治疗性抗体药物在临床上取得了巨大的成功,然而在有效性和安全性方面还有待提高,同时药物靶点过于集中造成了重复开发、资源浪费等问题。因此,医药企业在研发抗体药物时需要探寻差异化的研发策略,从而在激烈的市场竞争中生存和发展。文中从药物的来源、结构形式、靶点选择、药物作用机制和差异化药物特性等方面探讨了治疗性抗体药物的差异化研发策略。
Therapeutic antibody drugs have achieved great success in clinical practice. However, their efficacy and safety still need to be improved. At the same time, excessive concentration of drug targets will cause problems such as repeated development and waste of resources. Therefore, pharmaceutical companies need to explore differentiated discovery strategies when researching antibody drugs in order to survive and develop in the fierce market competition. In this paper, the differential development strategy of therapeutic antibody drugs is discussed from the aspects of drug sources and formats, drug target selection, drug mechanism and differential drug characteristics.
截至2020年3月,美国食品药品监督管理局(Food and drug administration,FDA)已批准90种抗体药物上市,2019年全球抗体药物市场规模超过1 400亿美元,增幅超过15%。随着我国“4+7”药品带量采购和一致性评价等政策的出台,生物创新药物的布局对于国内医药企业,特别是仿制药企业的转型和市场竞争力的提升尤为重要。目前,国内申报临床的各类生物药物中,治疗性抗体药物的占比超过一半[
截至2020年3月,FDA累计批准90种抗体药物,这些抗体药物有不同的来源和结构形式,本文对这些抗体药物的适应症(肿瘤、自身免疫性疾病和炎症、心血管疾病等)、药物靶点、类型(单克隆抗体、双特异性抗体、抗体药物偶联物)、来源(杂交瘤、噬菌体展示、转基因小鼠)和结构形式(鼠源抗体、嵌合抗体、人源化抗体、人抗体)进行了归纳和梳理(
FDA已批准上市治疗性抗体药物的归类(适应症、靶点、类型、来源和结构形式)
Classification of therapeutic antibody drugs approved by FDA (indications, targets, types, sources and structural formats).
选择合适的抗体药物靶点是治疗性抗体药物研发的关键,如
选择差异化且有潜力的药物靶点对于药企十分关键,尝试全新靶点的开发是可选的策略之一。英国桑格研究所的研究人员利用基因编辑CRISPR-Cas9技术对300多种人类癌细胞系、近两万个基因进行筛选,最终筛选出40个成熟药物靶点,227个潜在药物靶点和311个全新药靶点[
由于信号通路的复杂性和交互性,抗体药物可涉及多种作用机制[
深入研究抗体药物的作用机制是治疗性抗体药物差异化研发的关键,抗体药物的迭代总是伴随着对靶点和抗体作用机理的深入研究,以CTLA-4为例,最初认为靶向CTLA-4抗体的主要机制是阻断T细胞表面的CTLA-4与抗原递呈细胞表面的CD80和CD86的结合,从而促进T细胞活化杀伤肿瘤细胞。昂科免疫的刘阳等基于靶向CTLA-4的伊匹单抗在黑色素瘤治疗过程中出现的安全性问题深入研究,发现伊匹单抗的作用机制并不是主要依赖于T细胞,而是主要依赖于清除肿瘤微环境中的Treg细胞,伊匹单抗治疗的不良反应是由于细胞表面的CTLA-4被抗体带到溶酶体降解,形成CTLA-4功能缺失造成的。基于此作用机制,科研人员开发了ADCC功能更强且具备pH敏感性的抗体ONC-392,有望获得比伊匹单抗更安全、更有效的抗体药物[
针对同样的药物靶点,基于现有治疗药物的不足,研发具有差异化特性的抗体药物,达到更好疗效、更小副作用的目的,是目前差异化研究的重要方向,包含抗原表位、Fc效应功能、亲和力和免疫原性等多个方面。
