In a drug discovery career spanning more than two decades, Alex Lugovskoy has seen a lot of antibodies come and go. The vast majority of them work by inhibiting a cellular function. Lugovskoy, now the CEO of startup Diagonal Therapeutics, said he long hoped someone would come up with a way to develop antibodies that activate their targets.

在跨越20多年的药物发现生涯中，亚历克斯·卢戈夫斯科伊（AlexLugovskoy）看到了许多抗体的来来往往。它们中的绝大多数通过抑制细胞功能起作用。Lugovskoy现在是创业公司Diagonal Therapeutics的首席执行官，他说他一直希望有人能想出一种方法来开发激活其靶标的抗体。

With each passing year, no one did. So he took up the challenge himself..

年复一年，没有人这样做。所以他自己接受了挑战。

Diagonal uses computational and experimental techniques to understand what happens when an antibody binds to a receptor and which binding combinations will yield the desired effect. After developing its platform for the past two years, the startup this past week pulled back the curtain on its approach.

对角线使用计算和实验技术来了解抗体与受体结合时会发生什么，以及哪些结合组合会产生所需的效果。在过去两年开发平台后，这家初创公司在过去一周拉开了其做法的帷幕。

Diagonal also revealed $128 million in financing to support a pipeline that includes a lead program for a rare bleeding disorder that has no FDA-approved therapies..

Diagonal还透露了1.28亿美元的资金，用于支持一个管道，其中包括一个针对罕见出血性疾病的领先项目，该项目没有FDA批准的疗法。

Cambridge, Massachusetts-based Diagonal is not reinventing the wheel when it comes to antibodies. The company’s drugs leverage the biopharmaceutical industry’s more than 40 years of experience designing and manufacturing antibodies, Lugovskoy said. But he added that one key difference is that while Mother Nature can point the way to inhibit a target, it’s less clear how to engage a receptor to create a desired signaling effect.

在抗体方面，总部位于马萨诸塞州剑桥的Diagonal并没有重新发明轮子。Lugovskoy说，该公司的药物利用了生物制药行业40多年的抗体设计和制造经验。但他补充说，一个关键的区别是，虽然大自然母亲可以指出抑制目标的方法，但如何使受体产生所需的信号传导效果尚不清楚。

Each Diagonal antibody binds to two targets, bringing them together in a particular way. The many ways for an antibody to bind to various sites on receptors amounts to billions of potential combinations..

每种对角抗体都与两个靶标结合，以特定的方式将它们结合在一起。抗体与受体上不同位点结合的多种方式多达数十亿种潜在的组合。

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Health tech executives shared how their companies are putting innovative ideas into action to address the most pressing needs in healthcare, as part of the Vibe at ViVE by MedCity News.

卫生技术高管分享了他们的公司如何将创新想法付诸行动，以满足医疗保健领域最迫切的需求，这是MedCity News在ViVE上的一部分。

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“Filtering through all these combinations was not possible without our tech, that’s what we bring to the table,” Lugovskoy said.

Lugovskoy说：“如果没有我们的技术，过滤所有这些组合是不可能的，这就是我们要解决的问题。”

Alex Lugovskoy, photo by Diagonal Therapeutics

Alex Lugovskoy，Diagonal Therapeutics摄

Early in his career, Lugovskoy worked in drug discovery at Biogen. His experience also includes senior roles at Merrimack Pharmaceuticals, Morphic Therapeutic, and Dragonfly Therapeutics. After leaving Dragonfly in 2021, Lugovskoy said his thoughts returned to the question of why antibody research was so focused on inhibitors rather than agonists.

Lugovskoy在职业生涯早期曾在Biogen从事药物发现工作。他的经验还包括在Merrimack Pharmaceuticals，Morphic Therapeutics和Dragonfly Therapeutics担任高级职务。2021年离开蜻蜓队后，卢戈夫斯科伊（Lugovskoy）表示，他的想法又回到了为什么抗体研究如此专注于抑制剂而非激动剂的问题上。

But unlike the start of his career, more powerful technologies are now available that can be applied to agonist antibody R&D. He took the idea to Michael Gladstone, a partner at Atlas Venture. In 2022, they co-founded Diagonal, whose name is a portmanteau of the words “digital,” “agonist,” “antibody,” and “ligand.” The startup received seed financing from Atlas, Lightspeed Venture Partners, and Velosity Capital..

但与他职业生涯的开始不同，现在有了更强大的技术可以应用于激动剂抗体的研发。他将这个想法带给了Atlas Venture的合伙人迈克尔·格莱斯顿。2022年，他们共同创立了Diagonal，其名字是“数字”，“激动剂”，“抗体”和“配体”的组合。这家初创公司获得了Atlas，Lightspeed Venture Partners和Velosity Capital的种子融资。

Diagonal spent its first year testing its technology to see what it could do. The research eventually turned to hereditary hemorrhagic telangiectasia (HHT), a disorder caused by genetic mutations that lead to malformations in blood vessels that can rupture. HHT is often first noticed when patients develop frequent nosebleeds, but the condition also poses risks to the gastrointestinal tract and artery-vein connections in internal organs, particularly the lungs, liver, and brain..

对角线花了第一年的时间测试其技术，看看它能做什么。该研究最终转向遗传性出血性毛细血管扩张症（HHT），这是一种由基因突变引起的疾病，导致血管畸形，可能会破裂。当患者频繁流鼻血时，通常会首先注意到HHT，但这种情况也会对胃肠道和内脏器官（尤其是肺，肝和脑）的动静脉连接构成风险。

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Health tech executives shared how their companies are putting innovative ideas into action to address the most pressing needs in healthcare, as part of the Vibe at ViVE by MedCity News.

