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

Author

Listed:
  • Alex R. Nanna

    (The Scripps Research Institute
    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 Jr.

    (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)

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.

Suggested Citation

  • Alex R. Nanna & Xiuling Li & Even Walseng & Lee Pedzisa & Rebecca S. Goydel & David Hymel & Terrence R. Burke Jr. & William R. Roush & Christoph Rader, 2017. "Harnessing a catalytic lysine residue for the one-step preparation of homogeneous antibody-drug conjugates," Nature Communications, Nature, vol. 8(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01257-1
    DOI: 10.1038/s41467-017-01257-1
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