Evaluation of Potency and Specificity of Cryptophycin-Loaded Antibody-Drug Conjugates.

Autor: Bitsch P; Clemens-Schöpf Institute for Organic Chemistry and Biochemistry, Technical University of Darmstadt, Peter-Grünberg-Str. 4, 64287, Darmstadt, Germany., Dessin C; Organic and Bioorganic Chemistry, Faculty of Chemistry, University of Bielefeld, Universitätsstraße 25, 33615, Bielefeld, Deutschland., Bitsch S; Clemens-Schöpf Institute for Organic Chemistry and Biochemistry, Technical University of Darmstadt, Peter-Grünberg-Str. 4, 64287, Darmstadt, Germany., Voss J; Organic and Bioorganic Chemistry, Faculty of Chemistry, University of Bielefeld, Universitätsstraße 25, 33615, Bielefeld, Deutschland., Becker J; Clemens-Schöpf Institute for Organic Chemistry and Biochemistry, Technical University of Darmstadt, Peter-Grünberg-Str. 4, 64287, Darmstadt, Germany., Sharma P; Lantern Pharma Inc., 1920 McKinney Ave, 7th Floor, Dallas 75201, TX, USA., Biyani N; Lantern Pharma Inc., 1920 McKinney Ave, 7th Floor, Dallas 75201, TX, USA., Kochat H; The University of Tennessee, Health Science Center, 208 S., Dudley Street, Memphis, 38163, TN, USA., Sewald N; Organic and Bioorganic Chemistry, Faculty of Chemistry, University of Bielefeld, Universitätsstraße 25, 33615, Bielefeld, Deutschland., Kolmar H; Clemens-Schöpf Institute for Organic Chemistry and Biochemistry, Technical University of Darmstadt, Peter-Grünberg-Str. 4, 64287, Darmstadt, Germany.; Centre of Synthetic Biology, Technical University of Darmstadt, Peter-Grünberg-Str. 4, 64287, Darmstadt, Germany.
Jazyk: angličtina
Zdroj: Chembiochem : a European journal of chemical biology [Chembiochem] 2024 Oct 27, pp. e202400738. Date of Electronic Publication: 2024 Oct 27.
DOI: 10.1002/cbic.202400738
Abstrakt: An enhanced variant of the antimitotic toxin cryptophycin was conjugated to the anti-Her2 monoclonal antibody (mAb) Trastuzumab upon Michael addition. Either antibodies with freed hinge-region cysteines or THIOMAB formats with engineered cysteines in the mAbs light chain were added to a maleimide derivative of cryptophycin. These Antibody-Drug Conjugates (ADCs) showed retained binding to Her2 positive tumor cells and highly efficient cell killing in double-digit pM range on high Her2-expressing SK-BR-3 cells. Two ADCs (DAR 6, DAR 3) showed superior cell killing of the cell lines JIMT-1 and RT112 with medium receptor expression level in comparison with a DAR 6 MMAE ADC serving as reference. The observed cell cytotoxicity is target-dependent since no impact on cell viability was observed for low Her2-expressing MDA-MB468 cells. Particularly the DAR 3 ADC in THIOMAB format exhibiting desirable biophysical properties and high potency emerged as a promising candidate for further in vivo investigations.
(© 2024 Wiley-VCH GmbH.)
Databáze: MEDLINE
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