Development of a fully canine anti-canine CTLA4 monoclonal antibody for comparative translational research in dogs with spontaneous tumors.
Development of a fully canine anti-canine CTLA4 monoclonal antibody for comparative translational research in dogs with spontaneous tumors.
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DOI：
10.1080/19420862.2021.2004638
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发表时间：
2021-01
期刊：
影响因子：
5.3
通讯作者：
Siegel DL
中科院分区：
文献类型：
--
作者：
Mason NJ;Chester N;Xiong A;Rotolo A;Wu Y;Yoshimoto S;Glassman P;Gulendran G;Siegel DL
免疫检查点抑制剂（ICI） ipilimumab已经彻底改变了不同癌症组织学患者的治疗，包括黑色素瘤，肾细胞癌和非小细胞肺癌。然而，只有一小部分患者对治疗表现出显著的临床反应。尽管在使用CTLA4检查点阻断的临床试验中进行了大量的生物标志物发现工作，但没有单一的预后相关性作为结果的有效预测因子出现。客户拥有的、具有免疫能力的宠物狗发生自发肿瘤，表现出与人类癌症相似的特征，包括共同的染色体畸变、分子亚型、免疫特征、肿瘤异质性、转移行为和对化疗的反应。因此，他们代表了一个有价值的平行患者群体，研究新的预测性生物标志物和合理的治疗性ICI组合。然而，缺乏临床前使用的经过验证的、非免疫原性的犬ICIs阻碍了这种比较方法。为了解决这个问题，从一个综合的犬单链可变片段（scFvs）噬菌体展示库中分离出结合犬CTLA4的全犬单链可变片段（scFvs）。临床开发的主要候选药物是基于其与犬CTLA4的亚纳米级结合亲和力，以及其阻止CTLA4与CD80/CD86结合并促进T细胞增殖和效应功能的能力。体内小鼠研究显示药代动力学与同型对照IgG相似，没有短期不良反应的证据。这项工作为首次在犬体内分析CTLA4抗体铺平了道路，该抗体可促进免疫应答性癌症犬的抗肿瘤免疫，并为研究CTLA4检查点抑制的相关生物标志物和抵抗机制提供了重要的比较工具。
The immune checkpoint inhibitor (ICI) ipilimumab has revolutionized the treatment of patients with different cancer histologies, including melanoma, renal cell carcinoma, and non-small cell lung carcinoma. However, only a subset of patients shows dramatic clinical responses to treatment. Despite intense biomarker discovery efforts linked to clinical trials using CTLA4 checkpoint blockade, no single prognostic correlate has emerged as a valid predictor of outcome. Client-owned, immune competent, pet dogs develop spontaneous tumors that exhibit similar features to human cancers, including shared chromosome aberrations, molecular subtypes, immune signatures, tumor heterogeneity, metastatic behavior, and response to chemotherapy. As such, they represent a valuable parallel patient population in which to investigate novel predictive biomarkers and rational therapeutic ICI combinations. However, the lack of validated, non-immunogenic, canine ICIs for preclinical use hinders this comparative approach. To address this, fully canine single-chain variable fragments (scFvs) that bind canine CTLA4 were isolated from a comprehensive canine scFv phage display library. A lead candidate for clinical development was selected based on its subnanomolar binding affinity to canine CTLA4 and its ability to prevent CTLA4 binding to CD80/CD86 and promote T cell proliferation and effector function. In vivo mouse studies revealed pharmacokinetics similar to isotype control IgG with no evidence of short-term adverse effects. This work paves the way for in vivo analysis of the first fully canine, anti-canine CTLA4 antibody to promote anti-tumor immunity in dogs with immune-responsive cancers and provide an important comparative tool to investigate correlative biomarkers of response and mechanisms of resistance to CTLA4 checkpoint inhibition.
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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：
5
作者：
Chan, D. V.;Gibson, H. M.;Aufiero, B. M.;Wilson, A. J.;Hafner, M. S.;Mi, Q-S;Wong, H. K.
通讯作者：
Wong, H. K.
影响因子：
45.3
作者：
Lynch, Thomas J.;Bondarenko, Igor;Reck, Martin
通讯作者：
Reck, Martin
治疗性 ipilimumab 和 tremelimumab 抗体的 CTLA-4 结合特性非常相似
影响因子：
--
作者：
He M;Chai Y;Qi J;Zhang CWH;Tong Z;Shi Y;Yan J;Tan S;Gao GF
通讯作者：
Gao GF
影响因子：
16.6
作者：
Dubin K;Callahan MK;Ren B;Khanin R;Viale A;Ling L;No D;Gobourne A;Littmann E;Huttenhower C;Pamer EG;Wolchok JD
通讯作者：
Wolchok JD