文章：

用于癌症治疗的免疫刺激单克隆抗体

Immunostimulatory monoclonal antibodies for cancer therapy

原文发布日期：2007-02-01

DOI: 10.1038/nrc2051

类型: Review Article

开放获取: 否

要点：

1. Monoclonal antibodies (mAbs) have had a significant effect on current practice in oncology. Mechanisms of action include direct tumour cell destruction and indirect targeting of growth and pro-angiogenic mediators.
2. Using mAbs to stimulate the immune response against cancer cells is a new indirect mode of action, achieved by either blocking inhibitory 'immune checkpoint' receptors such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4, also known as CD152) or triggering activating receptors such as 4-1BB or CD40.
3. The list of mAbs that have clearly shown these kinds of effects in mouse tumour models is expanding, and can be grouped as mAbs that interfere with lymphocyte inhibitory receptors; mAbs that function as agonist or super-agonist ligands for co-stimulatory receptors; mAbs that enhance the activation and/or maturation of antigen-presenting cells (APCs); and mAbs that delete or inhibit immunosuppressive mechanisms such as regulatory T cells.
4. An obstacle to the application of immunostimulatory mAbs is their associated adverse toxicity, most commonly reversible autoimmunity and/or systemic inflammatory reactions.
5. Anti-CTLA-4, anti-4-1BB and anti-CD40 are the first immunostimulatory mAbs to reach the clinic. Anti-CTLA-4 is in phase III clinical trials for patients with malignant melanoma following successful phase II testing. Importantly, organ-specific autoimmunity was reported in about one third of patients and correlated with clinical response.
6. Synergistic combinations of immunostimulatory mAbs have been identified at the preclinical level, and combinatorial strategies with cancer vaccines, adoptive T-cell therapy, radiotherapy and chemotherapy will probably have important roles in future clinical development.

要点翻译：

1. 单克隆抗体（mAbs）对当前肿瘤学的实践产生了显著影响。其作用机制包括直接杀伤肿瘤细胞以及间接靶向生长和促血管生成介质。
2. 利用单克隆抗体刺激针对癌细胞的免疫反应是一种新的间接作用模式，通过阻断抑制性“免疫检查点”受体（如细胞毒性T淋巴细胞相关蛋白4，即CTLA-4，亦称CD152）或触发激活受体（如4-1BB或CD40）来实现。
3. 在小鼠肿瘤模型中明确显示此类效应的单克隆抗体名单正在不断扩大，可分为以下几类：干扰淋巴细胞抑制性受体的单克隆抗体；作为共刺激受体的激动剂或超激动剂配体的单克隆抗体；增强抗原呈递细胞（APCs）活化和/或成熟的单克隆抗体；以及删除或抑制免疫抑制机制（如调节性T细胞）的单克隆抗体。
4. 免疫刺激单克隆抗体应用的一个障碍是其相关的不良毒性，最常见的是可逆性自身免疫和/或全身性炎症反应。
5. 抗CTLA-4、抗4-1BB和抗CD40是首批进入临床的免疫刺激单克隆抗体。抗CTLA-4在成功完成II期试验后，目前正针对恶性黑色素瘤患者进行III期临床试验。重要的是，约三分之一患者报告出现器官特异性自身免疫反应，且该反应与临床疗效相关。
6. 在临床前水平已发现免疫刺激单克隆抗体的协同组合，且其与癌症疫苗、过继性T细胞疗法、放疗和化疗的联合策略很可能在未来的临床开发中发挥重要作用。

英文摘要：

Increasing immune responses with immunostimulatory monoclonal antibodies (mAbs) directed to immune-receptor molecules is a new and exciting strategy in cancer therapy. This expanding class of agents functions on crucial receptors, either antagonizing those that suppress immune responses or activating others that amplify immune responses. Complications such as autoimmunity and systemic inflammation are problematic side effects associated with these agents. However, promising synergy has been observed in preclinical models using combinations of immunostimulatory antibodies and other immunotherapy strategies or conventional cancer therapies. Importantly, mAbs of this type have now entered clinical trials with encouraging initial results.

摘要翻译： 

利用针对免疫受体分子的免疫刺激性单克隆抗体（mAbs）来增强免疫反应，是癌症治疗中一种新兴且令人振奋的策略。这类不断扩展的药物作用于关键受体，要么拮抗那些抑制免疫反应的受体，要么激活那些放大免疫反应的受体。然而，这类药物也带来了诸如自身免疫和全身性炎症等副作用问题。不过，在临床前模型中，免疫刺激性抗体与其他免疫治疗策略或传统癌症疗法联合使用已显示出良好的协同效应。重要的是，此类单抗现已进入临床试验阶段，并取得了令人鼓舞的初步结果。

原文链接：

Immunostimulatory monoclonal antibodies for cancer therapy