Orilanolimab(Syntimmune, Inc.)

iStock, Alona Horkova Contingent value rights are rising in a down market, helping to close the gap between buyer and seller expectations in biotech transactions. In today’s biotech markets, every drop of value in a deal is meaningful. That’s why companies are increasingly tacking on contingent value rights to claw just a little bit extra in future deal value potential. But there’s more to these often-complex add-ons, sometimes referred to as a type of earnout. Usually, a biotech has worked hard on an asset that a buyer doesn’t necessarily see the light on. Adding a CVR can provide potential value to a drug candidate that otherwise may be headed for the scrap heap. Brad Stewart, Life Sciences National Leader at advisory services firm BDO USA, said CVRs are a way to “close the gap” between a seller’s and a buyer’s expectations of an asset. “CVRs play a role when there’s a difference in people’s certainty on the outcome,” Stewart told BioSpace in an interview. “It lets you set aside something that’s not necessarily tangible. You can’t put a valuation on a feeling or a belief or that sort of thing, but you can put a valuation on an event occurring.” Sanofi has included CVRs in a number of recent deals, including with Blueprint Medicines and neuroscience biotech Vigil Neuroscience . In the latter deal, shareholders received $8 upfront plus the possibility of $2 per share down the line if oral TREM2 candidate VG-3927 achieves commercial sales. This valued the deal at $470 million without the CVR, and $600 million with the payout. Of course, as the name implies, these payouts are not guaranteed. Carefully Crafted CVRs CVRs must be carefully crafted, Stewart said, with verifiable events and sales targets to ensure there is no disagreement later. This is where good lawyers come in, to meet in the middle between a buyer and a seller with different ideas of what various assets are worth. Lawyers are also critical for litigating when disagreements do arise. Consider the case between Alexion and Syntimmune. The former agreed to buy the latter in September 2018 for $400 million and $800 million in milestones. The earnouts were based on several clinical trial milestones for the rare disease treatment ALXN1830. The program faced significant struggles—including the COVID-19 pandemic that upended the global biopharma business—and Alexion eventually dropped several indications that were subject to the earnout agreement. Then, in July 2021, AstraZeneca acquired Alexion and launched a portfolio review. As a result, the entire ALXN1830 program was terminated by the end of that year. Syntimmune’s investors filed suit. A court ruled in June that Alexion had breached its obligation to make “commercially reasonable efforts” to develop the programs as laid out in the earnout agreement. The decision to cut the program was “driven by AstraZeneca’s pursuit of merger synergies,” the court said in its ruling. Ultimately, AstraZeneca was ordered to pay $181 million, on top of a previous $130 million judgement issued in September 2024. “In the high-stakes world of pharmaceutical M&A and licensing, milestone