HLX3902: A Trispecific T‑Cell Engager Rewiring the Immune Desert in Prostate Cancer

HLX3902 is a STEAP1×CD3×CD28 trispecific T‑cell engager developed as a potential first‑in‑class immunotherapy for prostate cancer.
Prostate tumors are largely “cold” from an immunological standpoint. The microenvironment is immunosuppressive, T cells are scarce inside the tumor mass, and those that do infiltrate often burn out quickly after activation. Classical CD3‑only bispecific TCEs can force T cells to recognize tumor cells, but they provide only the initial trigger (Signal 1) through the TCR–CD3 complex, without the sustained costimulatory Signal 2 that normally comes from CD28. Without that second signal, the response is transient, and cells slip into exhaustion rather than durable memory.

HLX3902 is built to change that dynamic. It simultaneously grabs three targets: STEAP1 on the surface of prostate tumor cells, CD3 on T cells, and CD28 on the same T cells, effectively acting as a molecular bridge that brings the immune system into direct, signal‑rich contact with the tumor. STEAP1 is a strategic choice: it is highly and consistently expressed on prostate epithelial cells across disease stages, including castration‑resistant and metastatic disease, making it a stable handle for prostate‑specific targeting. By binding STEAP1 and CD3 in the same construct, HLX3902 forces the formation of immunological synapses between any available T cell and prostate tumor cells, triggering immediate cytotoxic activity against STEAP1‑positive targets.

In vitro, HLX3902 drives robust, target‑dependent tumor killing at very low T‑cell‑to‑tumor ratios, with greater T‑cell proliferation and a larger pool of memory‑like CD8 T cells than seen with bispecific CD3‑only constructs or even combinations of separate CD3 and CD28‑engaging molecules. In repeated‑challenge experiments, T cells treated with HLX3902 retain cytotoxic function over multiple rounds of antigen exposure, signaling that the integrated CD28 signal helps them resist exhaustion and maintain functional stamina. In humanized mouse models of STEAP1‑expressing prostate cancer-derived xenografts and more clinically relevant patient‑derived xenografts, HLX3902 achieves deep and sustained tumor control after a single low‑dose administration. Tumors show increased T‑cell infiltration, higher levels of activation markers, and a persistent intratumoral CD8.

An IND submission for HLX3902, to start clinical trials, is anticipated in Q1 2026.

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