As the "low-hanging fruit" in drug discovery becomes increasingly scarce, pharmaceutical companies are shifting their focus toward novel targets. At this year's AACR Annual Meeting, AstraZeneca unveiled preclinical data for AZD0516, a drug candidate targeting Six-Transmembrane Epithelial Antigen of the Prostate 2 (STEAP2). The announcement has once again brought the STEAP target into the spotlight.

STEAP Target: Bridging Tumor and Chronic Disease

STEAP refers to a family of six-transmembrane proteins, comprising four subtypes: STEAP1 to STEAP4. First identified in prostate cancer cells, this target involved in critical biological processes such as ion transport (e.g., iron and copper), intercellular communication, and redox reactions. It plays important roles in tumorigenesis, metabolic regulation, and inflammatory responses.

Under typical circumstances, STEAP1 is associated with tumor proliferation, metastasis, and immune evasion. It is highly expressed in prostate, bladder, and pancreatic cancers, making it the most extensively studied subtype to date. STEAP2 and STEAP3 are linked to androgen signaling pathways and are expressed in neuroendocrine tumors and certain solid tumors. STEAP4, on the other hand, is primarily involved in metabolic diseases such as obesity and diabetes, where it contributes to insulin resistance and inflammatory responses.

The broad mechanism of action and highly specific expression patterns of the STEAP family make it an ideal group of biomarkers and therapeutic targets.

STEAP R&D Development: TCEs, ADCs, and CAR-T Moving in Parallel

According to incomplete statistics, fewer than ten STEAP targeted drugs are currently in clinical stage worldwide. Among them, AMG509 (Xaluritamig), co-developed by Amgen and Baekje, is the most advanced in terms of clinical progress.

AMG509 is a bispecific T-cell engager (TCE) that targets both STEAP1 and CD3. Structurally, Amgen employs Xencor's Xmab?2+1 asymmetric technology, which consists of two identical humanized anti-STEAP1 Fab structural domain and one anti-CD3 scFv structural domain, with the latter linked to the former in coupling. The Fc structural domain is engineered to eliminate Fc effector function to enhance safety, while simultaneously increasing FcRn binding affinity to prolong half-life.

In preclinical models, AMG509 demonstrated significant activity in reducing prostate-specific antigen (PSA) levels. At the 2024 AACR Annual Meeting, Amgen presented Phase I clinical data on AMG 509 in patients with metastatic prostate cancer, reporting a PSA50 (≥50% reduction in prostate-specific antigen from baseline) rate of 49%, and a PSA90 rate of 28%. According to RECIST criteria, the high-dose cohort demonstrated an objective response rate (ORR) of 41% and a disease control rate (DCR) of 79%. Currently, AMG 509 is bypassing Phase II clinical trial and proceeding directly to Phase III clinical studies for prostate cancer, with preliminary completion expected by August 2028.

At this year's AACR Annual Meeting, AstraZeneca's AZD0516 made its debut. It is currently the only antibody-drug conjugate (ADC) in global development that targets STEAP2, constructed by linking an anti-STEAP2 monoclonal antibody to the topoisomerase I inhibitor exatecan via a cleavable linker. Preclinical research have shown that AZD0516 exhibits a half maximal inhibitory concentration (IC50) in the low nanomolar (nM) range, and is capable of inducing both single-strand and double-strand DNA breaks, suggesting strong tumor-killing potential. In prostate cancer cell lines and patient-derived xenograft (PDX) models, AZD0516 monotherapy achieved sustained tumor regression, demonstrating promising therapeutic effect and clinical potential.

Another company sharing research progress was AbbVie, whose ABBV-969 is an antibody-drug conjugate (ADC) targeting both prostate-specific membrane antigen (PSMA) and STEAP1. The molecule includes binding structural domain for PSMA and STEAP1, and carries a topoisomerase I inhibitor (Top1i) as its payload. As PSMA and STEAP1 are both highly expressed in prostate cancer and exhibit a degree of complementarity, this bispecific antibody ADC offers a more comprehensive approach to tumor cell clearance while reducing the likelihood of resistance development.

At the 2025 AACR Annual Meeting, AbbVie disclosed the structure of ABBV-969. Its antibody component is a DVD-Ig (Dual Variable Domain Immunoglobulin) constructed on an IgG1 backbone featuring L234A/L235A mutations and cysteine engineering at the C6V1 site. The molecule contains an inner variable domain targeting PSMA and an outer variable domain targeting STEAP1, with a drug-to-antibody ratio (DAR) of 2.

DXC008, developed by the Chinese biopharmaceutical company DAC Biotechnology, is an antibody-drug conjugate (ADC) targeting STEAP1, with a tubulysin B analogue as its cytotoxic payload. In addition to its high affinity for STEAP1, DXC008 also exhibits moderate affinity for PSMA. In xenograft models with high or moderate co-expression of STEAP1 and PSMA, a single 1 mpk dose of DXC008 demonstrated a robust and durable anti-tumor response. Currently, DXC008 is undergoing Phase I clinical research.

In addition to TCEs and ADCs, AstraZeneca is also developing a CAR-T therapy targeting STEAP2, named AZD0754. According to preclinical data disclosed at AACR, AZD0754 is engineered with a dominant-negative TGFβ receptor II (dnTGFβRII) to block TGFβ signaling transmission in T cells. AZD0754 is currently undergoing Phase I/II recruitment for clinical tests in STEAP2-positive prostate cancer.

At present, AMG509 by Amgen and Baekje appears poised to become the first milestone product to validate the druggability of STEAP1, potentially taking the lead in shaping the market landscape. As clinical data from TCE bispecific antibody, ADC, and CAR-T continue to emerge, competition in the STEAP-targeting pipeline is expected to intensify.

References：

1.https://investors.amgen.com/static-files/6d823d7d-2fd1-405a-8c0e-22aa91bee682.

2.Reilly R. ABBV-969: A first-in-class dual-targeting PSMA-STEAP1 drug conjugate for the treatment of metastatic castrate-resistant prostate cancer. Abstract ND03 presented at the American Association for Cancer Research Annual Meeting, 2025. Chicago, Illinois.

3.A novel prostate cancer-specific fluorescent probe based on extracellular vesicles targeting STEAP1 applied in fluorescence guided surgery.