A novel high-affinity human monoclonal antibody to mesothelin.
A novel high-affinity human monoclonal antibody to mesothelin.
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DOI：
10.1002/ijc.25557
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发表时间：
2011-05-01
影响因子：
6.4
通讯作者：
Pastan, Ira
中科院分区：
文献类型：
--
作者：
Ho, Mitchell;Feng, Mingqian;Fisher, Robert J.;Rader, Christoph;Pastan, Ira
间皮蛋白是一种糖基化磷脂酰肌醇锚定糖蛋白，在间皮瘤、卵巢癌等恶性肿瘤细胞表面高度表达。间充质蛋白与CA125(又称MUC16)之间的相互作用可能促进肿瘤在腹膜腔内的种植和转移。一种理想的治疗剂需要找到一种完全人源性的单抗(MAb)，它能与间充质蛋白或CA125结合，并抑制它们的相互作用。在这里，我们报告了一种新的人源抗间硫蛋白单抗的鉴定。HN1是从一个单纯的人源单链抗体噬菌体展示文库中分离到的一种针对间硫蛋白的人源单链抗体。为了研究甲型HN1病毒的潜在治疗作用，我们制备了含有γ1重链和κ轻链的全人免疫球蛋白，并将甲型HN1单链抗体与截短的假单胞菌外毒素A融合在一起，产生了一种免疫毒素。甲型HN1型免疫球蛋白具有非常强的抗体依赖细胞介导的细胞毒作用，可以杀死癌细胞。HN1以高亲和力(Kd=3 nM)结合人间皮蛋白的构象敏感表位。HN1的表位不同于SS1的表位，SS1是一种用于开发治疗性抗体的小鼠FV，目前正在进行临床试验。HN1与人间皮瘤、卵巢癌、肺腺癌和胰腺癌细胞上的细胞表面相关间皮蛋白结合。此外，HN1还可以从功能上阻断间皮蛋白和CA125在癌细胞上的相互作用。最重要的是，由于HN1免疫毒素可以杀死具有高细胞毒活性的表达间皮蛋白的癌细胞，我们认为它在表达间皮蛋白的癌症治疗和诊断方面具有巨大的潜力。
Mesothelin is a glycosylphosphatidylinisotol-anchored glycoprotein that is highly expressed on the cell surface of mesothelioma, ovarian cancer and other malignant tumors. The interaction between mesothelin and CA125 (also called MUC16) may facilitate the implantation and metastasis of tumors in the peritoneal cavity. A desirable therapeutic agent involves finding a fully human monoclonal antibody (mAb) that binds to mesothelin or CA125 and inhibits their interaction. Here we report the identification of a novel human mAb to mesothelin. HN1, a human single chain Fv specific for mesothelin, was isolated from a naïve human scFv phage display library. To investigate HN1 as a potential therapeutic, we generated a fully human IgG with the γ 1 heavy chain and the κ light chain, and an immuntoxin by fusing the HN1 scFv to a truncated Pseudomonas exotoxin A. The HN1 IgG kills cancer cells with very strong antibody-dependent cell-mediated cytotoxicity. HN1 binds a conformation-sensitive epitope in human mesothelin with high affinity (KD = 3 nM). The HN1 epitope is different from that of SS1, a mouse Fv used to develop therapeutic antibodies that are currently in clinical trials. HN1 binds to cell surface-associated mesothelin on human mesothelioma, ovarian cancer, lung adenocarcinoma and pancreatic cancer cells. In addition, HN1 can functionally block the interaction of mesothelin and CA125 on cancer cells. Most importantly, because the HN1 immuntoxin kills mesothelin-expressing cancer cells with high cytotoxic activity, we believe that it has significant potential for mesothelin-expressing cancer treatment and diagnosis.
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影响因子：
11.5
作者：
Onda, M;Willingham, M;Pastan, I
通讯作者：
Pastan, I
影响因子：
5.7
作者：
Feng Y;Xiao X;Zhu Z;Streaker E;Ho M;Pastan I;Dimitrov DS
通讯作者：
Dimitrov DS
影响因子：
2.9
作者：
Karlsson, R;Katsamba, PS;Myszka, DG
通讯作者：
Myszka, DG
影响因子：
6.4
作者：
Bateman, AC;AlTalib, RK;Herbert, A
通讯作者：
Herbert, A
DOI：
10.1007/978-1-59745-554-1_15
发表时间：
2009
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Ho, Mitchell;Pastan, Ira
通讯作者：
Pastan, Ira