作者: Zhang, Zhengguo ; Chen, Jianxiang ; Huang, Jiacheng ; Wang, Yufei ; Sun, Mengqing ; Zheng, Shusen ; Wang, Menglan ; Qi, Haoxiang ; Gong, Pengyu ; Qiao, Yiting ; Luo, Miao ; Pei, Yunxin

Specific tumor-targeted gene delivery remains an unsolved therapeutic issue due to aberrant vascularization in tumor microenvironment (TME). Some bacteria exhibit spontaneous chemotaxis toward the anaerobic and immune-suppressive TME, which makes them ideal natural vehicles for cancer gene therapy. Here, we conjugated ZIF-8 metal-organic frameworks encapsulating eukaryotic murine interleukin 2 (Il2) expression plasmid onto the surface of VNP20009, an attenuated Salmonella typhimurium strain with well-documented anti-cancer activity, and constructed a TME-targeted Il2 delivery system named Il2/ZIF-8@Salmonella. Both in vitro and in vivo experiments demonstrated that Il2/ZIF-8@Salmonella maintained the tumor-targeting feature of bacteria, and could be effectively phagocytosed by intratumoral macrophages, thus leading to the expression and secretion of IL2 in TME. The detailed analysis of tumor immune microenvironment (TIME) showed that one dose of combinatorial Il2/ZIF-8@Salmonella achieved synergistic actions on a potent remodeling of TIME, marked by the activation of cytotoxic T cells and M1-polarization of macrophages in TME, thus leading to significant anti-tumor effects in melanoma, orthotopic hepatocellular carcinoma, and pulmonary metastasis models. More importantly, Il2/ZIF-8@Salmonella exhibited high safety to major organs and hematopoietic systems. Taken together, we report a novel plasmid/ZIF-8@Salmonella system that simultaneously achieves effective TME-targeted delivery of therapeutic gene, as well as synergistic re-activation of TIME.

2024-10-01·Cell Reports Medicine

A PD-1-targeted, receptor-masked IL-2 immunocytokine that engages IL-2Rα strengthens T cell-mediated anti-tumor therapies

Article

作者: Dudgeon, Drew ; Olson, William C ; Wu, Jiaxi ; Amatulli, Michael ; Wang, Qingqing ; Bhavsar, Ramandeep ; Antao, Olivia Q ; Lin, John C. ; Murphy, Andrew J. ; Ni, Min ; Vazzana, Kristin ; Yancopoulos, George D ; Murphy, Andrew J ; Wei, Yi ; Antao, Olivia Q. ; Olson, William C. ; Chang, Aaron Y. ; Patel, Supriya ; Garg, Vidur ; Yancopoulos, George D. ; Huang, Tammy ; Chang, Aaron Y ; Crawford, Alison ; DiLillo, David J ; Ahmed, Hassan ; Ullman, Erica ; Bloch, Nicolin ; Krueger, Pamela ; Lin, John C ; Zhang, Tong ; Davis, Samuel ; Ramos, Willy ; Wang, Shunhai ; Macdonald, Lynn ; Adler, Christina ; Smith, Eric ; Mohrs, Katja ; Yan, Yuetian ; Guo, Chunguang ; DiLillo, David J. ; Hermann, Aynur

The clinical use of interleukin-2 (IL-2) for cancer immunotherapy is limited by severe toxicity. Emerging IL-2 therapies with reduced IL-2 receptor alpha (IL-2Rα) binding aim to mitigate toxicity and regulatory T cell (Treg) expansion but have had limited clinical success. Here, we show that IL-2Rα engagement is critical for the anti-tumor activity of systemic IL-2 therapy. A "non-α" IL-2 mutein induces systemic expansion of CD8⁺ T cells and natural killer (NK) cells over Tregs but exhibits limited anti-tumor efficacy. We develop a programmed cell death protein 1 (PD-1)-targeted, receptor-masked IL-2 immunocytokine, PD1-IL2Ra-IL2, which attenuates systemic IL-2 activity while maintaining the capacity to engage IL-2Rα on PD-1⁺ T cells. Mice treated with PD1-IL2Ra-IL2 show no systemic toxicities observed with unmasked IL-2 treatment yet achieve robust tumor growth control. Furthermore, PD1-IL2Ra-IL2 can be effectively combined with other T cell-mediated immunotherapies to enhance anti-tumor responses. These findings highlight the therapeutic potential of PD1-IL2Ra-IL2 as a targeted, receptor-masked, and "α-maintained" IL-2 therapy for cancer.

