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YH004 (4-1BB Humanized Monoclonal Antibody Injection) is a novel humanized antibody targeting the tumor necrosis factor receptor superfamily on the immune cells with a unique IgG1 subtype. YH004, as a 4-1BB agonist, can induce immune cell proliferation and cytokine expression to activate the immune response. The combination effect of YH004 antibody with Keytruda was observed in MC38/B16F10/EL4 models.

Mechanism of Action

4-1BB, also known as CD137, is a member of tumor necrosis factor (TNF) receptor family the same as OX40, and is encoded by the gene of the tumor necrosis factor receptor superfamily member 9 (TNFRSF9). Human 4-1BB is located on chromosome 1p36, 255aa long, and contains 17aa signal peptide, 169aa extracellular domain, 27aa transmembrane domain (p.187-213), and 42aa intracellular domain. Mouse 4-1BB is located at position 75.5 cM on mouse chromosome #4 and has approximately 60% sequence similarity to human 4-1BB.

4-1BB is an inducible costimulatory receptor expressed on activated CD4+ and CD8+ T cells, NKT, NK cells, DCs, macrophages, eosinophils, neutrophils and mast cells, as well as Tregs. In addition to constitutive expression of 4-1BB on APC and Foxp3+Tregs, 4-1BB expression is mostly induced on activated cells.

Many studies using 4-1BB-/-knockout mice have found that 4-1BB has an important effect on maintaining immune homeostasis and is essential for anti-tumor immune memory. At the same time, the significance of the 4-1BB pathway has also been demonstrated in CAR-T cell therapies approved for marketing by the US FDA, USA.

Preclinical trials in mice showed that the efficacy of YH004 alone and in combination was significantly better than those in the control group. Numerous preclinical and clinical data indicated a great potential for targeting 4-1BB for cancer immunotherapy, but hepatotoxicity caused by 4-1BB agonists hinders its further clinical development. In vitro functional analysis of YH004 showed comparable affinity for binding to human monkey 4-1BB, and no hepatotoxicity of YH004 was observed in an in vivo toxicology study in cynomolgus monkeys.

Clinical Study for 4-1BB

YH004 is currently in the IND preparation phase.