AACR 2021: A novel humanized B-hPD-1/hPD-L1/hTIGIT mouse model reveals enhanced efficacy of combined TIGIT and PD-L1 blockade against cancer

AACR 2021: A novel humanized B-hPD-1/hPD-L1/hTIGIT mouse model reveals enhanced efficacy of combined TIGIT and PD-L1 blockade against cancer

Author: Chonghui Liu, Xiaofei Zhou, Yanan Guo, Eugene Lin, Yuelei Shen

Immune checkpoint blockade targeting PD-1/PD-L1 has enjoyed tremendous success in the clinic against various advanced stage cancers, unleashing potent and durable immune-mediated control of tumors while vastly improving patient survival. However, only a portion of patients truly benefit, while other cancers, such as breast, prostate, pancreatic, and colon cancers, are largely resistant to PD-1/PD-L1 therapy alone. Targeting additional immunosuppressive proteins could boost the efficacy of anti-PD-1/PD-L1 therapy and bring the benefits of immunotherapy to more patients. TIGIT is a recently identified immune checkpoint protein mainly expressed by T and NK cells. CD155 (PVR) is a high-affinity receptor of TIGIT, while CD112 and CD113 bind it with weaker affinity. CD155 and CD112 can engage CD226, an NK activating receptor also expressed on some CD8+ T cells, and trigger killing of tumors. Competitive binding of TIGIT to CD155 and CD112 would prevent signaling through CD226. Therefore, anti-TIGIT blocking antibodies may enhance the function of NK cells and T cells. Preclinical studies have shown that inhibition of TIGIT promotes proliferation and function of T cells. Combined blockade of both TIGIT and PD1/PD-L1 has also shown superior efficacy over monotherapy against tumors in early phase clinical trials.

Given the intensive interest in combined TIGIT and PD-1/PD-L1 therapies for cancer, Biocytogen has established a novel human PD-1/PD-L1/TIGIT triple knock-in (TKI) mouse as a vital tool to pre-clinically evaluate the in vivo efficacy of combined human TIGIT and PD1/PD-L1 blocking agents against tumors compared to either alone. Exon 2 of the mouse PD-1 gene, exon 3 of mouse PD-L1, and exon 2 of mouse TIGIT were replaced by their human homologs in B-hPD-1/hPD-L1/hTIGIT mice. Human PD-1, PD-L1, and TIGIT proteins were expressed in homozygous B-hPD-1/hPD-L1/hTIGIT but not wildtype mice. Immune profiles of B-hPD-1/hPD-L1/hTIGIT mice were similar to those in wild-type C57BL/6 mice, and abnormalities were not observed. Importantly, we showed that combining anti-human PD-L1 and anti-human TIGIT antibodies significantly inhibited the growth of MC38-hPD-L1 tumor cells implanted into B-hPD-1/hPD-L1/hTIGIT mice. Thus, our novel hPD-1/hPD-L1/hTIGIT TKI mice will be very useful for investigating the in vivo efficacy of TIGIT antibodies currently in company pipelines both alone and combined with PD1/PD-L1 antibody drugs.


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