Exploiting Bias in a Non-Immune Human Antibody Library to Predict Antigenicity

Protein Eng Des Sel. 2011 Nov;24(11):845-53. doi: 10.1093/protein/gzr046. Epub 2011 Sep 9.

Abstract

Non-immune human antibody fragment libraries have generated antigen-binding proteins useful as prospective research, imaging, diagnostic and therapeutic agents. However, because the generation of such libraries relies on cloning antibody sequences from the circulating immune repertoire rather than truly naïve, germline sequences, their composition may reflect the deletion of autoreactive sequences, making them less suited for isolating binding clones to human antigens, but perhaps useful in applications where an in vitro handle on representative circulating antibody diversity is desired. Here we demonstrate that a large non-immune human scFv library is relatively depleted of sequences capable of recognizing human antigens as compared with orthologs antigens. Additionally, because this non-naïve, non-immune library may capture a representative section of antibody diversity, we explore its possible utility in conducting early pre-screens to predict the antigenicity of prospective therapeutics and find a correlation between the clinical immunogenicity of a small panel of protein therapeutics with their propensity for interacting with the library.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Antibody Affinity
  • Antigen-Antibody Complex / genetics
  • Antigen-Antibody Complex / immunology
  • Antigen-Antibody Complex / metabolism
  • Antigens / genetics
  • Antigens / immunology
  • Antigens / metabolism*
  • Humans
  • Molecular Sequence Data
  • Peptide Library*
  • Protein Binding
  • Protein Engineering / methods*
  • Single-Chain Antibodies / genetics
  • Single-Chain Antibodies / immunology
  • Single-Chain Antibodies / metabolism*

Substances

  • Antigen-Antibody Complex
  • Antigens
  • Peptide Library
  • Single-Chain Antibodies