Antibody-Drug Conjugates with Pyrrole-Based KSP Inhibitors as the Payload Class.

Autor: Lerchen HG; Bayer AG R&D Pharmaceuticals, Aprather Weg 18a, 42113, Wuppertal, Germany., Wittrock S; Bayer AG R&D Pharmaceuticals, Berlin, Germany., Stelte-Ludwig B; Bayer AG R&D Pharmaceuticals, Aprather Weg 18a, 42113, Wuppertal, Germany., Sommer A; Bayer AG R&D Pharmaceuticals, Berlin, Germany., Berndt S; Bayer AG R&D Pharmaceuticals, Berlin, Germany., Griebenow N; Bayer AG Animal Health, Lead Discovery, Monheim, Germany., Rebstock AS; Bayer AG Crop Science, Lyon, France., Johannes S; Bayer AG R&D Pharmaceuticals, Aprather Weg 18a, 42113, Wuppertal, Germany., Cancho-Grande Y; Bayer AG R&D Pharmaceuticals, Aprather Weg 18a, 42113, Wuppertal, Germany., Mahlert C; Bayer AG R&D Pharmaceuticals, Aprather Weg 18a, 42113, Wuppertal, Germany., Greven S; Bayer AG R&D Pharmaceuticals, Aprather Weg 18a, 42113, Wuppertal, Germany., Terjung C; Bayer AG R&D Pharmaceuticals, Aprather Weg 18a, 42113, Wuppertal, Germany.
Jazyk: angličtina
Zdroj: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2018 Nov 12; Vol. 57 (46), pp. 15243-15247. Date of Electronic Publication: 2018 Oct 15.
DOI: 10.1002/anie.201807619
Abstrakt: The number of cytotoxic payload classes successfully employed in antibody-drug conjugates (ADCs) is still rather limited. The identification of ADC payloads with a novel mode of action will increase therapeutic options and potentially increase the therapeutic window. Herein, we describe the utilization of kinesin spindle protein inhibitors (KSPi) as a novel payload class providing highly potent ADCs against different targets, for instance HER-2 or TWEAKR/Fn14. Aspects of technical optimization include the development of different linker attachment sites, the stabilization of ADC linkage to avoid payload deconjugation and finally, the tailor-made design of active metabolites with a long lasting intracellular exposure in the tumor matching the mode of action of KSP inhibition. These KSPi-ADCs are highly potent and selective in vitro and demonstrate in vivo efficacy in a broad panel of tumor models including complete regressions in a patient-derived urothelial cancer model.
(© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
Databáze: MEDLINE
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