Design and activity of a murine and humanized anti-CEACAM6 single-chain variable fragment in the treatment of pancreatic cancer.
Design and activity of a murine and humanized anti-CEACAM6 single-chain variable fragment in the treatment of pancreatic cancer.
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DOI：
10.1158/0008-5472.can-08-2707
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发表时间：
2009-03-01
期刊：
影响因子：
11.2
通讯作者：
Mahadevan D
中科院分区：
文献类型：
--
作者：
Riley CJ;Engelhardt KP;Saldanha JW;Qi W;Cooke LS;Zhu Y;Narayan ST;Shakalya K;Croce KD;Georgiev IG;Nagle RB;Garewal H;Von Hoff DD;Mahadevan D
胰腺导管腺癌（PDA）是一种致死性疾病，手术是局部疾病的唯一治愈方式;吉西他滨联合或不联合厄洛替尼仍然是不可切除或转移性疾病的标准治疗。CEACAM 6在人PDA中过表达，与阶段或等级无关，并且当失调时引起失巢凋亡抗性。由于鼠Mab 13-1在人PDA细胞系中具有靶特异性细胞毒性，我们设计了基于Mab 13-1的人源化抗CEACAM 6单链可变片段（scFv）。甘氨酸-丝氨酸接头的PEG化用于增强血浆半衰期。这些scFv以高亲和力结合CEACAM 6，表现出细胞毒性活性并诱导剂量依赖性PARP切割。用单独的人源化scFv处理的鼠PDA异种移植物模型引起肿瘤生长抑制（TGI），其与吉西他滨组合增强。免疫组织化学（IHC）显示显著的细胞凋亡，抑制血管生成和增殖，保留靶点。总的来说，我们的研究结果对开发针对PDA中CEACAM 6的新型抗体疗法具有重要意义。
Pancreatic ductal adenocarcinoma (PDA) is a lethal disease with surgery the only curative modality for localized disease; gemcitabine with or without erlotinib remains standard therapy for unresectable or metastatic disease. CEACAM6 is over-expressed in human PDA independent of stage or grade, and causes anoikis resistance when dysregulated. Because murine Mab 13-1 possesses target-specific cytotoxicity in human PDA cell lines, we designed humanized anti-CEACAM6 single chain variable fragments (scFv’s) based on Mab 13-1. PEGylation of the glycine-serine linker was used to enhance plasma half-life. These scFv’s bound CEACAM6 with high affinity, exhibited cytotoxic activity and induced dose-dependent PARP-cleavage. Murine PDA xenograft models treated with humanized scFv alone elicited tumor growth inhibition (TGI), which was enhanced in combination with gemcitabine. Immunohistochemistry (IHC) showed significant apoptosis, with inhibition of angiogenesis and proliferation, with preservation of the target. Collectively, our results have important implications for development of novel antibody-based therapies against CEACAM6 in PDA.