Pl. Mottram et al., IDARUBICIN-ANTI-CD3 - A NEW IMMUNOCONJUGATE THAT INDUCES ALLOANTIGEN-SPECIFIC TOLERANCE IN MICE, Transplantation, 64(5), 1997, pp. 684-690
Background. In testing new anti-CD3 agents for transplantation toleran
ce induction, an anti-CD3 monoclonal antibody was used as a carrier fo
r the cytotoxic drug idarubicin (IDA). Methods. Anti-CDS (KT3) was cov
alently coupled with IDA, producing the IDA-KT3 immunoconjugate, which
was tested for specificity by fluorometry and for inhibition of proli
feration of CD3(+) E3 cells ([H-3]thymidine uptake). KT3 and IDA-KT3 w
ere used to treat CBA recipients of BALB/c vascularized cardiac allogr
afts. Mice with hearts surviving >100 days were challenged with donor
and third-party (C57BL/6) skin. Results. Conjugation to IDA did not re
duce binding of KT3 to E3 cells, although the toxicity of IDA was redu
ced by conjugation. In BALB/c to CBA cardiac allografts (rejected in 1
2-17 days), both KT3 and IDA-KT3 (0.25-0.5 mg/20 g mouse i.p. at the t
ime of transplantation) induced tolerance. Hearts survived >100 days a
nd skin graft challenge showed indefinite survival of donor grafts but
not third-party grafts. KT3 was less toxic, as measured by tumor necr
osis factor-a release and blood glucose levels, than equivalent dosage
s of 145-2C11. At lower dosages (0.1 mg/20 g mouse), KT3-treated anima
ls rejected BALB/c allografts in 15 to 19 days, but IDA-KT3 induced lo
ng survival (>100 days) and donor-specific tolerance in 5 of 6 mice. C
onclusions. Coupling IDA to anti-CD3 reduced the in vivo toxicity of I
DA and improved the immunosuppressive performance of KT3, reducing the
side effects seen with other anti-CD3 agents. IDA-KT3 is a new, effec
tive, nontoxic tolerogen in this donor-recipient combination.