Abstract LB281: A preclinical therapeutic study of minibody 177Lu-DOTAGA-IAB56 targeting αVβ6 for the treatment of pancreatic cancer

Abstract Pancreatic cancer represents 3% of all cancers and 7% of all cancer deaths in the USA, with a majority of cases diagnosed late and with limited treatment efficacy. Radiopharmaceutical Therapy (RPT) using antibodies (Abs) is emerging as a new approach for the treatment of solid cancers. Due to the long circulation time in blood, full-length antibodies bear concerns for hematological exposure to radioactivity. Antibody fragments with lower molecular weight like minibodies (Mb, 80 kDa) show rapid blood clearance, thus reducing off-target exposure, while maintaining the high target affinity typical of immunoglobulins. Mbs consist of two scFv antigen-binding domains fused to the CH3 domain of human IgG. Integrin αVβ6 is mainly absent in healthy adult tissues but upregulated in a variety of carcinomas, including pancreatic cancer. In this preclinical proof of concept study, we evaluated a Mb targeting human αVβ6 (IAB56) as an RPT agent for the treatment of pancreatic cancer. To this end we first evaluated the β-emitter Mb 177Lu-DOTAGA-IAB56 in a dosimetry study in mice and extrapolated the organ exposures to humans. Then we tested its therapeutic efficacy in female Nu/J mice bearing the subcutaneous ductal adenocarcinoma xenograft CFPAC-1. The IAB56 Mb was conjugated with DOTAGA and radiolabeled with 177Lu. Doses of 1. 48 MBq/animal were administered intravenously (iv) in non-tumor bearing mice and biodistributions collected at 0. 5, 3, 6, 24, 48, 120 and 192 hours postinjection (p. i. ) to quantify time course uptake at major organs. Dosimetry data extrapolated from these biodistributions showed that exposure in humans at clearance organs (kidneys and liver), had an average dose of 3. 1 and 5. 0 Gy which is 8 times and 6 times below the published dosimetry thresholds of 23 Gy and 32 Gy respectively. Bone marrow and the lungs, two additional radiation sensitive sites, show doses of 0. 04 and 0. 4 Gy, 50. 0 times and 67. 5 times below the tox thresholds (2 Gy for bone marrow and 27 Gy for the lungs). The spleen had an average dose of 2. 2 Gy, which is 18. 2 times below the threshold of 40 Gy. Preclinical RPT studies were conducted in CFPAC-1 xenografts. A pancreatic carcinoma cell-line reported to have intermediate-to-low expression level of human αVβ6 (4-fold lower than BxPC3 pancreatic adenocarcinoma). When the tumor size reached 100-150 mm3 mice were randomized into three groups: vehicle, single dose of 18. 5 MBq, or two doses 11. 1 MBq and 8. 1 MBq 7 days apart of 177Lu radiolabeled DOTAGA-IAB56. A rapid tumor growth inhibition response for up to 36 days was observed in both RPT groups which evoked a significant improvement in survival compared to control. Overall, our data indicate the anti-αvβ6 Mb, IAB56 is efficacious for the treatment of pancreatic cancer supporting the use of this agent as a RPT approach for solid tumors. Citation Format: Leticia M. De Souza Cordeiro, Kelley C. Atkinson, Fang Jia, Argin Aivazian, Gareth E. Smith, Ian Wilson, Alessandro Mascioni. A preclinical therapeutic study of minibody 177Lu-DOTAGA-IAB56 targeting αVβ6 for the treatment of pancreatic cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr LB281.