Self-assembled antibody multimers through peptide nucleic acid conjugation

J Am Chem Soc. 2013 Jan 9;135(1):340-6. doi: 10.1021/ja309505c. Epub 2012 Dec 21.

Abstract

With the recent clinical success of bispecific antibodies, a strategy to rapidly synthesize and evaluate bispecific or higher order multispecific molecules could facilitate the discovery of new therapeutic agents. Here, we show that unnatural amino acids (UAAs) with orthogonal chemical reactivity can be used to generate site-specific antibody-oligonucleotide conjugates. These constructs can then be self-assembled into multimeric complexes with defined composition, valency, and geometry. With this approach, we generated potent bispecific antibodies that recruit cytotoxic T lymphocytes to Her2 and CD20 positive cancer cells, as well as multimeric antibody fragments with enhanced activity. This strategy should accelerate the synthesis and in vitro characterization of antibody constructs with unique specificities and molecular architectures.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Dimerization
  • Dose-Response Relationship, Drug
  • Humans
  • Immunoglobulin Fab Fragments / chemistry*
  • Immunoglobulin Fab Fragments / pharmacology
  • Leukocytes, Mononuclear / drug effects
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Peptide Nucleic Acids / chemistry*
  • Peptide Nucleic Acids / pharmacology
  • Structure-Activity Relationship
  • T-Lymphocytes / drug effects

Substances

  • Immunoglobulin Fab Fragments
  • Peptide Nucleic Acids