Combining alpha-Particle Radioimmunotherapy and Antibody–Drug Conjugates to Improve Outcomes in Pancreatic Cancer

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY: Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers, and five-year survival remains below 13%. PDAC is projected to be the second leading cause of U.S. cancer deaths by 2030. Therapeutic failure reflects antigen heterogeneity, stromal barriers, and dose-limiting toxicity, and there is a critical need for selective, durable treatment strategies. Alkaline phosphatase placental-like 2 (ALPPL2) is an oncofetal antigen upregulated in PDAC and largely absent in most adult tissues, providing a favorable therapeutic index. We developed M25, a fully human anti-ALPPL2 antibody, and used it to generate a 89Zr-immunoPET agent that showed selective uptake in PDAC xenografts. High tumor uptake and tumor-to-background ratios established in-vivo targetability and dosimetry feasibility. This R21 will establish an ALPPL2-directed therapy platform for PDAC, leveraging restricted ALPPL2 expression to concentrate high-linear-energy-transfer alpha radiation and microtubule- disrupting payloads in tumors while sparing normal tissues. Long-term objectives are to (i) create a quantitative imaging-to-therapy pathway that links target engagement and dosimetry to treatment design and (ii) define generalizable, biology-guided scheduling principles for combining α-radioimmunotherapy (α-RIT) with antibody- drug conjugates (ADCs). Specific Aim 1 engineers 225Ac-M25 as IgG, Fab, and F(ab′)2 formats and nominates a lead based on release specifications, tumor penetration, tumor-to-normal exposure, and absorbed dose. Aim 2 evaluates α-RIT plus the M25-MMAE ADC, aligning ADC-induced G2/M arrest with α-particle DNA damage to test biology-guided scheduling at sub-toxic doses; efficacy and safety will be assessed in orthotopic models. Exploratory Aim 3 evaluates feasibility of a dual-payload construct co-delivering 225Ac and MMAE, benchmarked against monotherapies and the optimized sequential regimen. Anticipated outcomes are a characterized 225Ac-ALPPL2 lead, a low-dose schedule-optimized combination with defined safety margins, and feasibility data for dual-payload therapy, advancing a tumor-selective path for PDAC aligned with NIH’s mission to reduce cancer morbidity and mortality.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE: Pancreatic ductal adenocarcinoma is among the deadliest cancers, highlighting the need for tumor-selective treatments that improve survival while limiting harm to healthy organs. This project will evaluate a tumor-targeted strategy in which an antibody delivers a chemotherapy-like payload that makes cancer cells more susceptible to precisely delivered radiation. Successful completion will establish a safer, more effective path for pancreatic cancer therapy and provide general principles for combining targeted radiotherapy with antibody–drug conjugates.