ANTI-CD3-ANTI-IL-2 RECEPTOR-BISPECIFIC MAB-MEDIATED IMMUNOMODULATION - LOW SYSTEMIC TOXICITY, DIFFERENTIAL EFFECT ON LYMPHOID-TISSUE, AND INHIBITION OF CELL-MEDIATED HYPERSENSITIVITY

An anti-CD3:anti-CD25 (CD3,25) bispecific mAb was developed with the o bjective of combining the advantages of the parent anti-CDS and anti-C D25 mAbs. The in vivo effects of the CD3,25 were examined in compariso n to the parent Abs. The CD3,25 was well tolerated in vivo, in contras t to the parent anti-CDS mAb, which induced systemic toxicity in recip ient animals. Anti-CD3 mAb induced cell death, lymphoblast formation, and T cell activation in peripheral lymphoid organs; these were observ ed to a lesser extent in CD3,25-treated animals. In the thymus, anti-C D3 caused a progressive depletion of the CD4(+)CD8(+) ''double positiv e'' thymocytes, which was not seen in CD3,25-treated animals. This fin ding suggests that monovalent CD3 binding is insufficient to induce th ymocyte apoptosis. Animals treated with a combination of anti-CD3 and anti-CD25 mAbs demonstrated changes in the lymphoid organs that were s imilar to anti-CD3-treated mice. This finding demonstrates that the ef fect of the CD3,25 is different than the sum of the parent Abs and sug gests that the bispecific nature of the CD3,25 results in a reagent wi th unique immunomodulatory properties. The functional efficacy of the CD3,25 was assessed in a murine model of delayed-type hypersensitivity . The CD3,25 was as effective as the anti-CD3 mAb in inhibiting the de layed-type hypersensitivity reaction and was more effective than the p arent anti-CD25 mAb. These data demonstrate that appropriately designe d bispecific mAbs can be used as effective immunosuppressive agents wi th low systemic toxicity.