Screening and antitumor effect of an anti‑CTLA‑4 nanobody.
Screening and antitumor effect of an anti‑CTLA‑4 nanobody.
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抗CTLA-4纳米抗体的筛选及抗肿瘤作用
DOI：
10.3892/or.2017.6131
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发表时间：
2018-03
期刊：
影响因子：
4.2
通讯作者：
Lu X
中科院分区：
文献类型：
--
作者：
Wan R;Liu A;Hou X;Lai Z;Li J;Yang N;Tan J;Mo F;Hu Z;Yang X;Zhao Y;Lu X
细胞毒性T淋巴细胞抗原-4（CTLA-4）是免疫应答的关键负调节因子。CTLA-4在T细胞活化后迅速上调，然后以比CD 28更高的亲和力与B7分子结合。CTLA-4可以通过提高T细胞完全活化所需的信号阈值来消除T细胞应答的起始，并且它还可以终止正在进行的T细胞应答。这种调节作用导致了单克隆抗体（mAb）的开发，其被设计为阻断CTLA-4活性以增强针对癌症的免疫应答。单克隆抗体有几个缺点，包括高生产成本和不稳定的行为。纳米抗体（Nanobodies，Nbs）是来源于骆驼科动物重链抗体的单结构域抗原结合片段，由于其小尺寸、高特异性和稳定性，其在癌症免疫治疗中具有高度吸引力。我们利用噬菌体展示技术从高质量的单峰骆驼免疫文库中筛选出CTLA-4特异性Nbs。对4个阳性菌落进行测序，并根据CDR 3区的氨基酸序列进行分类。这些Nbs识别CTLA-4上的独特表位，并且当用于PHA刺激的人T细胞时显示出高结合率。用抗CTLA-4纳米抗体16（Nb 16）治疗携带B16黑色素瘤的C57 BL/6小鼠延迟了黑色素瘤生长并延长了小鼠的存活时间。这些数据表明，从高质量噬菌体展示文库中选择的抗CTLA-4 Nbs可有效用于治疗患有肿瘤的患者。
Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a critical negative regulator of immune responses. CTLA-4 is rapidly upregulated following T-cell activation, and then binds to B7 molecules with a higher affinity than CD28. CTLA-4 may abolish the initiation of the responses of T cells by raising the threshold of signals required for full activation of T cells, and it also may terminate ongoing T-cell responses. This regulatory role has led to the development of monoclonal antibodies (mAbs) designed to block CTLA-4 activity for enhancing immune responses against cancer. mAbs have several disadvantages including high production cost and unstable behavior. Nanobodies (Nbs) are single-domain antigen-binding fragments derived from the camelid heavy-chain antibodies, which are highly attractive in cancer immunotherapy due to their small size, high specificity, and stability. We selected CTLA-4-specific Nbs from a high quality dromedary camel immune library by phage display technology. Four positive colonies were sequenced and classified based on the amino acids sequences in the CDR3 region. These Nbs recognized unique epitopes on CTLA-4 and displayed high binding rates when used on PHA-stimulated human T cells. Treatment of B16 melanoma-bearing C57BL/6 mice with anti-CTLA-4 nanobody 16 (Nb16) delayed melanoma growth and prolonged the survival time of mice. These data indicate that anti-CTLA-4 Nbs selected from a high quality phage display library may be effective for the treatment of patients with tumors.
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DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
影响因子：
8
作者：
Dumoulin, M;Conrath, K;Matagne, A
通讯作者：
Matagne, A
影响因子：
9.3
作者：
Vaneycken, Ilse;Govaert, Jochen;Devoogdt, Nick
通讯作者：
Devoogdt, Nick
DOI：
10.1007/978-1-61779-974-7_8
发表时间：
2012-01-01
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Vincke, Cecile;Gutierrez, Carlos;Muyldermans, Serge
通讯作者：
Muyldermans, Serge
影响因子：
2.9
作者：
Pérez, JMJ;Renisio, JG;Frenken, LGJ
通讯作者：
Frenken, LGJ