Isatuximab-IRFC

In September, Biogen named HI-Bio’s former chief medical officer, Uptal Patel, M.D., as leader of its new western outpost.\n On its face, Biogen’s May 2024 acquisition of Human Immunology Biosciences (HI-Bio) looks just like many other deals in the biopharma world. A $1.15 billion upfront payment to secure a phase 3-ready monoclonal antibody is notable, but hardly unprecedented. Most observers would expect Biogen to bring the late-stage prize into its pipeline and scrap the rest of the biotech\'s assets. But Biogen didn\'t do that. Instead, it decided to use the HI-Bio buy for more, morphing the absorbed biotech into a West Coast Hub that has restored the company’s presence in California and brought the pharma closer to its scientific origins. And, in September, Biogen named HI-Bio’s former chief medical officer, Uptal Patel, M.D., as leader of its new western outpost.Patel’s mandate is to lead an expansion into immunology, primarily through a trifecta of phase 3 trials for felzartamab, the anti-CD38 antibody that Biogen bagged by buying HI-Bio. But while felzartamab’s late-stage development “takes up most of the energy and oxygen,” Patel told Fierce in an interview, his team is also looking to expand the asset into new indications alongside other, earlier-stage candidates that Biogen has brought in, like a preclinical C5aR1 antagonist from Vanqua Bio.“Biogen has probably acquired a reputation for being a neuroscience-focused company, but really its roots are in immunology,” Patel said. The launch of the West Coast Hub has “catalyzed a doubling down” on that history.  Looking back to move ahead Since taking the helm of Biogen in November 2022, Christopher Viehbacher has aimed to spread the pharma’s wings and expand into new therapeutic areas beyond the neuroscience field that had once proved a fertile source of new medicines.“While we remain committed to neuroscience, my personal view is that is not diversified enough for a company of our size,” the CEO said in an April 2024 earnings call. “The reality of neuroscience is that this is a high-risk area.” This risk was clearly demonstrated when Biogen shelved three neuro programs due to a “lower quality of success” just before Viehbacher took over.By launching an immunology-focused West Coast Hub, Biogen hopes to channel the science that first sparked the company’s Swiss founding in 1978.“Early on, cytokine signaling, all sorts of pathways that were relevant to immune-related diseases, became important,” Patel explained to Fierce. “Then they became targets in the neuro-immunology space, particularly with multiple sclerosis.”Two of Biogen’s founding scientists went on to win the Nobel Prize: Walter Gilbert, Ph.D., in 1980 for developing DNA sequencing and Phillip Allen Sharp, Ph.D., in 1993 for the discovery of gene regions called introns.Biogen ran some of the first studies of an antibody targeting CD40, a well-known immunology target, as did Idec Pharmaceuticals, which merged with Biogen in 2003. But the trials of both companies’ assets were halted by the FDA due to a risk of dangerous blood clots.