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点击蓝字 关注我们 2025年11月10日，专注于PD-1激动剂的生物技术公司Anaptys Bio宣布其PD-1激动剂抗体Rosnilimab在中重度溃烂性肠炎患者（UC）的2期临床试验中未能达到临床主要及次要终点，后续将中断在该适应症的开发。 此前，Rosnilimab在类风湿性关节炎（RA）的2期临床试验中达到了主要终点，并显示出不错的治疗效果。 关于PD-1激动剂在自免和炎症类适应症中的成药性的争论再次摆上台面。 PD-1是百年一遇的药物靶点，以PD-1/PD-L1为代表的免疫治疗方案已经成为肿瘤免疫领域的基石疗法，撑起了数百亿美元的药物市场，并出现了PD-1/VEGF双抗，PD-1抗体联合ADC等革命性的第二代免疫治疗方案，真正满足了未满足的临床需求，为患者带来了临床获益和生存希望，成为最近十几年引领肿瘤药物开发的引擎，PD-1的发现者本庶佑也因此获得2018年的诺贝尔生理学或医学奖。 从宏观角度来讲，我们经常说肿瘤和自身免疫病是一个硬币的两面。肿瘤细胞的产生是由于细胞内不断累积的突变突破了免疫系统的监视和清除，并反过来限制了局部免疫微环境中免疫细胞的功能，从而在局部形成新的实体发展为危害健康的肿瘤。而自身免疫性疾病的起因在于自身抗原特异性T细胞的异常活跃，打破了自身的免疫耐受机制，从而对自身抗原和组织产生攻击和破坏。所以对于肿瘤免疫来讲，我们要重建免疫系统清除异常肿瘤细胞的能力；而对于自身免疫性疾病来讲，我们要限制自身抗原特异性免疫细胞尤其是T和B细胞的功能。 在药物研发历史上，有一个靶点既在自免领域获批了适应症，也在肿瘤免疫领域成为突破性疗法，这个靶点就是大名鼎鼎的CTLA-4。 2005年，BMS开发了CTLA-4的融合蛋白类药物Abatacept（阿巴西普），成功获批多项自免适应症，包括RA，银屑病关节炎（PsA）和幼年特发性关节炎（pJIA）等。2024年阿巴西普的全年销售额为36.82亿美元，虽然没有像多款TNF抑制剂药物一样成为超级重磅药物，但阿巴西普也是BMS最畅销的自免类产品，可谓差强人意。 2011年，同样是BMS，开发了针对CTLA-4的阻断性抗体Ipilimumab，被FDA批准用于治疗晚期黑色素瘤，为后续的肿瘤免疫疗法打响了第一枪。 可惜的是，由于CTLA-4复杂的生物学机制（如靶点蛋白的内吞和循环利用，pH对蛋白表面丰度的影响，CTLA-4在不同T细胞亚群的分布等），Ipilimumab在后续的临床开发中遇到了比较大的挑战，其适应症的广度及在临床运用中的认可度远远不及后来居上的PD-1单抗类药物。2024年Ipilimumab的全年销售额为46.7亿美元，与PD-1抗体药物Keytruda全年294.82亿美元的销售额不可同日而语。 再回到PD-1，其激动剂的开发几经波折。礼来是开发PD-1激动剂药物较早的药企。2023年5月18日，礼来在The New England Journal of Medicine 上发表了其PD-1激动剂抗体Peresolimab治疗RA的2期临床结果。 结果显示，Peresolimab在RA患者的2a期临床试验中显示出疗效，达到临床预设的主要终点。然而在随后的2024年，礼来宣布因为公司总体研发策略以及Peresolimab的风险/效益比问题而终止该款药物的开发，整个PD-1激动剂研发领域都因此蒙上了一层阴影。 Rosnilimab是继Peresolimab之后全球范围内临床进展最快的PD-1激动剂，相比于Peresolimab，Anaptys Bio宣称Rosnilimab具有全方位的优势。 2023年发表于Science Immunology的研究论文提供了开发PD-1激动剂抗体的示范。该项研究表明激动剂PD-1 抗体一般结合 PD-1 的膜近端区域，并与APC上的 Fc 受体结合，促成PD-1交联和抑制信号的传递。 Anaptys Bio在PD-1激动剂领域已经驶入无人区，目前适应症开发已经聚焦到RA领域，后续关键临床3期的结果将决定这一赛道的成败，一切有待临床数据的获得和揭示。 关于PD-1激动剂的药物开发和转化研究，有几点值得思考： 1. 在自免适应症中，PD-1阳性T细胞与自身抗原特异性T细胞overlap的程度。这是一个关键的问题，也是PD-1激动剂开发的基石。 2. PD-1激动剂抗体抑制自身反应性T细胞的效果不容易量化，而这一指标是决定药物疗效的重要依据。 3. PD-1的表达具有时空特异性，在临床试验中，是否可以通过biomarker将患者进行分层和筛选，达到更好的治疗效果。 4. PD-1激动剂的ADCC效应是否必需：从历史数据来看，PD-1不仅表达于效应T细胞，也表达于调节性T细胞，清除PD-1阳性细胞是否会导致负面效应？ 5. PD-1在免疫稳态中发挥重要功能，过度激活（如果会）是否会影响免疫稳态，导致长期的免疫低下，从而增加各种感染风险，甚至癌症发生的风险？ Reference： Alexandra Schnell et al., Cancer Research, 2020, 30:285. The yin and yang of co-inhibitory receptors: toward anti-tumor immunity without autoimmunity. Jay Tuttle et al., The New England Journal of Medicine, 2023, 388:1853. A Phase 2 Trial of Peresolimab for Adults with Rheumatoid Arthritis. Kensuke Suzuki et al., Science Immunology, 2023, 8: eadd4947. Anti-PD-1 antibodies recognizing the membrane-proximal region are PD-1 agonists that can down-regulate inflammatory diseases.

