Single nucleotide polymorphisms in the FcγR3A and TAP1 genes impact ADCC in cynomolgus monkey PBMCs.
Phenotypic variability is often observed in cynomolgus monkeys on preclinical studies and may, in part, be driven by genetic variability. However, the role of monkey genetic variation remains largely unexplored in the context of drug response. This study evaluated genetic variation in cynomolgus monkey FcγR3A and TAP1 genes and the potential impact of identified polymorphisms on antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro. Studies in humans have demonstrated that a single nucleotide polymorphism (SNP), F158V, in FcγR3A can influence response to rituximab through altered ADCC and that SNPs in TAP1/2 decrease natural killer (NK) cell activity against major histocompatibility complex (MHC) class I deficient cells, potentially through altered ADCC. Monkeys were genotyped for FcγR3A and TAP1 SNPs, and ADCC was assessed in vitro using peripheral blood mononuclear cells (PBMCs) treated with trastuzumab in the presence of NCI-N87 cells. FcγR3A g.1134A>C (exonic S42R), FcγR3A g.5027A>G (intronic), and TAP1 g.1A>G (start codon loss) SNPs were all significantly associated with decreased ADCC for at least one trastuzumab concentration ≥0.0001 μM when compared with wild type (WT). Regression analysis demonstrated significant association of the SNP-SNP pairs FcγR3A g.1134A>C/TAP1 g.1A>G and FcγR3A g.5027A>G/TAP1 g.1A>G with a combinatorial decrease on ADCC. Mechanisms underlying the decreased ADCC were investigated by measuring FcγR3A/IgG binding affinity and expression of FcγR3A and TAP1 in PBMCs; however, no functional associations were observed. These data demonstrate that genetic variation in cynomolgus monkeys is reflective of known human genetic variation and may potentially contribute to variable drug response in preclinical studies.
Drug Safety Research and Development, Pfizer, Inc., Groton, CT, USA.
Jonathan C
JC
Sanford
Drug Safety Research and Development, Pfizer, Inc., Groton, CT, USA.
Hong
H
Wu
Rinat-ORD-Pfizer, Inc., San Francisco, CA, USA.
Yasmina
Y
Abdiche
Drug Safety Research and Development, Pfizer, Inc., Groton, CT, USA.
Julie A
JA
Harney
Rinat-ORD-Pfizer, Inc., San Francisco, CA, USA.
Javier
J
Chaparro-Riggers
Drug Safety Research and Development, Pfizer, Inc., Groton, CT, USA. karissa.adkins@pfizer.com.
Karissa
K
Adkins
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2 / Q000235:genetics*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism; D000920:Antibody-Dependent Cell Cytotoxicity / Q000235:genetics*; D005838:Genotype; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008252:Macaca fascicularis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017452:Receptors, IgG / Q000235:genetics*
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000911:Antibodies, Monoclonal; D015395:Histocompatibility Antigens Class I; D017452:Receptors, IgG
ADCC; Cynomolgus monkey; FcγR3A; TAP1