SO-C101

– NKTR-0165 Demonstrates Selective Enhancement of Treg Cell Function Through Novel Agonistic Mechanism – – IND-Enabling Studies Underway for NKTR-0165 with First-in-Human Studies Planned in First Half of 2025 - SAN FRANCISCO, June 12, 2024 /PRNewswire/ -- Nektar Therapeutics (Nasdaq: NKTR) today announced the presentation of a poster highlighting new preclinical data on NKTR-0165 at the European Alliance of Associations for Rheumatology (EULAR) 2024 Congress. NKTR-0165 is a novel, first-in-class tumor necrosis factor receptor 2 (TNFR2) agonist and bivalent antibody designed to selectively stimulate TNFR2 receptor activity, without modulation of the TNFR1 signaling. TNFR2 signaling has been shown to be an important gatekeeper of inflammation and its absence or deficit is associated with a broad range of autoimmune diseases. TNFR2 is highly expressed on Tregs, neuronal cells and endothelial cells and has been shown to potentiate the suppressive effects and overall functional properties of regulatory T cells (Tregs). "The preclinical data presented at EULAR show that NKTR-0165 is a unique antibody that selectively binds to TNFR2 on Tregs to enhance its immunosuppressive activities, and could potentially become a first-in-class treatment for various autoimmune diseases, including ulcerative colitis and vitiligo," said Jonathan Zalevsky, Ph.D., Senior Vice President and Chief Research & Development Officer at Nektar. "By selectively binding to TNFR2, NKTR-0165 upregulates expression of proteins that are critical to Treg proliferation and function. Animal models show that NKTR-0165 reduces inflammation through the selective enhancement of Treg cell function via TNFR2 agonism. These data demonstrate a unique and differentiated profile for this bivalent antibody in the field of TNFR2 agonists." The poster presentation is available for download at . Key details and takeaways from the presentation are as follows: Abstract 3174: "A Novel Therapeutically Active Anti-TNFR2 Agonistic Antibody Promotes Treg Proliferation and Induction of Treg Functional Markers", Miyazaki, et al. NKTR-0165 shows selective TNFR2 binding and receptor agonism in human Tregs, with minimal binding and signaling activity in other TNFR2-expressing immune cells in vitro and in vivo. NKTR-0165 agonistic activity enhances Treg lineage stabilization and upregulates expression of proteins involved in Treg proliferation and function. NKTR-0165 demonstrates therapeutic efficacy in a KLH-induced delayed type hypersensitivity (DTH) model in human TNFR2 knock-in mice. About Nektar Therapeutics Nektar Therapeutics is a clinical-stage biotechnology company focused on developing treatments that address the underlying immunological dysfunction