Harnessing a catalytic lysine residue for the one-step preparation of homogeneous antibody-drug conjugates

Alex R. Nanna, Xiuling Li, Even Walseng, Lee Pedzisa, Rebecca S. Goydel, David Hymel, Terrence R. Burke, William R. Roush () and Christoph Rader ()
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Alex R. Nanna: The Scripps Research Institute
Xiuling Li: The Scripps Research Institute
Even Walseng: The Scripps Research Institute
Lee Pedzisa: The Scripps Research Institute
Rebecca S. Goydel: The Scripps Research Institute
David Hymel: Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health
Terrence R. Burke: Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health
William R. Roush: The Scripps Research Institute
Christoph Rader: The Scripps Research Institute

Nature Communications, 2017, vol. 8, issue 1, 1-9

Abstract: Abstract Current strategies to produce homogeneous antibody-drug conjugates (ADCs) rely on mutations or inefficient conjugation chemistries. Here we present a strategy to produce site-specific ADCs using a highly reactive natural buried lysine embedded in a dual variable domain (DVD) format. This approach is mutation free and drug conjugation proceeds rapidly at neutral pH in a single step without removing any charges. The conjugation chemistry is highly robust, enabling the use of crude DVD for ADC preparation. In addition, this strategy affords the ability to precisely monitor the efficiency of drug conjugation with a catalytic assay. ADCs targeting HER2 were prepared and demonstrated to be highly potent and specific in vitro and in vivo. Furthermore, the modular DVD platform was used to prepare potent and specific ADCs targeting CD138 and CD79B, two clinically established targets overexpressed in multiple myeloma and non-Hodgkin lymphoma, respectively.

Date: 2017
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DOI: 10.1038/s41467-017-01257-1

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