Bushey Ryan T, Moody M Anthony, Nicely Nathan L, Haynes Barton F, Alam S Munir, Keir Stephen T, Bentley Rex C, Roy Choudhury Kingshuk, Gottlin Elizabeth B, Campa Michael J, Liao Hua-Xin, Patz Edward F
Department of Radiology, Duke University Medical Center, Durham, NC 27710, USA.
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA; Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA; Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
Cell Rep. 2016 May 17;15(7):1505-1513. doi: 10.1016/j.celrep.2016.04.038. Epub 2016 May 5.
Some patients with cancer never develop metastasis, and their host response might provide cues for innovative treatment strategies. We previously reported an association between autoantibodies against complement factor H (CFH) and early-stage lung cancer. CFH prevents complement-mediated cytotoxicity (CDC) by inhibiting formation of cell-lytic membrane attack complexes on self-surfaces. In an effort to translate these findings into a biologic therapy for cancer, we isolated and expressed DNA sequences encoding high-affinity human CFH antibodies directly from single, sorted B cells obtained from patients with the antibody. The co-crystal structure of a CFH antibody-target complex shows a conformational change in the target relative to the native structure. This recombinant CFH antibody causes complement activation and release of anaphylatoxins, promotes CDC of tumor cell lines, and inhibits tumor growth in vivo. The isolation of anti-tumor antibodies derived from single human B cells represents an alternative paradigm in antibody drug discovery.
一些癌症患者从未发生转移，他们的宿主反应可能为创新治疗策略提供线索。我们之前报道了抗补体因子H（CFH）自身抗体与早期肺癌之间的关联。CFH通过抑制自身表面细胞溶解膜攻击复合物的形成来防止补体介导的细胞毒性（CDC）。为了将这些发现转化为癌症的生物疗法，我们直接从产生该抗体的患者的单个分选B细胞中分离并表达了编码高亲和力人CFH抗体的DNA序列。CFH抗体-靶标复合物的共晶体结构显示靶标相对于天然结构发生了构象变化。这种重组CFH抗体可引起补体激活和过敏毒素释放，促进肿瘤细胞系的CDC，并在体内抑制肿瘤生长。从单个人B细胞中分离抗肿瘤抗体代表了抗体药物发现的一种替代模式。
