{"created":"2023-05-15T14:52:40.111373+00:00","id":71909,"links":{},"metadata":{"_buckets":{"deposit":"35d52b5e-e3ea-4886-bb40-6e3a0ccaf5c9"},"_deposit":{"created_by":1,"id":"71909","owners":[1],"pid":{"revision_id":0,"type":"depid","value":"71909"},"status":"published"},"_oai":{"id":"oai:repo.qst.go.jp:00071909","sets":["10:28"]},"author_link":["708195","708191","708200","708201","708194","708198","708197","708196","708190","708199","708193","708192"],"item_10005_date_7":{"attribute_name":"発表年月日","attribute_value_mlt":[{"subitem_date_issued_datetime":"2016-02-19","subitem_date_issued_type":"Issued"}]},"item_10005_description_5":{"attribute_name":"抄録","attribute_value_mlt":[{"subitem_description":"Gastric cancer (GC) is one of the leading causes of cancer-related deaths in the world. Cytotoxic chemotherapeutic or molecularly targeted therapy agents for inoperable/progressive GC are currently available, for example, a humanized anti-HER2 antibody trastuzumab has been used for the treatment of HER2-positive GC patients. However, the therapeutic efficacy of pharmacotherapy is limited so far and the prognosis of patients with inoperable/progressive GC is still poor. To improve the clinical outcome of GC patients, novel antitumor strategies are required. Radioimmunotherapy (RIT) combines radiation therapy and immunotherapy, and has been emerged as an effective cancer therapy for non-Hodgkin’s lymphoma. RIT uses target-specific antibody conjugated to radioisotopes emitting particle radiation such as alpha- or beta-particles to achieve the targeted cell killing. Astatine-211 (At-211), an alpha-particle emitter, is of considerable interest for RIT because it deposits a large amount of energy within a few cell diameters and is highly cytotoxic by inducing irreparable DNA injuries. In this study, we investigated the efficacy of alpha-particle RIT using trastuzumab conjugated to At-211 ([At-211]trastuzumab) for the treatment of HER2-positive GC in a mouse xenograft model. Trastuzumab was conjugated with N-succinimidyl 3-trimethylstannyl-benzonate for At-211 labeling. The immunoconjugate (200 μg) was then labeled with At-211 (18.5-74 MBq), and the labeled antibody was purified by spin column. Specific activity of [At-211]trastuzumab was 239.5 ± 139.5 MBq/mg. Radiochemical purity was typically over 96% as determined by methanol precipitation. The stability of [At-211]trastuzumab in serum was 88.7% until 24 hours. The binding of [At-211]trastuzumab to HER2-positive human GC cells NCI-N87 (5 x 106 cells) was 72.8 ± 10.7% of input radioactivity, whereas 1.8 ± 0.5% to HER2-negative human GC cells MKN45 (5 x 106 cells). These results were comparable to the results of other radiolabeled trastuzumab antibodies such as an Indium-111 labeled trastuzumab. In vitro cytotoxicity studies showed that [At-211]trastuzumab (0.37 and 1.85 kBq) had a higher cytotoxicity to NCI-N87 cells compared to free form of At-211 and the equivalent protein amount of unlabeled trastuzumab. To investigate the effects of [At-211]trastuzumab on the tumor growth in vivo and bio-distribution of the radioimmunoconjugate, we established xenografts of NCI-N87 GC cells in nude mice. Bio-distribution studies revealed that the tumor uptake of [At-211]trastuzumab was increased over time, being 12.5 ± 4.0% injection dose/gram of tissue weight at 24 hours after injection of 0.5 MBq of [At-211]trastuzumab. A single administration of 0.5 MBq of [At-211]trastuzumab by intravenous injection significantly suppressed the tumor growth of subcutaneous xenografted tumors and prolonged the survival time compared to the xenograft mice injected with PBS or unlabeled trastuzumab. During the treatment, the counts of white blood cells and body weight in mice injected with 0.5 MBq of [At-211]trastuzumab temporarily decreased around 7 days after injection. However, the decrease was gradually recovered and they reached the comparable levels of control mice thereafter. Taken together, these findings suggest that [At-211]trastuzumab shows antitumor effects against HER2-positive human GC cells in vivo with acceptable toxicity and is a promising radioimmunotherapeutic agent for pharmacotherapy in HER2-positive GC.","subitem_description_type":"Abstract"}]},"item_10005_description_6":{"attribute_name":"会議概要（会議名, 開催地, 会期, 主催者等）","attribute_value_mlt":[{"subitem_description":"Tenth AACR-JCA Joint Conference on Breakthroughs in Cancer Research: From Biology to Therapeutics ","subitem_description_type":"Other"}]},"item_access_right":{"attribute_name":"アクセス権","attribute_value_mlt":[{"subitem_access_right":"metadata only access","subitem_access_right_uri":"http://purl.org/coar/access_right/c_14cb"}]},"item_creator":{"attribute_name":"著者","attribute_type":"creator","attribute_value_mlt":[{"creatorNames":[{"creatorName":"Hasegawa, Sumitaka"}],"nameIdentifiers":[{"nameIdentifier":"708190","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Li, Huizi"}],"nameIdentifiers":[{"nameIdentifier":"708191","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Morokoshi, Yukie"}],"nameIdentifiers":[{"nameIdentifier":"708192","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Nagatsu, Koutarou"}],"nameIdentifiers":[{"nameIdentifier":"708193","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Furukawa, Takako"}],"nameIdentifiers":[{"nameIdentifier":"708194","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Saga, Tsuneo"}],"nameIdentifiers":[{"nameIdentifier":"708195","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"長谷川 純崇","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"708196","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"李 惠子","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"708197","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"諸越 幸恵","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"708198","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"永津 弘太郎","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"708199","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"古川 高子","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"708200","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"佐賀 恒夫","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"708201","nameIdentifierScheme":"WEKO"}]}]},"item_language":{"attribute_name":"言語","attribute_value_mlt":[{"subitem_language":"eng"}]},"item_resource_type":{"attribute_name":"資源タイプ","attribute_value_mlt":[{"resourcetype":"conference object","resourceuri":"http://purl.org/coar/resource_type/c_c94f"}]},"item_title":"Preclinical evaluation of At-211-labeled trastuzumab, an alpha-particle radioimmunotherapeutic agent, for the treatment of gastric cancer.","item_titles":{"attribute_name":"タイトル","attribute_value_mlt":[{"subitem_title":"Preclinical evaluation of At-211-labeled trastuzumab, an alpha-particle radioimmunotherapeutic agent, for the treatment of gastric cancer."}]},"item_type_id":"10005","owner":"1","path":["28"],"pubdate":{"attribute_name":"公開日","attribute_value":"2016-03-08"},"publish_date":"2016-03-08","publish_status":"0","recid":"71909","relation_version_is_last":true,"title":["Preclinical evaluation of At-211-labeled trastuzumab, an alpha-particle radioimmunotherapeutic agent, for the treatment of gastric cancer."],"weko_creator_id":"1","weko_shared_id":-1},"updated":"2023-05-15T19:46:00.866748+00:00"}