Nihon University

SARASOTA, Fla. and AVENTURA, Fla., Nov. 10, 2023 /PRNewswire/ -- INVO Bioscience, Inc. (Nasdaq: INVO) ("INVO"), a healthcare services company focused on expanding access to advanced fertility treatment worldwide, and NAYA Biosciences Inc. ("NAYA"), a company dedicated to increasing patient access to breakthrough treatments in oncology and regenerative medicine, today jointly announced that following the closing of their pending merger, Dr. Peter Kash, Ed.D., MBA will join the combined company's Board of Directors as Vice Chairman. "I am delighted to join NAYA Biosciences upon the closing of its public merger," commented Dr. Peter Kash. "As an emerging leader in the growing Florida biosciences ecosystem, NAYA has a unique business model, with scalable revenue generation from its fertility business and disruptive clinical-stage therapeutics primed for pharma partnerships. I look forward to working closely with Daniel and his leadership team on their mission to accelerate the development and commercialization of life-changing therapies through agile leadership, access to public capital, and targeted acquisitions." "We welcome Peter to NAYA's board as we close our public merger with INVO and prepare to execute an ambitious growth strategy," added Dr. Daniel Teper, Chairman and CEO of NAYA Biosciences. "Peter's track record as an entrepreneur, banker, and investor will be a major asset for NAYA and we look forward to his contribution and impact accelerating our goal of increasing patient access to life-transforming therapies." Dr. Kash has over 36 years of leadership experience in the biotech industry. He is currently the cofounder and Vice Chairman of TargImmune Therapeutics (Switzerland) and cofounder and Managing Director of Camelot BioCapital. He was formerly a cofounder and partner and Chairman of Two River Group and President of Riverbank Capital Securities, specializing in helping create and finance several biotech companies including Kite Pharma, Edgemont Pharmaceuticals, and Intercept Pharmaceuticals. He has cofounded more than a dozen biotech companies and coraised in excess of $2 billion in private/public financing, helping creating more than $20 billion in peak aggregate market value. Dr. Kash has worked on Wall Street for 30 years including at Shearson Lehman Hutton and Paramount Capital. At Paramount he cofounded and helped finance PolaRx Biopharmaceuticals; developing the first cancer drug from China, Trisenox approved by the FDA. The portfolio companies have received a total of 6 FDA approvals to date. From 1990-1992 he was an Associate Professor of Marketing at Polytechnic University. During 1996-2000 he was an Adjunct Professor of Entrepreneurship at the Wharton Business School. During 2000-2002 he was a Visiting Professor of Entrepreneurship at the Graduate School of Business at Nihon University in Tokyo and in 2015 a Visiting Professor at Hebrew University. He has frequently lectured and served as a Keynote Speaker worldwide in many of the 70 countries he has visited. His education includes a B.S. in Management Science from S.U.N.Y. Binghamton and an MBA in International Banking and Finance from the Lubin School of Business at Pace University. He holds a Doctorate in Education at The Azrieli Graduate School of Yeshiva University. Dr. Kash completed post graduate classes on Making Boards of Directors More Effective at Harvard Business School. He has authored several books including a top international seller "Make Your Own Luck", (Prentice Hall), now in 8 languages distributed in more than 30 countries. About the Proposed Merger Under the terms of the merger agreement, pending approval of the transaction by INVO's, Cytovia Therapeutic, Inc. 