World's First STEAP1×CD3×CD28 Tri-Specific Antibody HLX3902 Approved for Clinical Development in China

Prostate cancer has long earned its reputation as an "immune cold" tumor — sparsely infiltrated by T cells, poor at presenting antigens, and rich in immune-suppressing factors. For patients with metastatic castration-resistant prostate cancer, the therapeutic options remain limited, and the unmet need is stark.

Now Shanghai Henlius Biotech, Inc. is taking a swing at the problem with a first-in-class approach. On June 17, China's Center for Drug Evaluation (CDE) approved the clinical development of HLX3902 Injection, a tri-specific antibody targeting STEAP1, CD3, and CD28, for the treatment of metastatic castration-resistant prostate cancer and other advanced solid tumors.

According to the company, HLX3902 is Henlius's first tri-specific antibody to receive clinical approval — and the world's first STEAP1×CD3×CD28 tri-specific antibody to advance into clinical trials.

A New Weapon Against "Cold" Tumors

The strategy hinges on STEAP1, a protein expressed in more than 85% of prostate tumors but virtually absent in normal tissues — making it an attractive therapeutic target. T-cell engagers (TCEs) that bind both CD3 on T cells and STEAP1 on tumor cells can redirect the immune system to attack cancer. But existing TCEs rely primarily on CD3-mediated primary activation signals, and in the harsh microenvironment of solid tumors, T cells lacking co-stimulatory signals tend to exhaust quickly, limiting durable anti-tumor effects.

HLX3902 adds a second signal to the mix. By simultaneously activating CD3 (the primary activation signal) and CD28 (the co-stimulatory signal), the tri-specific antibody aims to enhance T-cell activation, proliferation, and survival — even in environments with low T-cell infiltration.

Preclinical Promise

Preclinical data suggest the approach has teeth. HLX3902 induced target-dependent T-cell activation and cytotoxicity, outperforming conventional CD3 bispecific TCEs at low effector-to-target cell ratios. In repeated antigen stimulation models, the CD28 co-stimulatory signal enhanced T-cell activation, proliferation, and memory T-cell expansion, sustaining killing activity over time.

In vivo studies using C4-2/hPBMC and abiraterone-resistant PDX/hPBMC models showed significantly enhanced anti-tumor activity, accompanied by increased T-cell infiltration and improved function. Cynomolgus monkey studies demonstrated good tolerability and a manageable safety profile.

Going Global

HLX3902 had already received clinical trial authorization in Australia prior to the China approval. Henlius plans to conduct clinical research simultaneously in both countries, evaluating the safety, tolerability, and efficacy of the tri-specific antibody in patients with prostate cancer and other advanced solid tumors.

For a disease that has long resisted immunotherapy, the dual-signal approach offers a new angle of attack. Whether it can break through prostate cancer's immune defenses in patients remains to be seen — but the first shot has been fired.