“They learned from that, developed better assets, and have found really promising molecules that I think have a huge opportunity,” Patel said.One of these molecules, dapirolizumab pegol, has been jointly developed with UCB since 2003 and is currently being tested in a pair of phase 3 trials for systemic lupus erythematosus.It was the Idec merger that originally gave Biogen a home in California, but the company shuttered the San Diego campus in 2010.“Since then, the biotech ecosystem in the Bay Area and California sort of matured, but there hasn\'t been a real West Coast presence for Biogen,” Patel said. “It was really intentional to not just acquire us and have our team stay intact and continue to work on the West Coast, but to really develop a presence for Biogen here in South San Francisco,” the leader explained.HI-Bio’s Bay Area digs were modest, Patel added, with the hub since expanding to occupy an entire floor of Gateway of the Pacific’s Traverse center. There, Patel’s team works closely with Biogen’s bicoastal immunology research unit, led by San Francisco-based Nick Wilson, Ph.D., and can also benefit from the local talent pool.“This provided an opportunity to tap into the fantastic research and basic science infrastructure and talent on the West Coast,” Patel said.The hub has now grown to about 120 employees, a company spokesperson told Fierce, and Biogen plans to double the office space by the end of 2026 to make room for the still-expanding team.And while some turnover is always expected when one company buys another, Patel said, more than 90% of HI-Bio staff were retained in the first year after the acquisition.“What began as a 50-person site to cultivate HI-Bio’s culture and capabilities has grown into a 100-plus employee hub,” Jane Grogan, Ph.D., Biogen’s head of research, told Fierce in a statement. “Having an outpost in the region broadens our ability to attract top talent and take advantage of new opportunities both within and outside our walls to accelerate innovation for our pipeline.” Test trifecta Biogen’s leadership is convinced Patel is the right person to guide the pharma’s foray into immunology.“Dr. Patel brings a unique combination of clinical, development and research expertise that has deepened our understanding of immune-mediated diseases and advanced promising science into registrational studies,” CEO Viehbacher told Fierce in a statement. “His leadership in building the teams and global infrastructure necessary to launch three phase 3 trials this year reflects the speed and scale at which we aim [to] advance our immunology pipeline,” the CEO added.Those three phase 3 trials are for felzartamab, the star asset of Biogen’s HI-Bio acquisition. The pharma’s Pacific Coast outpost is now leading studies of the anti-CD38 antibody in the kidney conditions immunoglobulin A nephropathy, primary membranous nephropathy and antibody-mediated rejection of kidney transplants.CD38 is a well-established target for multiple myeloma, with Johnson and Johnson’s Darzalex (daratumumab) and Sanofi’s Sarclisa (isatuximab-irfc) fixtures on the market. German biopharma MorphoSys originally developed felzartamab to compete in the myeloma arena. Celgene