2024-07-01·INTERNATIONAL IMMUNOPHARMACOLOGY

Site-specific pegylated IL2 mutein with biased IL2 receptor binding for cancer immunotherapy

Article

作者: Dong, Xianchi ; Gai, Yanan ; Chen, Jian ; Jian, Tunyu ; Tong, Bei ; Lv, Han ; Niu, Guanting ; Leong, Sirou Grace ; Meng, Xiuhua ; Ding, Xiaoqin

While Interleukin 2 (IL2) has the capability to activate both NK and T cells robustly, its limited in vivo half-life, considerable toxicity, and tendency to boost Treg cells pose significant challenges, restricting its widespread application in cancer therapy. In this investigation, we engineered a novel IL2 variant (IL2-4M-PEG) with reduced CD25 binding activity and an extended half-life by substituting amino acids associated with CD25 binding and implementing site-directed PEGylation. IL2-4M-PEG notably amplifies effector cells over Treg cells. Furthermore, our findings reveal that IL2-4M-PEG, characterized by an extended half-life, exhibits anti-tumor effects in a mouse model. Consequently, this innovative IL2 holds the potential for enhancing combined cancer therapies in the future.

项与白细胞介素-2 (上海新生源医药集团) 相关的新闻（医药）

2024-04-22

·佰傲谷BioValley

超越偏向型，新型IL-2

IL-2的开发虽然是“前路未明”，但大家的热情还没跌到谷底。这家21年融资1.8亿美元的公司，选择交上一份临床前数据作为其进行中的1期试验的背后支持，以展示其IL-2药物超越主流的机制优势。近期，Asher Bio在AACR期刊Cancer Discovery上发表了两篇其候选产品AB248靶向实体瘤的临床前实验结果。许多开发肿瘤IL-2药物的公司走的药物设计路线是偏向型IL-2，即“非α亚基结合”，以结合IL-2Rβ，从而作为CD8+ 效应T细胞和NK细胞的长效增强增强剂，并限制Treg细胞的增殖。而AB248是一款选择性靶向CD8+ T细胞的IL-2顺式融合蛋白，可选择性激活CD8+ T细胞中的IL-2通路，一同抑制NK细胞和Treg细胞。（图源：官网）分析偏向型IL-2的毒性来源和有效性来源：为证明其CD8+ T细胞靶向性的思路才是更合理的，研究人员先对非α亚基的IL-2药物和免疫细胞的串扰进行评估。其结论包括：CD8+ T细胞是IL-2药物作用下起到免疫促进作用的主要细胞亚群。IL-2Rγ亚基结合T细胞和NK细胞的水平相似，但β亚基则更倾向于结合NK细胞，造成NK细胞整体增殖水平显著高于T细胞。同时，肿瘤浸润Treg细胞也会结合一部分β亚基。IL-2信号诱导NK细胞释放非抗原依赖性的IFN-γ等细胞因子，以产生脱靶细胞毒性。靶点选择：对CD8α和CD8β的分析表明，人外周血中约75%的CD8α+细胞是常规的CD8αβ+T细胞，其余的25%包括CD8αα+T细胞、γδT细胞和NK细胞。此外，大约20%的CD8T细胞和30%的NK细胞表达γδα。相反，CD8β对常规CD8αβ+T细胞表现出显著的特异性，在γδT细胞和NK细胞上仅有相对最低限度的表达。因此，研究人员选择CD8β为靶抗原。抗CD8β融合到Not-α IL-2(CD8-IL-2βγ)，或融合到没有IL-2Rα结合和IL-2Rβ结合减少的变异体(CD8-IL-2β*γ)，显示出对CD8+ T细胞的结合倾向性是对Treg细胞的500倍以上。因此，AB248被设计为含有IL2R突变蛋白，没有检测到IL2Rα结合，并减少了与IL-2βγ复合体信号的结合。CD8靶向的IL-2促进CD8+ T细胞免疫的机制CD8-IL2治疗肿瘤内广泛浸润的CD8+T细胞，增强了其效应作用，从而特异性地重激活功能失调的T细胞池，在抗PD-1的肿瘤中恢复T细胞功能，继而激发免疫活性。CD8-mIL2可以在比hrIL2和IL2v低1000倍的浓度下诱导CD8+T细胞的表达；在肿瘤浸润Treg和传统CD4+ T细胞高浓度的环境中CD8-mIL-2可做到仍不激活；诱导肿瘤内T细胞格局的转录重排；以TCR依赖性的方式诱导肿瘤特异性功能紊乱T细胞池免疫重激活；激活CD8+T细胞后，CD8-IL2不会对Tconv、Treg、NK细胞、B细胞和髓系细胞的激活和成熟产生明显影响；但在TME中，CD8-IL2介导的T细胞活化可能通过干扰素的作用影响其他TME常驻免疫细胞，放大其激活的免疫功能。CD8-IL2使功能障碍的T细胞恢复到效应活性的过程依赖于同步抗原识别，并且在数量上和质量上均优于PD-1阻断剂单药所实现的效果；CD8-IL2对T细胞亚群功能的影响也取决于功能障碍T细胞池处于早期还是晚期。