A Preclinical Program Utilizing ADAPTIR-FLEXTM to Target PSMA with High Affinity, and to CD3 with Low Affinity, for Treatment of Prostate Cancer
APVO442 is a bispecific antibody candidate designed to target Prostate Specific Membrane Antigen (PSMA), a tumor antigen that is highly expressed on prostate cancer cells with limited normal tissue expression, and CD3, a signaling component of the T-cell receptor complex. APVO442 contains two binding domains to PSMA to increase binding to this tumor antigen, and a single, lower affinity binding domain to CD3. The bispecific candidate is designed to induce target-specific T-cell killing of PSMA positive cancer cells while improving concentration of the drug at the tumor site. The drug candidate is built on Aptevo’s ADAPTIR-FLEX platform and leverages the unique properties of this technology to increase binding to PSMA while lower binding to T cells in the circulation. This design has potential to increase the amount of drug concentration at the site of PSMA-positive tumors and increase anti-tumor responses by tumor-infiltrating T cells.
APVO442 is designed to maximize anti-tumor responses:
- Optimized to increase bio-distribution to tumor: Low affinity, monovalent CD3 engagement is designed to reduce binding to peripheral T cells expressing CD3. The high affinity, bivalent anti-PSMA binding is designed to increase concentration of the drug at the tumor site to engage tumor-resident T cells.
- Reduced cytokine release: CD3-targeting therapeutics designed on the ADAPTIR-FLEX platform are like those designed on the ADAPTIR platform in that they retain high potency tumor killing based on preclinical studies while maintaining reduced cytokine release measured in controlled in vitro analyses.
APVO442 was compared to an in-house generated competitor candidate targeting PSMA and CD3. In these studies, APVO442 retains potent T-cell mediated tumor killing activity, but with reduced cytokine production in vitro compared to a competitor candidate targeting the same tumor antigen. This feature is shared with ADAPTIR based T-cell engagers. Reduced cytokine release may increase the patient’s ability to tolerate the drug and improve anti-tumor responses.
Summary: The ADAPTIR-FLEX structure, in combination with our unique anti-CD3 binding domains and bivalent binding to PSMA, has potential to increase anti-tumor responses by concentrating the drug at the tumor site and improving tolerability of patient’s responses to increasing drug concentrations. This approach may provide a safer and more tolerable treatment for patients with prostate cancer. The ADAPTIR-FLEX platform technology in combination with our unique anti-CD3 can be utilized to target addition solid tumor antigens with the potential to improve responses in additional solid tumor indications.