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.
CD40 (cluster of differentiation 40) is a tumor necrosis factor receptor superfamily member expressed on APC such as dendritic cells (DC), B cells, and monocytes as well as many non-immune cells and a wide range of tumors. Interaction with its trimeric ligand CD154 on activated T helper cells results in APC activation, which has been found to be essential in mediating a broad variety of immune and inflammatory responses including T cell-dependent immunoglobulin class switching, memory B cell development, and germinal center formation. Agonistic CD40 mAb have been shown to activate APC and promote anti-tumor T cell responses and to foster cytotoxic myeloid cells with the potential to control cancer in the absence of T-cell immunity. Thus, agonistic CD40 mAb may serves as a new antitumor drugs which are fundamentally different from mAb which block negative immune checkpoint such as anti-CTLA-4 or anti-PD-1.
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Targeting Strategy
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Gene targeting strategy for B-hPD-1/hCD40 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/hCD40 mice. The exons 2-7 of mouse Cd40 gene that encode the extracellular domain were replaced by human CD40 exons 2-7 in B-hPD-1/hCD40 mice. The B-hPD-1/hCD40 two knock-in model, was developed by breeding the B-hPD-1 mice and the B-hCD40 mice, has a functional mouse immune system.
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Details
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Phenotype
Protein Expression Analysis
Strain specific CD40 and PD-1 expression analysis in homozygous B-hPD-1/hCD40 mice by flow cytometry. Splenocytes were collected from WT and homozygous B-hPD-1/hCD40 (H/H) mice analyzed by flow cytometry with species-specific anti-PD-1 antibody and anti-CD40 antibody. Mouse CD40 and PD-1 were detected in WT. Human CD40 and PD-1 were exclusively detected in H/H B-hPD-1/hCD40 but not WT mice.
Strain specific CD40 and PD-1 expression analysis in homozygous B-hPD-1/hCD40 mice by flow cytometry. Splenocytes were collected from WT and homozygous B-hPD-1/hCD40 (H/H) mice stimulated with anti-CD3ε in vivo (7.5 μg/mice), and analyzed by flow cytometry with species-specific anti-PD-1 antibody. Mouse CD40 and PD-1 were detected in WT. Human CD40 and PD-1 were exclusively detected in H/H B-hPD-1/hCD40 but not WT mice.Combination therapy of PD-1 mAb (keytruda) and CD40 mAb
Antitumor activity of anti-hCD40 antibody Selicrelumab (in house) combined with anti-hPD-1 antibody keytruda in B-hPD-1/hCD40 mice. (A) Anti-hCD40 antibody Selicrelumab (in house) combined with anti-hPD-1 antibodies keytruda inhibited MC38-hPD-L1 tumor growth in B-hPD-1/hCD40 mice. Murine colon cancer MC38-hPD-L1 cells (5×105) were subcutaneously implanted into homozygous B-hPD-1/hCD40 mice (female, 6 week-old, n=8). Mice were grouped when tumor volume reached approximately 100-150 mm3, at which time they were treated with antibody Selicrelumab (in house) combined with anti-hPD-1 antibody keytruda with doses and schedules indicated in panel (B) Body weight changes during treatment. As shown in panel A, combination of anti-hCD40 and anti-hPD-1 antibody shows more inhibitory effects than individual groups, demonstrating that the B-hPD-1/hCD40 mice provide a powerful preclinical model for in vivo evaluating combination therapy efficacy of hCD40 antibodies and hPD-1 antibodies .Values are expressed as mean ± SEM.
Combination therapy of PD-1 mAb (keytruda) and CD40 mAb
Antitumor activity of anti-hCD40 antibody Selicrelumab (in house) combined with anti-hPD-1 antibody keytruda in B-hPD-1/hCD40 mice. (A) Anti-hCD40 antibody Selicrelumab (in house) combined with anti-hPD-1 antibodies keytruda inhibited MC38 tumor growth in B-hPD-1/hCD40 mice. Murine colon cancer MC38 cells (5×105) were subcutaneously implanted into homozygous B-hPD-1/hCD40 mice (female, 4 week-old, n=8). Mice were grouped when tumor volume reached approximately 100-150 mm3, at which time they were treated with antibody Selicrelumab (in house) combined with anti-hPD-1 antibody keytruda with doses and schedules indicated in panel (B) Body weight changes during treatment. As shown in panel A, combination of anti-hCD40 and anti-hPD-1 antibody shows more inhibitory effects than individual groups, demonstrating that the B-hPD-1/hCD40 mice provide a powerful preclinical model for in vivo evaluating combination therapy efficacy of hCD40 antibodies and hPD-1 antibodies . Values are expressed as mean ± SEM.
Combination therapy of PD-1 mAb (keytruda) and CD40 mAb
Antitumor activity of anti-hCD40 antibody Selicrelumab (in house) combined with anti-hPD-1 antibody keytruda in B-hPD-1/hCD40 mice. (A) Anti-hCD40 antibody Selicrelumab (in house) combined with anti-hPD-1 antibodies keytruda inhibited B16F10-hPD-L1 tumor growth in B-hPD-1/hCD40 mice. Murine colon cancer B16F10-hPD-L1 cells (5×105) were subcutaneously implanted into homozygous B-hPD-1/hCD40 mice (female, 8 week-old, n=8). Mice were grouped when tumor volume reached approximately 100-150 mm3, at which time they were treated with antibody Selicrelumab (in house) combined with anti-hPD-1 antibody keytruda with doses and schedules indicated in panel (B) Body weight changes during treatment. As shown in panel A, combination of anti-hCD40 and anti-hPD-1 antibody shows more inhibitory effects than individual groups, demonstrating that the B-hPD-1/hCD40 mice provide a powerful preclinical model for in vivo evaluating combination therapy efficacy of hCD40 antibodies and hPD-1 antibodies . Values are expressed as mean ± SEM.
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References
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- Nat Commun.2017 Feb 6; 8 :14369. doi: 10.1038/ncomms14369.
- EMBO J.1992 Nov;11(11):3887-95.
- Sci. Transl. Med. 10, eaan4488 (2018) doi: 10.1126/scitranslmed. aan4488
Strain specific CD40 and PD-1 expression analysis in homozygous B-hPD-1/hCD40 mice by flow cytometry. Splenocytes were collected from WT and homozygous B-hPD-1/hCD40 (H/H) mice analyzed by flow cytometry with species-specific anti-PD-1 antibody and anti-CD40 antibody. Mouse CD40 and PD-1 were detected in WT. Human CD40 and PD-1 were exclusively detected in H/H B-hPD-1/hCD40 but not WT mice.
Strain specific CD40 and PD-1 expression analysis in homozygous B-hPD-1/hCD40 mice by flow cytometry. Splenocytes were collected from WT and homozygous B-hPD-1/hCD40 (H/H) mice stimulated with anti-CD3ε in vivo (7.5 μg/mice), and analyzed by flow cytometry with species-specific anti-PD-1 antibody. Mouse CD40 and PD-1 were detected in WT. Human CD40 and PD-1 were exclusively detected in H/H B-hPD-1/hCD40 but not WT mice.