早期PD-1+ CD39-的CD8+ T细胞池和晚期PD-1+ CD39+ 的CD8+ T细胞池均可受到CD8-IL2作用产生颗粒酶B和提高表达水平，但是仅有后者表现出4-1BB水平提高。Cancer Discov.但同时，CD8-IL2也可能诱导肿瘤特异性功能紊乱T细胞重激活。CD8-IL2在肿瘤识别时仍然增加了功能障碍和过渡性T细胞中4-1BB的表达，意味着其可能同时通过TCR依赖和非依赖性信号促进T细胞再生。单药治疗效果：小鼠实验显示，对CD8-mIL2治疗有反应的小鼠产生了诱导的免疫记忆。肿瘤消退时体重没有减少，血液中CD8+ T细胞也同时表现出剂量依赖性、选择性扩张。Cancer Discov.据称，CD8-mIL-2和非α型IL-2相比，给药后对肿瘤免疫细胞的影响不同：(1)非α-mIL2诱导外周血中的NK细胞强烈扩张，对肿瘤内人群的变化较小；而CD8-mIL2则能促成CD8+T细胞高水平地、选择性地在血液和肿瘤部位扩张。(2)CD8-mIL2诱导的肿瘤内CD8+ T细胞扩增的幅度与观察到的外周血CD8+T细胞的扩增幅度相当，比预期效果更好。这可能是由于CD8+ 肿瘤浸润性淋巴细胞(TIL)所需的增殖诱导阈值较低，接受抗原信号后，细胞向肿瘤内迁移增加。(3)相比之下，CD8+T细胞顺式靶向IL-2更有力地增加了肿瘤内浸润的抗原特异性CD8+T细胞数量和功能的能力。小鼠体内的抗原反应性Tcm、Teff细胞和Tem细胞数量都增加了，而比例组成没有显著变化，支持CD8+T细胞选择性IL-2促进有效、有力、和持久的抗肿瘤免疫。联合PD-1治疗效果：CD8-mIL-2和PD-1联用在多个模型中均有显著且持久的抗肿瘤活性。Cancer Discov.肿瘤内mLama4反应细胞产生的耗竭相关标记物PD-1、TIM3、LAG3和TOX的水平在CD8-mIL2联合抗PD-1治疗的小鼠中显著降低，在其他组中则仅显示轻微影响。候选产品AB248在食蟹猴中也表现出和小鼠模型类似的CD8+T细胞结合和pSTAT5活性水平。Cancer Discov.其他同类产品Asher Bio也还有一款类似的CD8靶向IL-21产品AB821，选择性地靶向CD8 + T细胞。其官网介绍AB821对 CD8+ T细胞的选择性为>1000倍。2024年1月Science Translational Medicine上也发表了一篇CD8顺式靶向的IL-2药物临床前数据论文，用于驱动针对乙肝的抗病毒活性。2023年J Immunother Cancer.上则发表过一款BMS的特异性靶向CD8+ T细胞的IL-2/CD25融合蛋白。HD mIL-2/CD25优先刺激高亲和力IL-2R，但不刺激对中亲和力IL-2R具有优先活性的IL-2/抗IL-2复合物。小鼠模型显示，HDmIL-2/CD25融合蛋白提高了TME中CD8:Treg细胞比率，肿瘤特异性CD8+ 效应T细胞的频率和功能增加，耗竭表型减少，增加抗肿瘤记忆反应。小结偏向型IL-2的表现确实不佳。可能是由于其依赖于不同细胞类型中天然细胞因子受体的不同表达水平，因此无法实现高度可控的特异性。IL-2之“死”，与Treg“无关”。例如，IL-2Rβγ在作用于效应T细胞和NK细胞的同时，也可在Treg上表达，其抑制效果也会随着给药剂量增加而增强。NK细胞还是IL-2药物毒性的重要来源之一，响应非α亚基IL-2受体的免疫细胞以CD8+ T细胞为主。临床试验中，在最高有效剂量下，偏向型IL-2药物引起的NK细胞增殖水平显著高于CD8+ T细胞数倍。AB248目前正在一项开放标签的1a/1b期临床试验中进行研究(NCT05653882)，评估AB248作为单一疗法以及与帕博利珠单抗联合治疗复发性局部晚期或转移性实体瘤患者。参考文献：https://www.biospace.com/article/releases/-asher-bio-announces-publications-in-cancer-discovery-highlighting-the-differentiated-profile-of-ab248-its-cd8-t-cell-selective-il-2-product-candidate/?s=86Kelly D. Moynihan,et al; IL-2 targeted to CD8+ T cells promotes robust effector T cell responses and potent antitumor immunity. Cancer Discov 2024; https://doi.org/10.1158/2159-8290.CD-23-1266Paulien Kaptein,et al; CD8-targeted IL2 unleashes tumor-specific immunity in human cancer tissue by reviving the dysfunctional T cell pool. Cancer Discov 2024; https://doi.org/10.1158/2159-8290.CD-23-1263Francesco Andreata et al. ,CD8 cis-targeted IL-2 drives potent antiviral activity against hepatitis B virus.Sci. Transl. Med.16,eadi1572(2024).DOI:10.1126/scitranslmed.adi1572LaPorte KM, Hernandez R, Santos Savio A, et alRobust IL-2-dependent antitumor immunotherapy requires targeting the high-affinity IL-2R on tumor-specific CD8 T cells+Journal for ImmunoTherapy of Cancer 2023;11:e006611. doi: 10.1136/jitc-2022-006611········

