PD-L1 (Programmed cell death ligand-1), also known as B7-H1 and CD274, is mainly expressed in antigen-presenting cells (APCs) and activated T cells, and is one of the two ligands of PD-1. The interaction between PD1 and PD-L1 plays an important role in the negative regulation of the immune response. PD-L1 is highly expressed in a variety of solid tumors. PD-1 and PD-L1 interactions can reduce T Cell Activation and promote tumor immune escape. The PD-1/PD-L1 signaling pathway can be blocked and antitumor immune response can be restored by using by anti-PD-1 or anti-PD-L1 antibodies to block the binding of PD1 to PD-L1. TIGIT (T-cell immunoreceptor with Ig and ITIM domains), a member of the immunoglobulin family of PVR (poliovirus receptor), is a type I transmembrane protein. Similar to PD-1, TIM3, and LAG3, TIGIT is highly expressed in cancer tissues and competitively binds to TIGIT receptors with DNAM-1 proteins on the surface of NK cells to reduce the NK cell killing efficiency of cancer cells. Therefore, anti-TIGIT antibody can enhance NK cell ability to destroy tumor cells by facilitating DNAM-1 binding to TIGIT receptors. It has become the new generation of cancer immunotherapy checkpoint.
Gene targeting strategy of B-hPD-L1/hTIGIT mice. The exon 3 of mouse Pd-l1 gene that encodes the extracellular domain was replaced by human PD-L1 exon 3 in B-hPD-L1/hTIGIT mice. The exon 2 of mouse Tigit gene that encodes the extracellular domain was replaced by human TIGIT exon 2 in B-hPD-L1/hTIGIT mice.
Protein Expression Analysis
Splenocytes from B-hPD-L1/hTIGIT mice were analyzed by flow cytometry. mTIGIT+ cells were detectable in C57BL/6 mice, while hTIGIT+ cells were detectable in the homozygous B-hPD-L1/hTIGIT mice.
Splenocytes from B-hPD-L1/hTIGIT mice were analyzed by flow cytometry. mPD-L1+ cells were detectable in C57BL/6 mice, while hPD-L1+ cells were detectable in the homozygous B-hPD-L1/hTIGIT mice.
Combination therapy of hTIGIT Ab and PD-L1 Ab
Antitumor activity of anti-hTIGIT antibody combined with anti-hPD-L1 antibody in B-hPD-L1/hTIGIT mice. (A) Anti-hTIGIT antibody combined with anti-hPD-L1 antibody inhibited MC38-hPD-L1 tumor growth in B-hPD-L1/hTIGIT mice. Murine colon cancer MC38-hPD-L1 cells (5×105) were subcutaneously implanted into homozygous B-hPD-L1/hTIGIT mice (female, 5-8 week-old, n=7). Mice were grouped when tumor volume reached approximately 150±50 mm3, at which time they were treated with anti-hTIGIT antibody combined with anti-hPD-L1 antibody and schedules indicated in panel (B) Body weight changes during treatment. As shown in panel A, combination of anti-hTIGIT and anti-hPD-L1 antibody shows more inhibitory effects than individual groups, demonstrating that the B-hPD-L1/hTIGIT mice provide a powerful preclinical model for in vivo evaluating combination therapy efficacy of hTIGIT antibodies and hPD-L1 antibodies . Values are expressed as mean ± SEM.
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