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Bioconjug Chem. 2019 Jun 19;30(6):1702-1710. doi: 10.1021/acs.bioconjchem.9b00244. Epub 2019 May 24.

Dual Site-Specific Antibody Conjugates for Sequential and Orthogonal Cargo Release.

Author information

1
Robert F. Smith School of Chemical and Biomolecular Engineering , Cornell University , 120 Olin Hall, Ithaca , New York 14853 , United States.
2
Biological and Biomedical Sciences , Cornell University College of Veterinary Medicine , Ithaca , New York 14853 , United States.
3
Meinig School of Biomedical Engineering , Cornell University , Ithaca , New York 14853 , United States.

Abstract

Antibody-drug conjugates utilize the antigen specificity of antibodies and the potency of chemotherapeutic and antibiotic drugs for targeted therapy. However, as cancers and bacteria evolve to resist the action of drugs, innovative controlled release methods must be engineered to deliver multidrug cocktails. In this work, we engineer lipoate-acid ligase A (LplA) acceptor peptide (LAP) tags into the constant heavy and light chain of a humanized Her2 targeted antibody, trastuzumab. These engineered LAP tags, along with the glutamine 295 (Q295) residue in the heavy chain, were used to generate orthogonally cleavable site-specific antibody conjugates via a one-pot chemoenzymatic ligation with microbial transglutaminase (mTG) and LplA. We demonstrate orthogonal cargo release from these dual-labeled antibody bioconjugates via matrix metalloproteinase-2 and cathepsin-B-mediated bond cleavage. To the best of our knowledge, this is the first demonstration of temporal control on dual-labeled antibody conjugates, and we believe this platform will allow for sequential release and cooperative drug combinations on a single antibody bioconjugate.

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