Targeting checkpoints using monoclonal antibodies have demonstrated promising advantages in oncology compared to conventional chemotherapy or radiotherapy. According to recent studies, many researchers believe that tumor necrosis factor receptor type II (TNFR2) exhibits potency in cancer treatment. TNFR2 has restricted expression in the immune system and human tumors. Thus, the antagonistic TNFR2 antibody serves as a preferred alternative with better safety and selectivity to inhibit tumor immune evasion than other immune checkpoints (e.g. anti-PD-1, anti-PD-L1, and anti-CTLA-4) antibodies. Creative Biolabs has successfully established an optimized Magic™ “humanized” animal platform for our global clients to advance their novel drug development.
Immune checkpoints play a crucial role in maintaining the homeostasis in the body. The immune system relies on immune checkpoints to recognized the autologous and non-autologous cells. Autologous cells are protected from immune attack through the ligation of immune checkpoints, preventing the occurrence of autoimmune diseases. However, depending on this mechanism, the tumor cells could escape immune surveillance and then immune evasion happens. Thus, targeting the immune checkpoints has the potential to eliminate the immunosuppression.
TNFR2, also known as p75 or TNFRSF1B, is a member of the TNF receptor superfamily and expressed on tumor-infiltrating immunosuppressive CD4+FoxP3+ regulatory T cells (Tregs) and many types of human tumor cells, such as renal cell carcinoma, colon cancer, Hodgkin's lymphoma, multiple myeloma, cutaneous non-Hodgkin's lymphoma, and ovarian cancer cells. TNFR2 not only promotes cancer cell survival and tumor growth, but stimulates the activation and proliferation of Tregs as well. The limited expression of TNFR2 on Tregs makes it an ideal drug target in immunotherapy of tumor as systematic toxicity from an antibody-based therapy is less likely to occur.
TNFR2 signaling, induced by TNF, could augment cell proliferation and survival through the mobilization and nuclear entry of the transcription factor nuclear factor-κB (NF-κB). Recent studies found that blocking TNFR2 signaling through TNFR2 antagonistic antibodies resulted in: 1. inhibiting the activation of tumor-infiltrating Tregs which have high expression level of TNFR2 and thus eliminating the immunosuppression induced by Tregs; 2. promoting proliferation of tumor-reactive T effector cells (Teffs) and thus enhancing the immune response against tumor cells; 3. directly killing tumor cells which have abundant surface TNFR2 and inhibiting the growth and metastasis of tumor cells.
Fig.1 TNF signaling through TNFR1 and TNFR2 in cells. (Faustman, 2010)
Fig.2 TNFR2 signaling in the tumor environment (A) and Blockade of TNF-TNFR2 pathway. (Chen, 2010)
Immune checkpoint blockade has been investigated in clinical trials and showed great potential in various human cancer. Recently, antagonistic antibodies against human TNFR2 become potential therapeutics for cancer patients. With advanced technology, Creative Biolabs provides the TNFR2 immune checkpoint knock-in mice and related analysis services for clients from all over the world. Our professional R&D team will work closely with you to promote your project implementation. Please feel free to contact us for further discussions.
Creative Biolabs also offers other various Humanized Mouse Models you may be interested in:
References
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