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Modulating Therapeutic Activity and Toxicity of Pyrrolobenzodiazepine Antibody-Drug Conjugates with Self-Immolative Disulfide Linkers.
Pillow, Thomas H; Schutten, Melissa; Yu, Shang-Fan; Ohri, Rachana; Sadowsky, Jack; Poon, Kirsten Achilles; Solis, Willy; Zhong, Fiona; Del Rosario, Geoffrey; Go, Mary Ann T; Lau, Jeffrey; Yee, Sharon; He, Jintang; Liu, Luna; Ng, Carl; Xu, Keyang; Leipold, Douglas D; Kamath, Amrita V; Zhang, Donglu; Masterson, Luke; Gregson, Stephen J; Howard, Philip W; Fang, Fan; Chen, Jinhua; Gunzner-Toste, Janet; Kozak, Katherine K; Spencer, Susan; Polakis, Paul; Polson, Andrew G; Flygare, John A; Junutula, Jagath R.
Afiliación
  • Pillow TH; Genentech, Inc., South San Francisco, California. thomashp@gene.com.
  • Schutten M; Genentech, Inc., South San Francisco, California.
  • Yu SF; Genentech, Inc., South San Francisco, California.
  • Ohri R; Genentech, Inc., South San Francisco, California.
  • Sadowsky J; Genentech, Inc., South San Francisco, California.
  • Poon KA; Genentech, Inc., South San Francisco, California.
  • Solis W; Genentech, Inc., South San Francisco, California.
  • Zhong F; Genentech, Inc., South San Francisco, California.
  • Del Rosario G; Genentech, Inc., South San Francisco, California.
  • Go MAT; Genentech, Inc., South San Francisco, California.
  • Lau J; Genentech, Inc., South San Francisco, California.
  • Yee S; Genentech, Inc., South San Francisco, California.
  • He J; Genentech, Inc., South San Francisco, California.
  • Liu L; Genentech, Inc., South San Francisco, California.
  • Ng C; Genentech, Inc., South San Francisco, California.
  • Xu K; Genentech, Inc., South San Francisco, California.
  • Leipold DD; Genentech, Inc., South San Francisco, California.
  • Kamath AV; Genentech, Inc., South San Francisco, California.
  • Zhang D; Genentech, Inc., South San Francisco, California.
  • Masterson L; Spirogen Ltd., QMB Innovation Centre, London, United Kingdom.
  • Gregson SJ; Spirogen Ltd., QMB Innovation Centre, London, United Kingdom.
  • Howard PW; Spirogen Ltd., QMB Innovation Centre, London, United Kingdom.
  • Fang F; WuXi AppTec Co., Ltd., Shanghai, P.R. China.
  • Chen J; WuXi AppTec Co., Ltd., Shanghai, P.R. China.
  • Gunzner-Toste J; Genentech, Inc., South San Francisco, California.
  • Kozak KK; Genentech, Inc., South San Francisco, California.
  • Spencer S; Genentech, Inc., South San Francisco, California.
  • Polakis P; Genentech, Inc., South San Francisco, California.
  • Polson AG; Genentech, Inc., South San Francisco, California.
  • Flygare JA; Genentech, Inc., South San Francisco, California.
  • Junutula JR; Genentech, Inc., South San Francisco, California.
Mol Cancer Ther ; 16(5): 871-878, 2017 05.
Article en En | MEDLINE | ID: mdl-28223423
A novel disulfide linker was designed to enable a direct connection between cytotoxic pyrrolobenzodiazepine (PBD) drugs and the cysteine on a targeting antibody for use in antibody-drug conjugates (ADCs). ADCs composed of a cysteine-engineered antibody were armed with a PBD using a self-immolative disulfide linker. Both the chemical linker and the antibody site were optimized for this new bioconjugation strategy to provide a highly stable and efficacious ADC. This novel disulfide ADC was compared with a conjugate containing the same PBD drug, but attached to the antibody via a peptide linker. Both ADCs had similar efficacy in mice bearing human tumor xenografts. Safety studies in rats revealed that the disulfide-linked ADC had a higher MTD than the peptide-linked ADC. Overall, these data suggest that the novel self-immolative disulfide linker represents a valuable way to construct ADCs with equivalent efficacy and improved safety. Mol Cancer Ther; 16(5); 871-8. ©2017 AACR.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirroles / Benzodiazepinas / Inmunoconjugados / Anticuerpos / Neoplasias Límite: Animals / Humans Idioma: En Revista: Mol Cancer Ther Asunto de la revista: ANTINEOPLASICOS Año: 2017 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
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XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirroles / Benzodiazepinas / Inmunoconjugados / Anticuerpos / Neoplasias Límite: Animals / Humans Idioma: En Revista: Mol Cancer Ther Asunto de la revista: ANTINEOPLASICOS Año: 2017 Tipo del documento: Article Pais de publicación: Estados Unidos