's, and NAYA's stockholders and subject to key closing conditions, INVO will acquire 100% of the outstanding equity interests in NAYA by means of a reverse triangular merger of a wholly owned subsidiary of INVO with and into NAYA, with NAYA surviving as a wholly owned subsidiary of INVO (the "Merger"). In connection with the Merger, INVO will issue to the stockholders of NAYA newly issued common stock, representing, following such issuance, more than eighty percent (80%) of its issued and outstanding common stock, effectively resulting in a change of control. Among key closing conditions, INVO must obtain shareholder approval along with certain approvals from existing warrant holders, an estimated $5 million or more (at NAYA's discretion) in interim private financing in INVO at a premium to INVO's market price at time of financing ("Interim PIPE"), and a private offering by the combined company at a target price of $5.00, representing a premium to INVO's last offering of $2.85 per share. The merger target valuation is $12,373,780 for INVO and $90,750,000 for NAYA, based on a target stock price of $5.00 per share. Subject to the Interim PIPE, immediately following the closing of the Merger (but prior to the private offering), the equity holders of NAYA are expected to own approximately 88% of the issued and outstanding common stock of the combined company while the equity holders of INVO are expected to own approximately 12% of the issued and outstanding common stock of the combined company. The Merger has been unanimously approved by the board of directors of each company and is expected to close in the first quarter (Q1) of 2024. Glaser Weil Fink Howard Jordan & Shapiro LLP is serving as legal counsel to INVO. Pearl Cohen Zedek Latzer Baratz LLP is serving as legal counsel to NAYA. About NAYA Biosciences NAYA Biosciences is building a group of agile, disruptive, high-growth companies dedicated to increasing patient access to life-transforming treatments in oncology, fertility, and regenerative medicine. NAYA's capabilities in biology, cell and gene therapy, and artificial intelligence (AI) provide a synergistic platform for the accelerated clinical development and commercialization of these breakthrough treatments. NAYA Oncology aims to achieve clinical proof-of-concept for its two bispecific antibodies acquired from Cytovia Therapeutics, with the goal of advancing towards breakthrough outcomes for Hepatocellular Carcinoma and Multiple Myeloma patients. Clinical trials are expected to start in 2024. NAYA Fertility aims to increase accessibility to advanced fertility care through a growing network of INVO-owned and affiliated clinics and the commercialization of INVO's unique FDA-cleared INVOcell® device. NAYA Regenerative Medicine is evaluating the acquisition of clinic-stage assets aiming to restore biological function in patients with damaged tissues and organs. For more information, please visit . About INVO Bioscience We are a healthcare services fertility company dedicated to expanding the assisted reproductive technology ("ART") marketplace by making fertility care accessible and inclusive to people around the world. Our commercialization strategy is focused on the opening of dedicated "INVO Centers" offering the INVOcell® and IVC procedure (with three centers in North America now operational), the acquisition of US-based, profitable in vitro fertilization ("IVF") clinics and the sale and distribution of our technology solution into existing fertility clinics. Our proprietary technology, INVOcell®, is a medical device that allows fertilization and early embryo development to take place in vivo within the woman's body. This treatment solution is the world's first intravaginal culture technique for the