design has become a sophisticated application of probability theory, financial planning, and legal strategy,” lawyers from Clearly Gottleib wrote in a July analysis of the Alexion-Syntimmune case. Unstranded Assets CVRs can have a long tail, with the triggering event sometimes years away. This is the case for gene editing specialist Verve Therapeutics, which is also up for a CVR in its buyout agreement with Eli Lilly. The biotech agreed to be acquired for $10.50 per share—or about $1 billion total—plus a $3 CVR payable when the first patient is dosed with the base editing therapy VERVE-102 in a U.S. Phase III trial for atherosclerotic cardiovascular disease. This milestone must occur within 10 years of the transaction for the CVR to be payable. William Blair, which said the CVR could add $300 million in value to the deal, wrote in a June note to investors that the payout is likely and could occur in the first half of 2027. But William Blair noted that a “gating factor” to the CVR payout is that Verve will have to prove that VERVE-102 is safe in an ongoing Phase II trial. Verve ran into safety concerns with a prior candidate but has had better luck with the next-generation drug. The deal itself was considered “a bargain” for Lilly, the analysts said. Deals like this, with the potential for a long timeline before payout, can turn off many investors. “It’s just like a house,” Stewart said. “An all-cash purchase price is more valuable to some people than whatever combination of cash and mortgage and other things that may delay the closing.” That means venture capitalists, private equity firms or other fast-moving investors may want nothing to do with them, Stewart said. On the flip side, he continued, investors may want to park the money in a CVR in hopes that the markets will improve, so it depends on the investor base. “When there are investors who believe that what they have will fundamentally change the market, then that’s probably a smart bet from their perspective,” Stewart told BioSpace . But of course, very few products actually go on to shift paradigms. Stewart points to the rise of GLP-1s, saying that it’s unlikely anyone bet a hefty CVR on any of those assets given the improbability of their monumental rise. It does happen, but catching that lightning in a bottle is rare. “If you were the acquirer, you’d just be like, ‘Well, how about if I just give you an extra $100 [upfront] and never hear from you again,’ right?” Stewart said. “Because that’s the simpler way, because you don’t want five years from now . . . someone suing you who has this emotional attachment to an irrational outcome.” Bluebird bio’s go-private deal, which closed in June, showcases such a fight for more upfront cash over a CVR. The original deal would have entitled shareholders to $3 in cash per share, with a CVR of $6.84 per share if the company were to achieve certain net sales milestones. This would have meant a small upfront payment but potentially greater earnings down the line. Instead, bluebird executives held out for a bigger upfront payment, ultimately sealing the deal with an offer of $5 per share in cash