Convergent synthesis of hydrophilic monomethyl dolastatin 10 based drug linkers for antibody-drug conjugation.

Autor: Yang K; Sanofi Global R&D, 153 Second Avenue, Waltham, MA 02139, USA. Pradeep.Dhal@sanofi.com., Chen B; Sanofi Global R&D, 153 Second Avenue, Waltham, MA 02139, USA. Pradeep.Dhal@sanofi.com., Gianolio DA; Sanofi Global R&D, 153 Second Avenue, Waltham, MA 02139, USA. Pradeep.Dhal@sanofi.com., Stefano JE; Sanofi Global R&D, 153 Second Avenue, Waltham, MA 02139, USA. Pradeep.Dhal@sanofi.com., Busch M; Sanofi Global R&D, 153 Second Avenue, Waltham, MA 02139, USA. Pradeep.Dhal@sanofi.com., Manning C; Sanofi Global R&D, 153 Second Avenue, Waltham, MA 02139, USA. Pradeep.Dhal@sanofi.com., Alving K; Sanofi Global R&D, 153 Second Avenue, Waltham, MA 02139, USA. Pradeep.Dhal@sanofi.com., Gregory RC; Sanofi Global R&D, 153 Second Avenue, Waltham, MA 02139, USA. Pradeep.Dhal@sanofi.com., Brondyk WH; Sanofi Global R&D, 153 Second Avenue, Waltham, MA 02139, USA. Pradeep.Dhal@sanofi.com., Miller RJ; Sanofi Global R&D, 153 Second Avenue, Waltham, MA 02139, USA. Pradeep.Dhal@sanofi.com., Dhal PK; Sanofi Global R&D, 153 Second Avenue, Waltham, MA 02139, USA. Pradeep.Dhal@sanofi.com.
Jazyk: angličtina
Zdroj: Organic & biomolecular chemistry [Org Biomol Chem] 2019 Sep 21; Vol. 17 (35), pp. 8115-8124. Date of Electronic Publication: 2019 Aug 28.
DOI: 10.1039/c9ob01639b
Abstrakt: We report a modular approach to synthesize maleimido group containing hydrophilic dolastatin 10 (Dol10) derivatives as drug-linkers for the syntheses of antibody-drug conjugates (ADCs). Discrete polyethylene glycol (PEG) moieties of different chain lengths were introduced as part of the linker to impart hydrophilicity to these drug linkers. The synthesis process involved construction of PEG maleimido derivatives of the tetrapeptide intermediate (N-methylvaline-valine-dolaisoleucine-dolaproine), which were subsequently coupled with dolaphenine to generate the desired drug linkers. The synthetic method reported in this manuscript circumvents the use of highly cytotoxic Dol10 in its native form. By using trastuzumab (Herceptin®) as the antibody we have synthesized Dol10 containing ADCs. The presence of a discrete PEG chain in the drug linkers resulted in ADCs free from aggregation. The effect of PEG chain length on the biological activities of these Dol10 containing ADCs was investigated by in vitro cytotoxicity assays. ADCs containing PEG 6 and PEG 8 spacers exhibited the highest level of in vitro anti-proliferative activity against HER2-positive (SK-BR-3) human tumor cells. ADCs derived from Herceptin® and PEG 8 -Dol10, at a dose of 10 mg kg -1 , effectively delayed the tumor growth and prolonged the survival time in mice bearing human ovarian SKOV-3 xenografts.
Databáze: MEDLINE
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