Argos Therapeutics, Inc.

裸mRNA疫苗裸mRNA(未封装mRNA）疫苗，可经皮内或淋巴结内注射。淋巴结内给予非配方的mRNA，可以将抗原递送给APC细胞，原位激活T细胞，从而避免了抗原提呈细胞迁移的要求。在过去的5年里，只有少数临床试验使用裸mRNA疫苗治疗癌症患者。在一项1期临床试验中，对13例既往治疗后病情稳定、部分缓解或完全缓解的II、III、IV期黑色素瘤患者淋巴结内注射裸mRNA疫苗。这是一种个体化mRNA癌症疫苗，每个患者选择10个新表位。所有患者都对新表位疫苗产生了T细胞应答，在5名IV期黑色素瘤患者中有2名（40%）观察到与疫苗相关的临床应答。另外一项1期临床试验（NCT03394937）中，20例切除的黑色素瘤患者（IIc期、III期和IV期）接受了淋巴结内注射的裸mRNA疫苗（ECI-006）。该疫苗包括编码3种树突状细胞激活分子（TriMix）和5种肿瘤相关抗原mRNA。在第二个研究队列（NCT03394937）中，经过3-12个月的标准治疗后病情稳定的转移性黑色素瘤患者接受了ECI-006疫苗联合标准抗PD-1治疗；结果未公布。裸mRNA癌症疫苗，目前在ClinicalTrials.gov已经没有正在招募的临床研究。裸mRNA疫苗的主要问题是易被RNA酶降解。鱼精蛋白封装的mRNA疫苗鱼精蛋白是带正电荷的阳离子多肽，与带负电荷的mRNA形成复合物，保护分子免被降解。鱼精蛋白封装的mRNA疫苗，曾经在CureVac的RNActive疫苗被使用，进行过一些临床试验。不过临床疗效欠佳。RNActive疫苗将核苷修饰的mRNA分子与鱼精蛋白复合物结合，以增强蛋白表达和免疫原性。目前在ClinicalTrials.gov，已经没有正在招募的鱼精蛋白封装mRNA癌症疫苗临床研究。mRNA-lipoplex疫苗mRNA-lipoplex疫苗，带正电荷的阳离子脂质自然地与带负电荷的mRNA形成复合物，促进抗原提呈细胞的内吞作用。目前BioNtech和Genentech有多个项目在进行临床研究。BNT111和BNT113均已经进入2期临床（NCT04526899、NCT04534205）。BNT111BNT111是一种静脉注射脂质体RNA（RNA-LPX）疫苗，针对黑色素瘤四种非突变的肿瘤相关抗原（NY-ESO-1、Tyrosinase、MAGE-A3、TPTE）。Nature 202075%患者对至少一种肿瘤相关抗原产生免疫反应临床结果抗PD-1治疗+mRNA疫苗：6例（35%）PR，2例（12%）SDmRNA疫苗单药治疗：1例（3%）CR，3例（12%）PR，7例（28%）SDNature 2020mRNA-LNP疫苗脂质纳米颗粒（Lipid nanoparticle, LNP) 由可离子化的脂质、胆固醇、磷脂和脂联聚乙二醇衍生物组成。胆固醇和磷脂增加了稳定性，并支持脂质纳米颗粒的双层结构。聚乙二醇可以阻止mRNA-血浆蛋白结合，从而增加了纳米颗粒的循环周期。Nat Biotechnol . 2022脂质纳米颗粒受pH变化的影响，从而促进了mRNA的封装和宿主细胞的内吞作用。随着SARS-CoV-2  Vaccine 批准，mRNA-LNP疫苗备受关注。Moderna有两款疫苗进入临床阶段。mRNA-4157进入2期（NCT03897881）和MSD的K药联用，治疗高风险黑色素瘤。1期（NCT03313778）单药或者联用K药，治疗实体瘤。mRNA-5671在临床1期（NCT03948763）和MSD的K药联用，治疗非小细胞肺癌。Moderna官网mRNA-4157（先期编码20个新生抗原，继续临床试验增加至34个新生抗原），1期单药治疗肿瘤可切除患者，或与K药联合治疗不可切除的实体肿瘤患者，可诱导了新抗原特异性T细胞，并没有导致严重的不良事件（3级以上不良反应）。Moderna官网13例患者接受了mRNA-4157单药治疗，除1例患者外，所有患者在研究治疗中均无癌症生存，中位随访8个月。在接受联合治疗的19例可评估患者中，1例（5%）完全缓解，2例（11%）部分缓解，5例（36%）病情稳定，5例（36%）疾病进展，2例（11%）有未确诊的疾病进展。mRNA-5671疫苗针对4个KRAS突变，一期临床试验（NCT03948763），mRNA疫苗在KRAS突变的NSCLC、结直肠癌或胰腺癌患者或与K药联合使用。mRNA-DC疫苗树突状细胞不仅可以启动免疫，而且可以控制和调节免疫反应的类型，使它们成为mRNA递送的候选载体。在过去的30年里，研究的重点是在体内产生一种装载抗原的树突状细胞群，刺激癌症患者的强大和持久的CD8+和CD4+T细胞反应。（推荐阅读：艰难的DC疫苗，喜迎突破...）。与其他几类mRNA疫苗相比，树突状细胞mRNA疫苗，制备抗原和装载它们的体外操作相对费时费力。Argos Therapeutics 的Rocapuldencel-T在3期终止，大多数临床是以研究单位为主体。一般来说，mRNA负载的树突状细胞疫苗诱导适度的T细胞反应，临床疗效较低。一项由Argos Therapeutics 赞助，MD安德森肿瘤中心， Fred Hutchinson Cancer Research Center等著名肿瘤中心参与的3期临床（NCT01582672），最终因为缺乏临床疗效而终止。 Clin Cancer Res 2020推荐阅读Genentech/BioNtech阐明RNA疫苗副作用mRNA疫苗尝试自身免疫病，Treg是核心mRNA疫苗 | 四个关键质量属性mRNA疫苗作用机制参考资料Ann J. Barbier et al, The clinical progress of mRNA vaccines and immunotherapies，Nat Biotechnol . 2022 Jun;40(6):840-854. doi: 10.1038/s41587-022-01294-2.Lorentzen CL, Haanen JB, Met Ö, Svane IM. Clinical advances and ongoing trials of mRNA vaccines for cancer treatment. Lancet Oncol. 2022 Oct;23(10):e450-e458. doi: 10.1016/S1470-2045(22)00372-2.Sahin U, Oehm P, Derhovanessian E, et al. An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma. Nature 2020; 585: 107–12.Burris HA, Patel MR, Cho DC, et al. A phase I multicenter study to assess the safety, tolerability, and immunogenicity of mRNA-4157 alone in patients with resected solid tumors and in combination with pembrolizumab in patients with unresectable solid tumors. J Clin Oncol 2019; 37: 2523Figlin RA, Tannir NM, Uzzo RG, et al. Results of the ADAPT phase 3 study of rocapuldencel-T in combination with sunitinib as first-line therapy in patients with metastatic renal cell carcinoma. Clin Cancer Res 2020; 26: 2327–36近期热门视频更多精彩视频，尽在佰傲谷视频号，欢迎关注~本周好文推荐如需转载请联系佰傲谷并在醒目位置注明出处﹀ 点亮在看，传递信息♥

Only a handful of biotechs are going after LILRBs, components of the innate immune system. But after an initial crop of data out of Merck in autumn 2020, more interest sprung up in the area, and a former Merck franchise director has secured investor backing to try to catch up to his former employer. Zurich-area biotech ImmunOs Therapeutics reeled in a $74 million Series B to take that lead program into a Phase Ia study in Australia toward the end of this year, executives told Endpoints News . The drug, dubbed IOS-1002, is a multi-agent based on human leukocyte antigens (HLAs) that go after two versions of LILRB (1 and 2) and KIR3DL1. Merck’s antibody targets LILRB2, meanwhile, and in a Phase I solid tumor study in 2020, the Big Pharma’s drug — when combined with Keytruda — led to responses in eight out of 34 patients. Known as MK-4830, the drug is now in Phase II for non-small cell lung, colorectal, renal cell and small cell lung cancer. Charlene Liao, CEO of LILRB competitor Immune-Onc, previously described LILRBs as the PD-1 of T cells when her startup raised nearly the same amount last March. While ImmunOs is well behind in clinical development, the 20-employee biotech thinks the transatlantic financing round and its academic-founded science can beat out competitors. “We expect to be able to demonstrate superior monotherapy efficacy relative to what others are doing. We expect to go into a broader indication set because we’re multitasking against multiple immune checkpoints. And we also expect to see a more durable response,” CEO Sean Smith, a former franchise director for Merck’s Europe and Canada hospital portfolio, told Endpoints. ImmunOs will begin the Phase Ia trial in Australia and then expand into other regions, CBO and COO Jeff Abbey, the former Argos Therapeutics CEO, said in the joint interview. “We really had our pick of investors and, as Sean said, we wanted an international syndicate to really preserve our optionality going forward so that we’re well-funded and can continue to build out the company the way we want to build it out,” Abbey said. The fresh funds will bankroll the Phase I study and get the drug into a Phase II trial as well, the executives noted. The financing will also support another clinical entry in oncology and the biotech’s first human study foray in the autoimmune field. ImmunOs is “reverse-engineering” its immuno-oncology program to get into the autoimmune space, explained chief development officer Steve Coats. The former AstraZeneca R&D VP is building out ImmunOs’ US operations in Gaithersburg, MD, a Mid-Atlantic city he described as an “underappreciated technology center” that is close to universities, AstraZeneca acquisition MedImmune, FDA and the NIH. The Swiss biotech was spun out of the University of Basel and University of Zurich in 2017 and is based off the work of CMO Christoph Renner and CSO Osiris Marroquin Belaunzaran. Tuesday’s Series B was led by new investors Samsara BioCapital, Lightspeed Venture Partners and Gimv. Mission BioCapital, GL Capital, PEAK6 Strategic Capital and Fiscus Financial also joined for the first time, adding to the original 2019 backing from Pfizer Ventures, BioMed Partners and Schroder Adveq.

Kite Pharma – Frank Neumann was named Global Head of Clinical Development at Kite Pharma, a subsidiary of Gilead Sciences. He replaces Ken Takeshita, who has decided to leave the company to pursue another opportunity at the end of February. Neumann, who joins Kite from Verastem, Inc. Prior to Verastem, he served as Head of Oncology Clinical Research at bluebird bio. He also held various leadership roles of increasing prominence at Takeda Pharmaceuticals, including global clinical lead or medical team lead roles for two distinct cancer therapies. Neumann has also been a member of the oncology medical teams at AstraZeneca and Sanofi-Aventis. Werewolf Therapeutics – Tim Trost was named chief financial officer of Werewolf. Trost joins Werewolf from Asklepios BioPharmaceutical, Inc. (AskBio), where he served as CFO until the company’s acquisition by Bayer AG in October 2020. Prior to AskBio, Trost was CFO of Chimerix, Inc. Before that, he was CFO at Argos Therapeutics, Inc. and CFO at InteCardia, Inc. He also previously held leadership roles with Coastal Physician Group, Inc. IN8bio – Patrick McCall was named CFO of IN8bio, Inc. Most recently, he was vice president of Finance at Turnstone Biologics. Prior to that, Mr. McCall was the Senior Director of Finance and Corporate Controller for Catalyst Biosciences, a publicly-traded biotechnology company. McCall held previous positions of increasing responsibility at Apple, Chubb and began his career as an auditor at the accounting firm Deloitte. Dyne Therapeutics – Ashish Dugar was named senior vice president, global head of medical affairs of Dyne Therapeutics. Prior to joining Dyne, Dugar served as vice president and global head of medical affairs at Sarepta Therapeutics, Inc. Previously, he led all commercial and market access efforts for Intra-Cellular Therapies, Inc. as vice president and head of commercial development. Before that, he held leadership roles at companies including Roche and Pfizer. Dugar began his career at the National Institutes of Health. Metrion Biosciences – John Montana was appointed as a non-executive director of the board of directors at Metrion. Montana is currently Operating Partner at Forbion, the life science venture capital firm. His previous roles have included Corporate Vice President, Integrated Drug Discovery, at Charles River Labs, as well as multiple C-suite positions such as CSO at Argenta, CEO of Amedis, Head of Chemistry at Chiroscience, and various roles at GlaxoSmithKline. Relief Therapeutics – Thomaz Burckhardt resigned from the board of directors to focus on other professional duties. The company will conduct a search for his replacement. Caribou Biosciences – Jason O’Byrne was named CFO of Caribou. O’Byrne most recently served as senior vice president of Finance at Audentes Therapeutics. O’Byrne led financial operations of the gene therapy company, including strategic financial planning, SEC reporting, treasury, tax and procurement. Prior to Audentes, O’Byrne spent 13 years at Genentech/Roche, most recently serving as APAC Regional CFO based in Singapore. Gemini Therapeutics – Brian Piekos was named CFO of Gemini Therapeutics. Piekos joins Gemini from AMAG Pharmaceuticals, where he was most recently CFO and Treasurer. Prior to joining AMAG, he held leadership roles in Corporate Finance, Tax and Treasury at Cubist Pharmaceuticals. Piekos began his career as a healthcare investment banker at Needham & Company and Leerink Partners, now SVB Leerink. Calyx – U.K.-based Calyx added Richard Wallace to its executive team. Wallace will serve as Chief Digital and Information Officer (CDIO). He will be responsible for delivering and leading a robust, scalable, and high-performing product technology organization at Calyx. Wallace joins Calyx from Kantar Media & Worldpanel, where he served as Chief Information Officer, and has held similar roles at IAG / British Airways, G4S, and Santander. Lyell Immunopharma -- Charlie Newton was named CFO of Bay Area-based Lyell. Previously, Newton co-headed BofA Securities’ healthcare investment banking practice in the Americas. He advised biotechnology companies on mergers, acquisitions and financings including initial public offerings, follow-on common stock offerings, convertible debt offerings, investment grade note offerings and private placements. FARE – Virginia-based FARE named Susan B. Ralston as Chief Revenue Officer. Ralston will replace Sherry Fazio, who announced she is returning to consulting. Ralston has worked with FARE in the past. Among other things, she helped design and build the Board of Governors and Board of National Ambassadors to better position FARE to rapidly respond in the evolving landscape of food allergy and support the organization's growth. Her career has included service as Special Assistant to President George W. Bush and was actively involved in the creation of the President’s Advisory Commission on Asian Americans and Pacific Islanders. Cerevance – Naidong Ye was named vice president and head of chemistry, manufacturing and controls (CMC) at Boston-based Cerevance. Prior to joining Cerevance, Ye served as vice president of CMC for Millendo Therapeutics. Before Millendo, Ye was senior director, head of CMC operations for AstraZeneca’s Neuroscience Innovative Medicines. Earlier in his career, Ye served as chief technology officer for Dongguan Jinmeiji Pharmaceutical Co., and held leadership positions as both a scientist and CMC lead at several life sciences companies, including Pharmos Corporation, ViroPharma and Nycomed. Flagship Pioneering – Diego Miralles was named CEO-Partner and CEO of LARONDE, a Flagship Pioneering company. Andrew Oh was named Senior Partner. Miralles is a veteran pharmaceutical and biotech leader who joins Flagship from Vividion Therapeutics, Inc. where he was CEO. Prior to this role, he was President of Adaptive Therapeutics. Miralles also spent eleven years at Johnson & Johnson, where he most recently served as Global Head of Johnson & Johnson Innovation. Oh brings more than two decades of finance and pharmaceutical experience and most recently served as CFO of Flagship-originated Rubius Therapeutics. Prior to Rubius, Oh spent a decade as a portfolio manager at Leerink and Fidelity. Antios Therapeutics – Patrick Higgins was named to the board of directors of Atlanta-based Antios Therapeutics, Inc. His most recent position was as chief operating officer for Arbutus Biopharma. In a prior role, he was a co-founder and CEO of OnCore Biopharma. Before OnCore, he served as executive vice president, Commercial, for Pharmasset. Retrotope – Rick E. Winningham was named chairman of the board of directors of California-based Retrotope. Winningham currently serves as chairman and CEO of Theravance Biopharma. Before Theravance, Winningham was president of Bristol Myers Squibb’s Oncology/Immunology/Oncology Therapeutics Network. Recro Pharma – James Miller was appointed to the board of directors of Pennsylvania-based Recro Pharma. Miller is founder and former president of PharmSource. Most recently, he has served on the advisory boards of Ajinomoto Biopharma Services and C-Squared Pharma. Miller was previously a consultant in corporate strategy at the Boston Consulting Group and an economist at The World Bank. Cellares Corporation – Rodney Rietze was appointed to the advisory board of Cellares. Rietze will provide insights and support to guide further development of Cellares’ next-generation cell therapy manufacturing solution. He is co-founder and CEO of iVexSol Inc. Prior to this, Rietze was the director of strategic development and innovation at Novartis. Penrose TherapeuTx – Bhardwaj Desai was named chief development officer of Michigan-based Penrose. Desai has been a hematologist and oncologist for 30 years and for the last 16 years has been a leader in oncology clinical drug development for top pharmaceutical companies including Astellas, Pfizer, Hospira and Abbott/AbbVie. Most Read Today