Telomelysin

For the smaller companies attending the Biotechnology Innovation Organization's CEO and Investor Conference in New York, the mission was simple: find enough capital to keep going. Eli Lilly's Renee Williams arrived in New York City this week ready to mix and mingle with dozens of biotechs that had descended on the Big Apple itching to strike a deal. The draw was the Biotechnology Innovation Organization's CEO and Investor Conference, a business development bonanza centered on partnerships and dealmaking. For the smaller companies in attendance, the mission was simple: find enough capital to keep going. In a financing environment that remains perilous for new biotechs, the stakes are high.  Even so, Williams, who leads external innovation for Lilly's genetic medicine unit, cautioned against desperation.  “I definitely get the sense that people need to find a way to return for their investors, to return their own costs probably out of their pockets,” she said. “It's translating to perhaps maybe not typical business practices.”  While big-ticket licensing deals are at the top of the list for smaller biotechs, Williams highlighted Lilly's other offerings, such as data and strategy consulting in exchange for some royalties or commercialization rights. The proposal underscores how much the ball is in Big Pharmas court with respect to dealmaking—and what companies may need to give up in exchange for even a limited relationship with the industry's biggest players.  “Having dollars doesn't mean that you run your experiments in a way that necessarily we want to see them,” said Williams. Still, she emphasized the company is open for business, reiterating an often-heard call from pharma executives. But Big Pharmas need the biotech ecosystem just as much to top up their pipelines—hence why people like Williams were there, to meet the small biotech executives who could hold the next big thing.  The juxtaposition between Big Pharma's available cash to spend and the sheer volume of potential partnerships sets the scene for a competitive and dogged financing environment. It's been made even more difficult as IPOs have become increasingly difficult to pull off, M&A has not returned to expected volumes and trepidation has crept into private financing, particularly in follow-up raises. Yet the sentiment among conference attendees was largely hopeful.  That was certainly Talia Biran’s mood. As president of the U.S. subsidiary of the Japanese biotech Oncolys BioPharma, Biran is shopping for two distinct opportunities. The first is finding a commercial partner for the company’s soon-to-be-submitted oncolytic virus therapy, suratadenoturev, in Japan, with phase 2 data expected before the end of the year and an approval application slated to be submitted in 2024.  The other goal is to find a development partner in the U.S., where suratadenoturev is being tested in conjunction with chemoradiotherapy in a phase 1 trial and alongside Merck & Co.'s Keytruda in a phase 2 trial. The company has tried before with no luck. But this time is different, as Biran says Oncolys now has clinical data plus the prospect of bringing in revenue from Japan, bolstering the prospects of landing a coveted licensing deal. “I think the issue was that we didn't have data at the time that Oncolys tried a few years ago,” she said. “Now, four years fast forward, we have more convincing data that was generated in the U.S. that I feel more confident to showcase the virus and to get the licensing deal.” While Biran wishes Oncolys could commercialize the drug by itself, they simply can’t afford it. She guessed that before the end of the year, the company would at least be able to nail down a partner in Japan.  Ulrich Dauer, Ph.D., CEO of Vivoryon, finds himself in a similar situation as the company sets its sights on a phase 2 readout for Alzheimer’s disease treatment varoglutamstat in the first quarter of 2024. He says the goal is to find a partner to fund additional clinical development. His pitch comes as Alzheimer’s drug development is at a fever pitch, with Eisai’s lecanemab nabbing accelerated approval and Eli Lilly’s donanemab nearing a phase 3 readout. “Now having kind of the first successes, there seems to be an increasing interest to look on, you know, various approaches in the field and we are experiencing that,” said Dauer.  The inspired pursuit for more money that drove most companies at the conference means that the options for people like Williams were in abundance. Her pitch to them was succinct.  “People just have to come and ask—everything is not just give me a dollar. We have a lot to offer,” she said. 

