This phase 1 study will evaluate a novel hEGFRvIII-CD3-biscFv Bispecific T cell engager (BRiTE) in patients diagnosed with pathologically documented World Health Organization (WHO) grade 4 malignant glioma (MG) with an EGFRvIII (epidermal growth factor receptor variant III) mutation (either newly diagnosed or at first progression/recurrence). The primary objective is to evaluate the safety of BRiTE in such patients.

开始日期2026-12-01

申办/合作机构

Duke University

NCT06337318 / Recruiting临床3期IIT

Randomized Phase III Study of Mosunetuzumab vs. Rituximab for Low Tumor Burden Follicular Lymphoma

This phase III trial compares the effectiveness of rituximab to mosunetuzumab in treating patients with follicular lymphoma with a low tumor burden. Rituximab is a monoclonal antibody. It binds to a protein called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. Mosunetuzumab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. It is not yet known if giving rituximab or mosunetuzumab works better in treating patients with follicular lymphoma with a low tumor burden.

开始日期2025-04-28

申办/合作机构

National Cancer Institute

NCT06563596 / Not yet recruiting临床2期IIT

A Phase 2 Study of Epcoritamab, Zanubrutinib, and Rituximab (EZR) for Treatment of Relapsed or Refractory Follicular Lymphoma

The purpose of this study is to determine how effective and safe the combination of epcoritamab, zanubrutinib, and rituximab is in treating participants with relapse or refractory Follicular Lymphoma (FL).
* The names of the study drugs involved in this research study are:
* Epcoritamab (a type of antibody)
* Zanubrutinib (a type of Bruton tyrosine kinase inhibitor)
* Rituximab (a type of monoclonal antibody)

开始日期2025-02-01

申办/合作机构

Dana-Farber Cancer Institute, Inc.

[+2]

100 项与 CD3 相关的临床结果

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100 项与 CD3 相关的转化医学

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46,967

项与 CD3 相关的文献（医药）

2025-01-01·JOURNAL OF ETHNOPHARMACOLOGY

Periostracum Cicadae exhibits immunosuppressive effects on dendritic cells and contact hypersensitivity responses

Article

作者: Chen, Chao-Jung ; Chang, Wen-Te ; Lin, Ming-Kuem ; Lee, Meng-Shiou ; Lin, Wen-Hsin ; Chen, Pin-Wen ; Chuang, Cheng-Hsuan

ETHNOPHARMACOLOGICAL RELEVANCE:

Periostracum Cicadae (PC), the molted exoskeleton of the cicada Cryptotympana pustulata Fabricius, is frequently employed in Chinese herbal medicine. Based on traditional therapies and pharmacological studies, PC appears to have immunomodulatory activity. However, the specific impact of PC on immunomodulation, particularly its effect on dendritic cells (DCs), remains unknown. DCs act professionally as antigen-presenting cells that trigger adaptive immune responses, making them critical for immunomodulation.

MATERIALS AND METHODS:

The DCs derived from mouse bone marrow were used to examine the suppressive effect of PC extract on DC activation and maturation. The in vivo suppressive effect was evaluated using a mouse model of contact hypersensitivity (CHS) responses. The determination of the substances in the sample was performed by Liquid chromatography-mass spectrometry/mass spectrometry.

RESULTS:

The ethyl acetate extract of PC (PCEA) significantly decreased the expressions of proinflammatory cytokines (IL-12, interleukin [IL]-6, as well as tumor necrosis factor [TNF]-α) and surface markers CD80 and CD86 in lipopolysaccharide-stimulated DCs. In the 2,4-dinitro-1-fluorobenzene-induced CHS mouse model, PCEA treatment dramatically attenuated the severity of symptoms. This was evidenced by the alleviation of ear swelling and a reduction in the count of infiltrating CD3⁺ T cells in the tested ears. In addition, N-acetyldopamine dimer and trimer were identified as major components.

CONCLUSION:

This study is the first to show that components derived from PCEA inhibit the activation and maturation of DCs as well as CHS responses, indicating they have the potential for treating delayed-type hypersensitivity or DC-related immune disorders.

