Cynomolgus Monkey PBMCs (NHP-PC001)

The research focuses on the genetic variation in cynomolgus monkeys, particularly in the FcγR3A and TAP1 genes, and its impact on antibody-dependent cell-mediated cytotoxicity (ADCC). The study evaluated the influence of specific single nucleotide polymorphisms (SNPs) in these genes on ADCC, using peripheral blood mononuclear cells (PBMCs) treated with trastuzumab in the presence of NCI-N87 cells. It was found that SNPs such as FcγR3A g.1134A>C (exonic S42R), FcγR3A g.5027A>G (intronic), and TAP1 g.1A>G (start codon loss) were significantly associated with decreased ADCC at certain trastuzumab concentrations when compared to the wild type. Furthermore, regression analysis showed a significant association of SNP-SNP pairs FcγR3A g.1134A>C/TAP1 g.1A>G and FcγR3A g.5027A>G/TAP1 g.1A>G with decreased ADCC.

The significance of this research lies in demonstrating that genetic variation in cynomolgus monkeys reflects known human genetic variation. This finding is crucial for drug response studies in preclinical trials, as it indicates that these monkeys can be effective models for understanding human responses to drugs. This similarity in genetic variability between cynomolgus monkeys and humans could contribute to variability in drug response observed in preclinical studies. Furthermore, identifying functional SNPs in cynomolgus monkeys can enhance the translation of drug response data from these monkeys to humans, potentially improving the predictability and effectiveness of clinical trials.

Fig. 1 In vitro ADCC measured in cynomolgus monkey PBMCs between FcγR3A and TAP1 WT and variant carriers. a FcγR3A g.1134A (42S) compared with g.1134C (42R) animals. b FcγR3A g.5027A compared with g.5027 G animals. c TAP1 g.1A compared with g.1G. d TAP1 g.29C compared with g.29G. Statistically significant differences are indicated by asterisk (p < 0.05). Error bars represent standard deviation.

Fig. 2 In vitro ADCC measured in cynomolgus monkey PBMCs between TAP1 WT, heterozygote, and homozygote variant carriers. a TAP1 disruption allele carrier status. Here, homozygotes are defined as either homozygotes for TAP1 g.1G or TAP1 g.29C or as coheterozygotes. Heterozygotes for a single variant are considered heterozygote, and those with no variants are WT. b TAP1 g.1A>G carrier status. Asterisk indicates significant difference between WT and homozygote carriers at 0–0.001 μM trastuzumab (Tukey’s pairwise comparison, p < 0.05). c TAP1 g.29C>G carrier status. Error bars represent standard deviation

Reference

1. Jonathan C. Sanford., et al. "Single nucleotide polymorphisms in the FcγR3A and TAP1 genes impact ADCC in cynomolgus monkey PBMCs" Immunogenetics.(2017)