AACR会议临床结果临床1期细胞疗法

100 项与白细胞介素-2 (上海新生源医药集团) 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
胃肠道肿瘤	临床阶段不明	中国	上海新生源医药集团有限公司	-

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


EULAR2018	N/A	原发性干燥综合征 IL-2	190	Low-dose recombination human IL-2	衊鹹繭壓艱窪夢製窪鹽(築窪衊範鏇窪積顧窪願) = The ratio of Th17/Treg cells decreased rapidly in one week but increased to a higher level after one month 鏇膚膚膚夢壓鏇願齋簾 (鏇壓簾鹹簾膚窪選鬱鬱 ) 更多	积极	2018-06-13
				Standard therapy
SITC2015	N/A	黑色素瘤	5	Dendritic Cell Vaccine + High Dose IL-2 + Taurolidine	齋醖網築壓廠顧鏇顧鹽(憲鏇壓鹹艱衊繭廠鏇餘) = 製窪範艱蓋醖窪簾觸憲觸夢夢顧淵鏇膚鑰憲鹹 (製繭網獵觸糧範願衊鹽 )	积极	2015-11-04
				High Dose IL-2	齋醖網築壓廠顧鏇顧鹽(憲鏇壓鹹艱衊繭廠鏇餘) = 網鹽糧築製製築憲構窪觸夢夢顧淵鏇膚鑰憲鹹 (製繭網獵觸糧範願衊鹽 )