2024-12-31·The veterinary quarterly

Tertiary lymphoid organs in wild boar exposed to a low-virulent isolate of African swine fever virus

Article

作者: Barasona, José Á ; Porras, Néstor ; Rodríguez-Bertos, Antonio ; Kosowska, Aleksandra ; Sánchez-Vizcaíno, José M

Despite the great interest in the development of a vaccine against African swine fever (ASF) in wild boar, the immunological mechanisms that induce animal protection are still unknown. For this purpose, tertiary lymphoid organs (TLOs) of wild boar were characterised and compared with mucosa-associated lymphoid tissues (MALTs) by histopathology, histomorphometry and immunohistochemistry (CD3, CD79, PAX5, LYVE1, fibronectin). In addition, real-time polymerase chain reaction (qPCR) and immunohistochemistry (p72) were used to evaluate the presence of ASF virus (ASFV) in blood and tissues samples, respectively. TLOs were observed in animals infected with a low-virulent ASFV isolate (LVI), animals co-infected with low and high-virulent ASFV isolates (LVI-HVI) and animals infected only with the high virulence isolate (HVI). TLOs in LVI and LVI-HVI groups were located adjacent to the mucosa and presented a similar structure to MALT. Immunoexpresion of p72 observed in the inflammatory cells adjacent to TLOs/MALTs confirmed its development and reactivity generated by ASF attenuated isolates. Immunohistochemical evaluation, based on cellular composition (T and B lymphocytes), and histomorphometrical study revealed a more pronounced maturation of TLOs/MALTs in the LVI-HVI group. It is currently unclear whether these formations play a protective role by contributing to local immunity in chronic inflammatory diseases. However, the structural similarities between TLOs and MALTs and the location of TLOs close to the mucosa suggest that they may perform a similar function, facilitating a local protective response. Nevertheless, further investigations are warranted to assess the cellular and humoral dynamics of these lymphoid organs induced by attenuated isolates.

2024-12-31·OncoImmunology

Selective lysis of acute myeloid leukemia cells by CD34/CD3 bispecific antibody through the activation of γδ T-cells

Article

作者: Witsen, Maartje ; Stikvoort, Arwen ; Hahn, Paula ; Önfelt, Björn ; Jaramillo, Adrian C ; Al Agrafi, Faisal ; Gaballa, Ahmed ; Lehmann, Sören ; Arruda, Lucas C M ; Uhlin, Michael

Despite the considerable progress in acute myeloid leukemia (AML) treatment, relapse after allogeneic hematopoietic stem cell transplantation (HSCT) is still frequent and associated with a poor prognosis. Relapse has been shown to be correlated with an incomplete eradication of CD34+ leukemic stem cells prior to HSCT. Previously, we have shown that a novel CD34-directed, bispecific T-cell engager (BTE) can efficiently redirect the T-cell effector function toward cancer cells, thus eliminating leukemic cells in vitro and in vivo. However, its impact on γδ T-cells is still unclear. In this study, we tested the efficacy of the CD34-specific BTE using in vitro expanded γδ T-cells as effectors. We showed that the BTEs bind to γδ T-cells and CD34+ leukemic cell lines and induce target cell killing in a dose-dependent manner. Additionally, γδ T-cell mediated killing was found to be superior to αβ T-cell mediated cytotoxicity. Furthermore, we observed that only in the presence of BTE the γδ T-cells induced primary AML blast killing in vitro. Importantly, our results show that γδ T-cells did not target the healthy CD34^intermediate endothelial blood-brain barrier cell line (hCMEC/D3) nor lysed CD34+ HSCs from healthy bone marrow samples.

3,292

项与 CD3 相关的新闻（医药）

2024-09-21

·GlobeNewswire-Health Care

Tiziana Life Sciences Announces $4 Million Grant Awarded by National Institutes of Health to Study Anti-CD3 in Alzheimer’s Disease

