Exploiting light chains for the scalable generation and platform purification of native human bispecific IgG

Nat Commun. 2015 Feb 12:6:6113. doi: 10.1038/ncomms7113.

Abstract

Bispecific antibodies enable unique therapeutic approaches but it remains a challenge to produce them at the industrial scale, and the modifications introduced to achieve bispecificity often have an impact on stability and risk of immunogenicity. Here we describe a fully human bispecific IgG devoid of any modification, which can be produced at the industrial scale, using a platform process. This format, referred to as a κλ-body, is assembled by co-expressing one heavy chain and two different light chains, one κ and one λ. Using ten different targets, we demonstrate that light chains can play a dominant role in mediating specificity and high affinity. The κλ-bodies support multiple modes of action, and their stability and pharmacokinetic properties are indistinguishable from therapeutic antibodies. Thus, the κλ-body represents a unique, fully human format that exploits light-chain variable domains for antigen binding and light-chain constant domains for robust downstream processing, to realize the potential of bispecific antibodies.

MeSH terms

  • Antibodies, Bispecific / isolation & purification*
  • Antibodies, Monoclonal / metabolism
  • Chromatography, High Pressure Liquid
  • Humans
  • Immunoglobulin G / isolation & purification*
  • Immunoglobulin Heavy Chains / isolation & purification*
  • Immunoglobulin Light Chains / metabolism
  • Immunoglobulin kappa-Chains / metabolism
  • Neutralization Tests
  • Peptide Library
  • Protein Engineering / methods*
  • T-Lymphocytes / immunology

Substances

  • Antibodies, Bispecific
  • Antibodies, Monoclonal
  • Immunoglobulin G
  • Immunoglobulin Heavy Chains
  • Immunoglobulin Light Chains
  • Immunoglobulin kappa-Chains
  • Peptide Library