struck a deal for the antibody in 2013, but walked away less than two years later without saying why, though investors speculated Celgene was unimpressed by the asset’s phase 1 data. HI-Bio came knocking in 2022, licensing the ex-China rights to felzartamab and global rights to an anti-C5aR1 antibody except for greater China and South Korea. The company settles on felzartamab as its anti-CD38 choice after surveying the broader field, Patel said, and finding that MorphoSys’ candidate had the most compelling safety profile.“It was developed specifically for immune-related diseases, not people with myeloma,” Patel explained. While other anti-CD38 antibodies tend to destroy blood cells when given to macaques, felzartamab doesn’t, so MorphoSys was able to collect long-term preclinical safety data on its molecule.“That chronic safety package is really important, because some of these patients with immune diseases are younger and potentially have childbearing potential,” Patel said. Though Patel is convinced that felzartamab has best-in-class potential, the hub team is also working to fashion longer-lasting, more effective versions of the antibody that can be delivered subcutaneously.When it comes to felzartamab and the rest of the immunology program, the West Coast Hub has a certain level of autonomy from broader Biogen influence, Patel said. But when it comes to expanding the pipeline, those choices are made with input from the entire company.“We have to work closely and be aligned as an organization, with commercial, with business development, with the research and development organizations broadly,” Patel said. “Because I report to Chris, [who is] part of the team that\'s evaluating all of the company\'s portfolio, we\'re able to have those discussions as they come up.”It’s obvious what attracted Biogen to HI-Bio last year: a promising late-stage asset, deep expertise in immunology and the chance to reestablish a presence on the West Coast. But HI-Bio, too, has highlighted advantages to being acquired by the historic pharma.“What drew us to this acquisition by Biogen as a partner is their commitment to foundational science that really gets at the underlying causes of disease,” Patel said. Now “it\'s just a matter of having the kind of growth that everybody”—including patients, shareholders and the company itself—“wins from.”

一个曾经默默无闻的淋巴细胞表面标志物，如何成为多发性骨髓瘤的克星，并正在向自身免疫疾病和心脑共病领域拓展？CD38靶点药物的研发历程见证了医学研究的奇迹。1980年，科学家E.L. Reinherz和S.F. Schlossman首次发现CD38时，它只是作为胸腺细胞和活化T细胞的研究标记。近40年后，CD38靶向抗体已经彻底改变了多发性骨髓瘤等浆细胞疾病的治疗格局。如今，全球已有两款CD38靶点抗体药物获批上市——Darzalex（达雷妥尤单抗）和Sarclisa（Isatuximab）。其中达雷妥尤单抗更是销售额突破百亿美金的"重磅炸弹"药物，成为多发性骨髓瘤治疗的核心药物。 01 CD38的生物学特性与功能机制 CD38是一种45kDa的多功能跨膜糖蛋白，由300个氨基酸组成，最初被确定为淋巴细胞分化抗原。它在人体各种细胞类型上广泛分布，包括白血细胞、红血细胞、血小板、淋巴细胞、树突状细胞和内皮细胞等。CD38的主要功能是作为代谢酶催化烟酰胺腺嘌呤二核苷酸（NAD+）水解，同时合成环腺苷二磷酸核糖（cADPR）和烟酸腺嘌呤二核苷酸磷酸（NAADP）等第二信使。这些活性使CD38成为调控细胞内钙离子（Ca2+）稳态、NAD+代谢平衡、氧化应激和炎症反应的核心分子。CD38的表达不仅限于免疫细胞类型，如NK细胞、T细胞、B细胞、单核细胞、Treg细胞和Breg细胞，它还广泛表达于非造血组织，如心脏、大脑、胰腺和肺部。这使得CD38在多种生理和病理过程中发挥关键作用。 02 CD38靶点药物的作用机制 CD38靶向药物的作用机制主要包括两个方面：一是通过抑制CD38酶活性，减少生物活性物质的产生，从而影响钙离子平衡、细胞增殖、细胞凋亡、免疫调节等生物学过程；二是通过特异性结合CD38表面分子，诱导多发性骨髓瘤细胞凋亡和免疫细胞介导的细胞毒性。 