来自耶鲁大学癌症中心的研究人员报告称一种与自身免疫性疾病系统性红斑狼疮相关的抗体确实可能为某些癌症提供一种新治疗。这一研究在线发表在10月24日的《科学转化医学》（Science Translational Medicine）杂志上。
不同寻常的抗癌抗体
在如红斑狼疮这样的免疫疾病中，免疫系统没有消灭外来入侵者，转而攻击并损害了机体自身细胞和组织。研究人员在红斑狼疮中发现了靶向宿主DNA的抗体，其中的许多抗体是有毒的。一些红斑狼疮抗体进入到了活细胞和细胞核中。
加州大学洛杉矶分校的Richard H. Weisbart曾从红斑狼疮小鼠模型中分离出了一种不同寻常的细胞穿透红斑狼疮自身抗体3E10。这种抗体具有穿透健康和恶性细胞及细胞核的能力，却不会对正常细胞或组织造成伤害。
在知道这种能力后，耶鲁大学的研究人员展开了调查，了解3E10是否可用作药物传递载体。然而他们惊讶地发现这种抗体能够使癌细胞对放疗和化疗敏感，干扰了癌细胞通过DNA修复来维持自身的能力。
发现这种癌细胞敏感性的同时，研究人员进一步证实当单独使用3E10时可以选择性地杀死具有DNA修复缺陷的癌细胞，例如那些具有BRCA2基因突变的细胞。BRCA2是一种肿瘤抑制因子，当受损或缺失时可以导致如乳腺癌、卵巢癌、胰腺癌和前列腺等恶性肿瘤。
论文的主要作者、耶鲁大学癌症中心成员、遗传学教授、治疗放射学系教授和主任Peter M. Glazer 博士说：“发现3E10的这一特点为研究BRCA2相关癌症的治疗开辟了新途径。它也可能促使我们开发出如脑胶质瘤等其他类型癌症的新治疗。”
这一发现也有可能导致对红斑狼疮自身重要的新认识。耶鲁大学癌症中心成员、治疗放射学助理教授James E. Hansen 说：“我们的研究结果与人类疾病最直接的相关性是了解到了红斑狼疮抗体有可能被利用作为癌症的新治疗。它也为探究红斑狼疮抗体的生物学打开了新窗口，或可解释红斑狼疮患者乳腺癌、卵巢癌和前列腺癌出人意料的低发病率。它还有可能帮助解释红斑狼疮患者似乎对DNA损伤药剂非常敏感的原因。”
Targeting Cancer with a Lupus Autoantibody
James E. Hansen, Grace Chan, Yanfeng Liu, Denise C. Hegan, Shibani Dalal, Eloise Dray, , Youngho Kwon, Yuanyuan Xu, Xiaohua Xu, Peter M. Glazer
Systemic lupus erythematosus (SLE) is distinct among autoimmune diseases because of its association with circulating autoantibodies reactive against host DNA. The precise role that anti-DNA antibodies play in SLE pathophysiology remains to be elucidated, and potential applications of lupus autoantibodies in cancer therapy have not previously been explored. We report the unexpected finding that a cell-penetrating lupus autoantibody, 3E10, has potential as a targeted therapy for DNA repair–deficient malignancies. We find that 3E10 preferentially binds DNA single-strand tails, inhibits key steps in DNA single-strand and double-strand break repair, and sensitizes cultured tumor cells and human tumor xenografts to DNA-damaging therapy, including doxorubicin and radiation. Moreover, we demonstrate that 3E10 alone is synthetically lethal to BRCA2-deficient human cancer cells and selectively sensitizes such cells to low-dose doxorubicin. Our results establish an approach to cancer therapy that we expect will be particularly applicable to BRCA2-related malignancies such as breast, ovarian, and prostate cancers. In addition, our findings raise the possibility that lupus autoantibodies may be partly responsible for the intrinsic deficiencies in DNA repair and the unexpectedly low rates of breast, ovarian, and prostate cancers observed in SLE patients. In summary, this study provides the basis for the potential use of a lupus anti-DNA antibody in cancer therapy and identifies lupus autoantibodies as a potentially rich source of therapeutic agents.
