Efficient Payload Delivery by a Bispecific Antibody-Drug Conjugate Targeting HER2 and CD63.
Autor: | de Goeij BE; Genmab, Utrecht, the Netherlands. BGO@genmab.com., Vink T; Genmab, Utrecht, the Netherlands., Ten Napel H; Genmab, Utrecht, the Netherlands., Breij EC; Genmab, Utrecht, the Netherlands., Satijn D; Genmab, Utrecht, the Netherlands., Wubbolts R; Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands., Miao D; Concortis Biosystems Corp., San Diego, California., Parren PW; Genmab, Utrecht, the Netherlands.; Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.; Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands. |
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Jazyk: | angličtina |
Zdroj: | Molecular cancer therapeutics [Mol Cancer Ther] 2016 Nov; Vol. 15 (11), pp. 2688-2697. Date of Electronic Publication: 2016 Aug 24. |
DOI: | 10.1158/1535-7163.MCT-16-0364 |
Abstrakt: | Antibody-drug conjugates (ADC) are designed to be stable in circulation and to release potent cytotoxic drugs intracellularly following antigen-specific binding, uptake, and degradation in tumor cells. Efficient internalization and routing to lysosomes where proteolysis can take place is therefore essential. For many cell surface proteins and carbohydrate structures on tumor cells, however, the magnitude of these processes is insufficient to allow for an effective ADC approach. We hypothesized that we could overcome this limitation by enhancing lysosomal ADC delivery via a bispecific antibody (bsAb) approach, in which one binding domain would provide tumor specificity, whereas the other binding domain would facilitate targeting to the lysosomal compartment. We therefore designed a bsAb in which one binding arm specifically targeted CD63, a protein that is described to shuttle between the plasma membrane and intracellular compartments, and combined it in a bsAb with a HER2 binding arm, which was selected as model antigen for tumor-specific binding. The resulting bsHER2xCD63 (©2016 American Association for Cancer Research.) |
Databáze: | MEDLINE |
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