in autoimmune and chronic inflammatory diseases. Nektar's lead product candidate, rezpegaldesleukin (REZPEG, or NKTR-358), is a novel, first-in-class regulatory T cell stimulator being evaluated in two Phase 2b clinical trials, one in atopic dermatitis and one in alopecia areata. Our pipeline also includes a preclinical candidate NKTR-0165, which is a bivalent tumor necrosis factor receptor type II agonist antibody. Nektar, together with various partners, is also evaluating NKTR-255, an investigational IL-15 receptor agonist designed to boost the immune system's natural ability to fight cancer, in several ongoing clinical trials. Nektar is headquartered in San Francisco, California. For further information, visit and follow us on LinkedIn. Cautionary Note Regarding Forward-Looking Statements This press release contains forward-looking statements which can be identified by words such as: "could," "design," "develop," "potential" and similar references to future periods. Examples of forward-looking statements include, among others, statements we make regarding the therapeutic potential of NKTR-0165 and rezpegaldesleukin, observations from early data emerging from preclinical research of NKTR-0165, the potential of the technology incorporated into our drug candidates, and the future development plans for NKTR-0165 and rezpegaldesleukin. Forward-looking statements are neither historical facts nor assurances of future performance. Instead, they are based only on our current beliefs, expectations and assumptions regarding the future of our business, future plans and strategies, anticipated events and trends, the economy and other future conditions. Because forward-looking statements relate to the future, they are subject to inherent uncertainties, risks and changes in circumstances that are difficult to predict and many of which are outside of our control. Our actual results may differ materially from those indicated in the forward-looking statements. Therefore, you should not rely on any of these forward-looking statements. Important factors that could cause our actual results to differ materially from those indicated in the forward-looking statements include, among others: (i) our statements regarding the therapeutic potential of NKTR-0165 and rezpegaldesleukin are based on preclinical and clinical findings and observations and are subject to change as research and development continue; (ii) NKTR-0165 and rezpegaldesleukin are investigational agents and continued research and development for these drug candidates is subject to substantial risks, including negative safety and efficacy findings in future clinical studies (notwithstanding positive findings in earlier preclinical and clinical