A Phase 1 Study of JS014, a Recombinant Fusion Protein of Interleukin-21 and Humanized Anti-human Serum Albumin VHH Antibody as a Single Agent or in Combination With Pembrolizumab in Subjects With Advanced Cancer

This phase 1, first-in-human study uses a BOIN design to assess the safety and potential efficacy of JS014 at different dose levels as a single agent and in combination with fixed dose of pembrolizumab in subjects with advanced cancer.

开始日期2022-02-28

申办/合作机构

Anwita Biosciences, Inc.

[+1]

CTR20213180 / Recruiting临床1期

重组白介素 21-抗人血清白蛋白纳米抗体融合蛋白（JS014）单药及联合特瑞普利单抗在晚期肿瘤患者中的安全性、耐受性、药代动力学和初步疗效的 I 期临床研究

主要目的：评价 JS014 单药及联合特瑞普利单抗在晚期肿瘤患者中的安全性和耐受性；确定JS014单药及联合特瑞普利单抗在晚期肿瘤患者中的最大耐受剂量（MTD）和II期推荐剂量（RP2D）。次要目的：评价 JS014 单药及联合特瑞普利单抗在晚期肿瘤患者中的药代动力学（PK）特征；评价 JS014 单药及联合特瑞普利单抗在晚期肿瘤患者中的免疫原性；初步评价 JS014 单药及联合特瑞普利单抗治疗晚期肿瘤的有效性。评价 JS014 单药及联合特瑞普利单抗的药效学特征；探索性目的：探索相关生物标志物与临床疗效的关系。

开始日期2022-01-06

申办/合作机构

上海君实生物医药科技股份有限公司

100 项与 IL-21R 相关的临床结果

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100 项与 IL-21R 相关的转化医学

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0 项与 IL-21R 相关的专利（医药）

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项与 IL-21R 相关的文献（医药）

2024-12-31·Epigenetics

IL21R hypomethylation as a biomarker for distinguishing benign and malignant breast tumours

Article

作者: Yang, Rongxi ; Zhu, Qiang ; Zang, Zishan ; Liu, Chunlan ; Li, Hong ; Yin, Yifei ; Huang, Xuandong

Some benign and malignant breast tumours are similar in pathological morphology, which are difficult to be distinguished in clinical diagnosis. In this study, we intended to explore novel biomarkers for differential diagnosis of benign and malignant breast tumours. Methylation EPIC 850K beadchip and RNA-sequencing were used to analyse 29 tissue samples from patients with early-stage breast cancer (BC) and benign breast tumours for differently methylated and expressed genes. The altered methylation of IL21R was semi-quantitatively validated in an independent study with 566 tissue samples (279 BC vs. 287 benign breast tumours) using mass spectrometry. Binary logistic regression analysis was performed to evaluate the association between IL21R methylation and BC. BC-associated IL21R hypomethylation and overexpression were identified in the discovery round. In the validation round, BC patients presented significant IL21R hypomethylation compared to women with benign breast tumours (ORs ≥1.29 per-10% methylation, p-values ≤ 5.69E-14), and this hypomethylation was even enhanced in BC patients with ER-negative and PR-negative tumours as well as with triple-negative tumours. The methylation of IL21R showed efficient discriminatory power to distinguish benign breast tumours from BC (area under curve (AUC) = 0.88), and especially from ER-negative BC (AUC = 0.95), PR-negative BC (AUC = 0.93) and triple-negative BC (AUC = 0.96). We disclosed significant IL21R hypomethylation in patients with BC compared to women with benign breast tumours, and revealed the somatic change of DNA methylation could be a potential biomarker for molecular pathology of BC.