Sept. 19, 2024 -- Tiziana Life Sciences, Ltd. (Nasdaq: TLSA) (“Tiziana” or the “Company”), a biotechnology company developing breakthrough immunomodulation therapies with its lead development candidate, intranasal foralumab, a fully human, anti-CD3 monoclonal antibody, today announced the National Institutes of Health (NIH), National Institute on Aging have awarded a $4 Million grant to Dr. Howard Weiner as principal investigator at Brigham and Women’s Hospital to be the key research site, to study nasal anti-CD3 for the treatment of Alzheimer’s disease (AD). This significant grant will fund a key research study over the next several years, advancing preclinical and ultimately, clinical studies of intranasal anti-CD3 as a potential treatment for this devastating neurodegenerative condition. “Alzheimer’s disease is the most common form of dementia, affecting more than 6 million people in the United States alone. Despite extensive research, effective treatments remain limited, and the need for innovative therapeutic approaches is urgent,” commented Howard L. Weiner, M.D., Principal Investigator, Chairman of Tiziana’s Scientific Advisory Board and co-director of the Ann Romney Center for Neurologic Diseases at Brigham and Women’s Hospital, a founding member of Mass General Brigham healthcare system. The NIH grant will allow the acceleration of ongoing research efforts, including the advancement of preclinical studies and preparations for clinical trials. Specifically, the research will focus on the potential of anti-CD3 to modulate immune system activity, reduce neuroinflammation, and ultimately slow the progression of Alzheimer’s disease. The company’s proprietary formulation of anti-CD3 is administered intranasally where it binds to the T cell receptor, which then stimulates T regulatory cells for delivery to the central nervous system. Ivor Elrifi CEO of Tiziana Life Sciences commented, “We are thrilled to be able to progress our pipeline with this prestigious NIH grant, which underscores the potential of our anti-CD3 therapy to address a critical unmet need in Alzheimer’s disease. This funding will enable us to expand our research and move one step closer to developing a new therapeutic option for patients and families impacted by this debilitating condition. At Tiziana, we remain committed to advancing science that could improve the quality of life for patients through groundbreaking immunotherapies.” The NIH grant represents a major milestone in Tiziana’s development pipeline and is part of the company’s broader strategy to explore the use of anti-CD3 in a range of autoimmune and inflammatory diseases. Tiziana's team of scientists and clinical researchers are eager to build upon promising preclinical data that suggest anti-CD3 has the potential to alter disease progression in Alzheimer’s by targeting immune pathways involved in neurodegeneration. The company expects to initiate first-in-human clinical trials in Alzheimer’s Disease patients using its intranasal anti-CD3 monoclonal antibody in the coming months, marking an important step toward regulatory approval and commercialization. Foralumab, a fully human anti-CD3 monoclonal antibody, is a biological drug candidate that has been shown to stimulate T regulatory cells when dosed intranasally. At present, 10 patients with Non-Active Secondary Progressive Multiple Sclerosis (na-SPMS) have been dosed in an open-label intermediate sized Expanded Access (EA) Program with either an improvement or stability of disease seen within 6 months in all patients. The FDA has recently allowed an additional 20 patients to be enrolled in this EA program. In addition, intranasal foralumab is currently being studied in a Phase 2a, randomized, double-blind, placebo-controlled, multicenter, dose-ranging trial in patients with non-active secondary progressive multiple sclerosis (NCT06292923). Activated T cells play an important role in the inflammatory process. Foralumab, the only fully human anti-CD3 monoclonal antibody (mAb) currently in clinical development, binds to the T cell receptor and dampens inflammation by modulating T cell function, thereby suppressing effector features in multiple immune cell subsets. This effect has been observed in patients with COVID and with multiple sclerosis, as well as in healthy normal subjects. The non-active SPMS intranasal foralumab Phase 2 trial (NCT06292923) began screening patients in November of 2023. Immunomodulation by nasal anti-CD3 mAb represents a novel avenue for treatment of neuroinflammatory and neurodegenerative human diseases.[1],[2] Tiziana Life Sciences is a clinical-stage biopharmaceutical company developing breakthrough therapies using transformational drug delivery technologies to enable alternative routes of immunotherapy. Tiziana’s innovative nasal approach has the potential to provide an improvement in efficacy as well as safety and tolerability compared to intravenous (IV) delivery. Tiziana’s lead candidate, intranasal foralumab, which is the only fully human anti-CD3 mAb currently in clinical development, has demonstrated a favorable safety profile and clinical response in patients in studies to date. Tiziana’s technology for alternative routes of immunotherapy has been patented with several applications pending and is expected to allow for broad pipeline applications. [1] https://www.pnas.org/doi/10.1073/pnas.2220272120 [2] https://www.pnas.org/doi/10.1073/pnas.2309221120 The content above comes from the network. if any infringement, please contact us to modify.