AnaptysBio said it will provide an update on its plans for its PD-1 agonist in rheumatoid arthritis in the first half of next year.\n AnaptysBio has abandoned plans to develop rosnilimab for ulcerative colitis (UC) after the PD-1 agonist flunked a phase 2 study.The San Diego-based biopharma assessed rosnilimab in the midstage study of 136 patients with moderate to severe UC across the U.S. and Europe. The study’s main goal was to demonstrate a mean change from baseline as measured by the modified Mayo Score (mMS) at Week 12, with key secondary endpoints evaluating clinical response and clinical remission.Patients who received 400 mg of subcutaneous rosnilimab every four weeks or 800 mg every two weeks only achieved clinical remission rates of 7% , which was no better than the placebo cohort, Anaptys explained in a Nov. 10 release.“While preliminary data suggest an increase in remission rates between week 12 and week 24, week 24 remission rates did not meet our six-month target product profile,” Anaptys added.The results dent the high hopes for rosnilimab generated by a phase 2 win in rheumatoid arthritis (RA) in February. That success had offered some welcome clinical validation for Anaptys after the company had jettisoned an atopic dermatitis candidate three months early when the compound failed to reduce eczema area and itch severity in a phase 2b trial.“Rosnilimab was safe and well tolerated, but we are disappointed in the lack of adequate efficacy and will discontinue the UC trial,” Anaptys CEO Daniel Faga said in this morning’s release.The CEO attempted to focus investors\' attention on ANB033, a CD122 antagonist already undergoing a phase 1b study for celiac disease. “We plan to announce a phase 1b in another inflammatory disease in 2026,” Faga pointed out.Today’s decision to discontinue the UC trial for rosnilimab will save the company around $10 million, according to the release. Anaptys said it will provide an update on its plans for the PD-1 agonist in RA in the first half of next year, with this program needing to be funded by “strategic or other sources of capital without diluting our royalties.”Next year, AnaptysBio plans to split into two publicly traded companies. One entity will take forward the biopharma’s clinical-stage pipeline, and the other will oversee its royalty-based agreements, headlined by Jemperli, the PD-1 blocking antibody that Anaptys discovered and has since brought GSK $2.7 billion in sales as an endometrial cancer and solid tumor drug.