Treatment of human B cell lymphoma xenografts with a CD3 x CD19 diabody and T cells
Treatment of human B cell lymphoma xenografts with a CD3 x CD19 diabody and T cells
复制标题
DOI：
10.4049/jimmunol.165.2.888
复制
发表时间：
2000-07-15
影响因子：
4.4
通讯作者：
Little, M
中科院分区：
文献类型：
--
作者：
Cochlovius, B;Kipriyanov, SM;Little, M
抗CD 3 x抗肿瘤双特异性抗体的使用是癌症治疗中有吸引力的和高度特异性的方法。重组抗体技术现在提供了增强这种免疫构建体的效力的有力工具。我们设计了特异于B细胞上的人CD 19和TCR复合物的CD 3 β链的异二聚体双抗体。在大肠杆菌中生产并纯化后，我们分析了其亲和力、稳定性和药代动力学，并测试了其刺激T细胞增殖和介导体外CD 19（+）肿瘤细胞裂解的能力。使用携带人B细胞淋巴瘤的免疫缺陷小鼠在体内模型中研究了双抗体对肿瘤生长的影响。CD 3 x CD 19双抗体与CD 3-和CD 19-阳性细胞特异性相互作用，能够在肿瘤细胞存在下刺激T细胞增殖，并在活化的人PBL存在下诱导CD 19（+）细胞裂解。双抗体的裂解潜力在抗CD 28 mAb存在下增强，体内实验表明，与单链Fv片段相比，双抗体具有更高的稳定性和更长的血液保留时间。用双抗体和预活化的人PBL治疗携带B淋巴瘤异种移植物的免疫缺陷小鼠有效地抑制了肿瘤生长。抗CD 28单克隆抗体可进一步延长患者的生存时间。CD 3 × CD 19双抗体是一种强有力的工具，有助于B细胞白血病和恶性淋巴瘤患者微小残留病的免疫治疗。
The use of anti-CD3 x antitumor bispecific Abs is an attractive and highly specific approach in cancer therapy. Recombinant Ab technology now provides powerful tools to enhance the potency of such immunotherapeutic constructs. We designed a heterodimeric diabody specific for human CD19 on B cells and CD3 epsilon chain of the TCR complex. After production in Escherichia coli and purification, we analyzed its affinity, stability, and pharmacokinetics, and tested its capacity to stimulate T cell proliferation and mediate in vitro lysis of CD19(+) tumor cells. The effect of the diabody on tumor growth was investigated in an in vivo model using immunodeficient mice bearing a human B cell lymphoma. The CD3 x CD19 diabody specifically interacted with both CD3- and CD19-positive cells, was able to stimulate T cell proliferation in the presence of tumor cells, and induced the lysis of CD19(+) cells in the presence of activated human PBL, The lytic potential of the diabody was enhanced in the presence of an anti-CD28 mAb, In vivo experiments indicated a higher stability and longer blood retention of diabodies compared with single chain Fv fragments. Treatment of immunodeficient mice bearing B lymphoma xenografts with the diabody and preactivated human PBL efficiently inhibited tumor growth. The survival time was further prolonged by including the anti-CD28 mAb, The CD3 x CD19 diabody is a powerful tool that should facilitate the immunotherapy of minimal residual disease in patients with B cell leukemias and malignant lymphomas.