Methods.

Normal rhesus monkeys received a kidney transplant and α-CD3-IT alone (on day− to+ 2) or in combination with brief peritransplant adjunctive immunosuppressive therapy. Some received donor CD34+ cells. Blood chemistries, complete blood count, weight, liver, and kidney biopsies were examined for immunotoxin-related changes. Five spontaneously diabetic primates also received α-CD3-IT, three of whom had a pancreas islet transplant.

Results.

The main side effect of α-CD3-IT, vascular leak syndrome, was entirely prevented by adjunctive immunosuppressive therapy. Renal and liver function tests and biopsies revealed a lack of nephrotoxicity and hepatotoxicity. All had transient weight loss (14±5%). Without infusion of donor CD34+ cells, 97% had full weight recovery. Of those given donor CD34+ cells, 50% were euthanized for wasting.

Conclusions.

Side effects of α-CD3-IT are manageable and should not prevent therapeutic application.

Anti-CD3-immunotoxin (α-CD3-IT*) has shown outstanding potential to facilitate tolerance induction in nonhuman primates, a property attributed to its unusual efficiency in depleting the sessile lymphoid T cells as well as circulating T cells (1-3). A conjugate of monoclonal IgG1 anti-rhesus CD3ε (FN18) and the mutant diphtheria toxin CRM9, α-CD3-IT has< 0.1% of the systemic toxicity of wild-type diphtheria toxin (4, 5). The conjugate is directed predominantly to T cells via the antibody's high affinity for the CD3 receptor. Toxicity is achieved by CD3ε-mediated internalization of bound CRM9 toxin by way of the endosomal pathway and intracellular translocation (6). Other immunotoxins used to treat cancer or graft versus host disease have exhibited side effects of vascular leak syndrome, hepatotoxicity, and nephrotoxicity, dose-related complications that constrain effectiveness and clinical application (7-9). Before clinical testing of a cognate anti-human CD3ε-IT construct (10), it seems important to have available a comprehensive documentation of preclinical tolerability and side effects of the anti-nonhuman primate CD3ε-IT construct (10). Thus, we summarize our preclinical experience of tolerability and side effects of α-CD3-IT treatment in nonhuman primate kidney and islet transplant recipients.