SHIP1

Pictured: Flames attacking a brain/Nicole Bean for BioSpace Alois Alzheimer recognized more than a century ago the role of neuroinflammation in the development of the disease that would bear his name. “If you actually go back to his original drawings, he was drawing the cells, which today we know are microglia,” immune cells of the brain, said Bruce Lamb, executive director of the Paul and Carole Stark Neurosciences Research Institute at Indiana University School of Medicine and co-founder of Monument Biosciences, which is exploring neuroinflammation-targeted Alzheimer’s treatments. “So, he recognized way back, 120 years ago, that these cells were there” and that they could be playing a role in the disease process. Several studies have established a link between neuroinflammation and Alzheimer’s disease, and the culprit indeed appears to be microglia. “I think it’s very clear that, at least the minute amyloid is deposited in the brain and maybe even before, there’s a microglial response,” Lamb told BioSpace. And it’s this immune response that could be causing problems with neuronal function. Lamb said that over the last decade and a half, there has been a renewed interest in the role of microglia in Alzheimer’s, spurred in part by discoveries in the genetics of late-onset Alzheimer’s disease. Genome-wide association studies and the identification of rare mutations that occur in families have led to a list of Alzheimer’s-associated genes, and most of these are expressed in microglia, Lamb said. Meanwhile, transcriptomics, proteomics and metabolomics data from human cases and controls have revealed similar findings, he added. “A lot of the networks and pathways that are disturbed, especially in late-onset Alzheimer’s disease, are in these inflammatory networks.” Targeting TREM2 and More Working under the hypothesis that neuroinflammation contributes to the Alzheimer’s disease process, biotech companies are exploring different targets. Vigil Neuroscience is developing a candidate based on the role of TREM2-mediated microglial dysregulation in the disease process. Also targeting TREM2 is Alector Therapeutics, which describes its strategy as immuno-neurology. TREM2 is expressed on microglia in the brain, but it is really only expressed in response to amyloid deposits, Lamb explained. There is a signaling cascade downstream of TREM2 within the microglia, “and a lot of the other genes that are implicated in Alzheimer’s disease are also in microglia downstream of TREM2,” he said. At his own company, Lamb added, the team is initially targeting the PLCG2 and INPP5D genes, both of which are downstream of TREM2 and also have genetic associations with Alzheimer’s disease. Boston–based Cerevance is targeting a different gene, KCNK13, which is specific to and upregulated in the microglia. While others are also going after the NOD-like receptor protein 3 (NLRP3) inflammasome, Cerevance is looking to regulate inflammation only in the central nervous system, leaving peripheral immune cells ready and able to fight opportunistic infections, said CEO Craig Thompson. This is particularly important in Alzheimer’s, he added, because the patients tend to be older and frail. “Our thought was, is there a way to damped down the inflammation on the inflammasome but still [leave] other aspects of the NLRP3 that are helpful for normal immune system functioning?” In preclinical models, the company’s KCNK13-targeting asset, CVN293, had minimal impact on the peripheral immune system while reducing neuroinflammation in the brain, Thompson explained. Cerevance has shown that “we can tamp down the inflammation response, or the inflammasome, but keep all the other surveillance and other aspects of microglia still functioning as they should.” The company is now conducting a Phase I study of CVN293, with topline data expected in the second quarter of 2024. In Ohio, biotech NeuroTherapia was co-founded by anesthesiologist Mohamed Naguib, who found that microglia upregulated the cannabinoid type 2 (CB2) receptor, CEO Tony Giordano relayed in an interview with BioSpace. Naguib further found that “CB2 agonists were able to shift the microglia . . . from a proinflammatory phenotype to an anti-inflammatory phenotype,” which improved amyloid clearance and neuronal function in preclinical models, Giordano said. NeuroTherapia is developing a CB2 receptor agonist for Alzheimer’s disease called NTRX-07, which Giordano expects to enter Phase II trials in the third quarter of this year. “We believe that it’s the continued activation of the microglia and the production of the proinflammatory cytokines that starts to interfere with synaptic transmission and neuronal function,” Giordano explained. “Fortunately, it appears that if you can stop that activity, you’re going to get improvement in neuronal function.” A Multipronged Attack Ultimately, Giordano and Thompson agreed that treating Alzheimer’s disease will require a multifaceted attack. “Alzheimer’s is a very, very complex disease, and you’re not going to treat it with a single agent,” Giordano