Antibody-Drug Conjugates Targeting the Urokinase Receptor (uPAR) as a Possible Treatment of Aggressive Breast Cancer.

Autor: Harel ET; Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158, USA., Drake PM; Catalent Biologics, West, Emeryville, CA 94608, USA., Barfield RM; Catalent Biologics, West, Emeryville, CA 94608, USA., Lui I; Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158, USA., Farr-Jones S; Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA 94110, USA., Van't Veer L; Laboratory Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158, USA., Gartner ZJ; Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158, USA., Green EM; Biophysics Graduate Program and Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158, USA., Lourenço AL; Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158, USA., Cheng Y; Howard Hughes Medical Institute, University of California San Francisco, and Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158, USA., Hann BC; Preclinical Therapeutics Core, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA., Rabuka D; Catalent Biologics, West, Emeryville, CA 94608, USA., Craik CS; Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158, USA.
Jazyk: angličtina
Zdroj: Antibodies (Basel, Switzerland) [Antibodies (Basel)] 2019 Nov 05; Vol. 8 (4). Date of Electronic Publication: 2019 Nov 05.
DOI: 10.3390/antib8040054
Abstrakt: A promising molecular target for aggressive cancers is the urokinase receptor (uPAR). A fully human, recombinant antibody that binds uPAR to form a stable complex that blocks uPA-uPAR interactions (2G10) and is internalized primarily through endocytosis showed efficacy in a mouse xenograft model of highly aggressive, triple negative breast cancer (TNBC). Antibody-drug conjugates (ADCs) of 2G10 were designed and produced bearing tubulin inhibitor payloads ligated through seven different linkers. Aldehyde tag technology was employed for linking, and either one or two tags were inserted into the antibody heavy chain, to produce site-specifically conjugated ADCs with drug-to-antibody ratios of either two or four. Both cleavable and non-cleavable linkers were combined with two different antimitotic toxins-MMAE (monomethylauristatin E) and maytansine. Nine different 2G10 ADCs were produced and tested for their ability to target uPAR in cell-based assays and a mouse model. The anti-uPAR ADC that resulted in tumor regression comprised an MMAE payload with a cathepsin B cleavable linker, 2G10-RED-244-MMAE. This work demonstrates in vitro activity of the 2G10-RED-244-MMAE in TNBC cell lines and validates uPAR as a therapeutic target for TNBC.
Databáze: MEDLINE
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