Division of Medical Genetics, University of Washington, Seattle, USA.
Blood. 2010 Jan 21;115(3):592-600. doi: 10.1182/blood-2009-05-222463. Epub 2009 Nov 12.
Many tumors, including lymphomas, up-regulate expression of CD46 to escape destruction by complement. Tumor cells are therefore relatively resistant to therapy by monoclonal antibodies, which act through complement-dependent cytotoxicity (CDC). From an Escherichia coli expression library of adenovirus type 35 fiber knob mutants, we selected a variant (Ad35K(++)) that had a higher affinity to CD46 than did the natural Ad35 fiber knob. We demonstrated that incubation of lymphoma cells with recombinant Ad35K(++) protein resulted in transient removal of CD46 from the cell surface. Preincubation of lymphoma cells with Ad35K(++) sensitized cells to CDC, triggered by the CD20-specific monoclonal antibody rituximab. In xenograft models with human lymphoma cells, preinjection of Ad35K(++) dramatically increased the therapeutic effect of rituximab. Blood cell counts and organ histology were normal after intravenous injection of Ad35K(++) into mice that express human CD46. The presence of polyclonal anti-Ad35K(++) antibodies did not affect the ability of Ad35K(++) to enhance rituximab-mediated CDC in in vitro assays. The Ad35K(++)-based approach has potential implications in monoclonal antibody therapy of malignancies beyond the combination with rituximab.
许多肿瘤，包括淋巴瘤，上调 CD46 的表达以逃避补体的破坏。因此，肿瘤细胞相对抵抗通过补体依赖性细胞毒性（CDC）作用的单克隆抗体治疗。从腺病毒 35 型纤维旋钮突变体的大肠杆菌表达文库中，我们选择了一个变体（Ad35K(++）），其与天然 Ad35 纤维旋钮相比，对 CD46 的亲和力更高。我们证明，与重组 Ad35K(++)蛋白孵育淋巴瘤细胞会导致 CD46 从细胞表面短暂去除。用 Ad35K(++)预先孵育淋巴瘤细胞可使细胞对 CD20 特异性单克隆抗体利妥昔单抗引发的 CDC 敏感。在用表达人 CD46 的人类淋巴瘤细胞的异种移植模型中，Ad35K(++) 的预先注射极大地增强了利妥昔单抗的治疗效果。在静脉注射 Ad35K(++)到表达人 CD46 的小鼠中，血细胞计数和器官组织学均正常。多克隆抗 Ad35K(++)抗体的存在不影响 Ad35K(++)在体外测定中增强利妥昔单抗介导的 CDC 的能力。Ad35K(++) 为基础的方法除了与利妥昔单抗联合使用外，对恶性肿瘤的单克隆抗体治疗具有潜在的意义。
