Cell-type-restricted anti-cytokine therapy: TNF inhibition from one pathogenic source

Proc Natl Acad Sci U S A. 2016 Mar 15;113(11):3006-11. doi: 10.1073/pnas.1520175113. Epub 2016 Mar 2.

Abstract

Overexpression of TNF contributes to pathogenesis of multiple autoimmune diseases, accounting for a remarkable success of anti-TNF therapy. TNF is produced by a variety of cell types, and it can play either a beneficial or a deleterious role. In particular, in autoimmunity pathogenic TNF may be derived from restricted cellular sources. In this study we evaluated the feasibility of cell-type-restricted TNF inhibition in vivo. To this end, we engineered MYSTI (Myeloid-Specific TNF Inhibitor)--a recombinant bispecific antibody that binds to the F4/80 surface molecule on myeloid cells and to human TNF (hTNF). In macrophage cultures derived from TNF humanized mice MYSTI could capture the secreted hTNF, limiting its bioavailability. Additionally, as evaluated in TNF humanized mice, MYSTI was superior to an otherwise analogous systemic TNF inhibitor in protecting mice from lethal LPS/D-Galactosamine-induced hepatotoxicity. Our results suggest a novel and more specific approach to inhibiting TNF in pathologies primarily driven by macrophage-derived TNF.

Keywords: TNF; anti-cytokine therapy; autoimmunity; bispecific antibody; humanized mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Antibodies, Bispecific / genetics
  • Antibodies, Bispecific / immunology*
  • Antibodies, Neutralizing / genetics
  • Antibodies, Neutralizing / immunology
  • Antibody Specificity
  • Antigen-Antibody Reactions
  • Antigens, Differentiation / genetics
  • Antigens, Differentiation / immunology*
  • Antigens, Surface / immunology
  • Camelus / immunology
  • Chemical and Drug Induced Liver Injury / etiology
  • Chemical and Drug Induced Liver Injury / immunology
  • Chemical and Drug Induced Liver Injury / prevention & control
  • Chemical and Drug Induced Liver Injury / therapy*
  • Complementarity Determining Regions / chemistry
  • Complementarity Determining Regions / genetics
  • Complementarity Determining Regions / immunology
  • Galactosamine / toxicity
  • Genes, Synthetic
  • Humans
  • L Cells
  • Macrophages, Peritoneal / immunology
  • Macrophages, Peritoneal / metabolism*
  • Mice
  • Mutation
  • Random Allocation
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / immunology
  • Single-Chain Antibodies / genetics
  • Single-Chain Antibodies / immunology
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Antibodies, Bispecific
  • Antibodies, Neutralizing
  • Antigens, Differentiation
  • Antigens, Surface
  • Complementarity Determining Regions
  • Recombinant Fusion Proteins
  • Single-Chain Antibodies
  • Tumor Necrosis Factor-alpha
  • monocyte-macrophage differentiation antigen
  • Galactosamine

Associated data

  • GENBANK/KU677977
  • GENBANK/KU677978
  • GENBANK/KU695528
  • GENBANK/KU695529