As low-hanging fruit in drug discovery diminishes, pharmaceutical companies are turning to novel targets like the STEAP family. At this year’s AACR meeting, AstraZeneca unveiled preclinical data for AZD0516, their STEAP2-targeting drug, reigniting industry interest in this protein family.
The six-transmembrane epithelial antigen of prostate (STEAP) family comprises four isoforms (STEAP1-4) initially discovered in prostate cancer cells. These membrane proteins play crucial roles in:
Key STEAP isoforms and their associations:
| Isoform | Primary Functions | Disease Associations |
|---|---|---|
| STEAP1 | Tumor proliferation, immune evasion | Prostate, bladder, pancreatic cancers |
| STEAP2/3 | Androgen signaling pathway | Neuroendocrine tumors, solid tumors |
| STEAP4 | Insulin resistance, inflammation | Obesity, diabetes, metabolic syndrome |
The combination of broad mechanistic involvement and tissue-specific expression makes STEAP proteins ideal biomarkers and therapeutic targets.
Fewer than 10 STEAP-targeting therapies have reached clinical stages globally. The most advanced candidates include:
Developers: Amgen/Biogen
Mechanism: Bispecific T-cell engager (STEAP1 × CD3)
Technology: Xmab2+1 asymmetric platform featuring:
Clinical Performance (AACR 2024):
Development Status: Accelerated Phase III initiation for prostate cancer (expected completion August 2028)
Developer: AstraZeneca
Distinction: First STEAP2-targeting ADC
Structure:
Preclinical Highlights:
Developer: AbbVie
Unique Feature: Simultaneously targets PSMA and STEAP1
Design Elements:
Developer: Daxor Biopharma
Payload: Tubulysin B analog
Notable Features:
Developer: AstraZeneca
Innovation: STEAP2-targeting CAR-T with dnTGFβRII armoring
Current Status: Recruiting for Phase I/II prostate cancer trials
Amgen/Biogen’s AMG509 leads clinical development and may become the first STEAP-validating therapy. However, multiple modalities—including TCEs, ADCs, and CAR-Ts—are demonstrating promising activity, setting the stage for intense competition in this emerging target space.
Key References:
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