【翻译】单克隆抗体治疗肿瘤发展趋势Nature Reviews Drug Discovery 6, 349-356 (May 2007)
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Development trends for monoclonal antibody cancer therapeutics
单克隆抗体治疗肿瘤发展趋势
Janice M. Reichert1 & Viia E. Valge-Archer2
Abstract
摘要
Monoclonal antibodies are now established as a key therapeutic modality for a range of diseases.Owing to the ability of these agents to selectively target tumour cells, cancer has been a major focus of development programmes for monoclonal antibodies so far. Here, we overview trends in the clinical development and regulatory approval of monoclonal antibodies for cancer since 1980, with the aim of informing future research and development for this class of therapeutics.
目前单抗在多种疾病的治疗中占据重要位置。因其具有选择性靶向肿瘤细胞的优良特性，肿瘤迄今一直以开发特异性单克隆抗体为焦点。本文综述自1980年以来单抗在肿瘤临床治疗和调节中的发展趋势，以为未来单抗疗法的研发起到提示作用。
The treatment of cancer remains a formidable challenge owing to factors such as the difficulties in differentiating tumour cells from healthy cells to ameliorate the disease without causing intolerable toxicity to patients. Monoclonal antibodies (mAbs) represent an attractive approach to tackling this problem as they can be designed to selectively target tumour cells and elicit a variety of responses once bound. These agents can directly kill cells by carrying toxic material to the target or can orchestrate the destruction of cells in other ways, such as activating immune system components, blocking receptors or sequestering growth factors.
肿瘤的治疗仍然面临着的困难，无法区分恶变肿瘤细胞和正常健康细胞，因而一种既能杀死肿瘤细胞又不引起病人不可忍受的毒副作用是肿瘤治疗的目标。单克隆抗体提供了一种解决上述问题的方法，因为它既可以选择性识别肿瘤特异性靶标，一旦结合又可引起相关的治疗反应。这类药物可以通过几种不同的途径：携带毒素到达靶点、通过激活免疫反应来破坏靶细胞、中和受体或者阻断生长因子作用。
Therapeutic mAbs have been studied in the clinic for nearly three decades. Despite inauspicious beginnings, more than 400 therapeutic mAbs entered commercially sponsored clinical development during this time, with anticancer mAbs comprising approximately half of the total1. Advances in technology have vastly expanded the variety of mAbs available for study2, 3, while improved understanding of cancer biology has extended the list of potential targets4. To inform future efforts in the research and development of these innovative therapeutics, we analyse the trends in the clinical development and approval of commercially sponsored anticancer mAbs over more than 25 years. We do not attempt to discuss the therapeutic impact (such as efficacy, tolerability and effect on patient outcome) of mAbs in particular cancers and, given the vast amount of primary literature in this field, we provide references to relevant reviews that consider the research and data associated with the trends discussed.
单抗类药物用于临床研究已有将近60年的历史。除去失败的序曲，四百多种治疗性单抗已经进入由药商发起的临床实验中，其中一半以上为抗肿瘤单抗。抗体技术的进步为对更多的单抗进行研究提供了便利，同时对肿瘤认识的不断深入也提供了越来越多的靶标。为对未来这些创新疗法的研发指明道路，我们总结了25年来由药商发起的临床肿瘤治疗单抗的发展和审批历程。我们并不单就某种特殊的肿瘤及其治疗效果（见效快慢、耐受性以及病人缓解效果）进行讨论，我们将对整个领域的综合进展进行讲述，为诠释相关趋势我们将提供相关研究和数据参考文献以供读者查阅。
Approved anticancer mAbs
From 1980 to 2005, a total of 206 unique therapeutic mAbs were studied in clinical trials by commercial companies worldwide for a variety of cancer indications (Box 1). The candidates included in-licensed as well as self-originated mAbs, and probably represented the most promising anticancer mAbs produced in government, academic and commercial settings. To date, 12 of these anticancer mAbs have been approved for marketing in at least one country (Table 1). Anticancer mAbs had been in clinical study for 15 years before one — edrecolomab — was approved in Germany in 1995. This first approval was a harbinger because, with the exception of 1999, at least one anticancer mAb has been approved each year since 1997. The successes have come with setbacks, however; edrecolomab was withdrawn from the market when a post-approval study demonstrated that the treatment was inferior to the standard of care5.
