Extracellular antibody drug conjugates exploiting the proximity of two proteins

David J. Marshall, Scott S. Harried, John L. Murphy, Chad A. Hall, Mohammed S. Shekhani, Christophe Pain, Conner A. Lyons, Antonella Chillemi, Fabio Malavasi, Homer L. Pearce, Jon S. Thorson, James R. Prudent

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

The human Na+ /K+ -ATPase (NKA) is a plasma membrane ion pump that uses ATP to help maintain the resting potential of all human cells. Inhibition of the NKA leads to cell swelling and death. The results of this investigation show that on cancer cells, the NKA either comes in close proximity to, associate with or complexes to important cancer-related proteins, and thus can be targeted with a new type of precision therapy called the extracellular drug conjugate or EDC. The EDCs reported here exhibit EC50 values in the low to mid-picomolar range, and signal to noise ratios > 1,000:1, both of which are dependent on the cell surface expression of the NKA and corresponding cancer-related target. We demonstrate that a potent small molecule inhibitor of the NKA can be covalently attached to antibodies targeting CD20, CD38, CD56, CD147, or dysadherin, to create a series of selective and powerful EDCs that kill cancer cells extracellularly by a mechanism resembling necrosis. This is therefore a framework for the development of a new type of precision therapy wherein exquisite selectivity is achieved for targeting extracellular disease-related proteins.

Original languageEnglish
Pages (from-to)1760-1770
Number of pages11
JournalMolecular Therapy
Volume24
Issue number10
DOIs
StatePublished - Oct 1 2016

Bibliographical note

Publisher Copyright:
© The American Society of Gene & Cell Therapy.

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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