CD161

调控B细胞产生抗体的Tfh细胞数量异常增加会导致自身免疫性疾病，因此同时存在一种抑制性细胞群：滤泡调节T(follicular regulatory T cell,Tfr)细胞来维持正常免疫耐受。滤泡调节T细胞：起源、功能、定位随着对Tfr细胞的进一步了解，小鼠模型和人体内Tfr亚群表征、活性和免疫调节功能的差异认识也逐渐细化。chapter1：亚群分类和表征人和小鼠Tfr细胞中，按照来源均可分为nTfr、iTfr和cTfr亚群。自然Treg细胞的称为nTfr细胞；来源于Th细胞形成的外周Treg(pTreg)也能在免疫后几天内形成一部分iTfr；cTfr细胞则指在体内长期存活的记忆样循环中的Tfr细胞。（1）根据CD25分类的nTfrnTfr小鼠人表达CD25- Tfr亚群下调FoxP3、Helios、CD103、GITR和Blimp1，上调Bcl6、CXCR5和PD-1。CD25- Tfr亚群表达Helios+ BCL6hi CXCR5hi PD-1hi，表达水平与小鼠相似。CD25high Foxp3high亚群则表达额外的Treg效应分子如Entpd1、CTLA4、Icos和GZMB，并上调IL-10和CCR5的表达。CD25high Foxp3high亚群表达高水平的FOXP3、Entpd1、TIGIT、OX40、GITR、HELIOS、BLIMP1、CTLA4和IL-17RACD25+ nTfr细胞一般表达中等水平的CXCR5和PD1。分布CD25− nTfr亚群更多地分布在GCs内。在CXCR5和PD1高表达的基础上，人CD25− TfR细胞可能与小鼠CD25− Tfr一样定位于GC内。CD25- Tfr细胞在人扁桃体中的出现频率明显低于小鼠。CD25+ nTfr亚群则主要分布在GCs周围的滤泡中。CD25+ nTfr亚群主要定位在卵泡中。细胞因子Prdm1和IL-10主要由CD25+ nTfr细胞产生CD25+ nTfr亚群也表达IL-10，但不是产生比例最高的亚群。转化在GC应答的早期阶段：IL-2可能是通过触发Blimp1转录因子，从而抵消Bcl6介导的nTfr细胞CXCR5和PD-1的上调传导，从而阻断CD25+ nTfr细胞转化和移动。目前还不清楚是什么因素促使Tfh细胞转变为CD25hi Tfh细胞和iTfr细胞，可能是IL-2通过低亲和力的IL-2受体IL-2Rβ被Tfh细胞感知。在GC应答的后期阶段：IL-2下降，使得部分CD25+ nTfr→CD25- nTfr细胞，↑Bcl6+ CXCR5high PD-1high，同时转移到GC内分布。部分Tfr细胞上调Foxp3表达，下调IL-21产生相关的基因，从而进一步分化为iTfr细胞。International Immunology（2）iTfr细胞iTfr小鼠人来源在GC应答晚期，还有一部分CD25- Foxp3+ CD4+ T细胞积累，即Tfh来源的FoxP3+GC驻留T细胞，又称诱导的iTfr细胞。类似小鼠表达均为FOXP3+ AIOLOS+ LAG3+ CD127−，表达KLRB1和CD3 8的水平高于其他滤泡T细胞亚群。分布在CXCR5和PD-1高表达的基础上，iTfr细胞在GCs中更丰富。大多数Tfr细胞是nTfr细胞。 iTfr亚群平均数量高于nTfr亚群。在儿童扁桃体中，iTfr克隆的数量大约是nTfr克隆的两倍。细胞因子下调IL-21表达高表达IL-21和IL-10这部分细胞因子表达功能主要由nTfr产生。iTfr细胞则同时表达PRDM1和IL-10，并且与人nTfr细胞相比，再次刺激后产生IL-10的细胞比例更高。International Immunology（3）cTfr细胞cTfr小鼠人表达CXCR5+ ICOSint FoxP3+CD45RA− CXCR5+ FOXP3+，大多数cTfr细胞是HELIOS+ CD25+ CD127low与非滤泡Treg细胞相比，CD38在cTfr细胞上的表达有所上调。由于人iTfr细胞也上调CD38，所以猜测cTfr细胞很可能包括记忆性iTfr细胞和nTfr细胞。分布cTfr细胞可在二次免疫激活时被招募到SLO卵泡和GC中。International Immunologychapter2：功能活性功能活性小鼠人①Th/Tfh细胞增殖和细胞因子产生的调控Tfr细胞抑制Th细胞的激活及其增殖。Tfr细胞促进了共培养的B细胞和Tfh细胞的长期表观遗传变化，改变了它们的代谢调节，并减少了Glut1的表达。加入IL-21可以逆转Tfr介导的Glut1表达减少。类似小鼠②抑制B细胞反应与PC的形成TFR细胞可以在GC反应的高峰期直接抑制GC B细胞。该作用依赖于GC B细胞产生CCL3和Tfr对CCL3分泌细胞的趋化作用。人cTfr细胞能够抑制Tfh细胞体外激活的B细胞和PC的形成，其效果与nTreg细胞相似。nTfr细胞可能有助于限制GC B细胞以直接接触依赖的方式产生抗体分泌细胞。Tfr细胞产生高度保守的神经素，可被GC B细胞直接摄取。人Tfr细胞也产生神经素，类似小鼠Treg细胞，从而直接作用于GC B细胞。但其具体产生神经蛋白的亚群尚不明确。③转铁蛋白受体细胞与自身免疫性疾病的关系多种缺陷小鼠模型中都显示，Tfr缺陷小鼠会导致形成抗dsDNA抗体和系统性红斑狼疮(SLE)等自身免疫性疾病症状加重。在TFR细胞消融后，小鼠体内多种自身抗体上调。不同疾病中，Tfr水平和疾病关系相反。一种假设是，Tfr细胞对GC表现出普遍的非特异性抑制，限制了从扩增和分化为效应细胞的B细胞克隆的选择，从而保留更多非外来抗原性B细胞。负相关：在RA和SLE中，cTfr的频率都有增加和减少的报道。MS患者和重症肌无力患者的TFR细胞频率降低，重症肌无力患者的Tfr细胞与疾病的严重程度呈负相关。正相关：干燥综合征和强直性脊柱炎中，cTfr细胞频率增加与抗SSA/Ro、抗SSA/Ro自身抗体和轻微SGS的淋巴细胞浸润呈正相关。④外源抗原特异性B细胞的正向调节对免疫和感染的最佳B细胞反应需要Tfr细胞。人CD38+ iTfr细胞与GC B细胞共培养时，比CD38- nTfr亚群在体外实验中产生的IgG和IgA显著增加。人cTfr细胞不支持B细胞在细胞培养中存活和产生抗体。目前仅确认IL-10对于GC B细胞循环和亲和力成熟是重要的。IL-10介导的小鼠TfR细胞对GC B细胞的调节可能是非常不同的，因为表达IL-10的IL-25+nTfr细胞主要是自身抗原特异性的。⑤调节IgE反应Tfr细胞在调节IgE反应中可能扮演着相反的角色。通过调节IL-10的产生；通过神经素的直接调控。负向调节：可能是通过转铁蛋白受体介导的抑制IL-13的表达，进而B细胞向IgE的转换；以及通过nTfr细胞表达的神经素肽直接作用于B细胞。例如，儿童血清中的IgE滴度与扁桃体CD25+ Tfh细胞呈负相关，与人类扁桃体中Tfr细胞的总体频率呈正相关。同时，变应性鼻炎患者的cTfr细胞数量减少，经变应原免疫治疗后cTfr/cTfh比值恢复。正向调节：当GCs参与IgE PB反应时，IL-10可能支持GC B细胞在亮区和暗区之间的循环；同时支持变应原特异性B细胞的亲和力成熟来增强对外来抗原的IgG1和IgE应答。所有研究都表明Tfr缺陷伴随着总IgE的显著增加。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·····

Dr. D'Andrea brings more than 25 years of research and development experience to the company, expanding executive leadership team to advance pipeline WALTHAM, Mass., Jan. 18, 2024 /PRNewswire/ -- Immunitas Therapeutics ("Immunitas"), a clinical stage precision immunotherapy company committed to discovering and developing novel, differentiated therapeutics for patients with cancer, today announced the appointment of Annalisa D'Andrea, Ph.D., as Chief Scientific Officer (CSO). Dr. D'Andrea has more than 25 years of basic and translational research and development expertise in both large and small pharmaceutical and