N-nonyldeoxynojirimycin

在血液肿瘤领域，即使是当下大热的魔法子弹——ADC，也并非无往不利。先是去年，GSK的Blenrep在复发或难治性多发性骨髓瘤治疗上经历确证性试验的失败，迅速撤出美国市场。无独有偶，阿斯利康的Lumoxiti在欧盟上市仅五个月后，因商业原因，撤离欧洲毛细胞白血病市场，并将于今年8月，永久停止在美国市场分销该药。风潮似乎也蔓延到霍奇金淋巴瘤（HL）领域。目前，针对CD30阳性淋巴瘤已有多种新药及新型疗法，包括由Seagen开发被辉瑞相中的Adcetris。但ADC之前受到追捧的PD-1抑制剂，因相对低毒、安全可控等优势，正在HL患者中将治疗关口前移。守擂与攻擂的剑拔弩张，在近期召开的ASCO年会上，出现了一次短兵相接的较量。会上，BMS公布了Opdivo联合多柔比星、长春碱和达卡巴嗪（AVD方案）一线治疗HL的III期临床数据。相较于ADC联合AVD，Opdivo的联合疗法效果更优。Seagen想必不会任由Opdivo蚕食鲸吞，并入MNC后，这家Biotech有了更多的本钱发起反击。如果把时间线拉长，我们还可以看到Seagen在ADC与免疫疗法联合方面布局的草蛇灰线。1打破治疗僵局，ADC稳坐淋巴瘤江山作为一种淋巴系统恶性增殖性肿瘤，HL发病率约占所有淋巴瘤的10％。过去几十年来，放疗、化疗、免疫治疗等手段的发展，显著增加了HL患者的治愈率。可惜，复发、耐药以及死亡风险等问题依旧未被很好解决。正是在这一背景下，Seagen带着靶向CD30的ADC登场，改变了HL治疗范式。2011年，这款“元老”级别的产品Adcetris正式进入美国市场，用于治疗HL和系统性间变性大细胞淋巴瘤（sALCL），该药也是目前为止唯一一款淋巴瘤领域的CD30 ADC。Adcetris是ADC技术的升级迭代产物，由靶向CD30的嵌合抗体IgG1与微管蛋白抑制剂MMAE通过一种蛋白酶敏感连接子Vat-Cit偶联在一起，DAR为4。CD30已成为帮助淋巴瘤诊断及制定治疗决策的重要标志物，Adcetris通过靶向CD30，可将微管破坏剂特异性递送至CD30阳性细胞。围绕cHL和sALCL，Adcetris已获批六个适应症。创新作用机制使得Adcetris在多种CD30阳性淋巴瘤的临床研究中表现出色，其单药方案中位治疗R/R sALCL7个周期，总体患者缓解率（ORR）达86%，完全缓解率（CR）率达57%。良好的疗效使其也成为治疗R/R cHL的标准护理药物。NCCN V2.2023版指南已将其纳入cHL一线治疗首选，在针对难治和高复发风险以及二线及以后的患者也新增了Adcetris的身影。推出这款变革性ADC的Seagen，1997年由从BMS离开后的前高管ClayB Siegall联合创作，并很快登陆纳斯达克。在Seagen的ADC管线中，除了Adcetris外，目前还有Padcev、Tukysa和Tivdak等成熟产品。随着实打实的疗效和资本涌入，Seagen可观的商业化前景一度吸引制药巨头的关注。今年3月，辉瑞宣布将以430亿美元的价格收购Seagen。这是迄今有关ADC领域规模最大的一笔收购交易，两家公司预计该交易将在今年年底或明年初完成。从收入回报上看，Adcetris作为淋巴瘤治疗先锋，确实表现优异。2022年财报披露，Seagen全年总营收为20亿美元，产品净销售额同比增长23%至17亿美元，其中Adcetris贡献了8.39亿美元，同比增长19%。 此外，Seagen在今年第一季度销售额也持续攀升，同比增长34%，达到2.43亿美元。据SVB Securities预估，凭借一线治疗HL适应症，Adcetris可以在高峰期斩获销售额约7.8亿美元。辉瑞还表示，Seagen预计将以28%的年复合增长率，在2028年实现77亿美元的业绩收入，其中，Padcev和Adcetris是业绩增长的主要原因。2ASCO最新声：PD-1与ADC短兵相接但将视野转换到临床角度，可以发现，一直布局HL的Adcetris并非患者的唯一选择。机制方面，相比于PD-1，由于Adcetris偶联方式与第一代ADC类似，linker的稳定性仍待提高，脱靶毒性、存在未结合抗体以及药物抗体比（DAR）较大引起ADC聚集或快速清除，并且，大多数第二代ADC显示出较窄的治疗窗口，难以满足进一步的临床需求。也不乏有研究表示，对于更高危甚至自体造血干细胞移植（ASCT）和Adcetris治疗后仍发生疾病进展的患者，“PD-1双雄”Opdivo和Keytruda的研究数据都更加优效。目前，国内的派安普利单抗、卡瑞利珠单抗等PD-1抑制剂，都已经成功拿下后线治疗HL的适应症。尽管在想象空间更大的一线治疗HL领域，暂无挑战成功的免疫抑制剂。不过，也有药企跃跃欲试了。今年ASCO大会上，来自前东家BMS的Opdivo向Adcetris发起挑战。BMS汇报的SWOG-S1826，是一项迄今为止规模最大的晚期HL研究，也是成人和儿童小组之间的首次前瞻性AYA合作，旨在“头对头”评估新诊断AS HL患者中的N-AVD（Opdivo组）与BV-AVD（Adcetris组）的疗效和安全性。该III期研究纳入III-IV期HL患者，并按1:1的比例随机接受6个周期的N-AVD或BV-AVD治疗，主要终点是无进展生存期（PFS），次要终点包括总生存期（OS）、无事件生存期、患者报告的结果（PROs）和安全性。结果显示，与BV-AVD方案相比，Opdivo治疗组改善了AS HL患者的PFS，更大比例患者在一年内没有癌症生长。在976名患者的第二次中期分析（总PFS事件的50%）中，PFS终点超过研究方案规定的保守统计学界值。在中位随访时间为12.1个月的情况下，Opdivo组的PFS优于Adcetris组；1年PFS Opdivo组为94%，Adcetris组为86%。无事件生存结局也有利于N-AVD，接受Opdivo组治疗的患者的1年无事件生存率为91%，而接受Adcetris组的患者为84%。此外，City of Hope的Alex F Herrera还在2023年ASCO年会上透露，安全性方面，N-AVD组观察到更少的免疫相关不良事件，且接受放射治疗的患者比例低于1%。