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hIMB1636-MMAE, a Novel TROP2-Targeting Antibody-Drug Conjugate Exerting Potent Antitumor Efficacy in Pancreatic Cancer.
Sun, Li-Ping; Bai, Wei-Qi; Zhou, Dan-Dan; Wu, Xiao-Fan; Zhang, Lan-Wen; Cui, A-Long; Xie, Zi-Hui; Gao, Rui-Juan; Zhen, Yong-Su; Li, Zhuo-Rong; Miao, Qing-Fang.
Afiliación
  • Sun LP; NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Tiantan Xili, Beijing 100050, China.
  • Bai WQ; Department of Organic Chemistry, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Tiantan Xili, Beijing 100050, China.
  • Zhou DD; NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Tiantan Xili, Beijing 100050, China.
  • Wu XF; Department of Organic Chemistry, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Tiantan Xili, Beijing 100050, China.
  • Zhang LW; NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Tiantan Xili, Beijing 100050, China.
  • Cui AL; Department of Organic Chemistry, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Tiantan Xili, Beijing 100050, China.
  • Xie ZH; NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Tiantan Xili, Beijing 100050, China.
  • Gao RJ; NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Tiantan Xili, Beijing 100050, China.
  • Zhen YS; NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Tiantan Xili, Beijing 100050, China.
  • Li ZR; Department of Organic Chemistry, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Tiantan Xili, Beijing 100050, China.
  • Miao QF; NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Tiantan Xili, Beijing 100050, China.
J Med Chem ; 66(21): 14700-14715, 2023 11 09.
Article en En | MEDLINE | ID: mdl-37883180
Herein, we first prepared a novel anti-TROP2 antibody-drug conjugate (ADC) hIMB1636-MMAE using hIMB1636 antibody chemically coupled to monomethyl auristatin E (MMAE) via a Valine-Citrulline linker and then reported its characteristics and antitumor activity. With a DAR of 3.92, it binds specifically to both recombinant antigen (KD ∼ 0.687 nM) and cancer cells and could be internalized by target cells and selectively kill them with IC50 values at nanomolar/subnanomolar levels by inducing apoptosis and G2/M phase arrest. hIMB1636-MMAE also inhibited cell migration, induced ADCC effects, and had bystander effects. It displayed significant tumor-targeting ability and excellent tumor-suppressive effects in vivo, resulting in 5/8 tumor elimination at 12 mg/kg in the T3M4 xenograft model or complete tumor disappearance at 10 mg/kg in BxPc-3 xenografts in nude mice. Its half-life in mice was about 87 h. These data suggested that hIMB1636-MMAE was a promising candidate for the treatment of pancreatic cancer with TROP2 overexpression.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Inmunoconjugados Límite: Animals / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2023 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Inmunoconjugados Límite: Animals / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2023 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos