Development of CD46 targeted alpha theranostics in prostate cancer using 134 Ce/ 225 Ac-Macropa-PEG 4 -YS5.

Autor:	Bobba KN; Department of Radiology and Biomedical Imaging, University of California, San Francisco, California 94143, United States., Bidkar AP; Department of Radiology and Biomedical Imaging, University of California, San Francisco, California 94143, United States., Wadhwa A; Department of Radiology and Biomedical Imaging, University of California, San Francisco, California 94143, United States., Meher N; Department of Radiology and Biomedical Imaging, University of California, San Francisco, California 94143, United States., Drona S; Department of Radiology and Biomedical Imaging, University of California, San Francisco, California 94143, United States., Sorlin AM; Department of Radiology and Biomedical Imaging, University of California, San Francisco, California 94143, United States., Bidlingmaier S; Department of Anesthesia, University of California, San Francisco, California 94110, United States., Zhang L; Department of Medicine and the Department of Epidemiology and Biostatistics, University of California, Berkeley, California, United States., Wilson DM; Department of Radiology and Biomedical Imaging, University of California, San Francisco, California 94143, United States.; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California 94143-0981, United States., Chan E; Department of Pathology, University of California, San Francisco, California 94110, United States., Greenland NY; Department of Pathology, University of California, San Francisco, California 94110, United States., Aggarwal R; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California 94143-0981, United States.; Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, United States., VanBrocklin HF; Department of Radiology and Biomedical Imaging, University of California, San Francisco, California 94143, United States.; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California 94143-0981, United States., He J; Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, Virginia, 22908, United States., Chou J; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California 94143-0981, United States.; Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, United States., Seo Y; Department of Radiology and Biomedical Imaging, University of California, San Francisco, California 94143, United States.; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California 94143-0981, United States., Liu B; Department of Anesthesia, University of California, San Francisco, California 94110, United States.; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California 94143-0981, United States., Flavell RR; Department of Radiology and Biomedical Imaging, University of California, San Francisco, California 94143, United States.; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California 94143-0981, United States.; Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158-2517, United States.
Jazyk:	angličtina
Zdroj:	Theranostics [Theranostics] 2024 Jan 27; Vol. 14 (4), pp. 1344-1360. Date of Electronic Publication: 2024 Jan 27 (Print Publication: 2024).
DOI:	10.7150/thno.92742
Abstrakt:	Rationale: 225 Ac, a long-lived α-emitter with a half-life of 9.92 days, has garnered significant attention as a therapeutic radionuclide when coupled with monoclonal antibodies and other targeting vectors. Nevertheless, its clinical utility has been hampered by potential off-target toxicity, a lack of optimized chelators for 225 Ac, and limitations in radiolabeling methods. In a prior study evaluating the effectiveness of CD46-targeted radioimmunotherapy, we found great therapeutic efficacy but also significant toxicity at higher doses. To address these challenges, we have developed a radioimmunoconjugate called 225 Ac-Macropa-PEG 4 -YS5, incorporating a stable PEGylated linker to maximize tumoral uptake and increase tumor-to-background ratios. Our research demonstrates that this conjugate exhibits greater anti-tumor efficacy while minimizing toxicity in prostate cancer 22Rv1 tumors. Methods: We synthesized Macropa.NCS and Macropa-PEG 4/8 -TFP esters and prepared Macropa-PEG 0/4/8 -YS5 (with nearly ~1:1 ratio of macropa chelator to antibody YS5) as well as DOTA-YS5 conjugates. These conjugates were then radiolabeled with 225 Ac in a 2 M NH 4 OAc solution at 30 °C, followed by purification using YM30K centrifugal purification. Subsequently, we conducted biodistribution studies and evaluated antitumor activity in nude mice (nu/nu) bearing prostate 22Rv1 xenografts in both single-dose and fractionated dosing studies. Micro-PET imaging studies were performed with 134 Ce-Macropa-PEG 0/4/8 -YS5 in 22Rv1 xenografts for 7 days. Toxicity studies were also performed in healthy athymic nude mice. Results: As expected, we achieved a >95% radiochemical yield when labeling Macropa-PEG 0/4/8 -YS5 with 225 Ac, regardless of the chelator ratios (ranging from 1 to 7.76 per YS5 antibody). The isolated yield exceeded 60% after purification. Such high conversions were not observed with the DOTA-YS5 conjugate, even at a higher ratio of 8.5 chelators per antibody (RCY of 83%, an isolated yield of 40%). Biodistribution analysis at 7 days post-injection revealed higher tumor uptake for the 225 Ac-Macropa-PEG 4 -YS5 (82.82 ± 38.27 %ID/g) compared to other conjugates, namely 225 Ac-Macropa-PEG 0/8 -YS5 (38.2 ± 14.4/36.39 ± 12.4 %ID/g) and 225 Ac-DOTA-YS5 (29.35 ± 7.76 %ID/g). The PET Imaging of 134 Ce-Macropa-PEG 0/4/8 -YS5 conjugates resulted in a high tumor uptake, and tumor to background ratios. In terms of antitumor activity, 225 Ac-Macropa-PEG 4 -YS5 exhibited a substantial response, leading to prolonged survival compared to 225 Ac-DOTA-YS5, particularly when administered at 4.625 kBq doses, in single or fractionated dose regimens. Chronic toxicity studies observed mild to moderate renal toxicity at 4.625 and 9.25 kBq doses. Conclusions: Our study highlights the promise of 225 Ac-Macropa-PEG 4 -YS5 for targeted alpha particle therapy. The 225 Ac-Macropa-PEG 4 -YS5 conjugate demonstrates improved biodistribution, reduced off-target binding, and enhanced therapeutic efficacy, particularly at lower doses, compared to 225 Ac-DOTA-YS5. Incorporating theranostic 134 Ce PET imaging further enhances the versatility of macropa-PEG conjugates, offering a more effective and safer approach to cancer treatment. Overall, this methodology has a high potential for broader clinical applications. Competing Interests: Competing Interests: The authors have declared that no competing interest exists. (© The author(s).)
Databáze:	MEDLINE
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