免疫疗法临床2期

2024-09-21

·CPHI制药在线

恒瑞医药1类新药申报上市，一线治疗胃癌；达格列净二甲双胍缓释片首仿国内获批 | 制药在线一周药闻复盘

点击蓝字关注我们本周，热点不少。首先是审评审批方面，很值得关注的有两个，一个是达格列净二甲双胍缓释片首仿在中国获批上市，另一个是恒瑞医药一线治疗胃癌的1类新药申报上市；其次是研发方面，多个药取得重要进展，非常值得一说的是，恒瑞帕金森病新药启动Ⅲ期临床以及迪哲医药公布舒沃替尼最新肺癌研究数据，超92%患者靶病灶缩小；最后是交易及投融资方面，欧加农12亿美元收购Dermavant，获得本维莫德乳膏权益。本周盘点包括审评审批、研发、交易及投融资三大板块，统计时间为9.16-9.20，包含27条信息。审评审批 NMPA 上市批准 1、9月18日，NMPA官网显示，宣泰医药的达格列净二甲双胍缓释片获批上市，这是该品种国内首家获批的仿制药。达格列净二甲双胍缓释片是一种SGLT2抑制剂，原研由阿斯利康开发，于2023年6月在国内获批上市，用于治疗2型糖尿病。目前，国内多家药企的该品种仿制药已进入申报上市阶段，包括正大天晴、齐鲁制药、华海药业、石家庄四药及南京方生和等。申请 2、9月18日，CDE官网显示，奥默医药和仙琚制药联合开发的1类新药奥美克松钠注射液申报上市，预测用于治疗拮抗中度肌松和深度肌松。奥美克松钠（Aom0498）是其自主研发的新一代靶向肌松拮抗剂。 3、9月19日，CDE官网显示，恒瑞医药1类新药瑞拉芙普-α注射液（SHR-1701）申报上市，联合氟尿嘧啶类和铂类药物用于局部晚期不可切除、复发或转移性胃及胃食管结合部腺癌的一线治疗。SHR-1701是恒瑞医药自主研发并具有知识产权的抗PD-L1/TGF-βRII双功能融合蛋白，经查询，国内外尚无同类产品获批上市。 4、9月20日，CDE官网显示，EyePoint Pharmaceuticals、欧康维视（Ocumension）等联合开发的地塞米松植入剂（商品名：DEXYCU、OT-502）申报上市。OT-502是一种新型、可生物降解的缓释抗炎药物，旨在为眼科医生提供一种术毕单次注射缓释激素的选择。临床批准 5、9月18日，CDE官网显示，普方生物1类新药注射用PRO1286获批临床，拟用于治疗实体瘤患者。这是一款在研的EGFR与cMET靶向双特异性抗体偶联药物（ADC），2024年5月，Genmab公司已经完成对普方生物的收购，收购金额为18亿美元。 6、9月18日，CDE官网显示，恒瑞医药1类新药SHR-1905注射液获批临床，拟开发用于12-17周岁的青少年哮喘患者。SHR-1905为恒瑞医药研发的TSLP单克隆抗体，此前恒瑞与OneBio公司达成一项高达10.5亿美元的合作，将该产品在大中华区以外的全球范围内开发、生产和商业化独家权利授予OneBio公司。 7、9月18日，CDE官网显示，和记黄埔医药1类新药HMPL-760胶囊获批临床，适应症为联合R-GemOx（利妥昔单抗+吉西他滨+奥沙利铂）治疗复发/难治弥漫大B细胞淋巴瘤（R/RDLBCL）。HMPL-760是一款第三代非共价BTK抑制剂。 8、9月18日，CDE官网显示，上海医药1类新药SPH4336片获批临床，联合奥希替尼治疗KRAS突变型晚期实体瘤。SPH4336是一种新型高选择性口服抑制剂，具有广谱的抗肿瘤作用。该产品对CDK4/6靶点具有较高的选择性，同时具有广谱抗Rb阳性肿瘤活性。 9、9月18日，CDE官网显示，挚盟医药1类新药CB03-154片获批临床，拟开发治疗成人肌萎缩侧索硬化（又称“渐冻症”，ALS）。CB03-154片是一款KCNQ2/3选择性开放剂。