Abstract 2150: Pre-targeted radioimmunotherapy using self-assembling dis-assembling (SADA) bispecific antibodies for the treatment of appendiceal carcinoma

Abstract Malignant appendiceal epithelial tumors (AC) present a rare and diverse group of neoplasms.1 Treatment options are limited especially with peritoneal recurrence. Alpha and beta particle therapy using radioisotopes, especially when delivered by a pre-targeted radioimmunotherapy (PRIT) approach, can be effective with a wide therapeutic window. SADA-PRIT exploits an initial long plasma half-life of SADA tetramers for increased tumor uptake and when unbound, their disassembly to monomer with rapid renal clearance, thereby maximizing therapeutic indices across all critical normal tissues.2, 3 6-week old female BRG mice with subcutaneous (sq) or intraperitoneal (IP) patient derived AC xenograft (PDX) were treated with two doses of α-PRIT using [225Ac]-Proteus ([225Ac]Pr, or three doses of β- PRIT using [177Lu]DOTA, 4 all delivered by anti-GPA33-SADA. Isotope doses were chosen based on previous dosimetry and given one week apart.2 Toxicity, tumor response and survival were followed up to 180 days. Log rank Mantel Cox statistics was used for median survival (MS) comparison. Positive immunohistochemistry was confirmed in 26/26 AC surgical samples and 4/4 Patient derived xenografts (PDX). Similar IHC patterns were seen for B7H3 and HER2. Using GPA33-SADA in sq models α-PRIT (2 x 74 kBq 225Ac) produced an MS of 70 days, compared to 21 days in the antibody-only and [225Ac]Pr-only control group; β-PRIT (3 x 111 MBq) provided an MS of 68 days, compared to 27 days in the antibody-only and [177Lu]DOTA-only control groups. In the IP AC PDX model, all 10/10 mice in the α-PRIT group are healthy and tumor-free at 100+ days, compared to an MS of 42d in both antibody-only and [225Ac]Pr-only control groups (p <0.0001). Neither [225Ac]Pr or [177Lu]DOTA caused dose-limiting acute (<30 days) or long term (to 6 months) toxicities. Transient weight loss and leukopenia were reversible. Mild tubular degeneration was documented by histology at necropsy. Use of GPA33-SADA to deliver α-PRIT and β-PRIT induced major tumor responses and significantly prolonged survival in sq AC and ip AC tumor models. Minimal myeloid, renal, hepatic, or neural toxicities were seen. IHC results support future testing of cocktailing of SADAs (specific for GPA33, B7H3, and HER2) to overcome tumor heterogeneity while reducing on-target off-tumor side effects. Citation Format: Nicole Aguirre, Michelle Kim, Hong-Fen Guo, Karina Leung, Sebastian E. Carrasco, Irene Cheung, Michael B. Foote, Andrea Cercek, Sarah M. Cheal, Darren R. Veach, Steven M. Larson, Georgios Karagkounis, Garrett Nash, Nai-Kong Cheung. Pre-targeted radioimmunotherapy using self-assembling dis-assembling (SADA) bispecific antibodies for the treatment of appendiceal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2150.