HHAT

SAN DIEGO--(BUSINESS WIRE)-- Endeavor BioMedicines, a clinical-stage company developing therapies for of fibrotic disease and oncology, today announced the appointment of Paul Frohna, M.D., Ph.D., as its Chief Medical Officer. Dr. Frohna is a physician-scientist with over 20 years of experience in the biotech industry in the fields of translational medicine, clinical trial design, and clinical and regulatory strategy. “We’re pleased to welcome Paul as our Chief Medical Officer, and we look forward to his leadership as we progress our pipeline of therapies for patients with fibrosis and cancer,” said John Hood, Ph.D., Co-Founder, CEO and Chairman, Endeavor BioMedicines. “Paul’s deep experience as a physician-scientist and impressive track record in clinical development and translational medicine will be valuable additions to Endeavor as we advance our programs, including our Phase 2 trial of ENV-101 in idiopathic pulmonary fibrosis (IPF) and the first-in-human trial for our HER3-targeted ADC in oncology.” Dr. Frohna joins Endeavor from ImCheck Therapeutics in Marseille, France, where he served as Chief Medical Officer and Head of Research and Development responsible for overseeing programs in oncology and infectious disease. Prior to ImCheck, he was Chief Medical Officer at Bioniz Therapeutics, where he led clinical and regulatory affairs functions and was responsible for operational oversight of the company's clinical programs in T-cell leukemia and lymphoma as well as autoimmune diseases. Prior to this role, he held senior roles at Receptos Inc., ProFibrix, Inc. and Fibrogen. Dr. Frohna began his biotech career at Genentech where he patented and initially tested the therapeutic approach of B-cell depleting therapy for relapsing and progressive multiple sclerosis. “It is a privilege to join Endeavor as the company enters its next stage of growth," said Dr. Frohna. “I look forward to contributing my clinical development experiences in fibrosis and oncology to demonstrate the therapeutic promise of our pipeline of medicines in order to help patients who deserve better treatments for their deadly diseases.” Over the course of his career, Dr. Frohna has built and led departments and teams responsible for candidate selection, IND/CTA filings, Phase I to III clinical trials and global development partnerships. He has successfully designed and initiated translational and clinical programs for biologics, small molecules and stem cells across multiple therapeutic areas. He played critical roles in multiple development programs including Receptos' ozanimod (Zeposia® marketed by BMS), Profibrix’s Raplixa™ and Genentech's Rituxan®, Tarceva® and Raptiva® programs. Dr. Frohna received his pharmacy degree from the University of Texas at Austin College of Pharmacy, his Ph.D. in Pharmacology from the University of Pennsylvania School of Medicine, and his M.D. from Georgetown University School of Medicine. About Endeavor BioMedicines Endeavor BioMedicines, Inc., is a clinical stage company developing novel therapies for fibrosis and oncology. We combine best-in-class therapeutics with an evolved understanding of terminal diseases to develop medicines with the potential to reverse severe health conditions. Our lead program, ENV-101, is a Hedgehog signalling inhibitor currently in Phase 2 studies treating IPF. The second program is a HER3-targeted ADC that will begin clinical development in 2024 for the treatment of multiple solid tumors. At Endeavor, we are an innovative and focused team that has come together to develop therapeutics that help patients feel better and live longer. Please visit us on our website at and on our LinkedIn and X (formerly Twitter) pages. View source version on businesswire.com: Contacts Will Zasadny Evoke Canale Will.zasadny@evokegroup.com Source: Endeavor BioMedicines View this news release online at:

