Preclinical Comparison of [ ¹¹¹ In]In- and [ ²²⁵ Ac]Ac-DOTA-Trastuzumab IgG, F(ab′) ₂ and Fab for Theranostic SPECT/CT Imaging and α-Particle Radioimmunotherapy of HER2-Positive Human Breast Cancer

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Radioimmunotherapy (RIT) with α-particle-emitting, ²²⁵Ac complexed to trastuzumab may offer an alternative treatment for patients who progress on HER2-targeted therapies. Moreover, RIT with [²²⁵Ac]Ac-DOTA-trastuzumab could be combined with SPECT/CT imaging with [¹¹¹In]In-DOTA-trastuzumab in a theranostic approach. In this study, we compared DOTA-conjugated trastuzumab IgG, F(ab')₂ or Fab complexed to ¹¹¹In or ²²⁵Ac for SPECT/CT imaging and α-particle RIT of subcutaneous (s.c.) HER2-positive 164/8-1B/H2N.luc⁺ human BC tumors in NRG mice. SPECT/CT imaging and tumor and normal tissue uptake were compared in NRG or NOD-SCID mice coinjected i.v. with [¹¹¹In]In-DOTA-trastuzumab IgG, F(ab')₂ or Fab and [²²⁵Ac]Ac-DOTA-trastuzumab IgG, F(ab')₂ or Fab. Radiation absorbed doses in the tumor and normal organs for [²²⁵Ac]Ac-DOTA-trastuzumab IgG, F(ab')₂ or Fab were estimated based on the biodistribution of the [¹¹¹In]In-DOTA-trastuzumab IgG, F(ab')₂ or Fab. Normal tissue toxicity was assessed by hematology and blood biochemistry analyses and monitoring body weight in NRG mice injected i.v. with 2 and 4 kBq of [²²⁵Ac]Ac-DOTA-trastuzumab IgG, F(ab')₂ or Fab separated by 8 d. RIT studies were performed in NRG mice with s.c. 164/8-1B/H2N.luc⁺ tumors injected i.v. with 2 kBq and 4 kBq of [²²⁵Ac]Ac-DOTA-trastuzumab IgG, F(ab')₂ or Fab separated by 8 d or irrelevant [²²⁵Ac]Ac-DOTA-IgG₁, two doses of unlabeled trastuzumab IgG or 0.9% NaCl. A tumor growth index (TGI) was plotted vs time (d) and Kaplan-Meier median survival estimated. [¹¹¹In]In-DOTA-trastuzumab IgG or F(ab')₂ exhibited 4.1-fold and 3.3-fold significantly greater tumor uptake at 2 d postinjection (p.i.) than Fab at 24 h p.i. However, spleen uptake at 2 d p.i. for [¹¹¹In]In-DOTA-trastuzumab IgG was 3.3-fold significantly higher than F(ab')₂ and 13.2-fold higher than Fab at 24 h p.i. [¹¹¹In]In-DOTA-trastuzumab F(ab')₂ and Fab exhibited higher kidney uptake than IgG. Tumors were imaged by SPECT/CT with [¹¹¹In]In-DOTA-trastuzumab IgG and F(ab')₂ but were not well-visualized with [¹¹¹In]In-DOTA-trastuzumab Fab. The absorbed dose in the tumor was 2.2-fold greater for [²²⁵Ac]Ac-DOTA-trastuzumab F(ab')₂ than IgG and 3.4-fold greater than Fab. Hematological toxicity was observed for [²²⁵Ac]Ac-DOTA-trastuzumab IgG but not for [²²⁵Ac]Ac-DOTA-trastuzumab F(ab')₂ or Fab. No kidney or liver toxicity or decreased body weight was observed for any RIT agent. Tumor growth was significantly inhibited by [²²⁵Ac]Ac-DOTA-trastuzumab IgG, F(ab')₂ or Fab but [²²⁵Ac]Ac-DOTA-trastuzumab F(ab')₂ was most effective for increasing median survival (46 d vs 22 d for IgG and 29 d for Fab). We conclude that [¹¹¹In]In- and [²²⁵Ac]Ac-DOTA-trastuzumab F(ab')₂ exhibited superior properties for theranostic imaging and α-particle RIT of HER2-positive human BC xenografts in NRG mice.