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Theranostics 2020; 10(25):11359-11375. doi:10.7150/thno.48810 This issue Cite

Research Paper

Alpha radioimmunotherapy using 225Ac-proteus-DOTA for solid tumors - safety at curative doses

Sarah M. Cheal1, Michael R. McDevitt2,9, Brian H. Santich3,4, Mitesh Patel1, Guangbin Yang5, Edward K. Fung6, Darren R. Veach2,9, Meghan Bell1, Afruja Ahad1, Daniela Burnes Vargas1, Blesida Punzalan1, Naga Vara Kishore Pillarsetty2,9, Hong Xu3, Hong-fen Guo3, Sébastien Monette7, Adam O. Michel7, Alessandra Piersigilli7, David A. Scheinberg1,8, Ouathek Ouerfelli5, Nai-Kong V. Cheung1,3, Steven M. Larson1,2,9✉

1. Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY.
2. Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY.
3. Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY.
4. Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY.
5. Organic Synthesis Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY.
6. Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY.
7. Laboratory of Comparative Pathology, Memorial Sloan Kettering Cancer Center, Weill Cornell Medicine, and The Rockefeller University, New York, NY.
8. Immunology Program, Weill Cornell Medicine, New York, NY.
9. Department of Radiology, Weill Cornell Medicine, New York, NY

✉ Corresponding author: Steven M. Larson, MD, FACNM, FACR, 415 East 68th Street, Z-2064, New York, NY 10065. Tel: 646-888-2212; Fax: 212-717-3263; E-mail: larsonsorg; ORCID ID: orcid.org/0000-0002-6111-7507.

Citation:
Cheal SM, McDevitt MR, Santich BH, Patel M, Yang G, Fung EK, Veach DR, Bell M, Ahad A, Vargas DB, Punzalan B, Pillarsetty NVK, Xu H, Guo Hf, Monette S, Michel AO, Piersigilli A, Scheinberg DA, Ouerfelli O, Cheung NKV, Larson SM. Alpha radioimmunotherapy using 225Ac-proteus-DOTA for solid tumors - safety at curative doses. Theranostics 2020; 10(25):11359-11375. doi:10.7150/thno.48810. https://www.thno.org/v10p11359.htm
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Abstract

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This is the initial report of an α-based pre-targeted radioimmunotherapy (PRIT) using 225Ac and its theranostic pair, 111In. We call our novel tumor-targeting DOTA-hapten PRIT system “proteus-DOTA” or “Pr.” Herein we report the first results of radiochemistry development, radiopharmacology, and stoichiometry of tumor antigen binding, including the role of specific activity, anti-tumor efficacy, and normal tissue toxicity with the Pr-PRIT approach (as α-DOTA-PRIT). A series of α-DOTA-PRIT therapy studies were performed in three solid human cancer xenograft models of colorectal cancer (GPA33), breast cancer (HER2), and neuroblastoma (GD2), including evaluation of chronic toxicity at ~20 weeks of select survivors.

Methods: Preliminary biodistribution experiments in SW1222 tumor-bearing mice revealed that 225Ac could not be efficiently pretargeted with current DOTA-Bn hapten utilized for 177Lu or 90Y, leading to poor tumor uptake in vivo. Therefore, we synthesized Pr consisting of an empty DOTA-chelate for 225Ac, tethered via a short polyethylene glycol linker to a lutetium-complexed DOTA for picomolar anti-DOTA chelate single-chain variable fragment (scFv) binding. Pr was radiolabeled with 225Ac and its imaging surrogate, 111In. In vitro studies verified anti-DOTA scFv recognition of [225Ac]Pr, and in vivo biodistribution and clearance studies were performed to evaluate hapten suitability and in vivo targeting efficiency.