incubation of oocytes and sperm during fertilization and early embryo development. We believe the IVC procedure can deliver comparable results to traditional IVF and is a more effective treatment than intrauterine insemination ("IUI"). For more information, please visit and . Additional Information about the Proposed Merger and Where to Find It INVO will furnish to the U.S. Securities and Exchange Commission (the "SEC") a Current Report on Form 8-K regarding the Merger, which will include the Merger Agreement as an exhibit thereto. Shareholders and others wishing to obtain additional information regarding the Merger Agreement and the Merger are urged to review these documents, which will be available at the SEC's website ( ). In connection with the Merger, INVO and NAYA will materials with the SEC, including a registration statement on Form S-4 filed by INVO that will include a proxy statement of INVO that also constitutes a prospectus of INVO. A definitive proxy statement/prospectus will be distributed to stockholders of NAYA. This communication is not a substitute for the registration statement, proxy statement, or prospectus or any other document that INVO or NAYA (as applicable) may the SEC in connection with the proposed Merger. Before making any voting or investment decision, investors and security holders of INVO and NAYA are urged to read carefully and in their entirety the registration statement, the proxy statement/prospectus, and any other materials filed with or furnished to the SEC when they become available, as well as any amendments or supplements to these documents, as they contain or will contain important information about INVO, NAYA, the Merger Agreement, the Merger, and related matters. In addition to receiving the proxy statement/prospectus by mail, shareholders also will be able to obtain the full registration statement and the proxy statement/prospectus and the exhibits thereto, as well as other filings containing information about INVO, the Merger Agreement, the Merger, and related matters, without charge, from the SEC's website ( ), or at the SEC's public reference room at 100 F Street, NE, Room 1580, Washington, D.C. 20549. The information included on, or accessible through, INVO's or NAYA's website is not incorporated by reference to this communication. INVO, NAYA and certain of their directors, executive officers, and other members of management and employees may, under SEC rules, be deemed to be "participants" in the solicitation of proxies from INVO's shareholders with respect to the Merger. Information about the directors and executive officers of INVO will be set forth in the proxy statement/prospectus and in its Form 10-K for the year ended December 31, 2022, which was filed with the SEC on April 17, 2023. Information about the directors and executive officers of NAYA will be set forth in the joint proxy statement/prospectus. This announcement is not a solicitation of a proxy, an offer to purchase, or a solicitation of an offer to sell any securities and it is not a substitute for the Schedule 14A, the registration statement on S-4, the proxy statement/prospectus, or other filings that may be made with the SEC in connection with the Merger Agreement and the Merger. No Offer or Solicitation This communication does not constitute an offer to sell or the solicitation of an offer to buy any securities, nor a solicitation of any vote or approval with respect to the proposed transaction or otherwise. No offer of securities shall be made except by means of a prospectus meeting the requirements of Section 10 of the Securities Act of 1933, as amended, and otherwise in accordance with applicable law. Safe Harbor Statement This release includes forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. The Company invokes the protections of the Private Securities Litigation Reform Act of 1995. All statements regarding our expected future financial position, results of operations, cash flows, financing plans, business strategies, products and services, competitive positions, growth opportunities, plans and objectives of management for future operations, as well as statements that include words such as "anticipate," "if," "believe," "plan," "estimate," "expect," "intend," "may," "could," "should," "will," and other similar expressions are forward-looking statements. All forward-looking statements involve risks, uncertainties, and contingencies, many of which are beyond our control, which may cause actual results, performance, or achievements to differ materially from anticipated results, performance, or achievements. Factors that may cause actual results to differ materially from those in the forward-looking statements include those set forth in our filings at . We are under no obligation to (and expressly disclaim any such obligation to) update or alter our forward-looking statements, whether as a result of new information, future events or otherwise. CONTACT INVO Bioscience: Steve Shum 978-878-9505 sshum@invobio.com; INVO Investor Contact: Robert Blum (Lytham Partners, LLC) 602-889-9700 INVO@lythampartners.com NAYA Biosciences: Anna Baran-Djokovic 305-615-9162 anna@nayabiosciences.com NAYA Media & Investor Relations: David Schull and Nic Johnson (Russo Partners, LLC) 858-717-2310 david.schull@russopartnersllc.com nic.johnson@russopartnersllc.com View original content to download multimedia: SOURCE INVO Bioscience, Inc. Company Codes: NASDAQ-NMS:INVO, ISIN:US44984F1049

NDA includes robust data from a Phase 3 trial that demonstrated efficacy of daridorexant on improving Total Sleep Time and Latency for Sleep Onset, while maintaining a favorable safety profileSosei Heptares to receive JPY 1.5 billion milestone revenue in relation to the submission Tokyo, Japan and Cambridge, UK, 31 October 2023 – Sosei Group Corporation (“Sosei Heptares” or “the Company”; TSE: 4565) announces that Idorsia Pharmaceuticals Japan Ltd. (“Idorsia Japan”), a Sosei Group company, has submitted a New Drug Application (“NDA”) to the Japanese Pharmaceuticals and Medical Devices Agency (“PMDA”) for the approval of daridorexant (ACT-541468), a dual orexin receptor antagonist which has been co-developed with Mochida Pharmaceutical Co., Ltd. ("Mochida”), for the treatment of adult patients with insomnia. The NDA is supported by positive results of a randomized, double-blind, placebo-controlled Phase 3 study in Japan to investigate the efficacy and safety of daridorexant. The study met both primary and secondary efficacy endpoints. Daridorexant significantly improved subjective Total Sleep Time (“sTST”), a primary endpoint defined as the change from baseline compared to placebo at 28 days (p<0.001 for 50 mg, p=0.042 for 25 mg). Daridorexant also significantly improved sleep onset as measured by a decrease in subjective Latency for Sleep Onset (“sLSO”), a primary endpoint defined as the change from baseline compared to placebo at 28 days (p<0.001 for 50 mg, p=0.006 for 25 mg). The rate of adverse events was comparable between placebo and daridorexant at both treatment doses. Treatment-emergent adverse events (“TEAEs”) during the double-blind study period were reported in 23.5% and 22.7% of the patients treated with 50 mg and 25 mg daridorexant, respectively (24.4% for placebo). Sosei Heptares gained Japan and Asia-Pacific (ex-China) rights to daridorexant from Idorsia Pharmaceuticals Ltd (Allschwil, Switzerland) in July 2023 in the context of its acquisition of Idorsia Japan and Idorsia