Extracellular Antibody Drug Conjugates Exploiting the Proximity of Two Proteins

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, associ...

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Bibliographic Details
Published in:Molecular therapy 2016-10, Vol.24 (10), p.1760-1770
Main Authors: Marshall, David J, Harried, Scott S, Murphy, John L, Hall, Chad A, Shekhani, Mohammed S, Pain, Christophe, Lyons, Conner A, Chillemi, Antonella, Malavasi, Fabio, Pearce, Homer L, Thorson, Jon S, Prudent, James R
Format: Article
Language:English
Subjects:
Animals
Antibodies
Antibodies - chemistry
Antineoplastic Agents - administration & dosage
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Cancer
Cell Line, Tumor
Cell Proliferation - drug effects
Cell Survival - drug effects
Cells
Humans
Immunoconjugates - administration & dosage
Immunoconjugates - chemistry
Immunoconjugates - pharmacology
Metastasis
Mice
Molecular Structure
Molecular Targeted Therapy
Neoplasm Proteins - immunology
Neoplasm Proteins - metabolism
Neoplasms - drug therapy
Neoplasms - metabolism
Original
Polyethylene glycol
Proteins
Small Molecule Libraries - chemistry
Sodium-Potassium-Exchanging ATPase - antagonists & inhibitors
Sodium-Potassium-Exchanging ATPase - metabolism
Xenograft Model Antitumor Assays
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Summary: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.
ISSN:1525-0016
1525-0024
DOI:10.1038/mt.2016.119