Generating therapeutic monoclonal antibodies to complex multi-spanning membrane targets: Overcoming the antigen challenge and enabling discovery strategies

Methods. 2020 Aug 1;180:111-126. doi: 10.1016/j.ymeth.2020.05.006. Epub 2020 May 15.

Abstract

Complex integral membrane proteins, which are embedded in the cell surface lipid bilayer by multiple transmembrane spanning helices, encompass families of proteins which are important target classes for drug discovery. These protein families include G protein-coupled receptors, ion channels and transporters. Although these proteins have typically been targeted by small molecule drugs and peptides, the high specificity of monoclonal antibodies offers a significant opportunity to selectively modulate these target proteins. However, it remains the case that isolation of antibodies with desired pharmacological function(s) has proven difficult due to technical challenges in preparing membrane protein antigens suitable to support antibody drug discovery. In this review recent progress in defining strategies for generation of membrane protein antigens is outlined. We also highlight antibody isolation strategies which have generated antibodies which bind the membrane protein and modulate the protein function.

Keywords: Drug discovery; G protein-coupled receptors; Ion channels; Monoclonal antibodies; Transporters.

Publication types

  • Review

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology*
  • Antibodies, Monoclonal / isolation & purification*
  • Bacteria / metabolism
  • Drug Discovery / methods*
  • Gene Expression / genetics
  • Gene Expression / immunology
  • HEK293 Cells
  • Humans
  • Insecta / metabolism
  • Ion Channels / immunology*
  • Membrane Proteins / chemistry
  • Membrane Proteins / immunology*
  • Membrane Proteins / isolation & purification
  • Receptors, G-Protein-Coupled / chemistry
  • Receptors, G-Protein-Coupled / immunology*
  • Recombinant Proteins
  • Yeasts / metabolism

Substances

  • Antibodies, Monoclonal
  • Ion Channels
  • Membrane Proteins
  • Receptors, G-Protein-Coupled
  • Recombinant Proteins