Results: Intravenously (i.v.) administered 225Ac- or 111In-radiolabeled Pr in mice showed rapid renal clearance and minimal normal tissue retention. In vivo pretargeting studies show high tumor accumulation of Pr (16.71 ± 5.11 %IA/g or 13.19 ± 3.88 %IA/g at 24 h p.i. for [225Ac]Pr and [111In]Pr, respectively) and relatively low uptake in normal tissues (all average ≤ 1.4 %IA/g at 24 h p.i.). Maximum tolerated dose (MTD) was not reached for either [225Ac]Pr alone or pretargeted [225Ac]Pr at administered activities up to 296 kBq/mouse. Single-cycle treatment consisting of α-DOTA-PRIT with either huA33-C825 bispecific anti-tumor/anti-DOTA-hapten antibody (BsAb), anti-HER2-C825 BsAb, or hu3F8-C825 BsAb for targeting GPA33, HER2, or GD2, respectively, was highly effective. In the GPA33 model, no complete responses (CRs) were observed but prolonged overall survival of treated animals was 42 d for α-DOTA-PRIT vs. 25 d for [225Ac]Pr only (P < 0.0001); for GD2, CRs (7/7, 100%) and histologic cures (4/7, 57%); and for HER2, CRs (7/19, 37%) and histologic cures (10/19, 56%) with no acute or chronic toxicity.

Conclusions: [225Ac]Pr and its imaging biomarker [111In]Pr demonstrate optimal radiopharmacologic behavior for theranostic applications of α-DOTA-PRIT. For this initial evaluation of efficacy and toxicity, single-cycle treatment regimens were performed in all three systems. Histologic toxicity was not observed, so MTD was not observed. Prolonged overall survival, CRs, and histologic cures were observed in treated animals. In comparison to RIT with anti-tumor IgG antibodies, [225Ac]Pr has a much improved safety profile. Ultimately, these data will be used to guide clinical development of toxicity and efficacy studies of [225Ac]Pr, with the goal of delivering massive lethal doses of radiation to achieve a high probability of cure without toxicity.

Keywords: Ac-225, pretargeted radioimmunotherapy, pretargeting, radioimmunotherapy, TAT

Citation styles

APA
Cheal, S.M., McDevitt, M.R., Santich, B.H., Patel, M., Yang, G., Fung, E.K., Veach, D.R., Bell, M., Ahad, A., Vargas, D.B., Punzalan, B., Pillarsetty, N.V.K., Xu, H., Guo, H.f., Monette, S., Michel, A.O., Piersigilli, A., Scheinberg, D.A., Ouerfelli, O., Cheung, N.K.V., Larson, S.M. (2020). Alpha radioimmunotherapy using 225Ac-proteus-DOTA for solid tumors - safety at curative doses. Theranostics, 10(25), 11359-11375. https://doi.org/10.7150/thno.48810.

ACS
Cheal, S.M.; McDevitt, M.R.; Santich, B.H.; Patel, M.; Yang, G.; Fung, E.K.; Veach, D.R.; Bell, M.; Ahad, A.; Vargas, D.B.; Punzalan, B.; Pillarsetty, N.V.K.; Xu, H.; Guo, H.f.; Monette, S.; Michel, A.O.; Piersigilli, A.; Scheinberg, D.A.; Ouerfelli, O.; Cheung, N.K.V.; Larson, S.M. Alpha radioimmunotherapy using 225Ac-proteus-DOTA for solid tumors - safety at curative doses. Theranostics 2020, 10 (25), 11359-11375. DOI: 10.7150/thno.48810.

NLM
Cheal SM, McDevitt MR, Santich BH, Patel M, Yang G, Fung EK, Veach DR, Bell M, Ahad A, Vargas DB, Punzalan B, Pillarsetty NVK, Xu H, Guo Hf, Monette S, Michel AO, Piersigilli A, Scheinberg DA, Ouerfelli O, Cheung NKV, Larson SM. Alpha radioimmunotherapy using 225Ac-proteus-DOTA for solid tumors - safety at curative doses. Theranostics 2020; 10(25):11359-11375. doi:10.7150/thno.48810. https://www.thno.org/v10p11359.htm

CSE
Cheal SM, McDevitt MR, Santich BH, Patel M, Yang G, Fung EK, Veach DR, Bell M, Ahad A, Vargas DB, Punzalan B, Pillarsetty NVK, Xu H, Guo Hf, Monette S, Michel AO, Piersigilli A, Scheinberg DA, Ouerfelli O, Cheung NKV, Larson SM. 2020. Alpha radioimmunotherapy using 225Ac-proteus-DOTA for solid tumors - safety at curative doses. Theranostics. 10(25):11359-11375.

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