Pharmaceuticals Korea Co., Ltd. Daridorexant was approved in the US and Europe in January and April 2022, respectively, and is marketed by Idorsia in these and other approved territories as QUVIVIQ™. In December 2019, Mochida and Idorsia Pharmaceuticals Ltd entered into an exclusive license agreement for the co-development and co-marketing of daridorexant for insomnia and related disorders in Japan. Under the agreement, Mochida and Idorsia Japan have jointly developed daridorexant and plan to co-market daridorexant pending Idorsia Japan receiving Japanese PMDA approval. In relation to the filing of this NDA, Sosei Heptares will receive JPY 1.5 billion (US$10 million*). The milestone receipt will be recognized as revenue in the fourth quarter of the financial year ending 31 December 2023. * USD1 = JPY149.86 Makoto Uchiyama, M.D., Ph.D., medical advisor of the Japanese Phase 3 study, Director of Tokyo Adachi Hospital, Visiting Professor of Nihon University, and Visiting Professor of Toho University, commented: “Insomnia is highly prevalent in Japan and is recognized as an important national health issue. Patients with insomnia have trouble falling or staying asleep, as well as waking up earlier than desired, all of which lead to detrimental effects on both physical and mental health. Daridorexant is the first drug for a decade to have been clinically investigated in more than 100 centers in Japan and showed marked positive results in the studies. The Japanese Phase 3 trial showed that daridorexant increased total sleep time and shortened sleep latency in patients with insomnia without marked hangover symptoms the next morning, which clearly indicates its potency to improve core symptoms of insomnia. Such a promising outcome was likely due to the unique characteristics of the drug, a dual orexin receptor antagonist with an optimal elimination half-life.” Satoshi Tanaka, Dr Med Sci., President of Idorsia Pharmaceuticals Japan (a Sosei Group company), and Executive Officer and Executive Vice President of Sosei Heptares, added: “The team has worked rapidly to analyze the data and prepare the dossier for the PMDA so that we can bring daridorexant to patients as soon as possible. We will now work together with the authorities through the regulatory process, and in parallel, prepare the scientific publication and the commercial launch of 10, 25 and 50 mg tablets, which we hope to see in the second half of 2024. Together with the development partner Mochida, the whole team is eager to rapidly make daridorexant available to Japanese patients with insomnia.” QUVIVIQ™ is a registered trademark of Idorsia Ltd. -ENDS- Notes to Editors About Insomnia DisorderInsomnia disorder is defined as difficulty initiating or maintaining sleep, causing clinically significant distress or impairment in important areas of daytime functioning. This impact on sleep quantity or quality should be present for at least three nights per week, lasts for at least three months, and occurs despite an adequate opportunity to sleep. Insomnia is a condition of overactive wake signaling and studies have shown that areas of the brain associated with wakefulness remain more active during sleep in patients with insomnia. According to a survey by the Ministry of Health, Labour and Welfare in 2018, about 20% of Japanese adults struggle to get enough rest from sleep. Insomnia as a disorder is quite different from a brief period of poor sleep, and it can take its toll on both physical and mental health. It is a persistent condition with a negative impact on daytime functioning. Research has shown that poor quality sleep can affect many aspects of daily life, including the ability to concentrate, mood, and energy levels. The goal of treatments