biotech settings. Dr. D'Andrea brings to Immunitas a strong history of success in immunology therapeutic development, having led products from target selection through clinical evaluation. Her expertise will accelerate Immunitas' pipeline of highly differentiated, antibody-based therapeutics, including lead candidate IMT-009 which is currently dosing in the clinic and the company's second program, an antibody oligonucleotide conjugate designed to stimulate Toll-like receptor 9. Dr. D'Andrea has been an advisor for the Company and served as Acting CSO since September 2023. "Annalisa's leadership and deep drug development expertise has proven invaluable as we advanced our growing pipeline of novel precision immuno-oncology therapeutics over the past several months," said Amanda Wagner, Chief Executive Officer of Immunitas. "We are excited to welcome her as our full-time Chief Scientific Officer. Annalisa will spearhead translational development and progression of our research and discovery programs. Her experience will play a key role in shaping our scientific strategy as the company continues to bring novel differentiated therapies to patients." Dr. D'Andrea brings nearly three decades of experience leading drug discovery and development. In addition to her role at Immunitas, Dr. D'Andrea is also a Venture Partner at Longwood Fund, supporting the identification and advancement of promising biotechnology companies, and an independent board member for Engimmune Therapeutics. Most recently, Dr. D'Andrea served as President and CSO at ImmuneID, CSO at Kiniksa Pharmaceuticals and Vice President and Global Head of Discovery for Immunology and Inflammation at Roche, where she oversaw the discovery pipeline of drug candidates from inception to the clinic. She also previously held multiple roles at SRI International and at Chiron Vaccines. Dr. D'Andrea earned her doctoral degree from the University of Florence while training at the Wistar Institute at the University of Pennsylvania. She completed her postdoctoral studies at the DNAX Research Institute in Palo Alto, California. "I look forward to collaborating with this talented team to build on the foundation of strong science underpinning Immunitas' expanding portfolio and realize novel therapeutic options for people living with cancer," said Dr. D'Andrea. "Immunitas' unique approach to drug discovery and fully integrated research and development capabilities differentiate the organization and offer opportunity to translate innovative science into broad patient impact." About IMT-009 IMT-009 is a fully human, Fc-attenuated IgG1 monoclonal antibody that binds to CD161 and blocks its interaction with its ligand, CLEC2D. Preclinical data confirm that CD161 blockade with IMT-009 results in enhanced anti-tumor activity. IMT-009 is under evaluation in a Phase 1/2a clinical trial for use as a monotherapy and combination treatment for solid tumor and hematological malignancies. The Phase 1 study is designed to evaluate the safety, tolerability, pharmacodynamic biomarkers, and preliminary efficacy of IMT-009 as well as identify the Recommended Phase 2 Dose (RP2D). The trial will then transition into Phase 2 with multiple expansion cohorts to assess the safety and efficacy of IMT-009 alone or in combination with another antineoplastic agent. About Immunitas Therapeutics Immunitas is a clinical stage precision immunotherapy company committed to discovering and developing novel, differentiated treatments for patients with cancer. A focus on human data, combined with fully integrated internal R&D capabilities and parallel discovery efforts, allows Immunitas to start with and stay closer to the most relevant and translatable biology for patients, accelerating the