卫生技术高管分享了他们的公司如何将创新想法付诸行动，以满足医疗保健领域最迫切的需求，这是MedCity News在ViVE上的一部分。

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While Diagonal’s drug candidate does not fix the mutations at the root of HHT, it could address the signaling problems that lead to abnormal blood vessels. The mutated genes that cause HHT encode proteins in the TGF-beta signaling pathway. Diagonal designed an antibody that reactivates receptors in this pathway.

虽然Diagonal的候选药物不能修复HHT根部的突变，但它可以解决导致血管异常的信号问题。导致HHT的突变基因编码TGF-β信号通路中的蛋白质。对角线设计了一种抗体，可以重新激活该途径中的受体。

Lugovskoy said preclinical research showed Diagonal’s drug prevented and reversed the formation of pathological vascular malformations characteristic of HHT..

Lugovskoy说，临床前研究表明，Diagonal的药物可以预防和逆转HHT特有的病理性血管畸形的形成。

A second Diagonal program is in development for pulmonary arterial hypertension (PAH), a rare form of high blood pressure affecting the arteries leading from the heart to the lungs. The disease develops as the arteries narrow, making the heart work harder and also causing breathing difficulty. Unlike HHT, there are drugs for PAH.

第二个对角线计划正在开发中，用于治疗肺动脉高压（PAH），这是一种罕见的高血压形式，会影响从心脏到肺部的动脉。这种疾病随着动脉狭窄而发展，使心脏工作更加困难，并导致呼吸困难。与HHT不同，有治疗PAH的药物。

Vasodilators, drugs that widen blood vessels, have been a standard PAH treatment for years. Recently approved Winrevair, a fusion protein from Merck, takes a different approach, trapping proteins associated with driving the proliferation of cells that build up and make blood vessels narrower. Diagonal aims to bring yet another approach to PAH with agonist antibody intended to correct the signaling imbalance that is tipped toward cell proliferation..

血管扩张剂是一种扩张血管的药物，多年来一直是PAH的标准治疗方法。默克公司最近批准的融合蛋白Winrevair采用了一种不同的方法，它捕获了与驱动细胞增殖相关的蛋白质，这些蛋白质可以使血管变得更窄。Diagonal旨在通过激动剂抗体为PAH带来另一种方法，旨在纠正倾向于细胞增殖的信号失衡。

Lugovskoy said Diagonal’s technology can yield a working prototype of an agonist antibody in eight months or less, which is about the same time needed to develop an inhibitor antibody. As for safety, Lugovskoy said adverse effects haven’t been an issue so far, which he attributes to what these drugs are doing.

Lugovskoy说，Diagonal的技术可以在8个月或更短的时间内产生激动剂抗体的工作原型，这与开发抑制剂抗体所需的时间大致相同。至于安全性，卢戈夫斯科伊说，到目前为止，不良反应还不是一个问题，他将其归因于这些药物的作用。

Rather than creating a new signaling cascade, Diagonal is trying to restore signaling that should be there but was lost to disease..

Diagonal没有创建新的信号级联，而是试图恢复本应存在但因疾病而丢失的信号。

The Diagonal technology is indication agnostic and has produced agonist antibodies for four targets. Besides the HHT and PAH programs, the pipeline includes an antibody that activates IL-18 receptor signaling to spark anti-tumor effects. The fourth target remains undisclosed. Going forward, Diagonal’s focus is rare cardiovascular diseases driven by a genetic loss of function, Lugovskoy said.

对角线技术不知道适应症，并且已经产生了针对四个靶标的激动剂抗体。除了HHT和PAH程序外，该管道还包括一种激活IL-18受体信号传导以激发抗肿瘤作用的抗体。第四个目标仍未公布。Lugovskoy说，展望未来，Diagonal的重点是由遗传功能丧失引起的罕见心血管疾病。

Now that Diagonal has exited stealth mode, the company is looking for biopharma partners interested in applying the technology to therapeutic areas outside of the startup’s core cardiovascular focus..

既然Diagonal已经退出隐形模式，该公司正在寻找有兴趣将该技术应用于该初创公司核心心血管领域之外的治疗领域的生物制药合作伙伴。

Diagonal’s Series A financing was co-led by BVF Partners and Atlas. It includes the participation of Lightspeed, RA Capital Management, Frazier Life Sciences, Viking Global Investors, Velosity, and Checkpoint Capital. Most of the new capital will support the HHT program, which is funded all the way through clinical proof of concept, Lugovskoy said.

对角线的A系列融资由BVF Partners和Atlas共同领导。它包括Lightspeed、RA Capital Management、Frazier Life Sciences、Viking Global Investors、Velosity和Checkpoint Capital的参与。Lugovskoy说，大部分新资金将支持HHT项目，该项目一直通过临床概念验证获得资金。

He offered no timelines for that goal. The PAH program won’t get as far without additional funding..

他没有给出实现这一目标的时间表。如果没有额外的资金，PAH计划将无法取得进展。

“It gets us to IND,” Lugovskoy said, referring to an investigational new drug application. “But not much farther than that. As of right now, we are making decisions on the basis of emergent data all the time.”

“这让我们找到了IND，”Lugovskoy说，他指的是一份研究性新药申请。“但不远。截至目前，我们一直在根据紧急数据做出决策。”