Abstract LB282: Therapeutic efficacy and dosimetry for a 177-lutetium radiolabeled minibody targeting DLL3 in a preclinical model of small cell lung cancer

Abstract Small cell lung cancer (SCLC) is the most aggressive subtype of lung carcinoma with a 5-year survival rate below 7%. While the addition of anti-PD-1 antibody treatment has improved SCLC patient outcomes, nearly all patients relapse, indicating an unmet need for more efficacious therapeutics. Delta-like ligand 3 (DLL3) is an inhibitory Notch ligand that is over-expressed on the surface of SCLC tumor cells. Due to this, DLL3 has become a target of interest for SCLC treatment and several agents are in preclinical and clinical evaluation using different strategies such as antibody-drug conjugates, bispecific T cell engagers, and DLL3-targeting CAR-T. Minibodies are antibody fragments that provide optimal pharmacokinetics for the delivery of radioactive payloads. Their molecular weight of 80 kDa allows for rapid tumor uptake and faster circulation clearance than full-length antibodies. These scaffolds also present deeper tumor penetration relative to full-length antibodies, and higher target specificity and retention at the tumor site, with respect to small molecules. We hypothesized that a minibody targeting DLL3 (IAB57) would be a valid approach for radiopharmaceutical therapy (RPT) of SCLC and tested its efficacy in a preclinical model of SCLC. We conjugated the IAB57 minibody with DOTAGA and radiolabeled the protein with the β-emitter 177-Lu. Nu/J female mice were inoculated subcutaneously with the non-encapsulated lung carcinoma cell line SHP77, and the tumor size was measured 3 times per week until it reached 100-150 mm3. 24-hour biodistribution results revealed a tumor uptake of 18.8% injected dose per gram (%ID/gr). Mice were treated with 13.3 MBq and 13.6 MBq doses of 177-Lu-DOTAGA-IAB57 7 days apart to determine if there was a therapeutic effect and improved animal survival. A subgroup of mice was not treated and was considered controls. A time course biodistribution was performed to assess organs dosimetry. The dosimetry results were extrapolated to human organ exposure showing kidneys and liver uptakes of 2.2 and 4.6 Gy which is 10 times and 7 times below published exposure thresholds (23 Gy and 32 Gy respectively). Exposure at bone marrow (b.m., 0.1 Gy), spleen (1.5 Gy) and lungs (0.4 Gy) were 20 times, 27 times and 68 times below published toxicity thresholds (b.m.: 2 Gy; spleen: 40 Gy; lungs: 27 Gy). The RPT data showed a significant decrease in tumor size beginning on day 11 in the treated group compared to the control group. The decreased tumor size also coincided with a doubling in the survival rate. Overall, these results indicate that the IAB57 minibody targeting DLL3 is a promising and effective agent for RPT treatment of SCLC via β-emitting radionuclides. Citation Format: Kelley C. Atkinson, Leticia M. De Souza Cordeiro, Fang Jia, Argin Aivazian, Gareth E. Smith, Ian Wilson, Alessandro Mascioni. Therapeutic efficacy and dosimetry for a 177-lutetium radiolabeled minibody targeting DLL3 in a preclinical model of small cell lung 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(7_Suppl):Abstract nr LB282.