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

Autor: Chasman DI; Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA. dchasman@research.bwh.harvard.edu.; Harvard Medical School, Boston, MA, USA. dchasman@research.bwh.harvard.edu., Hyde CL; Pfizer Inc., 1 Portland Street, Cambridge, MA, USA., Giulianini F; Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA., Danning RD; Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA., Wang EQ; Pfizer Inc., New York, NY, USA., Hickling T; Pfizer Inc., 1 Portland Street, Cambridge, MA, USA., Ridker PM; Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.; Harvard Medical School, Boston, MA, USA., Loomis AK; Pfizer Inc., 1 Portland Street, Cambridge, MA, USA.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2022 Mar 11; Vol. 12 (1), pp. 4266. Date of Electronic Publication: 2022 Mar 11.
DOI: 10.1038/s41598-022-07997-5
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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