MacLean J A, Su Z, Colvin R B, Wong J T
Department of Pathology, Harvard Medical School, Massachusetts General Hospital, Boston 02114, USA.
J Immunol. 1995 Oct 1;155(7):3674-82.
An anti-CD3:anti-CD25 (CD3,25) bispecific mAb was developed with the objective of combining the advantages of the parent anti-CD3 and anti-CD25 mAbs. The in vivo effects of the CD3,25 were examined in comparison to the parent Abs. The CD3,25 was well tolerated in vivo, in contrast to the parent anti-CD3 mAb, which induced systemic toxicity in recipient animals. Anti-CD3 mAb induced cell death, lymphoblast formation, and T cell activation in peripheral lymphoid organs; these were observed to a lesser extent in CD3,25-treated animals. In the thymus, anti-CD3 caused a progressive depletion of the CD4+ CD8+ "double positive" thymocytes, which was not seen in CD3,25-treated animals. This finding suggests that monovalent CD3 binding is insufficient to induce thymocyte apoptosis. Animals treated with a combination of anti-CD3 and anti-CD25 mAbs demonstrated changes in the lymphoid organs that were similar to anti-CD3-treated mice. This finding demonstrates that the effect of the CD3,25 is different than the sum of the parent Abs and suggests that the bispecific nature of the CD3,25 results in a reagent with 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 delayed-type hypersensitivity reaction and was more effective than the parent anti-CD25 mAb. These data demonstrate that appropriately designed bispecific mAbs can be used as effective immunosuppressive agents with low systemic toxicity.
开发了一种抗CD3:抗CD25（CD3,25）双特异性单克隆抗体，目的是结合亲本抗CD3和抗CD25单克隆抗体的优点。与亲本抗体相比，研究了CD3,25在体内的作用。与在受体动物中诱导全身毒性的亲本抗CD3单克隆抗体不同，CD3,25在体内具有良好的耐受性。抗CD3单克隆抗体在外周淋巴器官中诱导细胞死亡、淋巴母细胞形成和T细胞活化；在接受CD3,25治疗的动物中，这些现象的程度较轻。在胸腺中，抗CD3导致CD4+CD8+“双阳性”胸腺细胞逐渐耗竭，而在接受CD3,25治疗的动物中未观察到这种情况。这一发现表明单价CD3结合不足以诱导胸腺细胞凋亡。用抗CD3和抗CD25单克隆抗体联合治疗的动物，其淋巴器官的变化与抗CD3治疗的小鼠相似。这一发现表明CD3,25的作用不同于亲本抗体的总和，并提示CD3,25的双特异性导致其具有独特的免疫调节特性。在小鼠迟发型超敏反应模型中评估了CD3,25的功能效力。CD3,25在抑制迟发型超敏反应方面与抗CD3单克隆抗体一样有效，并且比亲本抗CD25单克隆抗体更有效。这些数据表明，经过适当设计的双特异性单克隆抗体可用作全身毒性低的有效免疫抑制剂。
