Comparison of targeting two antigens (GPA33 versus HER2) for (225)Ac-pretargeted alpha-radioimmunotherapy of colorectal cancer Journal Article
| Authors: | Rinne, S. S.; Vargas, D. B.; Vaughn, B. A.; Katugampola, S.; Miller, B. W.; Veach, D. R.; Punzalan, B.; de Stanchina, E.; Yaeger, R.; Miranda, I. C.; Xu, H.; Guo, H.; Schwartz, J.; Fung, E. K.; Howell, R. W.; Larson, S. M.; Cheung, N. V.; Cheal, S. M. |
| Article Title: | Comparison of targeting two antigens (GPA33 versus HER2) for (225)Ac-pretargeted alpha-radioimmunotherapy of colorectal cancer |
| Abstract: | Purpose: Curative therapies remain a significant unmet need for advanced human colorectal cancer (CRC). The aim of this study was to establish a 3-step 225Ac-DOTA pretargeted radioimmunotherapy (PRIT) system for human CRC, targeting two individual antigens: glycoprotein A33 (GPA33) and human epidermal growth factor receptor 2 (HER2). Methods:In vitro cellular uptake and internalization assays, as well as survival assays (colony forming) were performed in GPA33- and HER2-positive SW1222 human CRC cells. In vivo biodistribution and therapy studies were performed with two human CRC xenograft mouse models. Results: For both antigens, treatment with up to 74 kBq 225Ac-DOTA-PRIT in SW1222-tumored mice significantly enhanced overall survival in comparison to controls, including histologic cures. The uptake of 225Ac at the tumor correlated with antigen expression (antigen expression for GPA33:HER2 is 5:1). Cellular assays showed no significant differences in internalized fraction or nucleus-associated radioactivity between the two targets. GPA33 had a higher absorbed dose to the nucleus (1.3 Gy vs. 0.65 Gy for HER2), resulting in reduced clonogenic survival. A single cycle of either GPA33 or HER2 DOTA-PRIT (37 kBq; 193.31 Gy and 113.91 Gy (relative biological effectiveness [RBE] = 5), respectively) was equally effective. No chronic nephrotoxicity was seen at ≤ 20 Gy (RBE = 5). The efficacy of GPA33-directed 225Ac-DOTA-PRIT was also confirmed in a patient-derived xenograft model. Conclusion: In summary, 225Ac-DOTA-PRIT to GPA33 or HER2 was highly effective and safe in preclinical models of human CRC. Tumor response to treatment could not be predicted by nuclear absorbed dose alone, highlighting the importance of comprehensive micro- and macro-dosimetry. This record is sourced from MEDLINE/PubMed, a database of the U.S. National Library of Medicine |
| Keywords: | treatment outcome; comparative study; mouse; animal; metabolism; animals; mice; radiotherapy; epidermal growth factor receptor 2; drug screening; xenograft model antitumor assays; cell line, tumor; colorectal neoplasms; disease model; tissue distribution; membrane glycoproteins; colorectal tumor; membrane protein; tumor cell line; receptor, erbb-2; disease models, animal; radioimmunotherapy; human epidermal growth factor receptor 2; erbb2 protein, human; actinium; procedures; actinium-225; pretargeted radioimmunotherapy; glycoprotein a33; humans; human; female; gpa33 protein, human; targeted alpha therapy |
| Journal Title: | Theranostics |
| Volume: | 15 |
| Issue: | 15 |
| ISSN: | 1838-7640 |
| Publisher: | Ivyspring International Publisher |
| Date Published: | 2025-06-20 |
| Start Page: | 7489 |
| End Page: | 7500 |
| Language: | English |
| DOI: | 10.7150/thno.116062 |
| PUBMED: | 40756357 |
| PROVIDER: | scopus |
| PMCID: | PMC12315807 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PDF -- MSK corresponding author is Sarah Cheal -- Source: Scopus |
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