studies); (iii) rezpegaldesleukin is in clinical development and NTKR-0165 is in preclinical development, and the risk of failure is high and can unexpectedly occur at any stage prior to regulatory approval; (iv) the timing of the commencement or end of clinical trials and the availability of clinical data may be delayed or unsuccessful due to challenges caused by health epidemics, regulatory delays, slower than anticipated patient enrollment, manufacturing challenges, changing standards of care, evolving regulatory requirements, clinical trial design, clinical outcomes, competitive factors, or delay or failure in ultimately obtaining regulatory approval in one or more important markets; (v) we may not achieve the expected cost savings we expect from our 2022 corporate restructuring and reorganization plan or our 2023 cost restructuring plan and we may undertake additional restructuring and cost-saving activities in the future, (vi) patents may not issue from our patent applications for our drug candidates, patents that have issued may not be enforceable, or additional intellectual property licenses from third parties may be required; and (vii) certain other important risks and uncertainties set forth in our Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission on May 10, 2024. Any forward-looking statement made by us in this press release is based only on information currently available to us and speaks only as of the date on which it is made. We undertake no obligation to update any forward-looking statement, whether written or oral, that may be made from time to time, whether as a result of new information, future developments or otherwise. Contact: For Investors: Vivian Wu of Nektar Therapeutics 628-895-0661 For Media: David Rosen of Argot Partners (212) 600-1902 [email protected] SOURCE Nektar Therapeutics

2024年4月22日，ImmunityBio公司宣布，FDA已批准Anktiva（N-803）联合卡介苗（BCG），用于治疗卡介苗不响应的非肌层浸润性膀胱癌 (NMIBC) 伴原位癌 (CIS)，伴或不伴乳头状瘤患者。该药物预计将于 2024 年 5 月中旬在美国上市。      关于N-803N-803（nogapendekin alfa inbakicept-pmln）是一种白细胞介素-15（IL-15）超激动剂复合物，由IL-15 突变体(IL-15N72D)与IL-15Rαsushi 结构域以及IgG1 Fc 融合蛋白结合而成， IL-15Rα sushi 结构域使得其无需通过像天然IL-15 所必需的反式呈递方式才能激活下游信号通路，且IgG1-Fc 片段极大延长了药物半衰期。此前，FDA 曾授予了N-803 快速通道资格和突破性疗法认定，2023 年10 月接受了N-803联合BCG的生物制剂许可申请(BLA)的重新提交。在一项单臂、多中心2期试验中，纳入了77例经尿道切除后伴有或不伴有Ta/T1乳头状病变的BCG无反应的高危NMIBC患者；患者接受N-803诱导，通过膀胱内滴注卡介苗，随后进行维持治疗长达37个月。在长达2年的时间里，每3个月通过膀胱镜检查和尿细胞学检查评估肿瘤状态，并在治疗开始后的前6个月内进行活检(随机或膀胱镜指导)。主要疗效指标为任何时间的CR和完全缓解(DOR)持续时间，CR的定义是膀胱镜检查阴性(如适用，有TURBT/活检)和尿细胞学检查阴性，结果显示：CR率为62% (95% CI: 51,73)；58%的CR患者DOR≥12个月，40%的患者DOR≥24个月。最常见的不良反应(≥15%)包括实验室检查异常，包括肌酐升高、排尿困难、血尿、尿频、尿急、尿路感染、钾升高、肌肉骨骼疼痛、寒战和发热。除了NMIBC外，N-803在胰腺癌上也展现出了一定的治疗潜力；在2022 ASCO GI上，Immunity Bio披露了N-803联合标准护理化疗、盐酸白蛋白多柔比星和PD-L1 t-haNK三线治疗胰腺癌的II期数据，结果显示：该方案的mOS达6.3m，相较于历史数据实现翻倍；安全性方面，3级及以上不良事件主要包括贫血、中性粒细胞减少和血小板减少等。