دورية أكاديمية
أعرض في EDS

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

التفاصيل البيبلوغرافية
العنوان: Development of CD46 targeted alpha theranostics in prostate cancer using 134 Ce/ 225 Ac-Macropa-PEG 4 -YS5.
المؤلفون: 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.
المصدر: Theranostics [Theranostics] 2024 Jan 27; Vol. 14 (4), pp. 1344-1360. Date of Electronic Publication: 2024 Jan 27 (Print Publication: 2024).
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Ivyspring International Publisher Country of Publication: Australia NLM ID: 101552395 Publication Model: eCollection Cited Medium: Internet ISSN: 1838-7640 (Electronic) Linking ISSN: 18387640 NLM ISO Abbreviation: Theranostics Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Wyoming, N.S.W. : Ivyspring International Publisher, 2011-
مواضيع طبية MeSH: Precision Medicine* , Prostatic Neoplasms*/diagnostic imaging , Prostatic Neoplasms*/drug therapy , Prostatic Neoplasms*/radiotherapy, Male ; Mice ; Animals ; Humans ; Mice, Nude ; Tissue Distribution ; Radiopharmaceuticals ; Chelating Agents ; Membrane Cofactor Protein
مستخلص: 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).)
References: JCI Insight. 2018 Sep 6;3(17):. (PMID: 30185663)
Science. 2001 Nov 16;294(5546):1537-40. (PMID: 11711678)
Curr Radiopharm. 2018;11(3):200-208. (PMID: 29732998)
Appl Radiat Isot. 2002 Dec;57(6):841-7. (PMID: 12406626)
Prostate Cancer Prostatic Dis. 2021 Sep;24(3):880-890. (PMID: 33746213)
Methods Enzymol. 2017;585:91-110. (PMID: 28109445)
Mol Pharm. 2018 Apr 2;15(4):1457-1466. (PMID: 29502411)
Cancer Biother Radiopharm. 2018 Oct;33(8):336-348. (PMID: 29889562)
J Nucl Med. 2023 Apr;64(4):549-554. (PMID: 36396453)
Clin Cancer Res. 2019 Jan 15;25(2):868-880. (PMID: 30352909)
J Nucl Med. 2022 Apr;63(4):584-590. (PMID: 34385334)
Bioconjug Chem. 2006 Nov-Dec;17(6):1551-60. (PMID: 17105236)
J Nucl Med. 2016 Dec;57(12):1941-1944. (PMID: 27390158)
Am Soc Clin Oncol Educ Book. 2014;:e126-31. (PMID: 24857092)
Mol Cancer Ther. 2010 Jul;9(7):2131-41. (PMID: 20587664)
Pharmacol Res. 2020 Oct;160:105070. (PMID: 32659429)
Mol Cancer Ther. 2008 Mar;7(3):569-78. (PMID: 18319332)
N Engl J Med. 2013 Jul 18;369(3):213-23. (PMID: 23863050)
Semin Nucl Med. 2020 Mar;50(2):119-123. (PMID: 32172796)
Angew Chem Int Ed Engl. 2017 Nov 13;56(46):14712-14717. (PMID: 28963750)
Clin Cancer Res. 2023 Dec 18;:. (PMID: 38109209)
Bioconjug Chem. 2021 Jul 21;32(7):1263-1275. (PMID: 34056896)
J Nucl Med. 2023 Jul;64(7):1076-1082. (PMID: 37201957)
Phys Med Biol. 2002 Feb 21;47(4):615-29. (PMID: 11900194)
Molecules. 2022 Aug 04;27(15):. (PMID: 35956909)
Clin Cancer Res. 2023 May 15;29(10):1916-1928. (PMID: 36917693)
J Radiol Prot. 2019 Jun;39(2):387-398. (PMID: 30716726)
Molecules. 2020 Dec 22;26(1):. (PMID: 33374953)
J Nucl Med. 2018 Jun;59(6):878-884. (PMID: 29545378)
Ther Adv Med Oncol. 2023 Mar 4;15:17588359231157632. (PMID: 36895851)
Curr Radiopharm. 2011 Oct;4(4):306-20. (PMID: 22202153)
N Engl J Med. 2021 Sep 16;385(12):1091-1103. (PMID: 34161051)
J Clin Invest. 2016 Dec 1;126(12):4640-4653. (PMID: 27841764)
Nucl Med Biol. 2021 Jan;92:228-240. (PMID: 33558017)
J Cancer Res Clin Oncol. 2018 Sep;144(9):1685-1699. (PMID: 29959569)
Theranostics. 2022 Oct 17;12(17):7203-7215. (PMID: 36438496)
J Exp Clin Cancer Res. 2023 Mar 11;42(1):61. (PMID: 36906664)
Clin Cancer Res. 2021 Mar 1;27(5):1305-1315. (PMID: 33293372)
Lancet. 2021 Feb 27;397(10276):797-804. (PMID: 33581798)
J Nucl Med. 2017 Oct;58(10):1624-1631. (PMID: 28408529)
Protein Cell. 2018 Jan;9(1):33-46. (PMID: 27743348)
J Nucl Med. 2021 Jul 1;62(7):1012-1015. (PMID: 33127622)
J Med Chem. 2022 May 12;65(9):6419-6430. (PMID: 35442675)
J Nucl Med. 2022 Jul 21;:. (PMID: 35863893)
J Clin Oncol. 2023 Nov 3;:JCO2300573. (PMID: 37922438)
Bioconjug Chem. 2017 Sep 20;28(9):2211-2223. (PMID: 28767228)
J Mater Chem B. 2021 Apr 7;9(13):2993-2997. (PMID: 33725072)
Nat Chem. 2021 Mar;13(3):284-289. (PMID: 33318671)
Int J Urol. 2018 Apr;25(4):345-351. (PMID: 29396873)
معلومات مُعتمدة: R01 CA279203 United States CA NCI NIH HHS
فهرسة مساهمة: Keywords: PEG linkers; YS5 antibody; actinium-225; cerium-134; macropa; targeted alpha therapy; theranostics
المشرفين على المادة: 0 (Radiopharmaceuticals)
0 (Chelating Agents)
0 (CD46 protein, human)
0 (Membrane Cofactor Protein)
تواريخ الأحداث: Date Created: 20240223 Date Completed: 20240226 Latest Revision: 20240309
رمز التحديث: 20240309
مُعرف محوري في PubMed: PMC10879874
DOI: 10.7150/thno.92742
PMID: 38389832
قاعدة البيانات: MEDLINE
الوصف
تدمد:1838-7640
DOI:10.7150/thno.92742