STEAP Targets in Focus: Emerging Therapies Across Cancer and Chronic Diseases

The Rising Promise of STEAP Targets in Modern Medicine

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.

STEAP Targets: Bridging Oncology and Metabolic Diseases

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:

• Ion transport regulation (iron, copper)
• Cell-to-cell communication
• Redox reactions
• Tumor progression
• Metabolic regulation
• Inflammatory responses

Key STEAP isoforms and their associations:

The combination of broad mechanistic involvement and tissue-specific expression makes STEAP proteins ideal biomarkers and therapeutic targets.

Current STEAP-Targeting Modalities in Clinical Development

Fewer than 10 STEAP-targeting therapies have reached clinical stages globally. The most advanced candidates include:

1. AMG509 (Xaluritamig) - TCE Approach

Developers: Amgen/Biogen
Mechanism: Bispecific T-cell engager (STEAP1 × CD3)
Technology: Xmab2+1 asymmetric platform featuring:

• Two STEAP1-binding Fab domains
• One CD3-targeting scFv
• Fc domain engineered for extended half-life

Clinical Performance (AACR 2024):

• PSA50 response: 49%
• PSA90 response: 28%
• ORR (high dose): 41%
• DCR: 79%

Development Status: Accelerated Phase III initiation for prostate cancer (expected completion August 2028)

2. AZD0516 - ADC Innovation

Developer: AstraZeneca
Distinction: First STEAP2-targeting ADC
Structure:

• STEAP2 monoclonal antibody
• Cleavable linker
• Exatecan payload (topoisomerase 1 inhibitor)

Preclinical Highlights:

• nM-range IC50 values
• Induces DNA strand breaks
• Shows durable tumor regression in PDX models

3. ABBV-969 - Dual-Targeting ADC

Developer: AbbVie
Unique Feature: Simultaneously targets PSMA and STEAP1
Design Elements:

• DVD-Ig format with:
  • Inner variable domain: PSMA-binding
  • Outer variable domain: STEAP1-binding
• Topoisomerase 1 inhibitor payload
• DAR: 2

4. DXC008 - Tubulin-Targeting ADC

Developer: Daxor Biopharma
Payload: Tubulysin B analog
Notable Features:

• Binds both STEAP1 and PSMA
• Shows strong antitumor activity at 1 mpk dose
• Currently in Phase I trials

5. AZD0754 - CAR-T Cell Therapy

Developer: AstraZeneca
Innovation: STEAP2-targeting CAR-T with dnTGFβRII armoring
Current Status: Recruiting for Phase I/II prostate cancer trials

Emerging Competitive Landscape

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:

1. Amgen Investor Relations: AMG509 Data
2. Reilly R. ABBV-969: A first-in-class dual-targeting PSMA-STEAP1 drug conjugate. AACR 2025.
3. Novel STEAP1-targeted probe for fluorescence-guided surgery. Nature Cancer 2024.