for insomnia is to improve sleep quality and quantity, as well as daytime functioning, while avoiding adverse events and next-morning residual effects. Current recommended treatment of insomnia includes sleep hygiene therapy, cognitive behavioral therapy, and pharmacotherapy. About the Orexin systemWake and sleep signaling is regulated by intricate neural circuitry in the brain. One key component of this process is the orexin system, which helps promote wakefulness. There are two forms of orexin neuropeptides – small protein-like molecules used by nerve cells (neurons) to communicate with each other in the brain – orexin A and orexin B. Orexin promotes wakefulness through its receptors OX1R and OX2R. Together, these neuropeptides and receptors make up the orexin system. The orexin system stimulates targeted neurons in the wake system – leading to the release of several chemicals (serotonin, histamine, acetylcholine, norepinephrine) – to promote wakefulness. Under normal circumstances, orexin levels rise throughout the day as wakefulness is promoted and then fall at night. Overactivity of the wake system is an important driver of insomnia. About the Japanese Phase 3 StudyThe Japanese Phase 3 study was a randomized, double-blind, placebo-controlled, parallel-group, multicenter study to investigate the efficacy and safety of daridorexant in patients with insomnia disorder. The primary objective of the study was to demonstrate the efficacy of 50 mg of daridorexant once daily at bedtime versus placebo for 4 weeks in patients with insomnia disorder. The efficacy of daridorexant was measured by patient reported total sleep time (“sTST”) and latency to sleep onset (“sLSO”). The primary efficacy endpoint was change from baseline to Week 4 in sTST and change from baseline to Week 4 in sLSO with 50 mg daridorexant versus placebo. The secondary efficacy endpoint was change from baseline to Week 4 in sTST and change from baseline to Week 4 in sLSO with 25 mg daridorexant versus placebo. The study also evaluated the dose effect of 50 or 25 mg of daridorexant versus placebo using other patient reported sleep measures. The study enrolled 490 patients, randomized 1:1:1 to daridorexant 50 mg, 25 mg or placebo. As insomnia often presents later in life, and older adults are more susceptible to experience fragmented sleep, early awakening, and daytime sleepiness, around 30% of the recruited population was at least 65 years of age. Key Literature Riemann, D., et al. Sleep. 2017;26(6):675-700.The Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM–5; American Psychiatric Association, 2013).Wardle-Pinkston S., et al. Sleep Med Rev. 2019;48.Mignot, E., et al. Lancet Neurol. 2022;21:125–39.Muehlan, C., et al. Expert Opin. Drug Metab. Toxicol. 2020;16(11):1063–1078.Muehlan, C., et al. J Psychopharmacol. 2020;34(3):326-335.Buysse, D.J., et al. Drug Discov Today Dis Models. 2011;8(4):129-137.Levenson, J.C., et al. Chest. 2015;147(4):1179-1192.Boof, M.L., et al. Eur J Clin Pharmacol. 2019;75(2):195-205.Clifford, B.S., et al. Trends Neurosci. 2001;24(12).726-31.Gotter, A.L., et al. BMC Neuroscience. 2013;14(1):14-19.Patel, D., et al. J Clin Sleep Med. 2018;14(06):1017–1024.Fietze I., et al. Drugs Aging. 2022 Oct;39(10):795-810.Kunz D, et al. CNS Drugs. 