该产品此前治疗ALS适应症已经获得美国FDA授予孤儿药资格。 10、9月19日，CDE官网显示，贝达药业的CFT8919胶囊获批临床，拟开发用于携带EGFR突变的非小细胞肺癌患者。这是贝达药业与C4Therapeutics合作开发的一种具有口服生物利用度的变构BiDAC™（双功能蛋白）降解剂。 11、9月19日，CDE官网显示，强生（Johnson&Johnson）1类新药bleximenib胶囊获批临床，拟用于治疗携带组蛋白-赖氨酸N-甲基转移酶2A重排（KMT2Ar）或核磷蛋白1基因突变（NPM1m）的复发/难治性急性髓系白血病（AML）成人患者。bleximenib是一款Menin-KMT2A相互作用抑制剂，正在国际范围内开展Ⅰ/Ⅱ期临床研究。 12、9月20日，CDE官网显示，百济神州1类新药注射用BGB-C354获批临床，拟开发治疗晚期实体瘤患者。BGB-C354是一款靶向B7-H3的抗体偶联药物（ADC），是百济神州在实体瘤领域布局的一款新分子实体，本次为该产品首次在中国获批临床。优先审评 13、9月19日，CDE官网显示，乐普生物的注射用维贝柯妥塔单抗（MRG003）拟纳入优先审评，用于治疗既往经至少二线系统化疗和PD-1/PD-L1抑制剂治疗失败的复发或转移性鼻咽癌（NPC）患者。该药物是进度最快的国产EGFR ADC。 FDA 上市批准 14、9月17日，FDA官网显示，默沙东的PD-1单抗帕博利珠单抗（商品名：Keytruda、K药）获批新适应症，用于联合培美曲塞和铂类化疗一线治疗不可切除的晚期或转移性恶性胸膜间皮瘤（MPM）。目前，全球仅3款创新疗法获批用于治疗MPM，包括纳武利尤单抗（BMS/小野制药）、TTFields（Novocure/再鼎医药）和K药。 15、9月17日，FDA官网显示，诺华的CDK4/6抑制剂瑞波西利与芳香化酶抑制剂(AI)获批，联合用于激素受体阳性/人类表皮生长因子受体2阴性（HR+/HER2-）的Ⅱ期和Ⅲ期早期乳腺癌(EBC)高复发风险患者（包括淋巴结阴性N0患者）的辅助治疗；广泛适用于复发风险较高的HR+/HER2-Ⅱ期和Ⅲ期EBC，将符合CDK4/6抑制剂辅助治疗条件的人群增加了约一倍。 16、9月18日，FDA官网显示，阿斯利康的贝那利珠单抗（Benralizumab、商品名：Fasenra）获批新适应症，用于治疗嗜酸性肉芽肿性多血管炎（EGPA）。贝那利珠单抗是一款抗IL-5受体（IL-5Rα）单抗，2017年11月，首次在美国获批上市，用于12岁及以上的重度嗜酸性粒细胞性哮喘（SEA）患者的附加维持治疗。2019年10月，预填充一次性自动注射笔获批，至此以后患者可自行注射用药。 17、9月18日，FDA官网显示，再生元和赛诺菲的度普利尤单抗（商品名：Dupixent）递交补充生物制品许可申请（sBLA），用于治疗慢性鼻-鼻窦炎伴鼻息肉（CRSwNP）青少年患者。度普利尤单抗是再生元和赛诺菲合作开发的一款抗IL-4Rα全人源单抗，成为了美国第一种针对12-17岁青少年CRSwNP患者的疗法。研发临床状态 18、9月18日，中国药物临床试验登记与信息公示平台官网显示，赛诺菲（Sanofi）启动了amlitelimab注射液的一项新的国际多中心（含中国）Ⅲ期临床研究，旨在评估该产品针对12岁及以上中重度特应性皮炎患者的疗效和安全性。Amlitelimab是一种皮下注射的完全人源化、非耗竭性单克隆抗体，它能与OX40L结合，旨在恢复促炎及调节性T细胞之间的免疫稳态。 19、9月18日，中国药物临床试验登记与信息公示平台官网显示，石药集团启动一项多中心、随机、开放、阳性对照Ⅲ期临床试验，比较其司美格鲁肽注射液和原研药治疗肥胖患者的有效性和安全性。