title: Extracellular Antibody Drug Conjugates Exploiting the Proximity of Two Proteins.
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 EC50values 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.
authors.affiliation: Centrose, Madison, Wisconsin, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Marshall
authors.affiliation: Centrose, Madison, Wisconsin, USA.
authors.forename: Scott S
authors.initials: SS
authors.lastname: Harried
authors.affiliation: Centrose, Madison, Wisconsin, USA.
authors.forename: John L
authors.initials: JL
authors.lastname: Murphy
authors.affiliation: Centrose, Madison, Wisconsin, USA.
authors.forename: Chad A
authors.initials: CA
authors.lastname: Hall
authors.affiliation: Centrose, Madison, Wisconsin, USA.
authors.forename: Mohammed S
authors.initials: MS
authors.lastname: Shekhani
authors.affiliation: Centrose, Madison, Wisconsin, USA.
authors.forename: Christophe
authors.initials: C
authors.lastname: Pain
authors.affiliation: Centrose, Madison, Wisconsin, USA.
authors.forename: Conner A
authors.initials: CA
authors.lastname: Lyons
authors.affiliation: Laboratory of Immunogenetics, Department of Medical Sciences, University of Torino, Torino, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Chillemi
authors.affiliation: Laboratory of Immunogenetics, Department of Medical Sciences, University of Torino, Torino, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Malavasi
authors.affiliation: Centrose, Madison, Wisconsin, USA.
authors.forename: Homer L
authors.initials: HL
authors.lastname: Pearce
authors.affiliation: Center for Pharmaceutical Research and Innovation, University of Kentucky College of Pharmacy, Lexington, Kentucky, USA.
authors.forename: Jon S
authors.initials: JS
authors.lastname: Thorson
authors.affiliation: Centrose, Madison, Wisconsin, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Prudent
mesh_terms: D000818:Animals; D000906:Antibodies / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000276:immunology / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry*; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D009363:Neoplasm Proteins; D054852:Small Molecule Libraries; D000254:Sodium-Potassium-Exchanging ATPase