Tina Zhang1, Daniel X. He1, Cunxiang Ju2, Mingkun Zhang2, Jessie JJ. Wang1, Likun Zhang1, Annie An1, Henry Q.X. Li1
1Crown Bioscience Inc., 16550 West Bernardo Drive, Building 5, Suite 525, San Diego, CA 92127; 2GemPharmatech Inc., 12 Xuefu Road, Nanjing, 210089 China
Immune checkpoint inhibitors, including anti-PD-1 and anti-CTLA-4 monoclonal antibodies, have led to impressive clinical outcomes in treating certain cancers. However, the overall success rate of immunotherapeutic drugs remains low, due to poor efficacy (cancer immunotherapeutic effect [CITE]) or unexpected safety risks such as immune-related adverse events (irAEs), underlining the importance of predictive preclinical animal models.
Notably, most immunotherapies cannot be modeled in xenograft tumor models, due to their immunodeficient phenotype, or syngeneic models, as most biologics are usually species-specific. Given these limitations, genetically engineered humanized mouse models (HuGEMM) and syngeneic cell lines (HuCell™), where human drug target gene(s) replace the original mouse ortholog(s), have been broadly used to assess species-restricted biologics for CITE. Since most irAEs in biologics are on-target toxicities, it is potentially possible to model the irAEs of biologics using non-tumor bearing HuGEMM. In this study, the PD-1/CTLA-4 double knock-in (dKI) HuGEMM is used as an example to provide more insights into irAE evaluation in preclinical models.
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