Idarubicin-anti-CD3: a new immunoconjugate that induces alloantigen-specific tolerance in mice

Transplantation. 1997 Sep 15;64(5):684-90. doi: 10.1097/00007890-199709150-00004.

Abstract

Background: In testing new anti-CD3 agents for transplantation tolerance induction, an anti-CD3 monoclonal antibody was used as a carrier for the cytotoxic drug idarubicin (IDA).

Methods: Anti-CD3 (KT3) was covalently coupled with IDA, producing the IDA-KT3 immunoconjugate, which was tested for specificity by fluorometry and for inhibition of proliferation of CD3+ E3 cells ([3H]thymidine uptake). KT3 and IDA-KT3 were used to treat CBA recipients of BALB/c vascularized cardiac allografts. Mice with hearts surviving >100 days were challenged with donor and third-party (C57BL/6) skin.

Results: Conjugation to IDA did not reduce binding of KT3 to E3 cells, although the toxicity of IDA was reduced by conjugation. In BALB/c to CBA cardiac allografts (rejected in 12-17 days), both KT3 and IDA-KT3 (0.25-0.5 mg/20 g mouse i.p. at the time of transplantation) induced tolerance. Hearts survived >100 days and skin graft challenge showed indefinite survival of donor grafts but not third-party grafts. KT3 was less toxic, as measured by tumor necrosis factor-a release and blood glucose levels, than equivalent dosages of 145-2C11. At lower dosages (0.1 mg/20 g mouse), KT3-treated animals rejected BALB/c allografts in 15 to 19 days, but IDA-KT3 induced long survival (>100 days) and donor-specific tolerance in 5 of 6 mice.

Conclusions: Coupling IDA to anti-CD3 reduced the in vivo toxicity of IDA and improved the immunosuppressive performance of KT3, reducing the side effects seen with other anti-CD3 agents. IDA-KT3 is a new, effective, nontoxic tolerogen in this donor-recipient combination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / toxicity
  • CD3 Complex / immunology*
  • Cell Division / drug effects
  • Epitopes
  • Graft Survival / immunology
  • Heart Transplantation / immunology
  • Idarubicin / immunology*
  • Immune Tolerance / immunology*
  • Immunoconjugates / pharmacology*
  • Isoantigens / immunology*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Skin Transplantation / immunology
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Antibodies, Monoclonal
  • CD3 Complex
  • Epitopes
  • Immunoconjugates
  • Isoantigens
  • Tumor Necrosis Factor-alpha
  • Idarubicin