timeline from discovery to the clinic. The Immunitas discovery engine combines deep expertise in single-cell genomics with customized machine learning approaches to elucidate immune cell populations that are key actors in immuno-oncology. The company was founded by Longwood Fund with leading scientists from Dana-Farber, MGH, the Broad, and MIT. Since its founding in 2019, Immunitas has raised a total of $97 million in venture funding from a strong syndicate of investors including Agent Capital, Alexandria Venture Investments, Evotec, Leaps by Bayer, Longwood Fund, M Ventures, Medical Excellence Capital, and Novartis Venture Fund. To learn more, visit .

Seasoned biotech executive James Wooldridge, M.D., named Chief Medical Officer to support advancement of immuno-oncology pipelineNew preclinical data to be presented at the American Society of Hematology 2023 Annual Meeting supports therapeutic potential of IMT-009 in hematological malignancies WALTHAM, Mass., Dec. 4, 2023 /PRNewswire/ -- Immunitas Therapeutics ("Immunitas"), a clinical stage precision immunotherapy company committed to discovering and developing novel, differentiated therapeutics for patients with cancer, today announced the appointment of James Wooldridge, M.D., as Chief Medical Officer (CMO). The company also announced it will present new data supporting continued clinical development of its lead program IMT-009 for solid tumors and hematological malignancies at the 65th American Society of Hematology Annual Meeting and Exposition (ASH 2023). Continue Reading Immunitas Therapeutics Announces Appointment of James Wooldridge as Chief Medical Officer and Upcoming Presentation at ASH 2023 Annual Meeting In the CMO role, Dr. Wooldridge will leverage his extensive oncology therapeutic development experience to support clinical advancement strategy for Immunitas' pipeline of highly differentiated, antibody-based immuno-oncology assets, including lead candidate IMT-009. Dr. Wooldridge has served as Acting CMO since June 2023 and has been an advisor to the Company since October 2022. "We are pleased to announce Jim's appointment as our Chief Medical Officer as we continue progressing toward our goal of providing groundbreaking therapeutic solutions for patients with cancer," said Amanda Wagner, Chief Executive Officer of Immunitas. "Over the past year advising Immunitas he has provided invaluable expertise, drawing from his extensive breadth of experience in immuno-oncology development to support advancement of our evolving pipeline. We are delighted to have him on board as our CMO as we continue clinical development of IMT-009 and progress our portfolio of highly differentiated immuno-oncology biologics." Dr. Wooldridge has more than 20 years of experience in clinical oncology research and drug development spanning the biotechnology, pharmaceutical, and academic sectors. He previously served as the Chief Medical Officer at Checkmate Pharmaceuticals leading up to the company's acquisition by Regeneron. Additionally, he held the role of Chief Medical Officer at Aeglea BioTherapeutics, where he oversaw development of enzyme-based treatments for rare genetic diseases and cancer. "I am excited to continue working with this team to further advance the Immunitas pipeline. Our lead program, IMT-009, targets the CD161/CLEC2D axis and is currently dosing in the clinic with key data expected in 2024. The talented Immunitas team has built on our unique expertise in this area to progress a second compelling program for tumors that have traditionally not responded to immune-therapy, and the company's approach to target discovery is deeply rooted in human biology," said Dr. Wooldridge. "I'm particularly excited by Immunitas' strategy to develop