2024-10-01·Journal of Leukocyte Biology

The IL-21/IL-21R signaling axis regulates CD4+ T-cell responsiveness to IL-12 to promote bacterial-induced colitis

Article

作者: Solaymani-Mohammadi, Shahram

AbstractIL-21/IL-21R signaling dysregulation is linked to multiple chronic intestinal inflammatory disorders in humans and animal models of human diseases. In addition to its critical requirement for the generation and development of germinal center B cells, IL-21/IL-21R signaling can also regulate the effector functions of a variety of T-cell subsets. The antibody-mediated abrogation of IL-21/IL-21R signaling led to the impaired expression of IFN-γ by mucosal CD4+ T cells from human subjects with colitis, suggesting an IL-21/IL-21R–triggered positive feedback loop of the TH1 immune response in the colon. Despite recent advances in our understanding of the mechanisms underpinning the regulation of proinflammatory immune responses by the IL-21/IL-21R signaling axis, it remains unclear how this pathway or its downstream molecules contribute to inflammation during bacterial-induced colitis. This study found that IL-21 enhances the surface expression of IL-12Rβ2, but not IL-12Rβ1, in CD4+ T cells, leading to TH1 differentiation and stability. Consistently, these findings also point to an indispensable role of the IL-12Rβ2 signaling axis in promoting proinflammatory immune responses during Citrobacter rodentium–induced colitis. Genetic deletion of the IL-12Rβ2 signaling pathway led to the attenuation of C. rodentium–induced colitis in vivo. The genetic deletion of the IL-12Rβ2 signaling pathway did not alter the host's ability to respond adequately to C. rodentium infection or the ability of Il12rb2−/− mice to express antigen-specific cytokines (IFN-γ, IL-17A). IL-21 is a pleiotropic cytokine exerting a wide range of immunomodulatory functions in multiple tissues, and its direct targeting may result in undesirable off-target consequences. These findings highlight the possibility for targeted manipulations of signaling cascades downstream of main regulators of proinflammatory responses to control invading pathogens while preserving the integrity of host immune responses. A better understanding of the novel mechanisms by which IL-21/IL-21R signaling regulates bacterial-induced colitis will provide insights into the development of new therapeutic and preventive strategies to harness IL-21/IL-21R signaling or its downstream molecules to treat infectious colitis.

2024-08-01·Journal of Clinical Investigation

A pathologically expanded, clonal lineage of IL-21–producing CD4+ T cells drives inflammatory neuropathy

Article

作者: Zhang, Shirley ; Su, Maureen A ; Hugo, Willy ; Seyedsadr, Maryamsadat ; Bang, Madison F ; Chen, Ho-Chung ; McCarthy, Ethan C ; Mohebbi, Mahnia ; Whitmire, Jason K ; Lechner, Melissa G

Inflammatory neuropathies, which include chronic inflammatory demyelinating polyneuropathy (CIDP) and Guillain Barré syndrome (GBS), result from autoimmune destruction of the PNS and are characterized by progressive weakness and sensory loss. CD4+ T cells play a key role in the autoimmune destruction of the PNS. Yet, key properties of pathogenic CD4+ T cells remain incompletely understood. Here, we used paired single-cell RNA-Seq (scRNA-Seq) and single-cell T cell receptor-sequencing (scTCR-Seq) of peripheral nerves from an inflammatory neuropathy mouse model to identify IL-21-expressing CD4+ T cells that were clonally expanded and multifunctional. These IL-21-expressing CD4+ T cells consisted of 2 transcriptionally distinct expanded cell populations, which expressed genes associated with T follicular helper (Tfh) and T peripheral helper (Tph) cell subsets. Remarkably, TCR clonotypes were shared between these 2 IL-21-expressing cell populations, suggesting a common lineage differentiation pathway. Finally, we demonstrated that IL-21 receptor-KO (IL-21R-KO) mice were protected from neuropathy development and had decreased immune infiltration into peripheral nerves. IL-21 signaling upregulated CXCR6, a chemokine receptor that promotes CD4+ T cell localization in peripheral nerves. Together, these findings point to IL-21 signaling, Tfh/Tph differentiation, and CXCR6-mediated cellular localization as potential therapeutic targets in inflammatory neuropathies.

