1. Academic Validation
  2. Novel Method for Preparation of Site-Specific, Stoichiometric-Controlled Dual Warhead Conjugate of FGF2 via Dimerization Employing Sortase A-Mediated Ligation

Novel Method for Preparation of Site-Specific, Stoichiometric-Controlled Dual Warhead Conjugate of FGF2 via Dimerization Employing Sortase A-Mediated Ligation

  • Mol Pharm. 2019 Aug 5;16(8):3588-3599. doi: 10.1021/acs.molpharmaceut.9b00434.
Mateusz Adam Krzyscik Łukasz Opaliński Jacek Otlewski
Abstract

Targeted therapies are rapidly evolving modalities of Cancer treatment. The largest group of currently developed biopharmaceuticals is antibody-drug conjugates (ADCs). Here, we developed a new modular strategy for the generation of cytotoxic bioconjugates, containing a homodimer of targeting protein and two highly potent Anticancer drugs with distinct mechanisms of action. Instead of antibody, we applied human Fibroblast Growth Factor 2 (FGF2) as a targeting protein. We produced a conjugate of FGF2 with either monomethyl Auristatin E (MMAE) or α-amanitin (αAMTN) as a cytotoxic agent and subsequently applied a sortase A-mediated ligation to obtain a dimeric conjugate containing both MMAE and αAMTN. The developed method ensures site-specific conjugation and a controlled drug-to-protein ratio. We validated our approach by demonstrating that dimeric dual warhead conjugate exhibits higher cytotoxic potency against Fibroblast Growth Factor receptor-positive cell lines than single-warhead conjugates. Our modular technology can be applied to Other targeting proteins or drugs and thus can be used for preparation of different bioconjugates.

Keywords

FGF2; MMAE; cancer; conjugates; sortase A; α-amanitin.

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