Basic Information
Description
PD-1 (Programmed death-1) is mainly expressed on the surface of T cells and primary B cells. The two PD-1 ligands, PD-L1 and PD-L2, are widely expressed on antigen-presenting cells (APCs). PD-1 interacts with its ligands and plays an important role in the negative regulation of the immune response. PD-L1 protein expression is detected in many human tumor tissues. PD-L1 expression in tumor cells could be induced by the microenvironment of tumor cells. PD-L1 expression is favorable for tumorigenesis and growth, for induction of anti-tumor T Cell Apoptosis, and for escaping responses by the immune system. Inhibition of PD-1 binding to its ligand can result in tumor cells that are exposed to the killing version of the immune system, and thus is a target for cancer treatments. 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.
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Targeting strategy
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Gene targeting strategy for B-hPD-1/hPD-L1/hTIGIT mice. The exon 2 of mouse PD-1 gene that encodes the extracellular domain was replaced by human PD-1 exon 2 in B-hPD-1/hPD-L1/hTIGIT mice. The exon 3 of mouse pdl1 gene that encode the extracellular domain was replaced by human PD-L1 exon 3 in B-hPD-1/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-1/hPD-L1/hTIGIT mice.
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Details
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Protein expression analysis
Strain specific PD-1, PD-L1 and TIGIT expression analysis in homozygous B-hPD-1/hPD-L1/hTIGIT mice by flow cytometry. Splenocytes were collected from WT and homozygous B-hPD-1/hPD-L1/hTIGIT (H/H) mice analyzed by flow cytometry with species-specific anti-PD-1 antibody. Mouse PD-1, PD-L1 and TIGIT were detectable in WT mice. Human PD-1, PD-L1 and TIGIT were exclusively detectable in homozygous B-hPD-1/hPD-L1/hTIGIT but not WT mice.
Strain specific PD-1, PD-L1 and TIGIT expression analysis in homozygous B-hPD-1/hPD-L1/hTIGIT mice by flow cytometry. Splenocytes were collected from WT and homozygous B-hPD-1/hPD-L1/hTIGIT (H/H) mice after stimulation with anti-CD3ε in vivo (7.5 μg/mice), and without stimulation, and analyzed by flow cytometry with species-specific anti-PD-1 antibody. Mouse PD-1, PD-L1 and TIGIT were detectable in WT mice. Human PD-1, PD-L1 and TIGIT were exclusively detectable in homozygous B-hPD-1/hPD-L1/hTIGIT but not WT mice. After anti-CD3ε stimulation, hPD-1 protein expression was significantly increased.
Combination therapy of anti-human PD-1 and anti-human TIGIT Ab, anti-human PD-L1 and anti-human TIGIT Ab.
Antitumor activity of of anti-human anti-human PD-L1 Atezolizumab (in house) combined with anti-human Triagolizumab(in house) in B-hPD-1/hPD-L1/hTIGIT mice. (A) anti-human PD-L1 Atezolizumab (in house) combined with anti-human Triagolizumab(in house) inhibited MC38-hPD-L1 tumor growth in B-hPD-1/hPD-L1/hTIGIT mice. Murine colon cancer MC38-hPD-L1 cells (5×105) were subcutaneously implanted into homozygous B-hPD-1/hPD-L1/hTIGIT mice(female, 9 week-old, n=5). Mice were grouped when tumor volume reached approximately 100-150 mm3, at which time they were treated anti-human PD-L1 Atezolizumab (in house) combined with anti-human Triagolizumab(in house) with doses and schedules indicated in panel . (B) Body weight changes durin g treatment. As shown in panel A, combination of anti-hPD-L1 and anti-hTIGIT antibody shows more inhibitory effects than individual groups, demonstrating that the B-hPD-1/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.
