CD46-Targeted Theranostics for PET and 225Ac-Radiopharmaceutical Therapy of Multiple Myeloma.

Autor:	Wadhwa A; Department of Radiology and Biomedical Imaging, University of California, San Francisco, California., Wang S; Department of Radiology and Biomedical Imaging, University of California, San Francisco, California.; School of Biomedical Engineering, ShanghaiTech University, Shanghai, China., Patiño-Escobar B; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California.; Department of Laboratory Medicine, University of California, San Francisco, California., Bidkar AP; Department of Radiology and Biomedical Imaging, University of California, San Francisco, California., Bobba KN; Department of Radiology and Biomedical Imaging, University of California, San Francisco, California., Chan E; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California.; Department of Laboratory Medicine, University of California, San Francisco, California., Meher N; Department of Radiology and Biomedical Imaging, University of California, San Francisco, California., Bidlingmaier S; Department of Anesthesia, University of California, San Francisco, California., Su Y; Department of Anesthesia, University of California, San Francisco, California., Dhrona S; Department of Radiology and Biomedical Imaging, University of California, San Francisco, California., Geng H; Department of Laboratory Medicine, University of California, San Francisco, California., Sarin V; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California.; Department of Laboratory Medicine, University of California, San Francisco, California., VanBrocklin HF; Department of Radiology and Biomedical Imaging, University of California, San Francisco, California.; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California., Wilson DM; Department of Radiology and Biomedical Imaging, University of California, San Francisco, California.; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California., He J; Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, Virginia., Zhang L; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California.; Department of Medicine, Department of Epidemiology and Biostatistics, University of California, San Francisco, California., Steri V; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California., Wong SW; Department of Medicine, Division of Hematology/Oncology, University of California, San Francisco, California., Martin TG; Department of Medicine, Division of Hematology/Oncology, University of California, San Francisco, California., Seo Y; Department of Radiology and Biomedical Imaging, University of California, San Francisco, California.; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California., Liu B; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California.; Department of Anesthesia, University of California, San Francisco, California., Wiita AP; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California.; Department of Laboratory Medicine, University of California, San Francisco, California.; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California.; Chan Zuckerberg Biohub, San Francisco, California., Flavell RR; Department of Radiology and Biomedical Imaging, University of California, San Francisco, California.; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California.; Department of Pharmaceutical Chemistry, University of California, San Francisco, California.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2024 Mar 01; Vol. 30 (5), pp. 1009-1021.
DOI:	10.1158/1078-0432.CCR-23-2130
Abstrakt:	Purpose: Multiple myeloma is a plasma cell malignancy with an unmet clinical need for improved imaging methods and therapeutics. Recently, we identified CD46 as an overexpressed therapeutic target in multiple myeloma and developed the antibody YS5, which targets a cancer-specific epitope on this protein. We further developed the CD46-targeting PET probe [89Zr]Zr-DFO-YS5 for imaging and [225Ac]Ac-DOTA-YS5 for radiopharmaceutical therapy of prostate cancer. These prior studies suggested the feasibility of the CD46 antigen as a theranostic target in multiple myeloma. Herein, we validate [89Zr]Zr-DFO-YS5 for immunoPET imaging and [225Ac]Ac-DOTA-YS5 for radiopharmaceutical therapy of multiple myeloma in murine models. Experimental Design: In vitro saturation binding was performed using the CD46 expressing MM.1S multiple myeloma cell line. ImmunoPET imaging using [89Zr]Zr-DFO-YS5 was performed in immunodeficient (NSG) mice bearing subcutaneous and systemic multiple myeloma xenografts. For radioligand therapy, [225Ac]Ac-DOTA-YS5 was prepared, and both dose escalation and fractionated dose treatment studies were performed in mice bearing MM1.S-Luc systemic xenografts. Tumor burden was analyzed using BLI, and body weight and overall survival were recorded to assess antitumor effect and toxicity. Results: [89Zr]Zr-DFO-YS5 demonstrated high affinity for CD46 expressing MM.1S multiple myeloma cells (Kd = 16.3 nmol/L). In vitro assays in multiple myeloma cell lines demonstrated high binding, and bioinformatics analysis of human multiple myeloma samples revealed high CD46 expression. [89Zr]Zr-DFO-YS5 PET/CT specifically detected multiple myeloma lesions in a variety of models, with low uptake in controls, including CD46 knockout (KO) mice or multiple myeloma mice using a nontargeted antibody. In the MM.1S systemic model, localization of uptake on PET imaging correlated well with the luciferase expression from tumor cells. A treatment study using [225Ac]Ac-DOTA-YS5 in the MM.1S systemic model demonstrated a clear tumor volume and survival benefit in the treated groups. Conclusions: Our study showed that the CD46-targeted probe [89Zr]Zr-DFO-YS5 can successfully image CD46-expressing multiple myeloma xenografts in murine models, and [225Ac]Ac-DOTA-YS5 can effectively inhibit the growth of multiple myeloma. These results demonstrate that CD46 is a promising theranostic target for multiple myeloma, with the potential for clinical translation. (©2023 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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