关注并星标CPHI制药在线溶瘤病毒（oncolytic virus，OVs）是一种新型肿瘤免疫疗法，其通过不同的调控机制在肿瘤细胞内复制、裂解肿瘤细胞，而不影响正常细胞生长。目前，溶瘤病毒主要有腺病毒（adenovirus，AD）、痘病毒、疱疹病毒、呼肠孤病毒和柯萨奇病毒等，给药方法有瘤内注射，静脉输送，胸腹腔、膀胱内注射和细胞载体四种。溶瘤病毒抗肿瘤机制溶瘤病毒选择性感染肿瘤细胞，在肿瘤细胞内进行自我复制来破坏肿瘤细胞，通过释放病原体相关分子(pathogen-associated molecular pattern molecules，PAMP)、肿瘤相关抗原(tumor-associated antigen，TAA) 、炎性因子、趋化因子等物质，激活机体免疫系统，直接或间接杀伤肿瘤细胞，将冷肿瘤转变为热肿瘤。①直接感染裂解肿瘤细胞而不感染正常细胞。病毒在进入肿瘤细胞后，大量复制造成肿瘤细胞的裂解，直接杀伤肿瘤细胞，同时在肿瘤组织内产生空间，增加免疫细胞的浸润和增殖。②释放肿瘤抗原，刺激机体免疫应答。肿瘤细胞裂解后释放危险相关分子( danger-associated molecular pattern molecules，DAMPs)、PAMP和TAA 募集抗原提呈细胞( antigen presenting cell，APC)，APC 将TAA呈递给杀伤性T细胞，产生免疫应答。同时激活 NF-κB 信号通路，诱导肿瘤坏死因子-α ( tumor necrosis factor-α，TNF-α) 和白细胞介素-6 ( interleukin-6，IL-6) 因子表达，产生炎性微环境，促进免疫细胞成熟和激活，增强抗肿瘤作用。③调节肿瘤微环境，逆转免疫抑制微环境。溶瘤病毒感染肿瘤细胞，可活化树突状细胞 (dendritic cells，DC) 细胞表面的模式识别受体(pattern recognition receptor，PRR)，逆转免疫抑制状态的DC 细胞，促进DC 细胞对肿瘤细胞的识别，上调 CXCL1 和CXCL5 等趋化因子的表达，诱导中性粒细胞浸润，逆转肿瘤部位免疫抑制微环境，增强抗肿瘤效应。④转基因改造促使免疫调节因子表达并增加肿瘤部位免疫细胞的浸润和增殖。基因改造后的溶瘤病毒在进入肿瘤细胞后，进一步表达炎性因子或对免疫细胞直接作用，激活机体免疫系统，杀伤残留的肿瘤细胞。⑤转基因改造促使趋化因子表达并增加免疫细胞归巢和浸润。基因改造后的溶瘤病毒在进入肿瘤细胞后，进一步表达趋化因子等，使肿瘤部位免疫细胞归巢，增强抗肿瘤作用。⑥破坏肿瘤相关血管。肿瘤的生长依赖肿瘤血管提供营养物质，因此，破坏肿瘤相关血管能够有效地抑制肿瘤的生长。研究表明，水泡性口炎病毒(VSV) 可以在体内直接感染并破坏肿瘤血管，而对正常血管没有影响。水泡性口炎病毒在肿瘤组织中扩散并进行复制，启动机体内由嗜中性粒细胞介导的炎症反应，从而导致肿瘤血管内微血栓的形成。肿瘤血管内的微血栓影响血管向肿瘤组织提供营养物质，最终导致肿瘤细胞缺少营养死亡。溶瘤病毒联合治疗现状溶瘤病毒是一种多功能抗癌药，选择性感染、复制并杀死肿瘤细胞。溶瘤病毒在多个临床试验中显示出不同的治疗效果，但很少长期诱导体内肿瘤的完全消退。而且，异质性肿瘤的选择性压力导致对溶瘤病毒的抗性。为了克服这些不足，临床上建立起许多新颖溶瘤病毒联合疗法，增强对肿瘤的杀伤力。01溶瘤病毒联合化疗或靶向治疗化疗是直接杀死恶性细胞，增强肿瘤细胞免疫原性，增强溶瘤病毒的细胞毒性，溶瘤病毒联合化疗具有协同作用，促进抗肿瘤免疫反应。溶瘤病毒联合化疗的机制包括：① 逃避抗病毒免疫反应，增强病毒溶瘤作用，改善 HSV、AD、麻疹病毒和呼肠孤病毒抗肿瘤功效；② 抵抗免疫，抑制肿瘤微环境。肿瘤微环境主要组成部分是调节性T 细胞（regulatory cells，Treg）和骨髓来源抑制性细胞（my eloid-derived suppressor cells，MDSC），二者能有效降低肿瘤免疫性。研究表明，肿瘤微环境内的MDSC积累会抑制抗肿瘤效应 T 细胞，促进肿瘤生长，吉西他滨、舒尼替尼、5-氟尿嘧啶（5-fluorouracil，5-Fu）等许多化学药物能清除MDSC，提高生存率。③ 调节肿瘤细胞免疫原性。阿霉素和 Ara-C能降低免疫检查点分子的表达，阻断其对浸润 T 细胞的抑制。化疗药物影响多个生物过程，如雷帕霉素及其类似物改变 mTOR 信号传导，增加溶瘤病毒靶向性，诱导自噬。溶瘤病毒联合化疗或单药治疗肿瘤均优于化疗。与联合化疗原理相同，靶向治疗能抑制癌细胞内异常的信号通路。联合使用BRAF、MRK 激酶抑制剂和 3 型呼肠孤病毒 [reovirus type 3（Dearing），RT3D]，通过细胞凋亡体外杀死细胞。RT3D 联合细胞毒性药物研究表明，RT3D 安全、可耐受，将RT3D 与常规抗癌药物联合使用，可实现协同作用。02溶瘤病毒联合放疗溶瘤病毒和放疗是肿瘤治疗的两个不同领域，为不重叠的细胞毒性谱。辐射能增强病毒的溶瘤作用，病毒能够提高细胞放疗敏感性，二者具有协同作用。溶瘤病毒是一种极具潜力的肿瘤治疗策略。最初认为溶瘤病毒的细胞毒性是增加病毒复制、增强肿瘤细胞感染和溶瘤作用，但目前大多认为溶瘤病毒阻止DNA 修复，使肿瘤细胞对辐射敏感，诱导细胞凋亡。溶瘤病毒与放疗联合抗肿瘤，疗效显著。高度减毒的牛痘病毒（VV，GL-ONC1）结合放疗，可提高抗肿瘤疗效；高剂量放疗增强腺病毒在前列腺癌细胞内的复制，抑制癌细胞的增殖。与单独治疗相比，HSV-1 联合放疗对疾病预后有明显改善作用，NVl066 联合放疗能显著缩小非小细胞肺癌和恶性间皮瘤的肿瘤体积。03溶瘤病毒联合免疫治疗溶瘤病毒虽然能够快速减少局部肿块大小，但不易产生持续性抗肿瘤免疫应答。免疫应答是溶瘤病毒疗法的关键组成部分，初始诱导很强，随后效应细胞的抗肿瘤活性被多种免疫调节剂（如 CTLA-4 和 PD-L1）抑制。在恶性黑色素瘤小鼠模型中，溶瘤麻疹病毒能够将抗CTLA-4 和抗 PD-L1 抗体靶向递送至肿瘤微环境，诱导较强的特异性抗肿瘤免疫反应，未发现免疫相关毒性。另一种黑色素瘤小鼠模型中，瘤内注射 NDV 联合抗CTLA-4 抗体能使肿瘤消退，存活时间延长。PDL1 产生于肿瘤细胞和浸润肿瘤细胞的过表达，与 T细胞上的 PD-1 结合，诱导 T 细胞凋亡，使肿瘤细胞逃逸。溶瘤病毒感染会增强免疫调节剂的表达，增强肿瘤细胞对 PD-1 或 PDL1 阻断的敏感性，引起抗肿瘤免疫反应。因此，溶瘤病毒联合免疫具有治疗价值。联合疗法增加肿瘤内 CD8+ T 细胞浸润，可能吸引肿瘤特异性 T 细胞，逆转对 PD-1 阻断疗法的耐药性。溶瘤病毒瘤内给药后CD4+和 CD8+ T 细胞全身性增加，CD8+ T 细胞表达PD-1、增加对肿瘤的浸润，而肿瘤细胞表达 PD-L1，可能限制了溶瘤病毒单药的抗肿瘤活性，临床活性优于单独使用任何一种疗法的预期。第一代溶瘤病毒仅具有肿瘤特异性，如H101、Reolysin 和 Telomelysin；第二代溶瘤病毒具有肿瘤特异性，含有1个功能性外源基因的表达，如T-VEC、JX-594和H102；第三代溶瘤病毒具有肿瘤特异性、免疫调节与免疫治疗功能，多于 1 个功能性外源基因的表达，外源基因功能相互协调，如 GO701 和 GV802。近年来，随着医疗水平的提升及技术的成熟，溶瘤病毒越来越频繁地应用于抗肿瘤治疗，为广大恶性肿瘤患者带来希望。抗肿瘤疗法中，目前最常用的两种溶瘤病毒是重组人 5 型腺病毒（安柯瑞，H101）与 T-VEC（talimogene laherparepvec）。H101 是一种经基因改造的溶瘤腺病毒，于2005年被国家食品药品监督管理总局（CFDA）批准用于联合化疗治疗鼻咽癌，是世界上最早的一款溶瘤病毒。T-VEC 是第二代单纯疱疹病毒Ⅰ型，于2015 年被美国食品药品监督管理局（FDA）批准用于治疗不能手术的黑色素瘤，随后于2016 年在欧洲获得批准。参考资料[1] 崔姣艳,蔡世杰。溶瘤病毒联合其他药物用于肿瘤治疗的研究进展[J]。中国新药杂志,2021,30(03):246-253。[2] 李平翠,杨帆,欧霞,张继虹,魏大巧。溶瘤病毒载体研究进展[J]。生物化学与生物物理进展,2021,48(03):237-245。DOI:10。16476/j。pibb。2020。0146。[3] 王磊,霍彬,霍小东,王海涛。溶瘤病毒抗肿瘤治疗的临床应用进展[J]。中国肿瘤临床,2021,48(11):581-586。作者简介：小泥沙，食品科技工作者，食品科学硕士，现就职于国内某大型药物研发公司，从事营养食品的开发与研究。智药研习社近期课程报名扫码发送MAH，免费报名直播讲座来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPhI制药在线▼点击阅读原文，进入智药研习社~