已批准的抗肿瘤单抗
1980到2005年间，世界各地制药公司发起共发起206个肿瘤治疗性单抗进入临床试验。这些候选药物中包括已有证书的（in-licensed）和首创（self-originated）单抗，大抵囊括了所有具有潜力成为抗肿瘤药物的单克隆抗体，无论来自政府机构、科研单位还是制药公司。到今天为止，其中的12个单抗已获准在至少一个国家上市。截至1995年第一个单抗药物—edrecolomab在德国上市，单抗药物的临床研究持续了15年。第一个药物堪称先驱，1997年以后，除1999年以外每年都有一个肿瘤治疗单抗药物获批上市。这些成功和挫折并存，然而，因在一项上市后（post-approval）研究中edrecolomab被证明比标准疗法疗效差，从市场被踢出。
The approved products are the result of years of work in two major research areas which are critical to the success of mAbs as targeted cancer therapeutics: development of engineering and production methods for the four main categories of mAbs (murine, chimeric, humanized and human), and study of modes of action (for example, tumour cell toxicity via radiation, cytotoxins, activation of immune system components or receptor/ligand blockade). Clinical studies initially focused on murine mAbs — the category most readily available in the 1980s — and on immunoconjugates that used radioactive elements or cytotoxins to kill tumour cells. However, only two murine immunoconjugates (both radiolabelled) have been approved to date. Of the currently approved anticancer mAbs, humanized products are the most numerous of the four categories and activation of immune system components or receptor/ligand blockade using unmodified or 'naked' mAbs are the most common modes of action.
已上市的单抗产品是两大领域多年研究的成果：不同来源抗体生产技术和工艺的进步（鼠单抗、嵌合抗体、人源化单抗以及全人单抗）和给药方式的进步（例如：肿瘤放射疗法毒性、阻断和激活免疫系统组分和受体、配体）。临床研究最初以鼠源单抗为主—19世纪80年代，抗体藕联放射性毒素非放射性有毒物质治疗。然而，直至今日，只有两个鼠源单抗（均为放射性毒素藕联）获准上市。就目前获准上市的单抗药物来讲，四种单抗种类以及免疫系统激活或者受体、配体裸抗体阻断剂中人源化单抗占据最大份额。
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此话题已收录于“单抗小组讨论话题集锦” By waynepionnet
Development trends for monoclonal antibody cancer therapeutics
单克隆抗体治疗肿瘤发展趋势
Janice M. Reichert1 & Viia E. Valge-Archer2
Abstract
摘要
Monoclonal antibodies are now established as a key therapeutic modality for a range of diseases.Owing to the ability of these agents to selectively target tumour cells, cancer has been a major focus of development programmes for monoclonal antibodies so far. Here, we overview trends in the clinical development and regulatory approval of monoclonal antibodies for cancer since 1980, with the aim of informing future research and development for this class of therapeutics.
目前单抗在多种疾病的治疗中占据重要位置。因其具有选择性靶向肿瘤细胞的优良特性，肿瘤迄今一直以开发特异性单克隆抗体为焦点。本文综述自1980年以来单抗在肿瘤临床治疗和调节中的发展趋势，以为未来单抗疗法的研发起到提示作用。
The treatment of cancer remains a formidable challenge owing to factors such as the difficulties in differentiating tumour cells from healthy cells to ameliorate the disease without causing intolerable toxicity to patients. Monoclonal antibodies (mAbs) represent an attractive approach to tackling this problem as they can be designed to selectively target tumour cells and elicit a variety of responses once bound. These agents can directly kill cells by carrying toxic material to the target or can orchestrate the destruction of cells in other ways, such as activating immune system components, blocking receptors or sequestering growth factors.
肿瘤的治疗仍然面临着的困难，无法区分恶变肿瘤细胞和正常健康细胞，因而一种既能杀死肿瘤细胞又不引起病人不可忍受的毒副作用是肿瘤治疗的目标。单克隆抗体提供了一种解决上述问题的方法，因为它既可以选择性识别肿瘤特异性靶标，一旦结合又可引起相关的治疗反应。这类药物可以通过几种不同的途径：携带毒素到达靶点、通过激活免疫反应来破坏靶细胞、中和受体或者阻断生长因子作用。
Therapeutic mAbs have been studied in the clinic for nearly three decades. Despite inauspicious beginnings, more than 400 therapeutic mAbs entered commercially sponsored clinical development during this time, with anticancer mAbs comprising approximately half of the total1. Advances in technology have vastly expanded the variety of mAbs available for study2, 3, while improved understanding of cancer biology has extended the list of potential targets4. To inform future efforts in the research and development of these innovative therapeutics, we analyse the trends in the clinical development and approval of commercially sponsored anticancer mAbs over more than 25 years. We do not attempt to discuss the therapeutic impact (such as efficacy, tolerability and effect on patient outcome) of mAbs in particular cancers and, given the vast amount of primary literature in this field, we provide references to relevant reviews that consider the research and data associated with the trends discussed.