以达雷妥尤单抗为例，它通过双重机制发挥治疗作用： (1) 一是直接与骨髓瘤细胞表面CD38结合，通过补体依赖的细胞毒性作用（CDC）、抗体依赖的细胞介导的细胞毒性作用（ADCC）和抗体依赖的细胞介导的吞噬作用（ADCP）、以及Fcγ受体介导的交联诱导凋亡的直接细胞毒性等多重机制直接杀死骨髓瘤细胞。 (2) 二是通过调节免疫微环境，使免疫抑制细胞Treg、Breg、MDSC逐渐耗竭，降低免疫抑制性CD38酶的活性、显著下调CD38+免疫抑制细胞、激活CD8+杀伤T细胞和CD4+辅助T细胞，进而两种T细胞协同作战，杀死骨髓瘤细胞。 03 CD38药物的发展历程 CD38药物的开发历程经历了从基础研究到临床应用的漫长道路： 早期发现阶段（1980-2005年） 1980年，CD38首次被科学家发现，最初用作胸腺细胞和活化T细胞研究的标记。在随后的二十多年里，研究人员逐渐认识到CD38在多发性骨髓瘤等肿瘤细胞上高表达，是多发性骨髓瘤细胞增殖和存活的重要因素。 药物开发阶段（2005-2015年） 2005年，达雷妥尤单抗成为CD38单抗候选抗体，是首个直接作用于骨髓瘤细胞的CD38单抗。基于临床试验的积极结果，2015年FDA批准兆珂®（达雷妥尤单抗）用于复发或难治性多发性骨髓瘤（R/R MM）治疗并成功上市。 适应症拓展阶段（2015年至今） 2018年，达雷妥尤单抗获FDA批准用于不适合自体干细胞移植的MM患者一线治疗。2019年，达雷妥尤单抗在中国首次获批单药治疗复发或难治性MM成年患者。近年来，CD38靶向治疗的应用进一步拓展到免疫球蛋白轻链（AL）淀粉样变性等疾病。更便捷的皮下注射剂型兆珂速®（达雷妥尤单抗注射液）也获批上市，将给药时间从几小时缩短到3-5分钟。 04 CD38药物在血液肿瘤领域的成就 CD38单抗在血液瘤领域应用成熟，取得了显著成就。全球已有两款CD38单抗上市——达雷妥尤单抗和伊莎妥昔单抗，用于治疗多发性骨髓瘤（MM）和免疫球蛋白轻链（AL）淀粉样变性等。达雷妥尤单抗在多发性骨髓瘤治疗中广泛获批，销售额突破百亿美金，且被纳入NCCN指南优先推荐。2022年全球销售额高达79.77亿美元，同比2021年增长了32.4%。如此迅猛的增长速度在血液肿瘤领域的治疗药物中并不常见，表现出达雷妥尤单抗在治疗浆细胞疾病中的重要作用和其巨大的临床需求。在AL淀粉样变性治疗中，达雷妥尤单抗联合方案可带来更优疗效。此外，CD38单抗在浆细胞白血病、前体T淋巴细胞白血病、慢性淋巴白血病等血液瘤中也展现出治疗潜力。 05 CD38药物在自身免疫疾病中的潜力 自身免疫领域是CD38单抗的新兴发展方向，展现出巨大的治疗潜力。基于CD38单抗对浆细胞的高效清除机制，其在自免领域也有较大的治疗潜力。 目前进度较快的适应症主要有： (1) 肾移植排斥：Felzartamab作为首个在晚期AMR中有效的CD38单抗，已开展III期临床，能缓解抗体介导的排斥反应。 (2) 膜性肾小球肾炎：Felzartamab的II期数据良好，已启动III期临床，可降低抗PLA2R抗体水平，稳定肾功能。 (3) IgA肾病：Felzartamab和Mezagitamab均有积极数据，能降低蛋白尿，稳定eGFR。 (4) 免疫性血小板减少：Mezagitamab和CM313后线治疗效果显著，可快速持续提升血小板水平。 (5) 系统性红斑狼疮（SLE）：CD38单抗能清除异常细胞，减少自身抗体，部分产品已开展相关临床。 06 CD38作为心脑共病新靶点的突破 近年来，科学家发现CD38可能在心脑交互调控中扮演关键角色，作为心脑共病的新靶点。CD38通过调控Ca2+信号、NAD+代谢、氧化应激和炎症反应参与心脑疾病的发生发展。 在心血管疾病方面，研究揭示了CD38在多类心脏病变中的关键作用： (1) 心肌缺血再灌注损伤模型中，CD38激活导致NADP(H)池耗竭，内皮依赖性舒张功能受损，而CD38敲除则通过激活SIRT1/FOXOs和Sirt3/FOXO3抗氧化通路发挥保护作用。 (2) 动脉粥样硬化形成过程中，CD38通过调节血管平滑肌细胞表型转换和巨噬细胞溶酶体胆固醇外流影响病变进展。 (3) 对于心力衰竭，CD38表达增加通过Ca2+-NFAT信号通路促进心肌肥厚和纤维化，而CD38抑制剂可改善血管重塑。 在神经系统疾病领域，CD38同样显示出多面性： (1) 多发性硬化症中，CD38是反应性星形胶质细胞中主要上调的NADase，其介导的NAD+消耗促进神经炎症和脱髓鞘过程。 (2) 抑郁症中，CD38表现出双重角色：一方面通过调节下丘脑催产素(OXT)释放影响社交行为和情绪反应；另一方面，在LPS诱导的抑郁模型中，CD38抑制通过改善神经炎症发挥抗抑郁作用。 (3) 对于阿尔茨海默病等认知障碍疾病，CD38缺失小鼠表现出淀粉样斑块减少和认知功能改善，提示其可能成为治疗靶点。 07 CD38靶向治疗的未来发展方向 CD38靶向治疗的未来发展方向包括多方面，展现出广阔前景。 新型抑制剂开发 目前CD38靶向药物主要分为四类：抗体类药物（如daratumumab和isatuximab）、NAD+类似物、黄酮类化合物（如木犀草素和芹菜素）以及噻唑并喹(氮杂)啉(酮)类化合物（如78c）。其中黄酮类化合物木犀草素能通过抑制CD38保护心脏免受缺血再灌注损伤，而78c则在心脑疾病模型中均显示出良好的保护效果。 联合治疗策略 CD38阻断可能与其他免疫检查点抑制剂（如抗CTLA-4抗体）或传统化疗药物产生协同作用，为联合治疗提供更多选择。特别是与PD-1/PD-L1抑制剂的联合使用，可能产生协同效应，提高治疗效果。 扩大适应症范围 随着对CD38作用机制理解的深入，其适应症范围可能进一步扩大。除了已经研究的癌症类型和自身免疫疾病外，CD38靶向药物可能应用于更多疾病领域，如心血管疾病、神经退行性疾病和代谢性疾病。 克服耐药性问题 近年来研究发现，CD38在第16位半胱氨酸上存在棕榈酰化修饰，该修饰可抑制泛素-蛋白酶体降解途径，显著提升CD38蛋白稳定性。基于这一发现，研究人员设计了靶向CD38棕榈酰化修饰的竞争性多肽CPPtat-S1，可显著降低CD38蛋白表达并抑制胰腺癌生长。这为克服CD38靶向治疗的耐药性问题提供了新思路。 08 中国在CD38研究中的贡献 中国研究人员和企业在CD38靶向治疗领域做出了重要贡献。温州医科大学附属眼视光医院团队揭示了腺苷代谢酶CD38棕榈酰化修饰的新机制，发现ZDHHC9和APT1分别为CD38棕榈酰化转移酶和去棕榈酰化酶。基于这一机制，他们设计了一种靶向CD38棕榈酰化修饰的竞争性多肽CPPtat-S1，该多肽通过阻断ZDHHC9与CD38的相互作用可显著降低CD38蛋白表达并抑制皮下模型中胰腺癌生长。多家国内创新药企业也在积极开发CD38靶向药物，如CM313等产品已在免疫性血小板减少等适应症中显示出良好的疗效和安全性。随着中国生物医药产业的快速发展，预计将有更多针对CD38的创新药物进入临床研究阶段，为全球CD38靶向治疗的发展贡献力量。 CD38靶点药物的开发历程体现了医学研究理念的演进——从单一疾病治疗到心脑共病整体调控的转变。从1980年发现至今，CD38已经从一个小小的淋巴细胞表面标志物，发展成为多领域疾病治疗的重要靶点。未来十年，随着对CD38信号通路理解的深入和新型抑制剂技术的不断发展，CD38靶向药物有望为肿瘤患者、自身免疫性疾病患者和心脑共病患者提供新的治疗选择，实现真正的精准医疗。 文章来源于网络、如有侵权请联系作者删除