Herrera还提到，N-AVD组更有PFS优势和有利的安全性，即使没有显示OS，也足以使N-AVD成为新护理标准，跻身一线治疗HL的阵营。如果以Opdivo为代表的PD-1疗法成功突围，届时，面对疗效、安全性都更胜一筹的Opdivo，Adcetris又该如何自处？3打不过就加入？Seagen见招拆招SWOG-S1826数据确实给HL患者带来新的希望，但Seagen相信，包括OS数据在内的长期指标，对于HL的治疗也同样重要。在给Fierce Pharma的一份声明中，Seagen表示需要更长时间的随访来评估OS和PROs。实际上，这并不是Adcetris第一次在HL领域面临PD-1的“头对头”挑战。相比Opdivo，PD-1的“老大哥”Keytruda很早就布局于此。一项名为KEYNOTE-204研究发表在Lancet Oncol杂志上，该研究是一项旨在“头对头”比较Keytruda和Adcetris治疗R/R cHL患者疗效的III期研究。结果来看，就主要终点PFS（含移植后临床和影像学数据），Keytruda组和Adcetris组的中位PFS分别为13.2个月和8.3个月；就次要终点的PFS（不含移植后临床和影像学数据），Keytruda组和Adcetris组的中位PFS分别为12.6个月和8.2个月。基于该研究结果，2020年，Keytruda获得FDA对其治疗的HL的全面批准。而如今，面对Opdivo等更多后来者的挑战，Seagen不得不有所反应。正如Herrera所说，尽管效果与PD-1相比处于下风，但Adcetris仍在早期HL一线治疗中占有一席之地，那么如何恰当地将其纳入HL治疗范式？针对该问题，Seagen在声明中提到，Seagen的最终目标，是实现HL最高的治愈率并能减轻患者的化疗负担，以此将Adcetris与Opdivo相结合，是一种合乎逻辑的方法。ADC联合免疫抑制剂在肿瘤治疗中早已屡见不鲜。4月3日，FDA加速批准了Keytruda联合Seagen另一款ADC Padcev的上市申请，用于一线治疗不适合接受以顺铂为基础化疗的局部晚期或转移性尿路上皮癌（la/mUC）。去年12月，Seagen在2022 ASH会议上，还公布了Adcetris的II期SGN35-027研究B部分和C部分结果。B部分和C部分旨在评估Adcetris联用Opdivo、多柔比星和达卡巴嗪（AN+AD方案）一线治疗12岁及以上cHL患者的疗效和安全性。其中，研究B部分共纳入57例晚期（伴纵隔大包块的II期、III期和IV期）cHL患者。结果显示，患者的CR率为88%，ORR为93%。估计的12个月PFS率为95%。而研究C部分共纳入125例早期（不伴纵隔大包块的I期和II期）cHL患者，其中76例患者可评估疗效。数据显示，患者的CR率为92%，ORR为95%，PFS尚在评估中。没有一款药物能够包治百病，即使是开创了肿瘤免疫治疗的PD-1单抗，也面临着响应率不高等难题。然而，不可否认的是，PD-1抗体药物已经成为肿瘤免疫治疗的基石，联合ADC不过是双抗等靶向PD-1策略的又一尝试。对于Seagen来说，重要的是如何令拳头产品尽可能延长生命周期，以支持这家Biotech进入下一个创新循环。ADC与PD-1的搭档能否令Seagen如愿，一切只能用时间来印证。参考资料：1.CD30学院 | 白鸥教授——复发难治HL：免疫治疗新时；Htology血液前沿2.ASCO: Seagen's top-selling drug under threat as Bristol Myers' Opdivo beats Adcetris in lymphoma；FIERCE pharma3.Seagen官网4.ASCO官网识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

Lund, Sweden – 16 April 2013 – BioInvent International AB (OMXS:BINV), a biotech company developing novel antibody therapeutics for treatment of cancer, today announced that the April 15, 2013 online issue of the highly prestigious cancer research journal Cancer Cell features a data publication demonstrating potent anti-cancer activity of BI-505 in multiple preclinical myeloma tumor models. BI-505 is currently in Phase I clinical testing and is furthest ahead among several novel antibody candidates that have emerged from the company’s unique function-first platform “F.I.R.S.T.?”, which enables combined target and antibody drug discovery. “BI-505 is BioInvent’s first therapeutic antibody isolated by target unbiased functional screening to enter clinical trials. BioInvent researchers identified this antibody based on its significant ability to confer tumor cell death in preclinical B cell cancer models, amongst