Mechanically interlocked functionalization of monoclonal antibodies

Krzysztof P. Bzymek, James W. Puckett, Cindy Zer, Jun Xie, Yuelong Ma, Jeremy D. King, Leah H. Goodstein, Kendra N. Avery, David Colcher, Gagandeep Singh, David A. Horne and John C. Williams ()
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Krzysztof P. Bzymek: Beckman Research Institute of City of Hope
James W. Puckett: Beckman Research Institute of City of Hope
Cindy Zer: Beckman Research Institute of City of Hope
Jun Xie: Beckman Research Institute of City of Hope
Yuelong Ma: Beckman Research Institute of City of Hope
Jeremy D. King: Beckman Research Institute of City of Hope
Leah H. Goodstein: Beckman Research Institute of City of Hope
Kendra N. Avery: Beckman Research Institute of City of Hope
David Colcher: Beckman Research Institute of City of Hope
Gagandeep Singh: Beckman Research Institute of City of Hope
David A. Horne: Beckman Research Institute of City of Hope
John C. Williams: Beckman Research Institute of City of Hope

Nature Communications, 2018, vol. 9, issue 1, 1-9

Abstract: Abstract Because monoclonal antibodies (mAbs) have exceptional specificity and favorable pharmacology, substantial efforts have been made to functionalize them, either with potent cytotoxins, biologics, radionuclides, or fluorescent groups for therapeutic benefit and/or use as theranostic agents. To exploit our recently discovered meditope–Fab interaction as an alternative means to efficiently functionalize mAbs, we used insights from the structure to enhance the affinity and lifetime of the interaction by four orders of magnitude. To further extend the lifetime of the complex, we created a mechanical bond by incorporating an azide on the meditope, threading the azide through the Fab, and using click chemistry to add a steric group. The mechanically interlocked, meditope–Fab complex retains antigen specificity and is capable of imaging tumors in mice. These studies indicate it is possible to “snap” functionality onto mAbs, opening the possibility of rapidly creating unique combinations of mAbs with an array of cytotoxins, biologics, and imaging agents.

Date: 2018
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DOI: 10.1038/s41467-018-03976-5

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