said. “It’s likely that you’re going to put together a cocktail and we really believe that neuroinflammatory inhibitors are going to be a part of that cocktail.” Thompson called Alzheimer’s “more of a constellation of diseases” and said that tackling it from multiple approaches will be “really important.” He teased that Cerevance is also looking at other approaches with some of its earlier compounds. While he wouldn’t reveal the targets, he said that, like KCNK13, “they’re very novel approaches.” Lamb added that anti-amyloid antibodies, including Eisai and Biogen’s Leqembi, appear to be working primarily through the microglia. “The microglia have these FC receptors which bind to the antibodies and then can actually remove amyloid from the brain,” he said. Amyloid-related imaging abnormalities (ARIA) has been the primary smudge on the surface of drugs like Leqembi and Eli Lilly’s donanemab. Lamb explained that this side effect is thought to be an inflammatory process. “We think it’s amyloid binding to blood vessels where there’s amyloid and that that is actually recruiting immune cells and leading to where there’s an immune dysfunction.” Accordingly, he said, there is a lot of interest in combination therapies with monoclonal antibodies and drugs targeting microglia “to either improve the removal of amyloid, or even better, prevent some of these side effects that are seen with these antibodies.” When asked which approach is most likely to lead to the next Alzheimer’s breakthrough, Lamb acknowledged he is biased, but said, “I certainly think the immune pathways . . . are near the front of that sort of discussion.” Heather McKenzie is a senior editor at BioSpace. You can reach her at heather.mckenzie@biospace.com. Also follow her on LinkedIn.

Investigators revealed how genetic changes in certain types of brain cells may contribute to the inflammatory response seen in Alzheimer's disease. Study by Brigham investigators revealed how genetic changes in certain types of brain cells may contribute to the inflammatory response seen in Alzheimer's disease Immune-regulating brain cells known as microglia are known to play a role in the progression of Alzheimer's disease (AD). A new study by investigators from Brigham and Women's Hospital, a founding member of the Mass General Brigham healthcare system, explores how the genetics of microglia contribute to neuroinflammation and, in turn, AD. The team revealed that a reduction of INPP5D, a gene found in microglia, results in neuroinflammation and increases the risk for AD. Their results, which have important implications for the design of microglia-centered therapeutics for Alzheimer's disease and related disorders, are published in Nature Communications. "We know that microglia play important roles in the healthy and diseased brain, but, in many cases the molecular mechanisms underlying this relationship are poorly understood," said corresponding author Tracy Young-Pearse, PhD, from the Department of Neurology at Brigham and Women's Hospital. "If we're able to identify and understand the significance of specific genes that play a role in neuroinflammation, we can more readily develop effective, targeted therapeutics." Neuroinflammation is important to monitor in people with neurodegenerative diseases, but it can be difficult to detect, especially in the early stages of AD. The earlier neurologists can identify it, the earlier they can treat it. Microglia are clearly involved in the process of neuroinflammation, but there are many unanswered questions regarding the molecular pathways involved. The team used a variety of experimental approaches to probe the relationship between levels of INPP5D and a specific type of brain inflammation, activation of the inflammasome. As part of their study, the team compared human brain tissue from patients with AD and a control group. They found lower levels of INPP5D in the tissues of patients with AD and when INPP5D was reduced, it activated inflammation. In parallel, they used living human brain cells derived from stem cells to study the intricate molecular interactions within microglia that mediate inflammatory processes with a reduction of INPP5D. These studies identified specific proteins that could be inhibited to block inflammasome activation in microglia. Although the team's work represents the most comprehensive analysis of INPP5D in the AD brain, it remains to be determined whether INPP5D should be targeted with therapeutics. The team notes that their findings suggest INPP5D activity in AD brains is complex and future studies are needed to understand if INPP5D can be targeted to prevent cognitive decline in patients with AD. "Our results highlight an exciting promise for INPP5D, but some questions still remain," said Young-Pearse. "Future studies examining the interaction between INPP5D activity and inflammasome regulation are essential to improve our understanding of microglia in AD and to help develop a comprehensive toolbox of therapeutics that can be deployed to treat each of the molecular roads that lead to AD."

