Fishwild D M, Aberle S, Bernhard S L, Kung A H
Department of Immunology, XOMA Corporation, Berkeley, California 94710.
Cancer Res. 1992 Jun 1;52(11):3056-62.
In vivo efficacy testing of monoclonal antibody-based drugs specific for human leukemias is hampered by the paucity of suitable animal models, due in part to the inability of many anti-human monoclonal antibodies to cross-react with antigens expressed in animal tissues or cells. Moreover, human leukemic cells have proven difficult to establish in immunosuppressed mice except as solid tumors. We report here the establishment of a murine model for human leukemia displaying features of human disease, such as growth of malignant cells and localization of such cells to lymphoid compartments, and the effective depletion of leukemic cells from these mice by an immunoconjugate. Human T-leukemia cells (CEM) injected into cyclophosphamide-pretreated NIH-III mice engrafted in all mice (n = 41), with CEM cells detected in the bone marrow, spleen, and blood 4 weeks after injection. There was no evidence of solid tumors. Treatment of CEM-engrafted mice with 4A2-RTA30, an immunoconjugate of an anti-CD7 monoclonal antibody and ricin A chain (RTA30), resulted in a 100- to 200-fold overall depletion of CEM cells from the spleen and the bone marrow (P less than 0.02). This depletion was specific and toxin-dependent, as a control immunoconjugate had no demonstrable effect (P greater than 0.5). Depletion of CEM cells was also observed after treatment with unconjugated anti-CD7 mAb, but this effect was not significantly different from controls (P greater than 0.1). Therefore, significant depletion of CEM cells required the presence of the ricin A chain moiety. Further investigations revealed that CEM cells recovered from NIH-III mice expressed less CD7 antigen, but remained sensitive to subsequent in vitro exposure to 4A2-RTA30. In conclusion, we have established a model for studying the efficacy of immunoconjugates and have successfully depleted human T-leukemic cells from lymphoid tissues in immunodeficient mice by treatment with an anti-CD7-RTA30 immunoconjugate.
用于人类白血病的基于单克隆抗体的药物的体内疗效测试受到合适动物模型匮乏的阻碍，部分原因是许多抗人单克隆抗体无法与动物组织或细胞中表达的抗原发生交叉反应。此外，除了作为实体瘤外，人类白血病细胞在免疫抑制小鼠中很难建立。我们在此报告建立了一种人类白血病小鼠模型，该模型具有人类疾病的特征，如恶性细胞的生长以及此类细胞在淋巴组织中的定位，并且通过免疫偶联物有效地清除了这些小鼠中的白血病细胞。将人类T白血病细胞（CEM）注射到经环磷酰胺预处理的NIH-III小鼠中，所有小鼠（n = 41）均发生移植，注射后4周在骨髓、脾脏和血液中检测到CEM细胞。没有实体瘤的证据。用抗CD7单克隆抗体与蓖麻毒素A链（RTA30）的免疫偶联物4A2-RTA30治疗CEM移植小鼠，导致脾脏和骨髓中的CEM细胞总体减少100至200倍（P小于0.02）。这种清除是特异性的且依赖毒素，因为对照免疫偶联物没有明显效果（P大于0.5）。用未偶联的抗CD7单克隆抗体治疗后也观察到CEM细胞的清除，但这种效果与对照无显著差异（P大于0.1）。因此，CEM细胞的显著清除需要蓖麻毒素A链部分的存在。进一步研究表明，从NIH-III小鼠中回收的CEM细胞表达的CD7抗原较少，但对随后的体外暴露于4A2-RTA30仍敏感。总之，我们建立了一个研究免疫偶联物疗效的模型，并通过用抗CD7-RTA30免疫偶联物治疗成功地从免疫缺陷小鼠的淋巴组织中清除了人类T白血病细胞。
