PMID- 35263013
OWN - NLM
STAT- MEDLINE
DCOM- 20220617
LR  - 20220913
IS  - 1752-8062 (Electronic)
IS  - 1752-8054 (Print)
IS  - 1752-8054 (Linking)
VI  - 15
IP  - 6
DP  - 2022 Jun
TI  - Allelic variation in HLA-DRB1 is associated with development of antidrug 
      antibodies in cancer patients treated with atezolizumab that are neutralizing in 
      vitro.
PG  - 1393-1399
LID - 10.1111/cts.13264 [doi]
AB  - The treatment of diseases with biologic agents can result in the formation of 
      antidrug antibodies (ADA). Although drivers for ADA formation are unknown, a role 
      for antigen presentation is likely, and variation in human leukocyte antigen 
      (HLA) genes has been shown to be associated with occurrence of ADA for several 
      biologics. Here, we performed an HLA-wide association study in 1982 patients 
      treated with the anti-PD-L1 antibody atezolizumab across eight clinical trials. 
      On average, 29.8% of patients were ADA-positive (N = 591, range of 13.5%-38.4% 
      per study) and 14.6% of patients were positive for ADA that were neutralizing in 
      vitro (neutralizing antibodies [NAb], N = 278, range of 6.4%-21.9% per study). In 
      a meta-analysis of logistic regression coefficients, we found statistically 
      significant associations between HLA class II alleles and ADA status. The 
      top-associated alleles were HLA-DRB1*01:01 in a comparison of ADA-positive versus 
      ADA-negative patients (p = 3.4 x 10(-5) , odds ratio [OR] 1.96, 95% confidence 
      interval [95% CI] 1.64-2.28) and HLA-DQA1*01:01 when comparing NAb-positive with 
      ADA-negative patients (p = 2.8 x 10(-7) , OR 2.31, 95% CI 1.98-2.66). Both 
      alleles occur together on a common HLA haplotype, and analyses considering only 
      NAb-negative, ADA-positive patients did not yield significant results, suggesting 
      that the genetic association is mainly driven by NAb status. In conclusion, our 
      study showed that HLA class II genotype is associated with the risk of developing 
      ADA, and specifically NAb, in patients treated with atezolizumab, but the effect 
      estimates suggest that immunogenetic factors are not sufficient as clinically 
      meaningful predictors.
CI  - (c) 2022 Genentech Inc. Clinical and Translational Science published by Wiley 
      Periodicals LLC on behalf of American Society for Clinical Pharmacology and 
      Therapeutics.
FAU - Hammer, Christian
AU  - Hammer C
AUID- ORCID: 0000-0003-4548-7548
AD  - Genentech, Inc., South San Francisco, California, USA.
FAU - Ruppel, Jane
AU  - Ruppel J
AD  - Genentech, Inc., South San Francisco, California, USA.
FAU - Kamen, Lynn
AU  - Kamen L
AD  - Genentech, Inc., South San Francisco, California, USA.
FAU - Hunkapiller, Julie
AU  - Hunkapiller J
AD  - Genentech, Inc., South San Francisco, California, USA.
FAU - Mellman, Ira
AU  - Mellman I
AD  - Genentech, Inc., South San Francisco, California, USA.
FAU - Quarmby, Valerie
AU  - Quarmby V
AD  - Genentech, Inc., South San Francisco, California, USA.
LA  - eng
PT  - Journal Article
PT  - Meta-Analysis
PT  - Research Support, Non-U.S. Gov't
DEP - 20220408
PL  - United States
TA  - Clin Transl Sci
JT  - Clinical and translational science
JID - 101474067
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Antibodies, Neutralizing)
RN  - 0 (HLA-DRB1 Chains)
RN  - 52CMI0WC3Y (atezolizumab)
SB  - IM
MH  - Alleles
MH  - *Antibodies, Monoclonal, Humanized/therapeutic use
MH  - *Antibodies, Neutralizing/immunology
MH  - *HLA-DRB1 Chains/genetics
MH  - Humans
MH  - *Neoplasms/drug therapy/genetics
PMC - PMC9199883
COIS- C.H., J.H., L.K., I.M., and V.Q. are employees of Genentech, Inc./Roche and Roche 
      stockholders. J.R. is a former employee of Roche and a Roche stockholder.
EDAT- 2022/03/10 06:00
MHDA- 2022/06/18 06:00
PMCR- 2022/06/01
CRDT- 2022/03/09 12:35
PHST- 2022/02/14 00:00 [revised]
PHST- 2021/07/13 00:00 [received]
PHST- 2022/02/18 00:00 [accepted]
PHST- 2022/03/10 06:00 [pubmed]
PHST- 2022/06/18 06:00 [medline]
PHST- 2022/03/09 12:35 [entrez]
PHST- 2022/06/01 00:00 [pmc-release]
AID - CTS13264 [pii]
AID - 10.1111/cts.13264 [doi]
PST - ppublish
SO  - Clin Transl Sci. 2022 Jun;15(6):1393-1399. doi: 10.1111/cts.13264. Epub 2022 Apr 
      8.