Idarubicin-anti-CD3: a new immunoconjugate that induces alloantigen-specific tolerance in mice.
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.
Mottram
P L
PL
University of Melbourne, Department of Surgery and Walter and Eliza Hall Institute for Medical Research, Royal Melbourne Hospital, Victoria, Australia.
Han
W R
WR
Murray-Segal
L J
LJ
Mandel
T E
TE
Pietersz
G A
GA
McKenzie
I F
IF
D000818:Animals; D000911:Antibodies, Monoclonal / Q000633:toxicity; D017252:CD3 Complex / Q000276:immunology*; D002455:Cell Division / Q000187:drug effects; D000939:Epitopes; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology; D015255:Idarubicin / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology*; D018796:Immunoconjugates / Q000494:pharmacology*; D007519:Isoantigens / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D016038:Skin Transplantation / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D000939:Epitopes; D018796:Immunoconjugates; D007519:Isoantigens; D014409:Tumor Necrosis Factor-alpha; D015255:Idarubicin