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Correlation between antidrug antibodies, pre-existing antidrug reactivity, and immunogenetics (MHC class II alleles) in cynomolgus macaque

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Abstract

Immunogenicity of biomolecules is one of the largest concerns in biological therapeutic drug development. Adverse immune responses as a result of immunogenicity to biotherapeutics range from mild hypersensitivity reactions to potentially life-threatening anaphylactic reactions and can negatively impact human health and drug efficacy. Numerous confounding patient-, product- or treatment-related factors can influence the development of an immune reaction against therapeutic proteins. The goal of this study was to investigate the relationship between pre-existing drug reactivity (PE-ADA), individual immunogenetics (MHC class II haplotypes), and development of treatment-induced antidrug antibodies (TE-ADA) in cynomolgus macaque. PE-ADA refers to the presence of antibodies immunoreactive against the biotherapeutic in treatment-naïve individuals. We observed that PE-ADA frequency against four different bispecific antibodies in naïve cynomolgus macaque is similar to that reported in humans. Additionally, we report a trend towards an increased incidence of TE-ADA development in macaques with high PE-ADA levels. In order to explore the relationship between MHC class II alleles and risk of ADA development, we obtained full-length MHC class II sequences from 60 cynomolgus macaques in our colony. We identified a total of 248 DR, DP, and DQ alleles and 236 unique haplotypes in our cohort indicating a genetically complex set of animals potentially reflective of the human population. Based on our observations, we propose the evaluation of the magnitude/frequency of pre-existing reactivity and consideration of MHC class II genetics as additional useful tools to understand the immunogenic potential of biotherapeutics.

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Abbreviations

ADA:

Antidrug antibody

bsAb:

Bispecific antibodies

MHC:

Major histocompatibility complex

TE-ADA:

Treatment emergent ADA

PE-ADA:

Pre-existing ADA

cyno:

Cynomolgus macaque

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Acknowledgments

Authors thank Wisconsin Nonhuman Primate Research Centre Genetics Services for generating MHC class II sequencing data.

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Authors and Affiliations

  1. Department of Drug Disposition, Lilly Research Laboratories; Eli Lilly and Company; Lilly Corporate Center, Indianapolis, IN, USA

    Natalia Kovalova, Patricia L Brown-Augsburger & Lukasz K Chlewicki

  2. Indiana Biosciences Research Institute, Indiana University – Purdue University Indianapolis, Indianapolis, IN, 46202, USA

    Victor J Wroblewski

Authors
  1. Natalia Kovalova
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  2. Michael D Knierman
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  3. Patricia L Brown-Augsburger
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  4. Victor J Wroblewski
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  5. Lukasz K Chlewicki
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Correspondence to Lukasz K Chlewicki.

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All of the authors in this report are employees of Eli Lilly and Company, Indianapolis, IN. The authors do not have any conflict of interest or financial disclosure to report.

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Kovalova, N., Knierman, M.D., Brown-Augsburger, P.L. et al. Correlation between antidrug antibodies, pre-existing antidrug reactivity, and immunogenetics (MHC class II alleles) in cynomolgus macaque. Immunogenetics 71, 605–615 (2019). https://doi.org/10.1007/s00251-019-01136-7

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  • DOI: https://doi.org/10.1007/s00251-019-01136-7

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