Monday, September 25, 2017 1:09:41 PM
Sep. 22 2017
Li R1, Chiguru S2, Li L2, Kim D3, Velmurugan R4, Kim D5, Devanaboyina SC1, Tian H6, Schroit A7, Mason R2, Ober RJ8, Ward ES9.
Author information
1Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center.Department of Radiology, University of Texas Southwestern Medical Center.Biomedical Engineering, Texas A&M University.Biomedical Engineering Graduate Program, University of Texas Southwestern Medical Center.Texas A&M University.China Pharmaceutical University.Department of Pharmacology, University of Texas Southwestern Medical Center.Department of Biomedical Engineering, Texas A&M University.Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center sally.ward@medicine.tamhsc.edu.
Abstract
In response to cellular stress, phosphatidylserine (PS) is exposed on the outer membrane leaflet of tumor blood vessels and cancer cells, motivating the development of PS-specific therapies. The generation of drug-conjugated PS-targeting agents represents an unexplored therapeutic approach, for which anti-tumor effects are critically dependent on efficient internalization and lysosomal delivery of the cytotoxic drug. In the current study, we have generated PS-targeting agents by fusing PS-binding domains to a human IgG1-derived Fc fragment. The tumor localization and pharmacokinetics of several PS-specific Fc fusions have been analyzed in mice and demonstrate that Fc-Syt1, a fusion containing the synaptotagmin 1 C2A domain, effectively targets tumor tissue. Conjugation of Fc-Syt1 to the cytotoxic drug, monomethyl auristatin E, results in a protein-drug conjugate (PDC) that is internalized into target cells and, due to the Ca²?-dependence of PS binding, dissociates from PS in early endosomes. The released PDC is efficiently delivered to lysosomes and has potent anti-tumor effects in mouse xenograft tumor models. Interestingly, whilst an engineered, tetravalent Fc-Syt1 fusion shows increased binding to target cells, this higher avidity variant demonstrates reduced persistence and therapeutic effects compared with bivalent Fc-Syt1. Collectively, these studies show that finely tuned, Ca²?-switched PS-targeting agents can be therapeutically efficacious.
Copyright ©2017, American Association for Cancer Research.
https://www.ncbi.nlm.nih.gov/pubmed/28939556
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