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Theranostics 2024; 14(4):1344-1360. doi:10.7150/thno.92742 This issue Cite

Research Paper

Development of CD46 targeted alpha theranostics in prostate cancer using ¹³⁴Ce/²²⁵Ac-Macropa-PEG₄-YS5

Kondapa Naidu Bobba¹, Anil P. Bidkar¹, Anju Wadhwa¹, Niranjan Meher¹, Suchi Drona¹, Alexandre M. Sorlin¹, Scott Bidlingmaier², Li Zhang³, David M. Wilson^1,4, Emily Chan⁵, Nancy Y. Greenland⁵, Rahul Aggarwal^4,6, Henry F. VanBrocklin^1,4, Jiang He⁷, Jonathan Chou^4,6, Youngho Seo^1,4, Bin Liu^2,4, Robert R. Flavell^1,4,8✉

1. Department of Radiology and Biomedical Imaging, University of California, San Francisco, California 94143, United States.
2. Department of Anesthesia, University of California, San Francisco, California 94110, United States.
3. Department of Medicine and the Department of Epidemiology and Biostatistics, University of California, Berkeley, California, United States.
4. UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California 94143-0981, United States.
5. Department of Pathology, University of California, San Francisco, California 94110, United States.
6. Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, United States.
7. Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, Virginia, 22908, United States.
8. Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158-2517, United States.

✉ Corresponding author: Robert R. Flavell, E-mail: robert.flavelledu.

Abstract

Rationale: ²²⁵Ac, 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 ²²⁵Ac, 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 ²²⁵Ac-Macropa-PEG₄-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 ²²⁵Ac in a 2 M NH₄OAc 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 ¹³⁴Ce-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 ²²⁵Ac, 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 ²²⁵Ac-Macropa-PEG₄-YS5 (82.82 ± 38.27 %ID/g) compared to other conjugates, namely ²²⁵Ac-Macropa-PEG_0/8-YS5 (38.2 ± 14.4/36.39 ± 12.4 %ID/g) and ²²⁵Ac-DOTA-YS5 (29.35 ± 7.76 %ID/g). The PET Imaging of ¹³⁴Ce-Macropa-PEG_0/4/8-YS5 conjugates resulted in a high tumor uptake, and tumor to background ratios. In terms of antitumor activity, ²²⁵Ac-Macropa-PEG₄-YS5 exhibited a substantial response, leading to prolonged survival compared to ²²⁵Ac-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 ²²⁵Ac-Macropa-PEG₄-YS5 for targeted alpha particle therapy. The ²²⁵Ac-Macropa-PEG₄-YS5 conjugate demonstrates improved biodistribution, reduced off-target binding, and enhanced therapeutic efficacy, particularly at lower doses, compared to ²²⁵Ac-DOTA-YS5. Incorporating theranostic ¹³⁴Ce 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.

Keywords: targeted alpha therapy, PEG linkers, YS5 antibody, macropa, actinium-225, cerium-134, theranostics

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