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Mol Cancer Ther. 2018 Jan;17(1):169-182. doi: 10.1158/1535-7163.MCT-17-0092. Epub 2017 Sep 22.

Targeting Phosphatidylserine with Calcium-Dependent Protein-Drug Conjugates for the Treatment of Cancer.

Author information

1
Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, College Station, Texas.
2
Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas.
3
Department of Biomedical Engineering, Texas A&M University, College Station, Texas.
4
Biomedical Engineering Graduate Program, University of Texas Southwestern Medical Center, Dallas, Texas.
5
China Pharmaceutical University, Nanjing, Jiangsu, China.
6
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas.
7
Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, College Station, Texas. sally.ward@tamu.edu.
8
Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, College Station, Texas.

Abstract

In response to cellular stress, phosphatidylserine is exposed on the outer membrane leaflet of tumor blood vessels and cancer cells, motivating the development of phosphatidylserine-specific therapies. The generation of drug-conjugated phosphatidylserine-targeting agents represents an unexplored therapeutic approach, for which antitumor effects are critically dependent on efficient internalization and lysosomal delivery of the cytotoxic drug. In the current study, we have generated phosphatidylserine-targeting agents by fusing phosphatidylserine-binding domains to a human IgG1-derived Fc fragment. The tumor localization and pharmacokinetics of several phosphatidylserine-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 phosphatidylserine binding, dissociates from phosphatidylserine in early endosomes. The released PDC is efficiently delivered to lysosomes and has potent antitumor effects in mouse xenograft tumor models. Interestingly, although 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 phosphatidylserine-targeting agents can be therapeutically efficacious. Mol Cancer Ther; 17(1); 169-82. ©2017 AACR.

PMID:
28939556
PMCID:
PMC5752623
[Available on 2019-01-01]
DOI:
10.1158/1535-7163.MCT-17-0092

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