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

Radioimmunotherapy (RIT) with α-particle-emitting, 225 Ac complexed to trastuzumab may offer an alternative treatment for patients who progress on HER2-targeted therapies. Moreover, RIT with [ 225 Ac]Ac-DOTA-trastuzumab could be combined with SPECT/CT imaging with [ 111 In]In-DOTA-trastuzumab in a theranostic approach. In this study, we compared DOTA-conjugated trastuzumab IgG, F(ab') 2 or Fab complexed to 111 In or 225 Ac 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 [ 111 In]In-DOTA-trastuzumab IgG, F(ab') 2 or Fab and [ 225 Ac]Ac-DOTA-trastuzumab IgG, F(ab') 2 or Fab. Radiation absorbed doses in the tumor and normal organs for [ 225 Ac]Ac-DOTA-trastuzumab IgG, F(ab') 2 or Fab were estimated based on the biodistribution of the [ 111 In]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 [ 225 Ac]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 [ 225 Ac]Ac-DOTA-trastuzumab IgG, F(ab') 2 or Fab separated by 8 d or irrelevant [ 225 Ac]Ac-DOTA-IgG 1, 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. [ 111 In]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 [ 111 In]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. [ 111 In]In-DOTA-trastuzumab F(ab') 2 and Fab exhibited higher kidney uptake than IgG. Tumors were imaged by SPECT/CT with [ 111 In]In-DOTA-trastuzumab IgG and F(ab') 2 but were not well-visualized with [ 111 In]In-DOTA-trastuzumab Fab. The absorbed dose in the tumor was 2.2-fold greater for [ 225 Ac]Ac-DOTA-trastuzumab F(ab') 2 than IgG and 3.4-fold greater than Fab. Hematological toxicity was observed for [ 225 Ac]Ac-DOTA-trastuzumab IgG but not for [ 225 Ac]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 [ 225 Ac]Ac-DOTA-trastuzumab IgG, F(ab') 2 or Fab but [ 225 Ac]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 [ 111 In]In- and [ 225 Ac]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.

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