An anti-CD103 antibody-drug conjugate prolongs the survival of pancreatic islet allografts in mice

Cell Death Dis. 2019 Sep 30;10(10):735. doi: 10.1038/s41419-019-1980-8.

Abstract

CD103 mediates T-cell infiltration and organ allograft rejection, and depletion of CD103-expressing cells is a promising therapeutic strategy for allograft intolerance. Recently, we verified that M290-MC-MMAF, an anti-CD103 antibody-drug conjugate, potently eliminates CD103-positive cells in vivo, with high specificity and minimal toxicity. However, the contribution of M290-MC-MMAF to blocking the CD103/E-cadherin pathway involved in transplant rejection remains unclear. Herein, we examined the impact of systemic administration of M290-MC-MMAF on allografts in an islet transplantation model. M290-MC-MMAF treatment maintained the long-term survival of islet allografts (>60 days) compared to mock injection or unconjugated M290 antibody treatment (<18 days). The change was associated with a decrease in CD103+CD8+ effector T cells and an increase in CD4+CD25+ regulatory T cells. CD103+CD8+ effector T-cell transfer or CD4+CD25+ regulatory T-cell depletion resulted in a rapid loss of allografts in long-surviving islet hosts. Moreover, M290-MC-MMAF treatment reduced IL-4, IL-6, and TNF-α expression levels and increased IL-10 expression in the grafts, which presented an immunosuppressive cytokine profile. In conclusion, targeting CD103 with M290-MC-MMAF induced immunosuppression and prolonged the survival of pancreatic islet allografts in mice, indicating the potential clinical value of M290-MC-MMAF in therapeutic interventions for allograft rejection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allografts / drug effects*
  • Allografts / immunology
  • Animals
  • Antibodies, Monoclonal, Murine-Derived / pharmacology
  • Antigens, CD / immunology*
  • Graft Rejection / drug therapy*
  • Graft Rejection / immunology
  • Humans
  • Immunoconjugates / pharmacology
  • Integrin alpha Chains / antagonists & inhibitors
  • Integrin alpha Chains / immunology*
  • Islets of Langerhans / drug effects*
  • Islets of Langerhans / growth & development
  • Islets of Langerhans / immunology
  • Islets of Langerhans Transplantation
  • Mice
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology

Substances

  • Antibodies, Monoclonal, Murine-Derived
  • Antigens, CD
  • Immunoconjugates
  • Integrin alpha Chains
  • M290SAP
  • alpha E integrins