4-1BB Immune Checkpoint Molecule for Drug Development

Overview of 4-1BB

4-1BB, also known as CD137 or TNFRS9, belongs to the tumor necrosis factor (TNF) receptor family, including multiple T cells co-stimulatory receptors, such as CD40, CD27, GITR, HVEM, and LIGHT. 4-1BB is expressed on a wide variety of cell types, including activated T cells, natural killer (NK) cells, dendritic cells (DCs), gamma-delta T cells, B cells, monocytes, and neutrophils. Its ligand, 4-1BBL, is localized to dendritic cells. 4-1BB and 4-1BBL interactions can trigger an activation signal in all these cell types. 4-1BB plays a critical role in sustaining effective T cell immune responses and in generating immunological memory. The expression profile of 4-1BB and its unique ability to potentiate robust effector responses in multiple lymphocytes relevant for tumor immunity make 4-1BB an appealing target for immunotherapy.

A multi-potent role of 4-1BB targeted immunotherapy. Fig.1 A multi-potent role of 4-1BB targeted immunotherapy. (Bartkowiak, 2015)

Immune Checkpoint 4-1BB in Cancer Immunotherapy

Anti-4-1BB agonistic monoclonal antibody (mAb) could induce more effector molecules released from CD8+ T cells, increase proliferation and decrease the apoptosis of CD8+ T cells, which all count for the enhanced anti-tumor immunity. The antitumor capacity of 4-1BB-targeted mAb has since been replicated in a variety of tumor models, including hepatocellular carcinoma, lymphoma, and colon cancer. Blockade of 4-1BB with antagonist mAb also synergizes with other checkpoint blockades. For instance, 4-1BB and PD-1-targeting combination therapy caused tumor regression in an ovarian cancer model. The action mechanism of 4-1BB-mediated tumor regression consists of multiple immune pathways, including 1) 4-1BB agonism inducing a potent, cytotoxic T-cell population that can infiltrate and lyse tumors. 2) 4-1BB stimulation promoting the secretion of type 1 cytokines, creating an inflammatory, immunogenic cytokine milieu within the tumor microenvironment. 3) 4-1BB ligation increasing the secretion of perforin and granzyme and activation of the Fas ligand effector system by CD8+ T cells and NK cells.

Clinical Trials of Anti-4-1BB mAbs

In recent years, great progress has been made in elucidating the expression, function, and therapeutic potential of 4-1BB. The clinical trials dedicated to 4-1BB agonists portend the viability of 4-1BB as an important immunotherapeutic target. The maximal clinical efficacy of 4-1BB will emerge in combination treatment strategies, and checkpoint inhibitors are a compelling class of partner candidates.

Services at Creative Biolabs

Equipped with a team of seasoned scientists, Creative Biolabs offers fast, reliable support for any phase of our clients' drug development projects for immune checkpoint 4-1BB.

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  1. Bartkowiak, T.; Curran, M.A. 4-1BB agonists: multi-potent potentiators of tumor immunity. Frontiers in oncology. 2015, 5:117.
  2. Chester, C.; et al. 4-1BB agonism: adding the accelerator to cancer immunotherapy. Cancer Immunology, Immunotherapy. 2016, 65(10):1243-8.

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