USE OF YTTRIUM-90-LABELED ANTI-TAC ANTIBODY IN PRIMATE XENOGRAFT TRANSPLANTATION

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Abstract
The high-affinity interleukin-2 receptor (IL-2R) is expressed by T cells activated in response to foreign histocompatibility antigens but not by normal resting cells. Thus, blockade of the interaction of IL-2 with its receptor could achieve selective immunosuppression. Accordingly, anti-Tac, a murine IgG2a class monoclonal antibody specific to the IL-2R, was used alone or in a chelated form with yttrium-90 (90Y), a pure beta emitter, to inhibit rejection of cardiac xenografts from Macaco fascicularis (cynomolgus) donors transplanted to the cervical or abdominal region of Macaca mulatta (rhesus) recipients (n=20). Animals received no immunosuppression (n=3, group I, controls), unmodified anti-Tac (n=5, 2 mg/kg q.o.d., group II), or 90Y-anti-Tac (n=5, 16 mCi, group III). To distinguish the nonspecific immunosuppressive effect of radiation, 90Y was administered bound to UPC-10 (n=4, 16 mCi, group IV), another murine monoclonal antibody that does not specifically recognize activated immunoresponsive cells. All immunosuppression was administered in divided doses during the first 2 weeks posttransplant. Group I animals rejected their grafts at 6.7±1 days and demonstrated a rise in soluble IL-2B levels at the time of rejection, indicating the generation of Tac-expressing and -releasing cells. Graft survival in group II was not prolonged compared with controls (mean survival 6.2±1 days; P 0.05). In contrast, graft survival in animals that received the designed dosage of 90Y-anti-Tac was significantly prolonged to an average of 38.4±5 days compared with groups I and II (P<0.005 and P<0.0005, respectively). Prolongation of graft survival occurred in animals that received 90Y-UPC-10 (mean survival 21.3±5 days, P<0.05 versus group I, P<0.01 versus group II). However, 90Y-UPC-10 was significantly less effective in prolonging graft survival than 90Y-anti-Tac, in which one-half the per-kilogram dosage of radioactivity was delivered in specific fashion via anti-Tac (P<0.025). Reversible nonlethal bone marrow suppression occurred without associated nephro- or hepato-toxicity, and virtually all animals developed antibodies to the murine monoclonal. Thus, the approach used in the present study, IL-2R-directed therapy with 90Y-anti-Tac, may have potential applications in organ transplantation and in the treatment of Tac-expressing neoplastic diseases.