Evaluation of an 131I-labeled HER2-specific single domain antibody fragment for the radiopharmaceutical therapy of HER2-expressing cancers

• Published in: Scientific reports 2022-02, Vol.12 (1), p.3020-3020, Article 3020
• Main Authors: Feng, Yutian, Meshaw, Rebecca, McDougald, Darryl, Zhou, Zhengyuan, Zhao, Xiao-Guang, Jannetti, Stephen A., Reiman, Robert E., Pippen, Erica, Marjoram, Robin, Schaal, Jeffrey L., Vaidyanathan, Ganesan, Zalutsky, Michael R.
• Format: Article
• Language: English
• Subjects: 631/67/1059/602; 639/638/903; 692/4028/67/1347; Breast cancer; Breast carcinoma; Cancer; ErbB-2 protein; High-performance liquid chromatography; Humanities and Social Sciences; Kidneys; Liquid chromatography; multidisciplinary; Nanobodies; Ovarian carcinoma; Ovaries; Pharmaceuticals; Prostheses; Purification; Radioisotopes; Science; Science (multidisciplinary); Tumors; Xenografts
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-07006-9

Radiopharmaceutical therapy (RPT) is an attractive strategy for treatment of disseminated cancers including those overexpressing the HER2 receptor including breast, ovarian and gastroesophageal carcinomas. Single-domain antibody fragments (sdAbs) exemplified by the HER2-targeted VHH_1028 evaluated herein are attractive for RPT because they rapidly accumulate in tumor and clear faster from normal tissues than intact antibodies. In this study, VHH_1028 was labeled using the residualizing prosthetic agent N -succinimidyl 3-guanidinomethyl 5-[ 131 I]iodobenzoate ( iso -[ 131 I]SGMIB) and its tissue distribution evaluated in the HER2-expressing SKOV-3 ovarian and BT474 breast carcinoma xenograft models. In head-to-head comparisons to [ 131 I]SGMIB-2Rs15d, a HER2-targeted radiopharmaceutical currently under clinical investigation, iso -[ 131 I]SGMIB-VHH_1028 exhibited significantly higher tumor uptake and significantly lower kidney accumulation. The results demonstrated 2.9 and 6.3 times more favorable tumor-to-kidney radiation dose ratios in the SKOV-3 and BT474 xenograft models, respectively. Iso -[ 131 I]SGMIB-VHH_1028 was prepared using a solid-phase extraction method for purification of the prosthetic agent intermediate Boc 2 - iso -[ 131 I]SGMIB that reproducibly scaled to therapeutic-level doses and obviated the need for its HPLC purification. Single-dose (SKOV-3) and multiple-dose (BT474) treatment regimens demonstrated that iso -[ 131 I]SGMIB-VHH_1028 was well tolerated and provided significant tumor growth delay and survival prolongation. This study suggests that iso -[ 131 I]SGMIB-VHH_1028 is a promising candidate for RPT of HER2-expressing cancers and further development is warranted.