这是国内第四款启动肥胖Ⅲ期临床的司美格鲁肽。 20、9月19日，Clinicaltrials官网显示，恒瑞登记了一项HRG2010治疗帕金森病的Ⅲ期临床（NCT06598735）。HRG2010胶囊是恒瑞自主研发的卡比多巴+左旋多巴新型复方缓释胶囊，以卡比多巴-左旋多巴缓释片为对照，主要终点指标为第21周「停药」时间与基线相比的变化。目前国内外已上市的同类产品主要包括多巴丝肼片（商品名：美多芭）、恩他卡朋双多巴片（商品名：达灵复）和卡左双多巴缓释片（商品名：息宁）。 21、9月19日，药物临床试验登记与信息公示平台显示，艾伯维登记了一项评估Epcoritamab+利妥昔单抗和来那度胺对比化学免疫疗法在既往未接受过治疗的滤泡性淋巴瘤受试者中的Ⅲ期临床试验。Epcoritamab是全球第3款获批的CD20×CD3双抗。临床数据 22、9月17日，默沙东和第一三共公布了patritumab deruxtecan治疗既往接受过EGFR-TKI治疗的局部晚期或转移性EGFR突变NSCLC患者的Ⅲ期HERTHENA-Lung02研究达到了PFS的主要终点。与铂联合培美曲塞诱导化疗后再接受培美曲塞维持化疗相比，该药治疗后患者实现显著的PFS统计学改善。该药是一款采用第一三共技术设计的潜在first-in-class靶向HER3的DXd抗体偶联药物（ADC）。 23、9月17日，迪哲医药公布了高选择性EGFR酪氨酸激酶抑制剂舒沃替尼片（商品名：舒沃哲）国际多中心注册临床研究“悟空1B”（WU-KONG1PartB、WU-KONG1B）临床数据。研究显示，舒沃替尼二/后线治疗EGFR20号外显子插入突变（exon20ins）非小细胞肺癌（NSCLC）各亚组获益与全球整体人群一致。2023年8月，该药在中国获批上市。 24、9月18日，阿斯利康（AstraZeneca）公布了第三代EGFR-TKI奥希替尼治疗Ⅲ期不可切除的EGFR突变非小细胞肺癌的临床（LAURA）结果，与安慰剂相比，奥希替尼将CNS进展或死亡风险降低了83%。此外，奥希替尼治疗的中位至远处转移时间（TTDM）也显示出具有临床意义的改善，12个月时接受奥希替尼治疗组患者TTDM累计发生率为11%，而接受安慰剂组治疗患者为37%。2024年6月，奥希替尼递交了该适应症的上市申请。 25、9月18日，和誉医药公布了小分子FGFR4抑制剂依帕戈替尼（ABSK011）在Ⅰ期临床试验中针对FGF19过表达的晚期肝细胞癌的临床数据。依帕戈替尼220mgBID组在经免疫检查点抑制剂（ICIs）和多靶点小分子酪氨酸激酶抑制剂（mTKIs）治疗的FGF19过表达肝细胞癌患者中展现出优异的有效性，其总体缓解率（ORR）达到44.8%，中位缓解持续时间（mDOR）为7.4个月，中位无进展生存期（mPFS）达到5.5个月。 26、9月19日，Aligos公布了甲状腺激素受体β(THR-β)激动剂ALG-055009在代谢功能障碍相关脂肪性肝炎(MASH)患者中的Ⅱa期HERALD研究的积极顶线结果。第12周，肝脏脂肪相对减少中位数高达46.2%，且剂量反应明显。交易及投融资 27、9月18日，欧加农（Organon）宣布，将收购Roivant子公司Dermavant Sciences。该交易预计将于2024年Q4完成。欧加农预计该交易不会导致其资本配置的优先级发生变化。根据协议条款，收购总交易额约为12亿美元，包括1.75亿美元的首付款、7500万美元的监管里程碑付款以及9.5亿美元的某些商业里程碑付款。 END 【智药研习社直播预告】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~