抗原表位(Epitope)指存在于抗原表面决定抗原特异性的化学基团,是抗原与抗体相互作用的区域。靶向B淋巴细胞表面CD20的利妥昔单抗和奥法木单抗,靶向肿瘤细胞表面HER2的曲妥珠单抗和帕妥珠单抗,靶向T细胞表面PD-1的纳武单抗和派姆单抗均有针对各自靶点不同的抗原表位[
抗体结合特异性抗原后可以通过激活补体或与免疫效应细胞表面Fcγ受体相结合发挥ADCC、ADCP和CDC等生物学效应。不同亚型IgG的生物学效应存在差异,目前上市的抗体药物以IgG1亚型为主,IgG4亚型的抗体也逐渐增多,随着对抗体作用机制和Fc效应的深入理解,不同IgG亚型的突变体已被应用到治疗性抗体的研发中以达到提高药效或降低副作用的目的[
提高抗体亲和力有助于改善抗体的特异性,减少用药剂量和降低毒副作用。因此,通常将高亲和力作为抗体药物筛选的重要指标之一,然而在一些情况下,高亲和力抗体反而会引起药效下降或安全性问题。研究表明,降低靶向EGFR、HER2等抗体的亲和力反而使抗体ADCC和CDC活性显著增强,这是因为降低抗体的亲和力可使抗体更倾向于以单价形式结合抗原,局部更容易形成抗体聚集,从而显著增强ADCC和CDC活性[
抗体药物的免疫原性与临床疗效密切相关,抗药物抗体(Anti-drug antibody,ADA)反应可能导致疗效的改变和潜在的严重副作用,如过敏性反应、输液反应、内源性免疫球蛋白交叉反应、药物不良事件、药物动力学改变[
消除或减少抗体药物的副作用是药物研发的重要目标,也是研发差异化抗体弥补现有抗体药物不足的有效策略。如靶向肿瘤细胞表面CD47的抗体可通过阻断CD47与巨噬细胞上的SIRPα的结合,解除“别吃我”信号,从而增强巨噬细胞吞噬肿瘤细胞的功能。然而,由于红细胞表面也广泛表达CD47,抗CD47的抗体可引起贫血和血小板减少等血液系统副作用,如Forty Seven研发的Magrolimab抗体[
抗体药物的其他特性,如稳定性和溶解度,也是抗体药物研发的方向。如诺华研发的靶向VEGF的人源化单链抗体片段Brolucizumab,通过阻止VEGF与VEGFR的结合,抑制眼底血管生成,用于治疗年龄相关性黄斑变性(Age-related macular degeneration,AMD)。Brolucizumab的分子量为26 kDa,溶解度高达120 mg/mL,治疗摩尔剂量约为同类产品阿柏西普的22倍,实现了3个月一次的给药间隔,从而减少药物眼内注射频率,满足患者的需求[
治疗性抗体药物产业发展迅猛,全球抗体药物市场已突破千亿美元,国内各大药企也将抗体药物作为研发重点,同时在国家政策的支持下,国内抗体药物产业实现了从基础研究到产业化的跨越,抗体药物的品种和市场规模持续增长,然而研究扎堆、创新不足、重复开发、资源浪费等问题制约了抗体药物产业的发展[
在靶点选择上,以PD-1、PD-L1抗体为代表的免疫检查点拮抗剂取得了巨大的成功,而免疫检查点激动剂,如ICOS、GITR、OX40、CD27和4-1BB等抗体的早期临床试验均未能达到高预期。以4-1BB抗体为例,百时美施贵宝(BMS)公司的Urelumab存在肝毒性问题,辉瑞公司的Utomilumab安全但无效,有证据表明问题出在药物上,而非靶标本身,Compass公司从抗体亚型、亲和力、受体动力学方面出发研制的CTX-471抗体具有独特的抗原表位和抗体特征,正在临床试验中,其临床结果值得期待[
规避竞争过于激烈的适应症也是药企的策略选择,如荣昌生物靶向HER2的抗体药物偶联物RC48-ADC,选择相对冷门的HER2阳性尿路上皮细胞癌作为适应症并在Ⅱ期临床试验中显示出优越的疗效,抢占了该适应症的先机。此外,借助CRO、CDMO服务企业的技术和能力平台推进抗体药物的研发也是很多药企的选择,如国内外多家药企通过使用药明生物拥有自主知识产权的WuXiBody双特异性抗体平台、WuXiUP超高效连续细胞培养生产平台和WuXia细胞系平台来加速生物药研发进程、提高效率和降低研发及生产成本,从而提升市场竞争力。同时,国内药企要提高市场竞争力,还需要摸索合适的商业化模式,如天境生物、信达生物等药企通过自主研发和全球合作等多元化商业模式,建立起具有全球竞争力的创新药物研发管线,获得了资本和市场的认同。由此可见,差异化抗体药物研发是生物学机制、技术和能力平台、临床研究策略和商业化模式多维度交互的过程,药企需要选择合适的策略和突破口,才能立足于竞争激烈的市场,进而共同努力推动整个抗体药物产业的健康发展。
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