Endeavor obtains exclusive worldwide rights to Hummingbird Bioscience’s anti-HER3 ADC to be developed for patients with HER3-expressing tumors Hummingbird Bioscience to receive upfront and milestone payments up to $430 million, plus royalties, from Endeavor BioMedicines Investigational New Drug (IND) application planned in first half of 2024 SAN DIEGO & HOUSTON & SINGAPORE--(BUSINESS WIRE)-- Hummingbird Bioscience Pte Ltd (“Hummingbird Bio”), a data-driven precision biotherapeutics company discovering and developing transformative biologic medicines for hard-to-treat diseases, and Endeavor BioMedicines (“Endeavor”), a clinical-stage company targeting the drivers of fibrosis and oncology, today announced that Endeavor has acquired exclusive worldwide rights to Hummingbird Bio’s antibody-drug conjugate (ADC), HMBD-501. The license agreement provides Endeavor with exclusive rights to HMBD-501, a next-generation HER3-targeted ADC with an exatecan payload that has been optimized for safety and efficacy. Under the terms of the license, Hummingbird Bio will be eligible to receive upfront and milestone payments up to $430 million, plus royalties on net sales. “This exclusive license with Hummingbird Bio provides Endeavor with a potential best-in-class HER3-ADC, with the opportunity to treat a large number of patients in multiple tumor types,” said John Hood, Ph.D., Co-Founder, CEO and Chairman of Endeavor. “HER3 is more broadly expressed on tumors than HER2 and is expressed on tumors that do not express HER2. This next generation ADC has the potential to address significant unmet clinical needs in areas left behind by HER2 agents.” HMBD-501 is a differentiated ADC generated by Hummingbird Bio’s proprietary antibody discovery and engineering platform and key state-of-the-art ADC technologies, enabling a potentially enhanced efficacy and safety pro to previous generation ADCs. HMBD-501 binds a novel epitope on the HER3 receptor, such that binding is unaffected by NRG1 (HER3 ligand) levels, allowing binding to HER3-expressing tumors even in high ligand contexts. “Hummingbird Bio has designed HMBD-501 to have a wider therapeutic index than current HER3 ADCs, maximizing the potential clinical benefit for patients, and we are delighted that Endeavor has recognized the potential of this ADC built with our proprietary antibody technology,” said Piers Ingram, Ph.D., Co-Founder and CEO of Hummingbird Bio. “We are pleased to license HMBD-501 to the experienced Endeavor team to bring the molecule into the clinic and a step closer to benefiting patients.” About HMBD-501 Multiple HER3-positive tumor settings have demonstrated response to HER3-ADC therapeutic approaches. HMBD-501 has been generated by combining our antibody discovery and engineering platform and state-of-the-art ADC technologies to enable a potentially enhanced efficacy and safety pro to previous generation ADCs. With key proprietary technologies enabling a differentiated molecule, HMBD-501 is poised to become a best-in-class HER3 ADC. About Endeavor BioMedicines Endeavor BioMedicines, Inc., is a clinical stage company targeting the drivers of fibrosis and oncology. We combine best-in-class therapeutics with an evolving understanding of terminal diseases to develop medicines with the potential to reverse severe health conditions. Our lead program, ENV-101, is a Hedgehog signalling inhibitor currently in Phase 2 studies treating IPF. At Endeavor, we are an innovative and focused team that has come together to develop therapeutics that help patients feel better and live longer. Please visit us on our website at and on our LinkedIn and X (formerly Twitter) pages. About Hummingbird Bioscience Hummingbird Bioscience is a data-driven precision biotherapeutics company discovering and developing transformative biologic medicines for hard-to-treat diseases. The Hummingbird Bioscience model combines computational and systems biology with wet lab drug discovery in a multi-disciplinary, collaborative environment spanning initial discovery through clinical development. Hummingbird Bioscience harnesses this integrated approach across target identification and patient selection, enabling the team to increase the efficiency of translating novel scientific insights while reducing the inherent risk in drug discovery and development. The company is currently developing two clinical-stage assets: HMBD-001, a humanized anti-HER3 monoclonal antibody targeting a novel epitope on HER3, and HMBD-002, a humanized anti-VISTA IgG4 monoclonal antibody. Both programs are currently in Phase I studies. At Hummingbird Bioscience, the commitment to rigorous science, teamwork and intellectual integrity underpins our passion to accelerate the journey of new drugs from concept to clinic. For more information, please visit , and follow Hummingbird Bioscience on LinkedIn, X (formerly Twitter), and YouTube.

