Development and Characterization of an Anti-Cancer Monoclonal Antibody for Treatment of Human Carcinomas.
Development and Characterization of an Anti-Cancer Monoclonal Antibody for Treatment of Human Carcinomas.
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DOI：
10.3390/cancers14133037
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发表时间：
2022-06-21
期刊：
影响因子：
5.2
通讯作者：
Arlen, Philip M.
中科院分区：
文献类型：
--
作者：
Tsang, Kwong Yok;Fantini, Massimo;Mavroukakis, Sharon A.;Zaki, Anjum;Annunziata, Christina M.;Arlen, Philip M.
关键词：
癌症可以生长并扩散到身体的不同部位。免疫疗法的目的是刺激免疫系统以选择性的方式消除癌细胞。肿瘤靶向单克隆抗体（mAb）可用作免疫疗法以刺激天然抗肿瘤免疫。本文综述了抗肿瘤单克隆抗体NEO-201的研究进展。NEO-201是一种IgG 1人源化mAb，可特异性结合结肠癌、卵巢癌、胰腺癌、非小细胞肺癌、头颈癌、宫颈癌、子宫癌和乳腺癌表达的CEACAM-5和CEACAM-6的肿瘤相关变体，但对大多数正常组织无反应性。NEO-201的独特之处在于它能够通过不同的机制对抗肿瘤生长。NEO-201通过抗体依赖性细胞介导的细胞毒性和补体依赖性细胞毒性与免疫系统成分结合，杀死表达其靶点的肿瘤细胞。NEO-201还可以通过阻断肿瘤细胞上表达的CEACAM-5与自然杀伤细胞上表达的CEACAM-1之间的相互作用，逆转CEACAM-1依赖性的NK细胞毒性抑制，或通过与人调节性T细胞结合，间接增强抗癌活性。NEO-201在识别抑制性调节性T细胞方面的特异性为癌症免疫疗法与靶向PD-1/PD-L1通路的检查点抑制剂的组合提供了基础。NEO-201是一种IgG 1人源化单克隆抗体（mAb），可与癌胚抗原相关细胞粘附分子（CEACAM）-5和CEACAM-6的肿瘤相关变体结合。NEO-201对结肠癌、卵巢癌、胰腺癌、非小细胞肺癌、头颈癌、宫颈癌、子宫癌和乳腺癌有反应，但对大多数正常组织无反应。NEO-201可通过抗体依赖性细胞介导的细胞毒性（ADCC）和补体依赖性细胞毒性（CDC）直接杀伤表达其靶标的肿瘤细胞，从而杀伤肿瘤细胞。我们探索了其可能增强免疫肿瘤杀伤的间接作用机制。NEO-201可以阻断肿瘤细胞上表达的CEACAM-5与自然杀伤（NK）细胞上表达的CEACAM-1之间的相互作用，从而逆转CEACAM-1依赖性的NK细胞毒性抑制。先前的研究已经证明了在非人灵长类动物中的安全性/耐受性，并且在美国国家癌症研究所（NCI）的第一次人类1期临床试验中。此外，临床前研究表明，NEO-201可以与人类调节性T（Treg）细胞结合。NEO-201在识别抑制性Treg细胞方面的特异性为癌症免疫疗法与靶向PD-1/PD-L1通路的检查点抑制剂的组合提供了基础。
Cancers can grow and spread to different parts of the body. The aim of immunotherapy is to stimulate the immune system to eliminate cancer cells in a selective manner. Tumor-targeting monoclonal antibodies (mAb) can be used as immunotherapy to stimulate innate antitumor immunity. In this review, we have described the development and characterization of an anti-cancers mAb NEO-201. NEO-201 is an IgG1 humanized mAb that binds specifically to tumor-associated variants of CEACAM-5 and CEACAM-6 expressed by colon, ovarian, pancreatic, non-small cell lung, head and neck, cervical, uterine and breast cancers, but is not reactive against most normal tissues. The peculiarity of NEO-201 is its ability to counteract tumor growth through different mechanisms. NEO-201 engages components of immune system to kill tumor cells expressing its target via antibody-dependent cell-mediated cytotoxicity and complement dependent cytotoxicity. NEO-201 can also indirectly enhance anti-cancer activity through the blockade of the interaction between CEACAM-5 expressed on tumor cells and CEACAM-1 expressed on natural killer cells to reverse CEACAM-1-dependent inhibition of NK cytotoxicity or through its binding to human regulatory T cells. The specificity of NEO-201 in recognizing suppressive regulatory T cells provides the basis for combination cancer immunotherapy with checkpoint inhibitors targeting the PD-1/PD-L1 pathway. NEO-201 is an IgG1 humanized monoclonal antibody (mAb) that binds to tumor-associated variants of carcinoembryonic antigen-related cell adhesion molecule (CEACAM)-5 and CEACAM-6. NEO-201 reacts to colon, ovarian, pancreatic, non-small cell lung, head and neck, cervical, uterine and breast cancers, but is not reactive against most normal tissues. NEO-201 can kill tumor cells via antibody-dependent cell-mediated cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC) to directly kill tumor cells expressing its target. We explored indirect mechanisms of its action that may enhance immune tumor killing. NEO-201 can block the interaction between CEACAM-5 expressed on tumor cells and CEACAM-1 expressed on natural killer (NK) cells to reverse CEACAM-1-dependent inhibition of NK cytotoxicity. Previous studies have demonstrated safety/tolerability in non-human primates, and in a first in human phase 1 clinical trial at the National Cancer Institute (NCI). In addition, preclinical studies have demonstrated that NEO-201 can bind to human regulatory T (Treg) cells. The specificity of NEO-201 in recognizing suppressive Treg cells provides the basis for combination cancer immunotherapy with checkpoint inhibitors targeting the PD-1/PD-L1 pathway.
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影响因子：
7.3
作者：
Ali AK;Nandagopal N;Lee SH
通讯作者：
Lee SH
DOI：
10.1158/1078-0432.ccr-09-2345
发表时间：
2010-01-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Campoli M;Ferris R;Ferrone S;Wang X
通讯作者：
Wang X
影响因子：
7.3
作者：
Fantini M;David JM;Saric O;Dubeykovskiy A;Cui Y;Mavroukakis SA;Bristol A;Annunziata CM;Tsang KY;Arlen PM
通讯作者：
Arlen PM
影响因子：
15.9
作者：
Gul, Nuray;Babes, Liane;van Egmond, Marjolein
通讯作者：
van Egmond, Marjolein
影响因子：
3.4
作者：
Fantini, Massimo;David, Justin M.;Tsang, Kwong Y.
通讯作者：
Tsang, Kwong Y.