2022 Dec 9. About Makoto Uchiyama, M.D., Ph.D.Director, Tokyo Adachi Hospital, TokyoVisiting Professor, Departments of Psychiatry and Sleep Medicine, Nihon University School of Medicine, TokyoVisiting Professor, Department of Psychiatry, Toho University School of Medicine, TokyoEducational Achievements and certificates:M.D., Tohoku University, School of Medicine, Sendai, 1980Ph.D., Tokyo Medical and Dental University, Tokyo, 1994Designated Physicians of Mental Health, Ministry of Health, Labor and Welfare, 1987Board Certified Physician of the Japanese Society of Sleep Research, 2002Certified Psychiatrist of the Japanese Board of Psychiatry, 2006Board-certified Clinical Neurophysiologist (EEG section), Japanese Society of Clinical Neurophysiology, 2006 Dr. Uchiyama serves as a consultant to Idorsia Pharmaceuticals Japan. About Idorsia Pharmaceuticals JapanIdorsia Pharmaceuticals Japan was established in 2018 to conduct clinical development and prepare the commercialization of innovative and promising compounds for patients in Japan. Idorsia Pharmaceuticals Japan is a wholly owned subsidiary of Sosei Group Corporation. About Sosei HeptaresSosei Heptares is a fully integrated biopharmaceutical company focused on bringing life-changing medicines based on world-class science to patients globally. Our vision is to become one of Japan’s global biopharmaceutical champions. Our global business combines our world-leading GPCR-targeted StaR® technology, structure-based drug design and early development capabilities in the UK with a highly experienced clinical development capability and a commercial operation in Japan. We are leveraging these capabilities to generate and advance a broad and deep pipeline of novel medicines across multiple therapeutic areas, including neurology, immunology, gastroenterology and inflammatory diseases. We intend to develop these opportunities for patients in Japan and globally both internally and through our partnerships with global biopharmaceutical companies and emerging technology companies. Sosei Heptares operates from key locations in Tokyo and Osaka (Japan), London and Cambridge (UK), Basel (Switzerland) and Seoul (South Korea). “Sosei Heptares” is the corporate brand and trademark of Sosei Group Corporation, which is listed on the Tokyo Stock Exchange (ticker: 4565). Sosei, Heptares, the logo and StaR® are trademarks of Sosei Group companies. For more information, please visit https://soseiheptares.com/LinkedIn: @soseiheptaresco | Twitter: @soseiheptaresco | YouTube: @soseiheptaresco Enquiries: Sosei Heptares – Media and Investor RelationsKentaro Tahara, VP Investor Relations and Corporate Strategy Shinichiro Nishishita, VP Investor Relations, Head of Regulatory DisclosuresMaya Bennison, Communications Manager+81 (0)3 5210 3399 | +44 (0)1223 949390 | IR@SoseiHeptares.com Idorsia Pharmaceuticals Japan – Product Information Drug Information Center +81 (0)3 5962 5674 MEDiSTRAVA Consulting (for International Media)Mark Swallow, Frazer Hall, Erica Hollingsworth+44 (0)203 928 6900 | SoseiHeptares@medistrava.com Sosei Group Corporation Forward-Looking StatementsThis press release contains forward-looking statements, including statements about the discovery, development, and commercialization of products. 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▎药明康德内容团队编辑好奇心引领我们向未知探索，挑战和勇气让我们在面对未知时保持前进。在探索科学世界的过程中，一位名叫本庶佑（Tasuku Honjo）的科学家坚持用6个“C”——保持好奇（have Curiosity）、拥抱挑战（embrace Challenge）、勇于探索（Courage to invest effor and time）、持续专注（Continue research with a lot of Concentration）和充满自信（Confidence that you can do it）作为自己科研生涯的基石和灯塔，使他在科学研究上取得了巨大的成功。本庶佑教授和詹姆斯·艾利森（James Allison）教授的发现建立了一种全新的癌症治疗准则，给无数癌症患者带来了新的希望。今天，药明康德内容团队将结合公开资料带大家走近这位充满好奇心、勇于挑战、敢于探索未知世界的科学家。▲本庶佑教授（图片来源：药明康德内容团队制作）潜移默化，埋下科学探索的种子本庶佑于1942年1月27日出生于日本京都的一个医学世家。他的父亲曾是京都大学医院的外科医生，家里很多亲戚也都是临床医生。在本庶佑小时候，父亲严格的教育风格以及出国深造经历练就的流利英语使他从小就被培养出了良好的学习态度和沟通技巧。小学时，本庶佑的兴趣主要在天文学，直到他的母亲给他读了一本关于日本著名微生物学家野口英世的传记，他的兴趣才开始发生了转变。野口英世的故事深深打动了本庶佑，尤其是他在极度贫困、严重烧伤使左手功能仅剩70%的情况下，通过付出惊人的努力，一次性获得医生执照的事迹，这激起了本庶佑对医生科学家的敬佩和憧憬。高中毕业时，本庶佑出于对医学专业的兴趣选择延续家族传统，报考了京都大学医学院。在大学里，他逐渐被分子生物学和生物化学所吸引，特别是读了一本叫做《生物学革命》（Revolution in Biology）的书后，本庶佑对这个领域充满了好奇和热情。书中提出的对癌症、DNA突变、分子手术等领域的惊人预测为他打开了新世界的大门。他相信，这将引导他更好地理解生命的本质，也将引领他的医学研究走向新的领域。