Tumor necrosis factor receptor superfamily member 9 (4-1BB) and Receptor tyrosine-protein kinase erbB-2 (HER2) complex (4-1BB/HER2)

The 4-1BB–HER2 interface is a therapeutic target concept involving the simultaneous engagement of the costimulatory receptor 4-1BB (CD137) and the tumor-associated antigen HER2 (ERBB2). 4-1BB is a member of the tumor necrosis factor receptor superfamily (TNFRSF) expressed on activated T cells and natural killer (NK) cells, where its activation promotes survival, expansion, and effector function (UniProt P41273). HER2 is a receptor tyrosine kinase frequently overexpressed in cancers such as breast, gastric, and esophageal, driving tumor growth and progression (UniProt P04626). Drugs targeting this interface, such as the bispecific fusion protein cinrebafusp alfa (PRS-343), are designed to use HER2-expressing tumor cells as a scaffold to cluster 4-1BB receptors on adjacent immune cells (Hinner et al., 2019, Clinical Cancer Research). This mechanism provides conditional agonism, ensuring that 4-1BB-mediated immune activation occurs primarily within the tumor microenvironment, thereby reducing the risk of systemic toxicities like hepatotoxicity that have hindered the development of monospecific 4-1BB agonists (Pieris Pharmaceuticals, 2021). By bridging the immune system and the tumor, this target interface aims to enhance the anti-tumor activity of T cells specifically where they are needed most.

Other names

CD137/HER2TNFRSF9/ERBB2HER2-targeted 4-1BB agonist4-1BB–HER2 interface

Conditional 4-1BB agonism mediated by HER2-dependent clustering