quantile–quantile (QQ) plots. (B) Manhattan plot restricted to the MHC region (chr6:29-33 Mb) derived from MHC-specific imputation. Antibody response phenotypes as indicated are in the same order, top to bottom, as phenotypes in (A) center to perimeter. Thin green dashed line and red dots as in (A).

Figure 2

Effects of index SNPs across the several measures of immunogenicity. Diameters of circles are proportional to the magnitude of variant effects (i.e. beta coefficients). Circles with red outlines indicate associations reaching genome-wide significance. See also Table S5.

Figure 3

Mapping of index non-synonymous variants and their proxies to structural models of DR1 and DQ1. (A) ADA positive status on DR1. Index non-synonymous variant at DRB1 residue 120 and its proxies at residues 96, 112, 166, and 180 shown as red spheres are mapped onto the crystal structure of DR1 (PDB ID: 3S4S). DRA1 and DRB1 peptides are represented in light and dark gray ribbons, respectively. A 13 residue peptide in the peptide-binding grove is indicated by a green coil. The index variant and its proxies map to the β2 beta-sandwich domain of DRB1. (B) ADA positive status on DR1 with CD4. Same representation of the DRB1 index variant 96 and its proxies as in (A), but now including CD4, making contact with the β2 beta-sandwich domain of DRB1. Also shown are residues in DRB1 inferred from mutagenesis to interfere with CD4-mediated T-cell response from Brogdon et al. (residues, 46, 54, 55, 56, orange spheres) and Konig et al. (residues, 137–143, cyan spheres). (C) ADA maximum titer top 10% and NAb positive status on DQ1. Index non-synonymous variant at DQB1 residue 71 and its proxies at residues 66, 67, 74, and 75 are mapped onto the crystal structure of DQ1 (PDB ID: 6DIG), and represented as spheres alternating in darker and lighter red to aid visualization. DRA1 and DRB1 peptides are represented in light and dark gray ribbons, respectively. A 13 residue peptide in the peptide-binding grove is indicated by a green coil. (D) ADA maximum titer on DR1. Index non-synonymous variant at residue 13 and its proxies at residues 9 and 11 are mapped onto the crystal structure of DR1 (PDB ID: 6CQN), and represented as red spheres. DRA1 and DRB1 peptides are represented in light and dark gray ribbons, respectively. A 13 residue peptide in the peptide-binding grove is indicated by a green coil.