title: Novel antibody drug conjugates containing exatecan derivative-based cytotoxic payloads.
abstract: Trastuzumab conjugates consisting of exatecan derivatives were prepared and their biological activities and physicochemical properties were evaluated. The ADCs showed strong efficacy and a low aggregation rate. The exatecan derivatives were covalently connected via a peptidyl spacer (Gly-Gly-Phe-Gly), which is assumed to be stable in circulation, and were cleaved by lysosomal enzymes following ADC internalization into tumor tissue. These anti-HER2 ADCs exhibited a high potency, specifically against HER2-positive cancer cell lines in vitro. The ADCs, bearing exatecan derivatives which have more than two methylene chains, exhibited superior cytotoxicity. It was speculated that steric hindrance of the cleavable amide moiety could be involved in the drug release. The adequate alkyl lengths of exatecan derivatives (13, 14, 15) were from two to four in terms of aggregation rate. The ADC having a hydrophilic moiety showed good efficacy in a HER2-positive and Trastuzumab-resistant breast carcinoma cell model in mice.
authors.affiliation: Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: nakada.takashi.g6@daiichisankyo.co.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakada
authors.affiliation: Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Masuda
authors.affiliation: Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Naito
authors.affiliation: Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Ashida
authors.affiliation: Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Morita
authors.affiliation: Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Miyazaki
authors.affiliation: Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kasuya
authors.affiliation: Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ogitani
authors.affiliation: Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Yamaguchi
authors.affiliation: Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Abe
authors.affiliation: Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Honda
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007276:Injections, Intraventricular; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008968:Molecular Conformation; D013329:Structure-Activity Relationship; D000068878:Trastuzumab / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C095887:exatecan; D000068878:Trastuzumab; D002166:Camptothecin
keywords: Anti-HER2; Antibody drug conjugate; Camptothecin; Cancer therapy; Cytotoxic payload; Exatecan; Linker; Oncology; Trastuzumab