此外，在《科学》杂志上发表的临床前数据表明，N-803和广泛中和抗体联合治疗，可能使免疫系统能够在不需要抗逆转录病毒治疗的情况下控制人类免疫缺陷病毒(HIV)。      关于IL-15药物IL-15作为一种T 细胞生长因子，主要由单核细胞和巨噬细胞产生，与反应细胞上的IL-15 受体（IL-15R）结合，具有介导T 细胞、NK细胞和B 细胞增殖与活化，诱导细胞毒性淋巴细胞（CTL）产生等作用。IL-15 主要有两种不同的信号呈递机制，即顺式呈递和反式呈递，在顺式呈递中，IL-15 先与跨膜形式或可溶性形式存在的IL-15Rα 结合，再与IL-15Rβγ 结合。在反式呈递中，IL-15Rα 在IL-15 产生细胞（树突状细胞和巨噬细胞等）的表面表达，将IL-15 反式呈递至携带IL-15Rβ/γc 受体的应答细胞（NK 或记忆CD8+T 细胞等），这可能在协调免疫系统的先天性和适应性分支中起关键作用。IL-15 与IL-5R 的特异性结合可以激活JAK-STAT5 信号转导分子，进而导致PI3K/Akt 和Ras/Raf/MAPK等多条信号通路的级联激活，最终发挥其生物学效应。此外，IL-15Rα也可以从膜上脱落，与IL-15 结合后以游离的形式存在，与IL-15Rβ/γc受体远距离激活。由于IL-15 能够促进免疫细胞的活化和增殖，因此在免疫治疗中发挥着非常重要的作用。IL-15 不会引起活化的T 细胞凋亡，且能维持记忆性T 细胞的存活，进而实现长期治疗的目的。然而，IL-15 在免疫治疗中的应用也面临着一些挑战，例如，IL-15 过度分泌可能导致免疫系统的过度激活，进而诱发机体炎症反应、自身免疫性疾病、感染性疾病和肿瘤等。由于IL-15 信号通路需要通过IL-15Rα 的sushi 结构域实现，因此受到体内IL-15Rα 表达量限制。此外，IL-15 较短的半衰期（在人体中小于1 小时）和严格的转录后调控极大地限制了IL-15的临床应用，最常见的应对策略是通过增加分子大小来减少肾脏消除、或者融合新生儿Fc 受体（FcRn）；除此之外，考虑到IL-15 维持记忆CD8+ T 细胞稳态和增殖的独特能力，将其应用于CAR-T工程中也有望实现更强的抗肿瘤效力。据不完全统计，目前全球在研的IL-15药物仅200种，已进入临床阶段的药物约90种。除N-803外，SOTIO开发的皮下给药制剂SOT101、恒瑞医药的SHR-1501、奥赛康的ASKG315、博际生物的BJ-001等同样值得关注。      关于非肌层浸润性膀胱癌膀胱尿路上皮癌（UC）是全球发病率排名第十三的常见癌症，分为NMIBC（占70%）和肌层浸润性膀胱癌（MIBC，占30%）两大类。该疾病的高发年龄为50-70岁，男性尿路上皮癌的发病率为女性的3-4倍。2020年，全球尿路上皮癌病例51.6万人，预计到2025年将达到58.6万人，到2030年预计达到66.3万人。在中国，尿路上皮癌2020年新发病例约7.7万人，预计到2025年将达到9.1万人，到2030年将达到10.6万人。NMIBC是指局限于膀胱黏膜层（Ta）及固有层（T1），肌层未见浸润的膀胱恶性肿瘤，包括Ta、T1、Tis期，其中Ta占70%，T1占20%，Tis占10%。根据复发风险及预后的不同，NMIBC分为低危NMBIC、中危NMIBC、高危NMIBC和极高危NMIBC。根据危险度分组选择手术方式、膀胱灌注及随访方案，NMIBC的常规治疗是经尿道膀胱肿瘤切除术（TURBT），由于NMIBC患者术后复发率高，推荐所有NMIBC患者进行术后辅助性膀胱灌注治疗。常用的灌注化疗药物包括丝裂霉素、吉西他滨、表柔比星等，没有证据显示采用不同化疗药物的维持灌注方案疗效有显著差别。尽管指南推荐化疗灌注和BCG膀胱灌注，仍有约50%的患者在5年内发生肿瘤复发。肿瘤复发后患者的标准疗法是根治性膀胱切除术，根治性膀胱切除术使患者失去正常的储尿和排尿功能，严重影响患者的生活质量和心理健康。因此，对于化疗和BCG无应答NMIBC患者而言，新药的研发十分关键。近年来获批的代表性药物包括：2020年1月，FDA批准帕博利珠单抗（“K药”）作为一种单药疗法，用于治疗不符合或已选择不进行膀胱切除术（切除膀胱）的卡介苗（BCG）无应答、高风险、伴CIS、伴或不伴乳头状肿瘤的NMIBC患者。2022年12月，FDA批准Ferring的基因疗法nadofaragene firadenovec-vncg（商品名为Adstiladrin）上市，用于治疗BCG无响应的高风险NMIBC患者，这些患者伴有CIS，可能携带或不携带乳头状肿瘤。      关于ImmunityBioImmunityBio是一家处于临床阶段的免疫疗法公司，总部位于美国加利福利亚州，致力于研发新一代疗法，以驱动免疫原性机制，用于治疗癌症和传染病。2024年1月，Oberland Capital向ImmunityBio提供高达3.2亿美元的特许权使用费融资和股权投资，其中2.1亿美元的总收益于2023年12月29日到期。这笔额外的资金为该公司提供了重要的财务资源，以加快其商业化进程，期待获得监管部门的批准，并在更广泛的泌尿系统癌症领域拓展其产品线。此次募集资金还将用于资助正在进行的业务运营和临床试验，将N-803的适应症扩展到多种实体瘤。参考资料1、公司官网2、聂亚丹,贺毅,孙作厘,等.IL-15的免疫调节功能及其相关疾病研究进展[J/OL].生理科学进展,1-12[2024-04-23].https://doi.org/10.20059/j.cnki.pps.2024.01.1169.3、长江证券、西南证券4、泌趣横生、36氪封面图来源：pixabay版权声明/免责声明本文为授权转载文章。本文仅作信息交流之目的，不提供任何商用、医用、投资用建议。文中图片、视频、字体、音乐等素材或为药时代购买的授权正版作品，或来自微信公共图片库，或取自公司官网/网络，部分素材根据CC0协议使用，版权归拥有者，药时代尽力注明来源。如有任何问题，请与我们联系。衷心感谢!药时代官方网站:www.drugtimes.cn联系方式:电话:13651980212微信:27674131邮箱:contact@drugtimes.cn卷起来了！为什么是Claudin18.2「星起点」助你起飞：50万资金扶持+行业专家辅导！拜耳Co.Lab上海正式启动招募入驻企业点击阅读原文，了解更多！