Apoxis SA

Richard Davies, Deputy Chairman of Alvotech, elected as Chairman of the BoardGertjan Bartlema, formerly at Celgene and Amgen, appointed as Chief Executive OfficerPeter Greaney, formerly at ADC Therapeutics and Celgene, appointed as Chief Business OfficerAppointments add significant industry experience to accelerate development of lead asset IMM-101 and bring it to patients in need of effective therapies Uxbridge, UK – 10 May 2023 – Immodulon, a late-stage clinical company developing a highly differentiated cancer immunotherapy that primes the patient’s own innate immune system, today announces it has elected Richard Davies as Chairman of the Board and appointed Gertjan Bartlema as Chief Executive Officer and Peter Greaney as Chief Business Officer. This new team brings decades of industry experience from leading global pharmaceutical companies including Celgene, Amgen, Hospira, ADC Therapeutics and Alvotech. Their expertise will be crucial in guiding IMM-101 through late-stage clinical development and maximising its potential for patients. Richard Davies, Chairman of the Board, said: “I am excited to join Immodulon’s Board of Directors as Chairman at this pivotal time for the company. Immodulon has generated compelling Phase 2 data with IMM-101, which has the potential to make a real impact on the treatment of pancreatic cancer where patients have limited new treatment options. Gertjan and Peter are highly experienced biotech executives and I look forward to supporting them and the Board in realising IMM-101’s true potential, providing a new therapy for patients suffering from pancreatic cancer and maximising the return for investors.” Gertjan Bartlema, Chief Executive Officer of Immodulon, added: “Having joined the Immodulon Board last year, I am honoured to take on the role of leading the company towards its goal of improving outcomes for patients with pancreatic cancer. I am excited to work with the team to accelerate the clinical development of IMM-101 in combination with Abraxane (nab-paclitaxel) and gemcitabine. I’m inspired by this opportunity of making a meaningful impact with this potential new treatment regimen for patients suffering from pancreatic cancer.” Richard Davies Richard has over 30 years’ pharmaceutical industry experience and is currently Deputy Chairman of the Board of Directors for Alvotech. Richard served as CEO of BONESUPPORT AB, a public Scandinavian orthobiologics company, CEO of Auregen SA, a tissue engineering company and Chief Commercial Officer of Hospira, at the time the world’s largest injectable drug manufacturer, subsequently acquired by Pfizer. Additionally, Richard spent 9 years at Amgen in a range of senior management roles across various geographies after beginning his early career at Eli Lilly. Richard holds a BSc in Applied Chemistry from the University of Portsmouth and an MBA from the University of Warwick. Gertjan Bartlema Gertjan is a global biotech leader with over 25 