tens of billions antibodies present in the company’s human antibody library n CoDeR®”, said Björn Frendéus, Ph.D., Vice President, Preclinical Research of BioInvent International AB and senior author on the paper. “BI-505 binds very specifically to intercellular adhesion molecule 1 (ICAM-1), a receptor which is highly expressed on multiple myeloma cancer cells as well as implicated in myeloma pathogenesis and development of drug-resistance, the current inevitable end-stage of this aggressive disease”. ICAM-1 is a cell adhesion molecule that has previously been pursued as target for antibody based therapy, but then in chronic inflammatory and autoimmune diseases, based on its well-characterized role in inflammation. Cristina Glad, CEO of BioInvent, said, “BI-505 is one of several antibodies that BioInvent is developing for treatment of cancer. BI-505 induces cell death in target tumor cells and activates host antitumor immunity in a manner that would not have been predicted from currently available information on the biology of ICAM-1. This molecule illustrates how our unique F.I.R.S.T.™ platform broadens the therapeutic target space by uncovering previously unrecognized functions of known targets, pointing to their therapeutic utility in new indications”. Background information: About BI-505 The candidate drug BI-505 is a human antibody that specifically binds to the ICAM-1 adhesion protein (also known as CD54). Expression of ICAM -1 is increased on myeloma cells, which makes it a suitable target for a candidate drug. BI-505 exerts its antimyeloma activity by inducing cell death in myeloma cells and by engaging patient´s immune cells to attack myeloma cells. In several animal models, BI-505 has been shown to kill tumor cells more efficiently than existing drugs. The first results from the phase I study of BI-505 in patients in advanced stages of the malignant disease multiple myeloma were reported earlier this year. The preliminary analysis showed that BI-505 has an advantageous safety profile. In dose groups where extended therapy was offered, 24% of these severely ill patients demonstrated stable disease for at least two months, indicating effect of BI-505. The number of newly diagnosed patients with multiple myeloma worldwide is estimated to more than 40,000 per year. BI-505 has received Orphan Drug Designation in both Europe and the US for the indication multiple myeloma. This provides BioInvent with market exclusivity for treatment of multiple myeloma with an antibody against ICAM-1 for up to 10 years after marketing approval is granted. About F.I.R.S.T.