Tolerability and Side Effects of Anti-CD3 Immunotoxin (αCD3-IT) in Preclinical Testing in Kidney Allograft Recipients

Abstract

322 αCD3-IT has shown potential to promote allograft tolerance in nonhuman primates owing to its unusual efficiency in depleting PBL and sessile lymph node (LN) T cells. Common side effects of vascular leak syndrome (VLS) hepatotoxicity and rash have limited host tolerability of most immunotoxins in the past. We postulated that the unique combined properties of αCD3-IT, i.e., stability of the mAb-mutated diphtheria conjugate, high specificity and affinity for the CD3ε receptor and efficient intracellular translocation would limit the systemic side effects that have hindered IT therapy to date. Normal male rhesus macaques underwent kidney transplantation with intrinsic nephrectomy and received either αCD3-IT (n=21) or αCD3 mAb (n=5) at a total dose of 133-150 μg/kg over 3 days, beginning 12-16h pretransplant. Some received additional treatment with 15-deoxspergualin (DSG; 2.5 mg/kg for 4 to 14 days) and methylprednisone (MP for 3 days at a tapering dose from 7 mg/kg). We examined blood chemistries, CBC, plasma cytokines, weight changes, and 24h liver biopsies for IT related side effects. The main side effect of αCD3-IT was VLS, characterized by increased body weight, edema, cytokine release, and decreased serum albumin without proteinuria. DSG and MP entirely prevented the VLS. Liver function tests and CBC values(tabulated below) were similar in recipients given αCD3-IT andαCD3 mAb. Liver biopsies showed an absence of hepatotoxicity after IT with or without DSG/MP. Rash occurred in 20% and resolved in 48h without special treatment. Transient weight loss (14 ±5%) occurred in all recipients; of IT-treated recipients followed long-term for >3-18 months, 1/19 was euthanized for persistent low weight. Despite a mean 95% and 86% decrease in PBL and LN T cells, respectively, at 1wk post-transplant, and 50% recovery by 2 months, no evidence of increased infection or neoplasia was seen. In summary, side effects of αCD3-IT are manageable and should not prevent therapeutic application. Table