years’ industry experience in finance, business development and operations. Most recently, Gertjan was CEO of VICO Therapeutics BV, a privately held Netherlands-based company. Prior to VICO, Gertjan spent 12 years at Celgene where he started as part of their initial European management team based in Switzerland. As a member of its New Jersey based corporate business development team, he played a key role in the acquisition of Abraxis BioScience, adding Abraxane to Celgene’s portfolio. Gertjan started his career at Amgen and over a 9-year period held various roles at its European (Switzerland) and corporate headquarters in the US. Gertjan holds an MSc in Economics from Maastricht University, Netherlands. Peter Greaney, PhD Peter is a highly experienced business development executive, with over 20 years’ international industry expertise. Previously, Peter served as Head of Corporate Development at ADC Therapeutics where he played an integral role transforming the company from a private R&D biotech to a NYSE-listed public biotech with a commercial therapeutic product. Prior to ADC Therapeutics, Peter spent 12 years at Celgene in a number of roles of increasing responsibility in Switzerland and the US across medical, commercial and business development and played a key role integrating Abraxane into the Celgene portfolio. Peter began his career as a Preclinical Senior Scientist at Apoxis. Peter holds a BSc in Cell Biology from the University of East Anglia and a PhD in Molecular and Cellular Biology from the University of Nottingham. -Ends - Notes to Editors About Immodulon Therapeutics LtdImmodulon is a late-stage clinical company developing a highly differentiated cancer immunotherapy approach that primes the patient’s own innate immune system with the aim to significantly enhance the efficacy of a broad range of anti-cancer therapies, including chemotherapy and checkpoint inhibitors. Immodulon is developing IMM-101, a heat-killed formulation of the mycobacterium M. obuense, as a broad-spectrum immunomodulatory agent that has promising potential in a range of difficult-to-treat tumours including those considered to be immunologically “cold,” such as pancreatic ductal adenocarcinoma. Immodulon has generated promising, positive Phase 2 data with IMM-101 in pancreatic cancer in combination with gemcitabine. These data show that IMM-101 is safe and effective, prolonging progression-free survival for a sub-group of patients with metastatic disease compared to gemcitabine alone. IMM-101 is due to enter a pivotal pancreatic cancer study. Contacts: ImmodulonGertjan Bartlema, CEOG.Bartlema@immodulon.comPeter Greaney, CBOP.Greaney@immodulon.com MEDiSTRAVA Consulting Frazer Hall, Sandi Greenwood, Eleanor Perkin Immodulon@medistrava.com+44 (0)203 928 6900