upfront for shareholders if they declined the CVR. This helped raise the deal value from about $30 million upfront to just under $50 million. CVRs also run the risk of becoming meaningless even if the milestones are met. Steward points to policies like the Most Favored Nation drug pricing proposal from the White House, which seeks to set drug prices to those paid in other equivalent nations. If you had a CVR tied to a sales benchmark for a drug that ultimately had a lower price than expected, you might miss out. “You can’t really blame the acquiring company for that,” Stewart said. In the case of GLP-1s, Stewart pointed to compounding pharmacies and their impact on sales as a consideration in a CVR negotiation. Despite the blockbuster market potential for weight loss drugs, sales are harder to predict due to this external factor. Still, the markets are currently very welcoming to CVR negotiations, according to Stewart. Biotechs are struggling and running out of cash. Many are hunting for partners that may never materialize, leaving stranded assets in need of a home. “This is a way to unstrand some of them,” Stewart said. CVRs still happen when markets are hot, but often a buyer will want to close a deal quickly and adding on another $100 million upfront to do so is the best way to seal the deal and avoid protracted negotiations. “You don’t necessarily see CVRs used as much in very up markets or at very high valuations [because] there’s just a lot more competition for deals going on. People are fighting. The acquirers . . . are looking to close deals quickly so that they’re not being competed against or losing out to another party,” Stewart said. “In a down market, there’s dramatically less competition, typically, and so creativity has to be something that’s used there.”

-01-引言IgG是适应性免疫反应的重要成分，也是最普遍的抗体类别，具有独特的特征。与其他免疫球蛋白相比，IgG具有高循环水平、长半衰期和从母亲转移到后代的能力而增强，这和与新生儿Fc受体（FcRn）的相互作用密切相关。FcRn以pH依赖的方式结合IgG的Fc部分，并保护它们免受细胞内降解。它还允许它们在极化细胞之间运输，极化细胞将组织分隔开，如内皮细胞和上皮细胞。此外，当与抗原结合的IgG形成IgG免疫复合物时，FcRn的功能增强了细胞免疫反应。除了IgG的保护作用外，IgG自身抗体与许多病理状况有关。因此，FcRn阻断是一种新的、有效的策略，可降低致病性IgG自身抗体的循环水平，并减少IgG介导的疾病。-02-一、FcRn的结构在人类中，FcRn重链由位于染色体19q13.35上的Fcγ受体和FCGRT基因编码。该基因包含七个外显子和六个内含子，其中外显子2-5编码信号肽和胞外α1-α2-α3结构域，外显子6编码跨膜结构域，而外显子7编码细胞质尾部。FCGRT同源基因存在于大多数哺乳动物中，编码的蛋白质显示出与人类受体的高度保守性。FcRn的α1-α2-α3结构域与MHC I类分子具有高度的结构同源性，并与β2-微球蛋白（β2m）非共价结合，形成异二聚体。-03- 二、FcRn的细胞分布和表达在新生儿阶段以后，FcRn在成年人中也有表达，广泛存在于人体组织中，包括上皮细胞、内皮细胞、肝细胞、角质细胞以及各种造血细胞类型。在免疫细胞中，FcRn在髓系细胞中的表达尤其高，如单核细胞、组织驻留巨噬细胞、树突状细胞（DC）和中性粒细胞；在淋巴细胞中，B细胞中存在低水平的FcRn，但在T细胞或自然杀伤（NK）细胞中未检测到FcRn。FcRn的表达受细胞因子或感染性刺激等因素的调节，在FCGRT中发现了许多转录因子结合位点。在体外，通过肿瘤坏死因子（TNF）刺激肠上皮细胞系、人原代单核细胞和THP-1单核细胞系，FcRn表达迅速增加，并依赖于NF-κB与FCGRT内含子的结合。Toll样受体激动剂脂多糖和CpG寡脱氧核苷酸也增加THP-1细胞中FcRn的表达。-04-三、FcRn与配体的相互作用IgG Fc的FcRn结合发生在CH3和CH2结构域界面，这种结合涉及Fc残基I253、T254、H310、H433和H435，它们介导人FcRn上与E115和D130的各种氢键和盐桥相互作用。组氨酸上咪唑侧链的存在提供了一个pH依赖性开关，由此在pH 5-6时，基团带正电荷，允许FcRn–IgG相互作用；而在pH 7.4时，它是中性的，并且失去了相互作用。因此，IgG Fc工程允许开发在酸性或中性pH下与FcRn具有不同亲和力的IgG变体，以增强FcRn结合，从而延长IgG半衰期或迫使IgG抗体降解。此外，FcRn也以pH依赖的方式与白蛋白结合。-05-四、FcRn的生理功能pH依赖性配体结合对FcRn的被动和主动免疫功能至关重要。被动功能包括循环和转运，这允许FcRn从细胞内降解中挽救单体IgG，并将其运输到细胞外；主动功能涉及母体IgG和OVA免疫复合物(IgG-IC)结合并增强先天性和适应性免疫。FcRn作为循环受体与其他抗体同种型相比，IgG的半衰期非常长。