这项研究发现了TP53的非洲特异性变异——Y107H，并证明了PADI4是p53蛋白介导的肿瘤抑制的重要调节因子。这些研究结果揭示了非洲裔癌症的差异、个性化的医疗方法和p53介导的肿瘤抑制的关键靶基因 据世界卫生组织国际癌症研究署（IARC）发布的最新数据，2020年全球新发癌症病例1929万例，新增癌症死亡病例996万例。癌症是全世界死亡的主要原因，也被称为“众病之王”。随着人均寿命的增长，癌症的发病率还将进一步增加。癌症的发生发展是一个涉及细胞多重调控通路的复杂的、多步骤的过程，其中原癌基因和抑癌基因的失衡就是一个关键诱因。 自1979年被发现以来，p53基因（TP53）一直是肿瘤学研究的焦点之一。在Pubmed数据库中用p53为关键词搜索，可以找到超过十万篇文献。在 Nature 杂志2017年的一项统计中，p53基因以绝对优势位列过去几十年最热门研究基因榜第一名。 在多种肿瘤中，p53是一个拥有广泛而强大功能的抑癌基因，被誉为“基因组守护者”。p53会响应细胞中的各种应激源（例如DNA损伤）而被激活。p53的激活会促进DNA修复，或促进异常的细胞受控死亡，从而阻止癌症的发生和发展。因此，p53基因突变在许多癌症中非常常见，约一半的癌症患者携带了p53基因突变。p53基因的突变是癌症发生、发展、治疗耐药性和预后不良的重要驱动力。 近日，美国威斯塔研究所（Wistar Institute）的研究人员在 Cancer Discovery 期刊发表题为：An African-specific variant of TP53 reveals PADI4 as a regulator of p53-mediated tumor suppression 的研究论文。 该研究在非洲裔美国人中发现一种罕见的TP53突变体，其DNA结合域的107号氨基酸由酪氨酸突变为组氨酸（Y107H），TP53-Y107H突变影响了表观遗传修饰因子PADI4，由此揭示了PADI4是p53介导的肿瘤抑制的调节因子。 TP53编码关键的肿瘤抑制因子p53，它可以调节许重要的细胞过程，包括转录、代谢、细胞周期阻滞、凋亡、衰老和免疫信号传导等。打个形象的比喻，p53就像是细胞中忠实的警卫，承担着从自身组织中清除有缺陷或失活的细胞的关键作用，以此保证细胞机能有条不紊地进行。 正因为TP53发挥着如此重要的功能，一旦发生突变和功能失活，其后果将十分致命。据统计，TP53是癌症中最常见的突变基因，约一半的人类肿瘤中都存在TP53突变。然而，p53蛋白介导的肿瘤抑制的关键靶基因仍未确定。 在这项最新研究中，研究团队试图确定p53是如何抑制肿瘤的——通过探索特殊的TP53突变如何不能抑制肿瘤。通俗来说，就是进行了思维上的“范式转变”，即不在纠结于“p53有什么作用”，而是聚焦“当p53不在抑制癌症时，它不能做什么”。 鉴于非洲裔美国人的癌症负担是世界上所有种族中最大的，研究团队在癌症数据集中筛选了TP53的突变体，并选择了一种名为Y107H的非洲裔特异性变异，它存在于大约0.001%的非洲血统个体中。 Y107H小鼠的癌症风险显著增加 与其他畸形种系变异P47S和G334R一样，核磁共振和晶体结构显示Y107H在结构上与野生型p53十分相似，并且Y107H变异保留了大部分野生型p53功能，仅在p53靶基因的转录激活方面存在缺陷。 接下来，研究团队使用CRISPR基因编辑技术构建了TP53-Y107H肿瘤细胞系和小鼠模型，通过比较哪些基因可以被野生型p53激活但未被Y107H突变体激活，研究人员找到了一个名为PADI4的表观遗传修饰因子，该基因在一些人类肿瘤中容易发生突变失活。 Y107H变异体的p53靶基因亚群的转录激活受损，包括PADI4、PLTP和HHAT 进一步研究显示，PADI4有助于免疫系统识别肿瘤，它通过修饰肿瘤蛋白的氨基酸残基来做到这一点——PADI4可以将精氨酸分解瓜氨酸，这是一种非天然氨基酸，免疫系统会将其视为异常入侵物并攻击靶细胞，从而抑制和清除肿瘤细胞。 有趣的是，PADI4也显示了其他几个p53畸形变体（例如P47S和G334R）的转录激活受损，这表明PADI4对p53的功能突变非常敏感，很可能是p53蛋白介导的肿瘤抑制的关键靶基因。 PADI4与p53相互作用并具有肿瘤抑制特性 不仅如此，研究团队还通过生物信息学方法找到p53和PADI4共同控制的基因，并创建一个基因子集：研究人员分析了TCGA数据库中的6万个肿瘤数据，并确定了5个由野生型p53和PADI4共同调控在一起的基因，这些基因在Y107H突变体中不能被激活。这个5基因标记可以预测癌症的生存，肿瘤的免疫浸润以及免疫疗法的疗效。 p53-PADI4基因标记可以预测癌症患者的生存和抗PD-1免疫疗法的反应 总而言之，这项研究发现了TP53的非洲特异性变异——Y107H，并证明了PADI4是p53蛋白介导的肿瘤抑制的重要调节因子。这些研究结果揭示了非洲裔癌症的差异、个性化的医疗方法和p53介导的肿瘤抑制的关键靶基因，未来可以用于预测免疫疗法的疗效和癌症患者预后，为新的癌症监测方法的研发开辟前路。