项与 IL-21R 相关的新闻（医药）

2024-10-30

·PipelineReview

Anaveon announces presentation of new data on development compounds ANV700 and ANV600 at the Society for Immunotherapy of Cancer 2024 Annual Meeting

– First presentation of ANV700, a targeted IL-21 employing proximity activated potentiation of cytokine signaling – – New mechanistic data provide insights into the mode of action of ANV600, currently in clinical development – BASEL, Switzerland I October 30, 2024 I Anaveon, a clinical stage, immuno-oncology company, today announced that it will present posters on ANV700 and ANV600 at the Society for Immunotherapy of Cancer (SITC) 39th Annual Meeting being held from Friday, November 8, 2024, to Sunday, November 10, 2024, in Houston, Texas. “ANV700 is a novel powerful PD-1 targeted therapeutic which focuses IL-21 signaling on T cells in the tumor microenvironment with the potential to reverse exhaustion,” said Christoph Huber, Chief Scientific Officer of Anaveon . “We will further develop this molecule towards clinical studies to determine the therapeutic benefit in patients.” Posters will be available on the virtual meeting platform and at anaveon.com beginning Nov. 7 at 9 a.m. CST. Details of the poster presentations: Saturday, Nov. 9, 12:15 – 1:45 pm CST Poster #960 Title: ANV700 is a novel proximity-activated IL-21 receptor agonist designed to selectively reinvigorate tumor-reactive PD-1 expressing T cells Authors: A. Rau, N. Egli, P. Murer, L. Petersen, C. Stocker, K. Richter, C. Huber Poster #954 Title: ANV600, a cis-signaling αPD-1/IL-2Rβ/γ agonist, expands both CD4+ and CD8+ tumor-specific T cells by acting in the tumor microenvironment and draining lymph nodes Authors: P. Murer, A. Zurbach, L. Petersen, N. Egli, A. Katopodis, C. Huber Anaveon is developing selective cytokine receptor agonists with the potential to therapeutically enhance a patient’s immune system to respond to tumors. ANV419, currently in Ph II studies in multiple cancer indications, is designed to preferentially signal through the IL-2 beta/gamma receptor resulting in strong proliferation of effector cells in patients. The follow-on compound, ANV600, targets the selective IL-2 receptor moiety to intratumoral effector cells and may have therapeutic benefit in less immunogenic tumors. These novel types of therapeutics, if approved, could potentially have a wide utility in oncology, including in combination with checkpoint inhibitors, cell therapies, vaccines, and radiotherapy. About Anaveon: Anaveon is a biotechnology company located in Basel, Switzerland. Using our immunological knowledge and expertise in protein engineering, we develop medicines to deliver meaningful benefits to cancer patients. Our lead compounds, ANV419 and ANV600, are currently in clinical trials in solid tumors. Find out more at > anaveon.com SOURCE: Anaveon

免疫疗法AACR会议临床2期临床1期

2024-09-20

·PRNewswire

CD (Suzhou) Biopharma Announces FDA Clearance for Phase I Clinical Trial of CD-001

SUZHOU, China, Sept. 20, 2024 /PRNewswire/ -- CD (Suzhou) Biopharma has received clearance from the U.S. Food and Drug Administration (FDA) for its Investigational New Drug (IND) application of CD-001, entering a Phase I first-in-human trial. CD-001, the company's leading clinical candidate, is built on its proprietary Bispecific Fusion Protein (BsFP) platform. This potential therapy, designed to target PD-1 positive CD8+ T cells using an anti-PD-1 antibody and engineered IL-21 mutant, aims to address unmet medical needs in oncology and viral infections. "The FDA's clearance of this IND reinforces our unwavering commitment to advancing groundbreaking immunotherapies." said Dr. Jian Xu, CEO of CD Biopharma. "CD-001 shows promise as a first-in-class and best-in-class treatment, and preclinical studies have demonstrated its effectiveness in various mouse tumor models, with excellent tolerance observed in non-human primates. We are excited to move forward with patient enrollment and expect initial clinical data in the upcoming months." About CD (Suzhou) Biopharma Founded in 2021, CD Biopharma is a rapidly advancing clinical-stage biotech company focused on developing innovative therapies across a broad spectrum of immunotherapy areas, including oncology, viral infections, and autoimmune diseases. The company's proprietary Bispecific Fusion Protein (BsFP) platform and IMmune-Enhanced (IME) cell technology, which enable advanced cell modification, continue to drive breakthrough research and clinical outcomes that transform patient care. CD Biopharma is headquartered in Suzhou, China, with additional research operations in Beijing, China. For more information, visit . CONTACT: E-mail: [email protected] SOURCE CHENGDIAN (SUZHOU) BIOPHARMACEUTICAL CO., LTD WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