并购临床3期申请上市抗体药物偶联物上市批准

2024-09-21

·生物制药小编

印度公司相中的最佳三抗？

印度仿制药公司Glenmark Pharmaceuticals似乎相中了业内潜在最佳的三抗。 Glenmark Pharmaceuticals是1977年成立的印度老牌仿制药企，近年来正在寻求转型，其瑞士盟友Ichnos Sciences之前就与Glenmark Pharmaceuticals达成了合作联盟，建立了一家合资公司Ichnos Glenmark Innovation。近日，Ichnos Sciences宣布，已在Nature Cancer发表关于该公司CD3/BCMA/CD38三抗ISB 2001的临床前数据。结果显示，ISB 2001比强生的teclistamab（CD3xBCMA双抗）更有效地缩小了小鼠的多发性骨髓瘤肿瘤，并杀死了人体组织中的癌细胞，引起的T细胞因子分泌更少，因此比现有多发性骨髓瘤双抗更有优势的治疗窗口。现有疗法的弊端近年来，BCMA双抗和BCMA-CAR-T已经改变了多发性骨髓瘤（MM）的治疗格局，但是现有疗法仍然存在一些弊端。特别是治疗过后的复发问题仍待解决。比如说，单药使用后就存在TAA表达下调，抗原丢失等问题，这类现象在CD38单抗daratumumab和BCMA-CAR-T中都能够观察到。靶标达异质性可能是导致问题的原因之一，一些低CD38/BCMA表达的异质性肿瘤就会在杀伤后扩增。一些MM细胞甚至会在BCMA-CAR-T治疗后发生BCMA阴性突变导致耐药性逐渐增加。另外，缓解深度似乎也是复发的关键因素。早先的荟萃性研究就表明，杀死微小残留病（MRD）阴性肿瘤是MM治疗成功的保障。为了解决这些问题，多靶点策略或许是这些问题的最佳解决方案，近年来CD3xBCMA双抗teclistamab+CD38单抗daratumumab的组合就被提上日程。CD38单抗无法清除的MRD就可能有赖于CD3xBCMA双抗teclistamab，反之亦然。相似的策略还有同时靶向BCMA和CD38的CAR-T。目前来看，多药联用已经展现出了较为优异的临床数据，联合方案可以获得较高的初始ORR，值得期待或许OS和PFS数据的读出。虽然如此，CRS（细胞因子综合征）问题一直是TCEs在人体内应用时的阻碍，尤其是当teclistamab+daratumumab共同应用时，更加应该担忧治疗窗口。患有严重或危及生命的CRS的患者需要重症监护，需要采取安全缓解措施。三抗ISB 2001的对应优势 ISB 2001运用了Ichnos Sciences的BEAT平台（基于T细胞受体的抗体的双特异性接合）能够将T细胞表面蛋白CD3的结合位点连接到抗体重链上，重链上同时兼有BCMA结合位点，Y型的另外一边重链则能够靶向CD38。相较于teclistamab+daratumumab的组合，ISB 2001在临床前的体外和体内数据都更为优异。相比于BMS已经放弃的alnuctamab以及强生的teclistamab，ISB 2001具有20-260倍的杀癌效力。为了进一步测试ISB 2001的杀癌能力，研究人员将人类骨髓瘤细胞移植到小鼠身上，并用抗体治疗。在0.1mg/kg的剂量下，ISB 2001完全根除了所有八只小鼠的肿瘤；同时，接受teclistamab治疗的小鼠没有完全消退，只达到了30.8%的肿瘤生长抑制。而在CRS问题上，ISB 2001也具有一定潜在优势，虽然细胞毒性上，ISB 2001比teclistamab高10-100倍，但ISB 2001在体外诱导了相似的细胞因子分泌。这表明T细胞活化和细胞溶解活性所需的TCR刺激浓度远低于CRS发生的阈值。这解释了为什么ISB 2001尽管细胞毒性高，但并未显著增加CRS的风险。因此理论上来说，ISB 2001有更大的治疗窗口。目前这家公司已经招募了20人的ISB 2001的I期临床，预计相关数据将在今年晚些时候发布。对于Glenmark来说，或许更值得担心的是市场和工艺，就在上个月BMS放弃了CD3xBCMA双抗alnuctamab，原因是市场竞争，疗效更优的ISB 2001是否能凭借性价比杀入未来市场值得一看。参考来源： Carretero-Iglesia, L., Hall, O.J., Berret, J. et al. ISB 2001 trispecific T cell engager shows strong tumor cytotoxicity and overcomes immune escape mechanisms of multiple myeloma cells. Nat Cancer (2024). https://doi.org/10.1038/s43018-024-00821-1 https://iginnovate.com/2024/09/11/igi-announces-publication-in-nature-cancer-on-isb-2001-igis-innovative-trispecific-antibody-for-relapsed-refractory-multiple-myeloma/

免疫疗法细胞疗法