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

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.