截至目前，全球已上市的作用于CD22靶点的药物有两种活性成分，inotuzumab ozogamicin（奥加伊妥珠单抗）和moxetumomab pasudotox，具体药物信息如下表所示。表1 全球已上市作用于CD22靶点的药物情况数据来源：药智数据，药智咨询整理奥加伊妥珠单抗是全球首个用于治疗复发性或难治性前体B细胞ALL的靶向CD22的ADC；而以moxetumomab pasudotox为活性成分的药物Lumoxiti于2018年9月在美国上市，用于治疗复发或难治性毛细胞白血病（hairy cell leukemia，HCL）。除已批准上市药物外，国内注册申报的以CD22为靶点的药物信息如下表所示。其中CD22单抗的主要布局企业有优时比和深圳龙瑞；此外，还有作用于CD22的双抗在研药物。表2 CD22靶点药物国内注册申报情况注：（1）此表不含申请类型为补充申请、复审、进口再注册的注册申请。（2）-：为在审评中。数据来源：药智数据，药智咨询整理热门靶点CD22的作用机制CD22是一种分子量为135kD的细胞表面跨膜唾液糖蛋白，属于免疫球蛋白超家族。CD22在骨髓（BM）和脾脏B细胞个体发育的早期阶段表达，也由分离自不同淋巴区室的B淋巴细胞表达。CD22在60%-90%的B-ALL个体中表达，并在与抗原结合时迅速内化，因此，CD22成为细胞毒性药物的有效切入点。CD22在活化B淋巴细胞的细胞表面表达上调，并存在于前体B细胞（pro-B和pre-B淋巴细胞）的细胞质中。当抗原提呈细胞（APC）表达的唾液酸（Sialic acid）与CD22结合时，免疫受体酪氨酸抑制基序（ITIMs）的酪氨酸残基被磷酸化。磷酸化的ITIMs连接到Src同源2域的磷酸酶-1和-2（SHP-1和SHP-2）和Src同源2域的肌醇磷酸酶-1（SHIP-1），诱导B细胞受体（BCR）介导的信号转导下调。其具体作用机制如图1所示。图1 人类CD22结构、相互作用和生物活性图片来源：参考资料1靶向CD22 ADC：奥加伊妥珠单抗奥加伊妥珠单抗（Inotuzumab Ozogamicin）是由辉瑞公司（Pfizer Inc.）开发的一种靶向CD22的抗体-药物偶联物（antibody-drug conjugate,ADC），由三个部分组成：①重组人源化免疫球蛋白G亚型4（IgG4）kappa抗体伊珠单抗，可特异性识别人CD22；②N-乙酰-γ-刺孢霉素，可导致双链DN断裂；③可酸解的连接子，由4-(4'4-乙酰苯氧基)-丁酸（AcBut）和3-甲基-3-巯基丁烷酰肼（被称为二甲酰肼，将N-乙酰-γ-刺孢霉素与伊珠单抗共价结合）组成。图2 奥加伊妥珠单抗化学结构式图片来源：参考资料2非临床数据表明，由于ADC可与表达CD22的肿瘤细胞结合，进而实现ADC-CD22复合物内化，通过水解断开连接子，随后在细胞内释放出N-乙酰基-γ-刺孢霉素二甲基酰肼。N-乙酰-γ-刺孢霉素二甲酰肼的活化可诱导双链脱氧核糖核酸（DNA）断裂，然后促使细胞周期停滞和细胞凋亡，因此奥加伊妥珠单抗具有抗癌活性。图3 奥加伊妥珠单抗在肿瘤细胞中的作用机制图片来源：参考资料3一项纳入了326例复发性或难治性B-ALL成人患者的全球、开放标签、随机对照Ⅲ期临床试验结果显示，与标准疗法（标准强化化疗）相比，奥加伊妥珠单抗组的完全缓解率（CR）更高(80.7%[95%CI,72.1-88.7]vs.29.4%[95%CI,21.0-38.8],P<0.001)；在取得完全缓解的所有患者中，接受奥加伊妥珠单抗治疗的患者其最小病灶残留（MRD）的阴性率也更高（78.4%vs.28.1%,P<0.001）；无进展生存期(5.0个月[95%CI,3.7-5.6]vs.1.8个月[95%CI,1.5-2.2],风险比0.55(95%CI,0.31–0.96),P=0.03)和总生存期更长(7.7个月[95%CI,6.0-9.2]vs.6.7个月[95%CI,4.9-8.3],风险比0.45(97.5%CI,0.34–0.61),P<0.001)[3]。奥加伊妥珠单抗最早于2017年6月28日获欧盟药物管理局（EMA）批准上市（EMEA/H/C/004119），商品名为BESPONSA，作为单药用于治疗复发性或难治性CD22阳性前体B细胞急性淋巴细胞性白血病（ALL）成人患者。2017年8月17日获美国FDA批准（761040）用于治疗复发性或难治性前体B细胞ALL成人患者。2021年12月20日获中国国家药品监督管理局（NMPA）批准（国药准字SJ20210033），用于复发性或难治性前体B细胞ALL成年患者。