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211At-labeled immunoconjugate via a one-pot three-component double click strategy: practical access to ?-emission cancer radiotherapeutics.

ABSTRACT: ?-Emission radiotherapeutics has potential to be one of most effective cancer therapeutics. Herein, we report a facile synthesis of an 211At-labeled immunoconjugate for use as an ?-emission molecular targeting therapy. We synthesized a tetrazine probe modified with closo-decaborate(2-), a prosthetic group that forms a bioavailable stable complex with 211At. Our one-pot three-component double-click labeling method was used to attach decaborate to trastuzumab (anti-HER2 antibody) using decaborate-tetrazine and TCO-aldehyde probes without reducing the antibody binding affinity. Labeling the decaborate-attached trastuzumab with 211At produced in the cyclotron at the RIKEN Nishina Center, at which highly radioactive 211At can be produced, readily furnished the 211At-labeled trastuzumab with a maximum specific activity of 15 MBq ?g-1 and retention of the native binding affinity. Intratumor injection of the 211At-labeled trastuzumab in BALB/c nude mice implanted with HER2-expressing epidermoid cancer cells yielded efficient accumulation at the targeted tumor site as well as effective suppression of tumor growth.

SUBMITTER: Fujiki K

PROVIDER: S-EPMC6385556 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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211At-labeled immunoconjugate via a one-pot three-component double click strategy: practical access to α-emission cancer radiotherapeutics.

Fujiki Katsumasa K Kanayama Yousuke Y Yano Shinya S Sato Nozomi N Yokokita Takuya T Ahmadi Peni P Watanabe Yasuyoshi Y Haba Hiromitsu H Tanaka Katsunori K

Chemical science 20181221 7

α-Emission radiotherapeutics has potential to be one of most effective cancer therapeutics. Herein, we report a facile synthesis of an 211At-labeled immunoconjugate for use as an α-emission molecular targeting therapy. We synthesized a tetrazine probe modified with closo-decaborate(2-), a prosthetic group that forms a bioavailable stable complex with 211At. Our one-pot three-component double-click labeling method was used to attach decaborate to trastuzumab (anti-HER ...[more]

PMID: 30881623

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Project description:Antibodies labeled with alpha-emitter astatine-211 have previously shown effective in intraperitoneal (i.p.) treatments of ovarian cancer. In the present work we explore the use of investigational farletuzumab, aimed at the folate receptor alpha. The aim was to evaluate the biodistribution and therapeutic effect of 211At-farletuzumab in in-vitro and in-vivo experiments and, using models for radiation dosimetry, to translate the findings to expected clinical result. The activity concentration used for therapy in mice (170?kBq/mL) was chosen to be in agreement with an activity concentration that is anticipated to be clinically relevant in patients (200?MBq/L). For biodistribution, using intravenous injections and mice carrying subcutaneous (s.c.) tumors, the animals were administered either 211At-farletuzumab (n?=?16); or with a combination of 125I-farletuzumab and 211At-MX35 (n?=?12). At 1, 3, 10 and 22?h, mice were euthanized and s.c.-tumors and organs weighted and measured for radioactivity. To evaluate therapeutic efficacy, mice were inoculated i.p. with 2?×?106 NIH:OVCAR-3 cells. Twelve days later, the treatments were initiated by i.p.-administration. Specific treatment was given by 211At-labeled farletuzumab (group A; n?=?22, 170?kBq/mL) which is specific for OVCAR-3 cells. Control treatments were given by either 211At-labeled rituximab which is unspecific for OVCAR-3 (group B; n?=?22, 170?kBq/mL), non-radiolabeled farletuzumab (group C; n?=?11) or PBS only (group D; n?=?8). The biodistribution of 211At-farletuzumab was similar to that with 125I as radiolabel, and also to that of 211At-labeled MX35 antibody. The tumor-free fraction (TFF) of the three control groups were all low (PBS 12%, unlabeled specific farletuzumab 9% and unspecific 211At-rituximab 14%). TFF following treatment with 211At-farletuzumab was 91%. The current investigation of intraperitoneal therapy with 211At-farletuzumab, delivered at clinically relevant 211At-mAb radioactivity concentrations and specific activities, showed a 6 to 10-fold increase (treated versus controls) in antitumor efficacy. This observation warrants further clinical testing.

Dataset Information

211At-labeled immunoconjugate via a one-pot three-component double click strategy: practical access to ?-emission cancer radiotherapeutics.

Publications

<sup>211</sup>At-labeled immunoconjugate <i>via</i> a one-pot three-component double click strategy: practical access to α-emission cancer radiotherapeutics.

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