Design and Synthesis of Megamolecule Mimics of a Therapeutic Antibody

Justin A. Modica, Tsatsral Iderzorig, Milan Mrksich*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


This communication describes the design, synthesis, and biological activity of a megamolecule mimic of an anti-HER2 antibody. The antibody mimic was prepared by linking two Fabs from the therapeutic antibody trastuzumab, which are fused through the heavy chain variable domain to either cutinase or SnapTag, with a linker terminated in an irreversible inhibitor for each enzyme. This mimic binds HER2 with comparable avidity to trastuzumab, has similar activity in a cell-based assay, and can arrest tumor growth in a mouse xenograft BT474 tumor model. A panel of 16 bivalent anti-HER2 antibodies were prepared wherein each varied in the orientation of the fusion domain on the Fabs. The analogs displayed a range of cytotoxic activity, and surprisingly, the most active mimic binds to cells with a 10-fold lower avidity than the least active variant suggesting that structure plays a large role in their efficacy. This work suggests that the megamolecule approach can be used to prepare antibody mimics having a broad structural diversity.

Original languageEnglish (US)
Pages (from-to)13657-13661
Number of pages5
JournalJournal of the American Chemical Society
Issue number32
StatePublished - Aug 12 2020

ASJC Scopus subject areas

  • General Chemistry
  • Biochemistry
  • Catalysis
  • Colloid and Surface Chemistry


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