免疫疗法临床申请临床1期

2024-05-10

·今日头条

发挥促癌作用！暨南大学林雪嘉/尹芝南团队揭示肝癌靶向治疗策略

本文为转化医学网原创，转载请注明出处作者：Rainbow 导读：免疫监视失调与代谢功能障碍相关脂肪性肝炎（MASH）驱动的肝细胞癌（HCC）的发展密切相关；然而，其潜在机制仍不清楚。在研究中，研究人员旨在确定白细胞介素-21受体（IL-21R）在MASH驱动的肝细胞癌中的作用。 5月8日，暨南大学林雪嘉、尹芝南共同通讯在期刊《Molecular Cancer》上在线发表题为“Interleukin-21 receptor signaling promotes metabolic dysfunction-associated steatohepatitis-driven hepatocellular carcinoma by inducing immunosuppressive IgA + B cells”的研究论文，研究结果探讨了IL-21R在MASH驱动的肝癌发生中的促癌作用，并阐明了IL-21R通过IL-21R-STAT-1-c-Jun/c-Fos-IgA调节轴激活IgA的机制。因此，靶向IL-21R信号转导代表了癌症治疗的潜在治疗策略。 https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-024-02001-2 研究背景 01 肝细胞癌（HCC）是最常见的恶性肿瘤，在全球恶性肿瘤中发病率第五高，死亡率第三高。病毒感染、饮酒和肥胖是肝细胞癌的主要原因。随着乙型肝炎病毒（HBV）和丙型肝炎病毒（HCV）感染防治的最新进展，病毒性肝炎引起的肝癌负担正在下降；然而，代谢功能障碍相关脂肪性肝病（MASLD）引起的肝细胞癌患病率明显增加，以前称为非酒精性脂肪性肝病（NAFLD）。在全球范围内，四分之一的人口患有NAFLD，其中约20%的人患有非酒精性脂肪性肝炎（NASH），现在称为代谢功能障碍相关脂肪性肝炎（MASH）。 MASH 的主要特征是脂肪变性、纤维化和慢性炎症，可进展为肝硬化，进而发展为肝细胞癌。一般来说，MASH是代谢综合征的肝脏表现，与肥胖、胰岛素抵抗和血脂异常有关，但不符合该定义的瘦MASH患者也可以被诊断出来。尽管每年诊断为MASH相关肝细胞癌的患者比例仍然相对较低，但由于全球肥胖和糖尿病发病率的迅速增加，MASH将不可避免地在不久的将来成为肝细胞癌最常见的病因。因此，迫切需要对MASH相关肝细胞癌的肿瘤发生进行更广泛的探索，以开发有效的治疗策略来防止从MASH进展为肝细胞癌。研究发现 02 在本研究中，研究人员发现IL-21R-STAT1-c-Jun/c-Fos-IgA调节通路在MASH驱动的肝癌发生过程中被激活，导致免疫抑制性IgA + B细胞的诱导，从而抑制CTL的激活，并最终促进体内MASH驱动的肝细胞癌。研究发现支持IL-21/IL-21R在肿瘤发生中的免疫抑制作用。据研究人员所知，这是首次尝试探究IL-21R在MASH驱动的肝癌发生中的功能，并阐明IL-21R诱导IgA + B细胞的机制。研究结论 03 综上所述，研究结果探讨了IL-21R在MASH驱动的肝癌发生中的促癌作用，并阐明了IL-21R通过IL-21R-STAT-1-c-Jun/c-Fos-IgA调节轴激活IgA的机制。因此，靶向IL-21R信号转导代表了癌症治疗的潜在治疗策略。参考资料： https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-024-02001-2 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。热门·直播/活动 🕓 上海｜06月14日-16日 ▶ 第六届上海国际癌症大会将于6月14-16日在上海举办，学科交叉，共同推进肿瘤研究与诊治多模态！ 🕓 北京｜09月20日-21日 ▶ 第五届单细胞技术应用研讨会暨空间组学前沿研讨会欢迎您的参与！点击对应文字查看详情

临床结果临床研究