好奇心引领，踏上免疫学探索道路在医学院的日子使本庶佑厌倦了对解剖学拉丁名和疾病症状的死记硬背，他开始将大量的时间投入到生物化学家早石修（Osamu Hayaishi）教授的实验室中。在那里，他不仅得到了科学上的指导，还学会了打高尔夫和品酒——这些娱乐活动在后来为他带来了不少乐趣。在早石修教授的实验室，本庶佑体会到了只是基于好奇心解决科学问题的快乐。1967年，他偶然读到了一篇有趣的论文，描述的是一种对所有活细胞能量产生至关重要的分子NAD，此分子在白喉毒素（diphtheria toxin）使蛋白质合成酶EF-2失活的过程中是必不可少的，而这一点与当时人们的认知完全不同，所有人都认为白喉毒素应该是通过直接阻断EF-2的活性发挥其功能的。为了探究NAD在这一过程中究竟发挥了什么作用，本庶佑开展了实验，并很快获得了答案——白喉毒素是一种催化NAD的ADP-核糖基转移到EF-2的酶。1968年，他将这一成果发表在了Journal of Biological Chemistry杂志上。这一成功的案例为本庶佑增添了巨大的信心，并决定毕业后追随导师和父亲的脚步接受更大的挑战，到国际科学环境中去闯一闯。幸运的是，他被华盛顿卡内基研究所（Carnegie Institution of Washington）聘为博士后，继续他的研究生涯。约一年后，一场关于免疫球蛋白（Ig）基因组织的研讨会彻底改变了他的研究方向。当时，所有的生物学家都在致力于解决这样一个问题，动物能够针对几乎每一种他们遇到的外来抗原产生特异性的抗体，这种B淋巴细胞产生抗体的巨大多样性究竟是怎么实现的？这个问题激起了本庶佑巨大的好奇心，于是他决定加入有望帮助他找到答案的最佳地点——美国NIH菲利普·莱德（Philip Leder）教授的实验室，开始了他在分子免疫学上的长期探索之旅。排除万难，建设本国分子生物学研究文化在美国接受4年的深造后，本庶佑又一次面临了人生的重大选择：回日本？还是留在美国？那时，日本大学的资金和设施还无法支持他进行先进的分子生物学研究。但他还是毅然决然地选择回日本。一是他希望他的孩子们能在本国体验本土文化，二是他期待在日本建立强大的分子生物学研究文化，一如他的导师早石修教授为生物化学研究所做的那样。本庶佑教授的建设计划选择从东京大学开始。但即便是当时被认为是日本最好的大学，他还是发觉那里不论是科学精神还是基础设施，都与他当年在早石修教授实验室中感受过的相去甚远。尽管有很多困难，本庶佑教授没有抱怨，而是从零开始，亲力亲为地搭建起实验室。▲本庶佑教授（图片来源：药明康德内容团队制作）当时，为了配置一个在日本很难找到的基础设备——凝胶干燥器，他曾走到秋叶原，买来材料自己制作了一个。本庶佑教授在建设实验室上的全身心投入使不少优秀的医学生自愿在课后加入到他的研究中去。经过近三年的努力，本庶佑教授的实验室开始产出真正有意义的数据，并提出了类别转换重组（CSR）的DNA缺失假设模型。该研究受到了当时《自然》杂志的主编米兰达·罗伯逊（Miranda Robertson）女士在新闻和观点版块中的高度赞扬。发现PD-1，肿瘤治疗迈入免疫疗法时代1991年5月，本庶佑教授的实验室在研究T细胞的选择性繁殖过程中，发现了一个在细胞死亡和生长过程中表达的基因，他们将它命名为PD-1。尽管初期的实验结果并未符合预期，但持续的探索使他们在1997年发现，PD-1缺失会导致小鼠产生自身免疫症状。进一步的研究使他们开始相信，PD-1是免疫系统的负调节因子，并有望成为治疗免疫调节失调疾病的有效靶点。1998年3月，本庶佑教授及其团队成员开启了一系列针对PD-1的研究，希望找到能治疗癌症、感染、自身免疫疾病和移植排斥反应等疾病的潜在疗法。而由于阻断PD-1比增强其功能更简单，因此研究人员们首先把目标适应症放在了癌症上。在这一过程中，他们发现PD-1缺失小鼠的骨髓瘤的生长速度比野生型小鼠要慢。这让本庶佑教授相信，PD-1是极好的癌症治疗靶点。随着研究的继续，本庶佑教授及其合作伙伴在2001年底证实，PD-1阻断可以阻止多种类型的肿瘤在小鼠体内生长。2005年，本庶佑教授自己的团队证实了PD-1抗体疗法可以阻止B16黑色素瘤从脾脏扩散到肝脏。▲PD-1抗体与CTLA-4抗体作用图（图片来源：药明康德内容团队制图）在确认了PD-1是抗肿瘤疗法的有力靶点后，本庶佑教授积极投身于相关疗法的临床转化，在2003年与日本医药公司Ono Pharmaceutical共同申请了抗PD-1疗法的专利，并开启了该治疗方法的研发。然而，他们的研发过程遭遇了一些困难，尤其是在寻找临床试验合作伙伴时。就在此时，美国的生物制药公司Medarex发现了他们的专利申请，并向Ono提出了合作提议。经过一段时间的协商，Medarex和Ono在2005年达成了协议，共同开发抗PD-1疗法。对于针对PD-1的疗法开发能够如此迅速地推进，本庶佑教授认为自己非常幸运，如果没有这次偶然的机会，PD-1癌症药物的开发可能会推迟很多年，这对全球数千万迫切等待新疗法的癌症患者来说将是巨大的损失。PD-1抗体的临床试验结果也不负众望，尤其是在治疗晚期黑色素瘤、肺癌或肾癌方面取得了很好的疗效。在日本，1名对现有疗法耐药的卵巢癌患者在接受PD-1阻断治疗后实现了完全治愈，2名接受PD-1抗体治疗的患者在5年后依然没有复发，这进一步证实了PD-1抗体的治疗价值。经过多年的努力，2014年时，PD-1抗体Opdivo在日本率先获批，用于治疗黑色素瘤，并逐渐得到全球的认可，肿瘤治疗开始逐步迈入免疫疗法的新时代。尾声近年来，以PD-1/PD-L1抑制剂为代表的免疫疗法已成为癌症治疗领域的明星。除了黑色素瘤，非小细胞肺癌、头颈癌、淋巴瘤等十几种恶性肿瘤也已从这些疗法中获益，人类抗击癌症的历史已因它们的到来而改变。2018年，詹姆斯·艾利森教授和本庶佑教授因“发现了通过抑制负性免疫调节来治疗癌症的方法”共享了当年的诺贝尔生理学或医学奖，以表彰他们在癌症治疗方面所做的贡献。▲本庶佑教授（图片来源：药明康德内容团队制作）本庶佑教授获得诺贝尔奖时已是76岁高龄，但他的梦想并没有停止，还坚持每天去实验室，学习更多有关免疫调节的知识，希望有一天能够通过免疫疗法治愈这个星球上所有的癌症患者。除此以外，他表示自己还有两个愿望等待去完成，一个是希望为日本的年轻科学家创立更多的基金，帮助他们实现科研梦想；二是他希望在80岁之前，他的高尔夫球成绩能与他的年龄相等。本庶佑教授一直将科学研究比作高尔夫球比赛，每一次尝试都是全新的挑战，每一次决策都需要全力以赴，以避免大的失误。在面临挑战和困难时，本庶佑教授始终持有坚定的信念和决心，并遵守着他的6“C”原则。他的故事不仅启示我们如何追求知识和真理、挑战现状，更告诉我们要有毅力和信心，相信只要我们坚持下去，成果总会来的。让我们向这位伟大的科学家致敬！大家都在看▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料：[1] Tasuku Honjo Facts. Retrieved June 9, 2023, from https://www.nobelprize.org/prizes/medicine/2018/honjo/facts/[2] Tasuku Honjo Biographical. Retrieved June 9, 2023, from https://www.nobelprize.org/prizes/medicine/2018/honjo/biographical/[3] Hideyo Noguchi. Retrieved June 9, 2023, from https://en.wikipedia.org/wiki/Hideyo_Noguchi[4] The entrepreneur behind the cancer immunotherapy revolution. Retrieved June 9, 2023, from https://www.statnews.com/2019/04/29/nils-lonberg-entrepreneur-behind-cancer-immunotherapy-revolution/[5] Honjo, T., Nishizuka, Y., Hayaishi, O., and Kato, I. (1968) Diphtheria toxin-dependent adenosine diphosphate ribosylation of aminoacyl transferase II and inhibition of protein synthesis. Journal of Biological Chemistry 243, 3553–3555.免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新