™ The F.I.R.S.T.™ screening system is based on BioInvent’s n-CoDeR® library and is a proprietary antibody technology for “fishing” library antibodies targeting surface receptors, “antigens”, which show promising characteristics in primary cancer patient cells. This functional approach to target identification allows for the selection of functionally superior high-affinity antibodies at an early stage in the drug discovery process. F.I.R.S.T.™ is an acronym for Functional Interrogation of Recombinant antibody librarieS for Therapeutic candidates. The n-CoDeR® library contains more than 20 billion (2 x 10¹º) highly diverse, fully human antibody fragments. About BioInvent BioInvent International AB, listed on the NASDAQ OMX Stockholm (BINV), is a research-based pharmaceutical company focused on discovery and development of innovative antibody-based drugs against cancer. The Company's pipeline currently includes three product candidates for the treatment of cancer. The company's competitive position is underpinned by n-CoDeR®, a proprietary antibody development platform. The scope and strength of this platform is also used to develop antibody-based drugs in collaboration with partners who finance the development of the new drug, and provide BioInvent the right to milestone payments and royalties on sales. These partners include Bayer HealthCare, Daiichi Sankyo, Mitsubishi Tanabe and Servier. More information is available at For further information, please contact: Cristina Glad President and CEO +46 (0)46 286 85 51 +46 (0)708 16 85 70 cristina.glad@bioinvent.com The Trout Group Christine Yang Vice President Phone: +1 646 378 2929 E-mail: cyang@troutgroup.com BioInvent International AB (publ) Co. reg. No. 556537-7263 Visiting address: Sölvegatan 41 Mailing address: 223 70 LUND Phone: +46 (0)46 286 85 50 info@bioinvent.com Legal disclaimer The press release contains statements about the future, consisting of subjective assumptions and forecasts for future scenarios. Predictions for the future only apply as the date they are made and are, by their very nature, in the same was as research and development work in the biotech segment, associated with risk and uncertainty. With this in mind, the actual outcome may deviate significantly from the scenarios described in this press release. Information disclosed in this press release is provided herein pursuant to the Swedish Securities Markets Act and/or the Swedish Financial Instruments Trading Act. The information was submitted for publication at 8.30 a.m. CET on April 16, 2013.