novel therapeutics using a biomarker-driven approach early in development, and I greatly look forward to continuing my work with this team to bring new therapies to patients." The data to be presented at ASH 2023 further supports the therapeutic potential of IMT-009 in hematological malignancies. IMT-009 is a monoclonal, Fc silent, fully human Immunoglobulin G1 (IgG1) antibody that binds to CD161 with high affinity, selectively blocking interactions with its ligand CLEC2D. Previously reported preclinical data confirm that blocking CD161 with IMT-009 restores activation of effector functions of both CD161+ T and NK cells, enhancing cytotoxicity toward target tumor cells. IMT-009 is currently being evaluated in a Phase 1/2a clinical trial for use as monotherapy and combination treatment in both solid tumors and heme malignancies (NCT05565417). "The new data to be shared at ASH 2023 adds to the growing body of evidence supporting IMT-009's potential as a differentiated treatment approach for hematologic malignancies, in addition to the strong data we have generated in solid tumors. Together with data presented at SITC 2023 that demonstrated proof-of-concept for our second program, a myeloid and B cell modulating anti CLEC2D-Toll-like receptor 9 (TLR9) agonist conjugate, these data provide further compelling support for our approach targeting the CLEC2D/CD161 axis as a novel ligand-receptor pathway for immunotherapeutic intervention," said Amanda Wagner, Chief Executive Officer of Immunitas. Presentation Details for ASH 2023: Title: Anti CD161 antibody IMT-009 is a novel immunotherapeutic agent that effectively blocks the inhibitory CLEC2D/CD161 axis in CLEC2D+ B Cell hematological malignancies reinvigorating T and NK cell function leading to anti-tumor benefit Abstract Number: 2815 Date/Time: Sunday, December 10, 2023, 6:00 – 8:00 pm PT About IMT-009 IMT-009 is a fully human, Fc-attenuated IgG1 monoclonal antibody that binds to CD161 and blocks its interaction with its ligand, CLEC2D. Preclinical data confirm that CD161 blockade with IMT-009 results in enhanced anti-tumor activity. IMT-009 is under evaluation in a Phase 1/2a clinical trial for use as a monotherapy and combination treatment for solid tumor and hematological malignancies. The Phase 1 study is designed to evaluate the safety, tolerability, pharmacodynamic biomarkers, and preliminary efficacy of IMT-009 as well as identify the Recommended Phase 2 Dose (RP2D). The trial will then transition into Phase 2 with multiple expansion cohorts to assess the safety and efficacy of IMT-009 alone or in combination with another antineoplastic agent. About Immunitas Therapeutics Immunitas is a clinical stage precision immunotherapy company committed to discovering and developing novel, differentiated treatments for patients with cancer. A focus on human data, combined with fully integrated internal R&D capabilities and parallel discovery efforts, allows Immunitas to start with and stay closer to the most relevant and translatable biology for patients, accelerating the timeline from discovery to the clinic. The Immunitas discovery engine combines deep expertise in single-cell genomics with customized machine learning approaches to elucidate immune cell populations that are key actors in immuno-oncology. The company was founded by Longwood Fund with leading scientists from Dana-Farber, MGH, the Broad, and MIT. Since its founding in 2019, Immunitas has raised a total of $97 million in venture funding from a strong syndicate of investors including Agent Capital, Alexandria Venture Investments, Evotec, Leaps by Bayer, Longwood Fund, M Ventures, Medical Excellence Capital, and Novartis Venture Fund. To learn more, visit . SOURCE Immunitas Therapeutics, Inc.