Abstract 6030: Optimizing the therapeutic index of targeted α-particle radioimmuotherapy (TART) of HER2-positive breast cancer tumors in NRG mice with 225Ac-labeled trastuzumab

Abstract Introduction: Our aim was to optimize the therapeutic index of TART of HER2-positive BC in NRG mice by studying the effectiveness and normal tissue toxicity of trastuzumab IgG, F (ab’) 2 or Fab modified with DOTA for complexing the α-particle emitter, 225Ac. Methods: The toxicity of 225AcAc-DOTA-trastuzumab IgG, F (ab’) 2 and Fab were assessed in NRG mice (n=5) injected i. v. with 2 and 4 kBq (total 80 μg) separated by 8 d. Body weight was monitored and complete blood cell (CBC) counts and alanine aminotransferase (ALT) and creatinine (CRE) were measured at 14 d post-injection (p. i. ). TART was performed in NRG mice (n=7) with s. c. HER2-positive 164/8-1B/H2N. luc+ xenografts injected i. v. with 2 and 4 kBq (total 80 μg) separated by 8 d of 225AcAc-DOTA-trastuzumab IgG, F (ab’) 2 or Fab. Control mice received irrelevant 225AcAc-DOTA-IgG, trastuzumab or saline. The tumor growth index (TGI=tumor volume/initial tumor volume) was measured and Kaplan-Meier median survival estimated. Tumor and normal tissue uptake (%ID/g) of 225AcAc-DOTA-trastuzumab IgG, F (ab’) 2 and Fab (4 kBq) in tumor-bearing NRG mice were measured up to 14 d p. i. . Results: 225AcAc-DOTA-trastuzumab F (ab’) 2 and Fab caused no decrease in CBC, while 225AcAc-DOTA-trastuzumab IgG decreased white blood cells by 4. 5-fold, platelets by 7. 5-fold, red blood cells by 1. 2-fold and hematocrit by 1. 2-fold compared to saline-treated mice. 225AcAc-trastuzumab F (ab’) 2 or Fab caused no increase in ALT or CRE. Body weight was not decreased in all groups of mice. 225AcAc-DOTA-trastuzumab IgG, F (ab’) 2 or Fab inhibited tumor growth (TGI at 15 d = 2. 5, 1. 8, and 1. 9, respectively) vs. saline or trastuzumab (TGI= 6. 3 and 5. 2; P=0. 0047 and 0. 0028). Median survival was increased to 46 d for mice treated with 225AcAc-DOTA-trastuzumab F (ab’) 2 vs. 29 d for Fab (P=0. 008), 22 d for IgG (P=0. 0005) and 15 d for saline (P=0. 0005). Median survival for mice treated with 225AcAc-DOTA-IgG was 20 d and for trastuzumab was 22 d. Tumor uptake of 225AcAc-DOTA-trastuzumab IgG and F (ab’) 2 at 48 h p. i. were 10. 6 ± 0. 6 and 8. 7 ± 0. 8, respectively, while uptake of 225AcAc-DOTA-trastuzumab Fab at 18 h p. i. was 3. 1 ± 0. 5 %ID/g. Elimination from the blood was slowest for 225AcAc-DOTA-trastuzumab IgG followed by F (ab’) 2 then Fab. Spleen and liver uptake were greatest for 225AcAc-DOTA-trastuzumab IgG but much lower for F (ab’) 2 and Fab. Kidney uptake was highest for 225AcAc-DOTA-trastuzumab Fab. Conclusion: 225AcAc-DOTA-trastuzumab F (ab’) 2 provided the highest therapeutic index, inhibiting tumor growth and improving survival while minimizing toxicity. TART with 225AcAc-DOTA-trastuzumab F (ab’) 2 is a promising new treatment for HER2-positive BC that could be more effective than trastuzumab. Citation Format: Misaki Kondo, Zhongli Cai, Conrad Chan, Raymond M. Reilly. Optimizing the therapeutic index of targeted α-particle radioimmuotherapy (TART) of HER2-positive breast cancer tumors in NRG mice with 225Ac-labeled trastuzumab abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 6030.