Development of a STEAP1-Targeted Prostate Cancer Specific Antibody Drug Conjugate Platform with Immunostimulatory
John Shuhan Wang1, Sirajbir S Sodhi1, Li-Chung Tsao2
1Duke University School of Medicine.
Background:
Patients with prostate cancer who develop androgen pathway modulation resistant (APMR) disease face lethal outcomes despite advances in androgen receptor-pathway inhibitors, chemotherapy, and PSMA-directed radioligands. Antibody-drug conjugates (ADCs) have demonstrated transformative efficacy in multiple malignancies, yet ADCs evaluated in patients with metastatic APMR have largely focused on direct tumor cytotoxicity without assessing immune mechanisms that may underpin durable therapeutic responses. Whether immune activation contributes to ADC efficacy in prostate cancer remains unexplored.
Methods:
We applied immune-centric design principles to ADC development targeting six transmembrane epithelial antigen of the prostate 1 (STEAP1), a prostate-lineage restricted, androgen receptor-regulated surface antigen. vandortuzumab-based ADCs were generated using multiple clinically validated linker-payload platforms. Constructs were evaluated using in vitro assays of Fcγ receptor engagement, antigen presentation, and T-cell activation, followed by in vivo testing in bone-metastatic and syngeneic immunocompetent APMR models.
Results:
STEAP1 specific Fcγ receptor engagement was required for optimal antigen presentation and downstream T-cell activation. Among tested payloads, exatecan-based ADCs demonstrated the strongest immunostimulatory activity. In bone-metastatic and immunocompetent APMR models, vandortuzumab-exatecan mediated durable tumor control and induced adaptive immune memory capable of preventing tumor rechallenge.
Conclusions:
These findings identify immune activation as an important determinant of ADC efficacy in APMR and demonstrate that vandortuzumab-exatecan functions as an immune-engaging ADC capable of inducing durable anti-tumor responses. Incorporating immune activation into ADC design may improve the therapeutic potential of ADCs for patients with advanced prostate cancer.
Insights
New antibody-drug conjugates (ADCs) targeting STEAP1 show promise for advanced prostate cancer by activating the immune system. Vandortuzumab-exatecan ADCs induce durable anti-tumor responses and immune memory in models of androgen pathway modulation resistant disease.
Area of Science:
- Oncology
- Immunology
- Drug Development
Background:
- Androgen pathway modulation resistant (APMR) prostate cancer has poor outcomes despite current therapies.
- Existing antibody-drug conjugates (ADCs) for APMR prostate cancer primarily focus on direct tumor killing, neglecting immune mechanisms.
- The role of immune activation in ADC efficacy for prostate cancer is largely unexplored.
Purpose of the Study:
- To investigate immune-centric antibody-drug conjugate (ADC) design targeting STEAP1 for APMR prostate cancer.
- To evaluate the immunostimulatory potential and anti-tumor efficacy of novel vandortuzumab-based ADCs.
Main Methods:
- Developed vandortuzumab-based ADCs targeting STEAP1 using various linker-payload platforms.
- Assessed Fcγ receptor engagement, antigen presentation, and T-cell activation in vitro.
- Tested ADC efficacy in bone-metastatic and immunocompetent APMR preclinical models.
Main Results:
- STEAP1 engagement was crucial for optimal antigen presentation and T-cell activation.
- Exatecan-based ADCs exhibited the strongest immunostimulatory effects.
- Vandortuzumab-exatecan achieved durable tumor control and induced adaptive immune memory in APMR models.
Conclusions:
- Immune activation is a key factor in ADC efficacy for APMR prostate cancer.
- Vandortuzumab-exatecan acts as an immune-engaging ADC, providing durable anti-tumor responses.
- Integrating immune activation strategies into ADC design may enhance treatment for advanced prostate cancer.
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