表3 奥加伊妥珠单抗上市历程数据来源：药智数据，药智咨询整理ALL&现有治疗手段急性淋巴细胞白血病（Acute Lymphoblastic Leukemia,ALL）是一种血液恶性肿瘤，由于淋巴母细胞增殖失控分化受阻，导致其在骨髓和延髓外的累积，进而抑制正常造血。在大多数情况下，ALL的原因是未知的，但也有一些已知的危险因素，包括一些以DNA修复机制损伤为特征的疾病（如共济失调-毛细血管扩张症）以及唐氏综合征。此外，受到放射性辐射和暴露于骨髓毒性化学物质，如氯霉素或苯唑，也会促进ALL的发展。《中国成人急性淋巴细胞白血病诊疗指南（2021年版）》中指出，急性淋巴细胞白血病（ALL）是成人最常见的急性白血病之一，约占成人急性白血病的20%-30%[5]。虽然初治成人ALL患者在多药联合化疗后完全缓解（Complete Remission,CR）率可达80%以上，但大多数患者最终出现复发，５年的长期生存率仅有20%-40%[6]。根据免疫表型，ALL可分为急性B淋巴细胞白血病（B-ALL）和急性T淋巴细胞白血病（T-ALL）两种，其中B-ALL占60%-70%[7]。根据白血病细胞的抗原表达特征，B-ALL可分为前期B-ALL（Pro-B）、普通型B-ALL（Commom-B）、前B-ALL（Pre-B）和成熟B-ALL（Mature-B），一般将前3种分型统称为前体B细胞急性淋巴细胞白血病（BCP-ALL）。成人B-ALL现有治疗手段如图4所示。图4 成人急性B淋巴细胞白血病治疗综述图片来源：参考资料1结语在世界各国，癌症是死亡的主要原因，也是延长预期寿命的一个重要阻碍。近年来，随着肿瘤免疫研究的深入，免疫治疗，包括单克隆抗体治疗和细胞治疗等在肿瘤治疗中越来越受到关注。奥加伊妥珠单抗作为全球首个用于治疗复发性或难治性前体B细胞ALL的靶向CD22的ADC，为患者带来更多的选择。我们期待有更多新的治疗药物和手段来满足目前肿瘤治疗中尚未满足的临床需求。参考资料：[1]Lanza F,Maffini E,Rondoni M,Massari E,Faini AC,Malavasi F.CD22 Expression in B-Cell Acute Lymphoblastic Leukemia:Biological Significance and Implications for Inotuzumab Therapy in Adults.Cancers(Basel).2020 Jan 28;12(2):303.doi:10.3390/cancers12020303.[2]奥加伊妥珠单抗美国说明书[3]Yurkiewicz IR,Muffly L,Liedtke M.Inotuzumab ozogamicin:a CD22 mAb-drug conjugate for adult relapsed or refractory B-cell precursor acute lymphoblastic leukemia.Drug Des Devel Ther.2018 Jul 24;12:2293-2300.doi:10.2147/DDDT.S150317.[4]Kantarjian HM,DeAngelo DJ,et al.Inotuzumab Ozogamicin versus Standard Therapy for Acute Lymphoblastic Leukemia.N Engl J Med.2016 Aug 25;375(8):740-53.[5]中国成人急性淋巴细胞白血病诊断与治疗指南（2021年版）[J].中华血液学杂志,2021,42(9):705-716.[6]梁爱斌,李萍.成人急性淋巴细胞白血病诊断与治疗中国指南2021年版解读（Ph阴性，非复发难治部分）[J].临床血液学杂志,2022,35(03):165-167.DOI:10.13201/j.issn.1004-2806.2022.03.003.[7]张叶.急性B淋巴细胞白血病关键基因筛选及GPSM1基因在急性B淋巴细胞白血病中的生物学功能研究[D].中国医科大学,2021.声明：本内容为作者独立观点，不代表药智网立场。如需转载，请务必注明文章作者和来源。对本文有异议或投诉，请联系maxuelian@yaozh.com。责任编辑 | summer转载开白 | 马老师 18996384680（同微信）商务合作 | 王存星 19922864877（同微信） 阅读原文，是受欢迎的文章哦