在小鼠中，FcRn敲除导致血清IgG1、IgG2a、IgG2b和IgG3水平显著降低。野生型小鼠中IgG1的半衰期为9天，而FcRn缺陷小鼠的半衰期仅为约1.4天。在人类中，血清IgG的半衰期同样最长，为20-23天。FcRn通过在早期内体的酸性pH下结合到Fc区域，并通过在细胞表面的胞吐作用在中性pH下释放IgG，来回收挽救IgG。另一方面，当FcRn缺失时，大型多聚体IgG-IC不能有效回收，但降解速度更快。多聚IgG IC结合细胞表面（中性pH）上的IgG的Fc受体（FcγRs），在那里它们通过受体介导的内吞作用被吸收到内体中，允许在酸性pH下与FcRn和FcγR共同结合。多聚IgG-ICs主要被运送到FcRn+LAMP1+溶酶体，这可能对FcRn的抗原呈递功能很重要。FcRn作为转运受体除了其循环功能外，FcRn在维持IgG的组织分布方面也发挥着重要作用。在新生啮齿类动物中进行的研究表明，它们通过FcRn在肠道上皮细胞的转运，从摄入的母乳中被动获取IgG。此外，还能够通过FcRn在肠上皮细胞和其他位置的固有层和肠腔之间双向转移IgG。主动免疫功能FcRn和FcγRs在髓系细胞的细胞表面和细胞内高水平表达，其直接参与对IgG-IC的先天免疫反应。例如，IgG-IC促进先天免疫细胞产生促炎细胞因子的能力涉及FcRn。IgG-IC在中性pH条件下结合细胞表面的FcγRs受体，当IgG-IC被吸收到内体中时，它们在微酸性pH下与FcRn结合。作为对IgG-IC的反应，FcRm积极诱导中性粒细胞、单核细胞、巨噬细胞细胞和树突状细胞产生促炎细胞因子IL-12、IL-23、TNF和IL-6。此外，FcRn还促进中性粒细胞中IgG介导的吞噬作用。最后，一旦IgG-IC被表达FcγR的细胞吸收，FcRn还增强了树突状细胞和巨噬细胞对CD4+T细胞的抗原呈递，以及树突状细胞对CD8+T细胞抗原的交叉呈递。FcRn在这些抗原呈递途径中的积极参与导致相互作用的免疫细胞极大地增强了T细胞的活化、扩增和IL-2、IFN-γ的产生，这可能会进一步放大免疫应答。-06-五、FcRn的病理生理功能FcRn–IgG的相互作用提供了对大多数传染病的必要保护，并可能参与抗肿瘤反应，但FcRn与致病性和自身反应性IgG的相互作用也可能促进自身免疫性疾病。IgG介导的自身免疫性疾病是一类广泛的临床疾病，可分为两类：第一类包括自身抗体的特异性已被明确识别并直接参与疾病发病机制的疾病，如重症肌无力（MG）和天疱疮相关疾病。第二类包括复杂的自身免疫性疾病，如炎症性肠病（IBD）、类风湿性关节炎（RA）和多发性硬化症（MS），其中IgG抗体参与更广泛的免疫途径。自身抗体介导的皮肤疾病，如获得性大疱性表皮松解症（EBA）、大疱性类天疱疮和天疱疮，涉及FcRn。FcRn缺陷小鼠在VII型胶原免疫或被动抗体转移EBA模型中免于起泡，并且这些小鼠具有较低水平的VII型胶原特异性抗体。出现EBA的小鼠可以用FcRn阻断剂成功治疗，从而减少皮肤中循环的致病性抗VII型胶原IgG沉积。此外，自身免疫性血液病，如免疫性血小板减少性紫癜（ITP），也可通过FcRn阻断治疗改善。FcRn也参与了IBD的发病机制，因为针对共生微生物和潜在自身抗体的IgGs可导致该疾病。在野生型小鼠的结肠炎模型中比在FCGRT−/−小鼠中更严重，具有更大的临床病理损害。总之，这些研究清楚地确立了FcRn在自身免疫性疾病发病机制中的作用。FcRn参与这些疾病可能发生在多个层面，包括其半衰期延长、IgG或IgG-IC在组织中的传递、免疫效应器功能的调节及其与经典FcγRs的关系。此外，FcRn也可能通过在组织损伤部位特定细胞类型中的表达介导其疾病相关效应。-07-六、靶向FcRn的药物治疗阻断FcRn通路的药物包括靶向FcRn单克隆抗体药物和体外重组的Fc片段蛋白，相关领域的药物产品包括：Fc重组蛋白药物Efgartigimod 以及单抗 Rozanolixizumab、M281和 SYNT001等。EfgartigimodEfgartigimod是荷兰生物技术公司Argenx开发的产品，是人源IgG1的Fc结构的体外重组蛋白片段。该产品利用Argenx的专有的点突变技术分别在5个位点对Fc片段的序列进行了突变，突变后的Fc蛋白和FcRn的结合力在中性和酸性的条件下得到了显著增强。该产品拟用的适应症包括：重症肌无力、天疱疮、免疫性血小板减少症以及慢性炎症性脱髓鞘性多发性神经疾病（CIDP）。2020年5月底Argenx公司宣布，Efgartigimod在治疗抗乙酰胆碱受体（AChR）抗体阳性全身性重症肌无力（gMG）患者的关键性3期临床试验中，达到了主要研究终点。2021年12月，Efgartigimod作为全球首款FcRn拮抗剂获美国食品药品监督管理局(FDA)批准。2021年1月再鼎医药与Argenx达成独家授权合作，负责Efgartigimod在大中华区的开发和商业化工作。Nipocalimab(M281)M281是美国生物医药公司Momenta的核心产品管线。其分子本质是去糖基化的全人源IgG1抗体，靶向FcRn，去掉了抗体的Fc功能。Nipocalimab在预防胎儿和新生儿溶血性疾病方面获得了孤儿药认定和罕见儿科疾病认定。目前已经处于临床 III 期研究阶段。2020年 8 月 ，强生宣布以 65 亿美元收购Momenta，从而将该产品纳入到旗下。Rozanolixizumab(UCB-7665)Rozanolixizumab是来自布鲁塞尔生物技术公司UCB Biopharma的一种皮下给药的人源化IgG4抗体，能特异性结合人FcRn，阻断FcRn与IgG的相互作用，抑制循环中的IgG，诱导致病性IgG自身抗体的清除。II 期临床研究显示，其总IgG和抗-AChR抗体滴度平均降低68%，目前正处于 III 期研究中。Batoclimab(RVT1401)Batoclimab是来自和铂医药的一种完整的人源单克隆抗体，与FcRn结合，阻断FcRn-IgG相互作用以加速自身抗体的降解，治疗各种致病性IgG介导的自身免疫疾病。该产品曾在中国被纳入突破性治疗品种，目前正在开展多种适应症的临床研究。Orilanolimab (SYNT001)SYNT001是一种人源化的IgG4抗体，靶向FcRn，适应症为温热体型自身免疫性溶血性贫血（WAIHA）、寻常型天疱疮（PV）或天疱疮（PF）。-08-结语过去30多年的研究使我们对FcRn在包括结构、组织细胞分布以及生理和病理学功能有了深刻的了解。对这些研究成果的临床转化包括治疗性抗体和Fc融合蛋白的工程化、工程白蛋白分子作为载体蛋白的开发以及FcRn阻断剂的成功开发。相信，随着科学界和工业界对FcRn生物学的进一步理解和这些现有方法的使用，该领域可能会出现更多的治疗机会。参考资料：1.The therapeutic age of the neonatal Fc receptor. Nat Rev Immunol.2023 Feb 1;1-18.2. Next-generation Fc receptor-targeting biologics for autoimmune diseases. Autoimmun Rev.2019 Oct;18(10):102366识别微信二维码，添加抗体圈小编，符合条件者即可加入抗体圈微信群！请注明：姓名+研究方向！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。