单抗类药物用于临床研究已有将近60年的历史。除去失败的序曲，四百多种治疗性单抗已经进入由药商发起的临床实验中，其中一半以上为抗肿瘤单抗。抗体技术的进步为对更多的单抗进行研究提供了便利，同时对肿瘤认识的不断深入也提供了越来越多的靶标。为对未来这些创新疗法的研发指明道路，我们总结了25年来由药商发起的临床肿瘤治疗单抗的发展和审批历程。我们并不单就某种特殊的肿瘤及其治疗效果（见效快慢、耐受性以及病人缓解效果）进行讨论，我们将对整个领域的综合进展进行讲述，为诠释相关趋势我们将提供相关研究和数据参考文献以供读者查阅。
Approved anticancer mAbs
From 1980 to 2005, a total of 206 unique therapeutic mAbs were studied in clinical trials by commercial companies worldwide for a variety of cancer indications (Box 1). The candidates included in-licensed as well as self-originated mAbs, and probably represented the most promising anticancer mAbs produced in government, academic and commercial settings. To date, 12 of these anticancer mAbs have been approved for marketing in at least one country (Table 1). Anticancer mAbs had been in clinical study for 15 years before one — edrecolomab — was approved in Germany in 1995. This first approval was a harbinger because, with the exception of 1999, at least one anticancer mAb has been approved each year since 1997. The successes have come with setbacks, however; edrecolomab was withdrawn from the market when a post-approval study demonstrated that the treatment was inferior to the standard of care5.
已批准的抗肿瘤单抗
1980到2005年间，世界各地制药公司发起共发起206个肿瘤治疗性单抗进入临床试验。这些候选药物中包括已有证书的（in-licensed）和首创（self-originated）单抗，大抵囊括了所有具有潜力成为抗肿瘤药物的单克隆抗体，无论来自政府机构、科研单位还是制药公司。到今天为止，其中的12个单抗已获准在至少一个国家上市。截至1995年第一个单抗药物—edrecolomab在德国上市，单抗药物的临床研究持续了15年。第一个药物堪称先驱，1997年以后，除1999年以外每年都有一个肿瘤治疗单抗药物获批上市。这些成功和挫折并存，然而，因在一项上市后（post-approval）研究中edrecolomab被证明比标准疗法疗效差，从市场被踢出。
The approved products are the result of years of work in two major research areas which are critical to the success of mAbs as targeted cancer therapeutics: development of engineering and production methods for the four main categories of mAbs (murine, chimeric, humanized and human), and study of modes of action (for example, tumour cell toxicity via radiation, cytotoxins, activation of immune system components or receptor/ligand blockade). Clinical studies initially focused on murine mAbs — the category most readily available in the 1980s — and on immunoconjugates that used radioactive elements or cytotoxins to kill tumour cells. However, only two murine immunoconjugates (both radiolabelled) have been approved to date. Of the currently approved anticancer mAbs, humanized products are the most numerous of the four categories and activation of immune system components or receptor/ligand blockade using unmodified or 'naked' mAbs are the most common modes of action.
已上市的单抗产品是两大领域多年研究的成果：不同来源抗体生产技术和工艺的进步（鼠单抗、嵌合抗体、人源化单抗以及全人单抗）和给药方式的进步（例如：肿瘤放射疗法毒性、阻断和激活免疫系统组分和受体、配体）。临床研究最初以鼠源单抗为主—19世纪80年代，抗体藕联放射性毒素非放射性有毒物质治疗。然而，直至今日，只有两个鼠源单抗（均为放射性毒素藕联）获准上市。就目前获准上市的单抗药物来讲，四种单抗种类以及免疫系统激活或者受体、配体裸抗体阻断剂中人源化单抗占据最大份额。
