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
Authors: Kondo Misaki , Cai Zhongli , Chan Conrad , Reilly Raymond M. 
Published: March 2024

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 [225Ac]Ac-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 [225Ac]Ac-DOTA-trastuzumab IgG, F(ab’)2 or Fab. Control mice received irrelevant [225Ac]Ac-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 [225Ac]Ac-DOTA-trastuzumab IgG, F(ab’)2 and Fab (4 kBq) in tumor-bearing NRG mice were measured up to 14 d p.i..
Results: [225Ac]Ac-DOTA-trastuzumab F(ab’)2 and Fab caused no decrease in CBC, while [225Ac]Ac-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. [225Ac]Ac-trastuzumab F(ab’)2 or Fab caused no increase in ALT or CRE. Body weight was not decreased in all groups of mice. [225Ac]Ac-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 [225Ac]Ac-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 [225Ac]Ac-DOTA-IgG was 20 d and for trastuzumab was 22 d. Tumor uptake of [225Ac]Ac-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 [225Ac]Ac-DOTA-trastuzumab Fab at 18 h p.i. was 3.1 ± 0.5 %ID/g. Elimination from the blood was slowest for [225Ac]Ac-DOTA-trastuzumab IgG followed by F(ab’)2 then Fab. Spleen and liver uptake were greatest for [225Ac]Ac-DOTA-trastuzumab IgG but much lower for F(ab’)2 and Fab. Kidney uptake was highest for [225Ac]Ac-DOTA-trastuzumab Fab.
Conclusion: [225Ac]Ac-DOTA-trastuzumab F(ab’)2 provided the highest therapeutic index, inhibiting tumor growth and improving survival while minimizing toxicity. TART with [225Ac]Ac-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(6_Suppl):Abstract nr 6030.