前言——NAMPT是个啥？NAMPT(Nicotinamide Phosphoribosyl Transferase，烟酰胺磷酸核糖转移酶)是NAD(Nicotinamide Adenine Dinucleotide，简称辅酶I)补救合成过程中的一个限速酶，它能催化烟酰胺（NAM）合成β-烟酰胺单核苷酸(NMN), NMN进而在NMNAT作用下转化为NAD。所以，NAM作为NAD的前体之一，在NAM转化为NAD的过程中，如果对NAMPT酶进行抑制，导致NAM无法合成NMN，最终导致NAD的合成受限。NAD是一种转递质子的辅酶，参与细胞物质代谢、能量合成、DNA修复等多项重要生理活动，维持足够的细胞内NAD含量对于所有细胞的存活至关重要，肿瘤患者体内细胞内与细胞外NAMPT均比正常对照有明显升高。 2018年Seagen探索了NAMPT抑制剂作为payload的可能性，相关结果发表在2018年的AACR会议上。近期，拜耳科学家在Bioconjugate Chemistry期刊上也发表了利用NAMPT抑制剂作为payload的研究文章。本篇我们主要以拜耳的这篇paper为主线对NAMPT抑制剂的payload平台做以解析，另外用Seagen的数据作为补充。01 先初步设计3种不同的liner-payload看看效果首先设计了EC1-EC3 3个linker-payload,母核结构如下：具体的结构如下图，linker接头均采用马来酰亚胺的接头，linker和payload之间我自己用红色的线给隔开，其中EC1和EC2为不可裂解linker；EC3采用的为mc-VA的酶切型linker，payload和EC1一样。接下来同时在C4.4a、HER2、B7H3 3个靶点上进行了开发。细胞活性上：payload相同的情况下，可裂解的linker EC3细胞活性明显好于不可裂解的linker EC1。关于细胞活性，小编补充：ADC细胞杀伤活性的检测，文献大多采用CTG试剂盒进行检测，其原理是基于细胞内ATP的水平；其实检测细胞活性的方法非常多，基于的原理也千差万别，拜耳的检测也是用的CTG的试剂盒，但Seagen在2018年的文献中提过，该方法做出的ADC的in vitro体外活性数值和in vivo动物药效并不完全一致，反而是以NAD水平的检测方法与in vivo动物药效对应关系更好。拜耳的科学家在此步检测时用的基于ATP水平的CTG检测法，但在单独筛选payload和后续优化ADC后也均采用两种指标同时作为检测手段，这提示研发人员一定要深刻的理解自己所研究药物发挥作用的机制，从而开发适合自己的活性assay，准确可靠的体外活性assay往往能事半功倍。02  基于药代进一步优化liner-payload 对EC3偶联的ADC进行了药代分析，发现除了本身的毒素Compound4外，还存在完整的linker-payload p-14,以及衍生出来的其他磷酸化产物。于是，接着优化第一步：更改linker,避免毒素部分过早的从抗体上发生解离。因为环状的MC接头在体内容易被带有巯基的抗体或者蛋白取代（发生交换反应），改成带负电的线性succinic amide接头后则不再与其他巯基交换，理论上药代上性质会更稳定，于是产生了EC4；第二步：降低代谢物旁观效应，扩大安全窗口。在EC4的基础上，payload上增加了一个喹啉基团，同时辅以PEG链增加水溶性帮助获得更高DAR值，产生了EC5。细胞活性上看，不管是单独的payload还是偶联成ADC后，EC5并没有取得意想中的效果，于是后续用EC4偶联的ADC进行体内药效评价。值得一提的是，EC4偶联的B7-H3-EC4，细胞活性的IC50可达低至7pM的水平，而HER2-EC4的IC50更是在0.3pM以下。03 in vivo动物药效 B7H3 ADC（DAR=7.8）治疗组，5 mg/kg剂量下, 7day一次，给药3次，7只小鼠中6只肿瘤完全消失，1只肿瘤缩小。此外，动物的体重也稳步上升，提示较好的安全性。HER2 ADC（10 mg/kg剂量下, 7day一次，共给药7次），治疗后7只小鼠肿瘤全部缩小（T/C=0.13），且停止治疗后肿瘤没有重新生长。C4.4a治疗组（10 mg/kg剂量下, 7day一次，共给药7次），8只小鼠中3只小鼠肿瘤缩小，5只小鼠疾病稳定（SD）。另外，该两组动物体重均有不同程度的下降，这个跟给药剂量和给药次数过多可能有关系，但同时也表明存在潜在的有效性风险。小编补充：MDA-MB-453细胞系是同时表达HER2和C4.4a的，HER2的表达量为C4.4a的4倍（80,000 antigen/cell VS 20,000 antigen/cell ）,此处也能看出，抗原表达量更高时，药效确实会更好。04 NAMPT抑制剂开发状况 目前针对NAMPT抑制剂已有两款小分子处在临床阶段，padnarsertib（KPT-9274，由Karyopharm Therapeutics Inc开发，国内徳琪医药合作开发，目前处于临床II期）；OT-82（由OncoTartis Inc开发，目前处于临床I期）。而在此之前也曾有过针对NAMPT抑制剂开发的尝试，比如由Apoxis 开发的daporinad（APO-866）在细胞活性上IC50上可达1nM，但后来在连续三项分别针对B细胞慢性淋巴细胞白血病 (B-CLL) 、皮肤T细胞淋巴瘤(CTCL)、黑色素瘤的临床中均折戟沉沙。nM这个水平的细胞活性，单独用作化药治疗会因为毒性太强导致安全窗口过窄而做不出有效性，但作为ADC payload来用的话或许是大有空间的。另外，关于NAMPT抑制剂，此处我能想到的一个潜在风险是，抑制了NAD的补救合成途径后，其他旁路途径是否还可以作为补充，以及补充的效果如何仍待仔细研究一下，具体临床效果怎么样，还需期待拜耳的后续。参考文献[1] Sampath, Deepak, Misner, et al. Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) as a therapeutic strategy in cancer, 2015.[2] Valentina, Audrito, Antonella, et al. Targeting metabolic reprogramming in metastatic melanoma: the key role of nicotinamide phosphoribosyltransferase (NAMPT), 2019.[3] Niels Böhnke, Markus Berger, Nils Griebenow, et al. A Novel NAMPT Inhibitor-Based Antibody− Drug Conjugate Payload Class for Cancer Therapy, 2022. （拜耳paper）[4] Neumann C S , Olivas K C ,Anderson M E , et al. Targeted Delivery of Cytotoxic NAMPT Inhibitors Using Antibody-Drug Conjugates, 2018. （Seagen paper）识别微信二维码，添加生物制品圈小编，符合条件者即可加入微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。