PY-314

近几年，髓样细胞在多种病理过程中的作用逐渐被关注，髓样细胞上表达的触发受体-2（TREM2）被认为是一个主要的病理诱导免疫信号中枢，目前对TREM2的关注主要集中于阿尔兹海默病和癌症领域。01靶点介绍TREM2是免疫球蛋白超家族的跨膜受体。TREM2的配体包含大量阴离子分子，它们是游离的，可以与细胞膜结合，其中包含细菌产物、DNA、脂蛋白和磷脂。TREM2包括信号肽、包含免疫球蛋白结构域和短柄序列的胞外结构域、跨膜螺旋和胞质尾部。Trem2结构而对小鼠巨噬细胞的研究表明，TREM2通过跨膜结构域中带相反电荷的残基与衔接蛋白DNAX激活蛋白12（DAP12）和DAP10结合。在TREM2与配体相互作用后，这些共同受体被磷酸化，并招募激活细胞内信号转导机制。DAP12介导脾脏酪氨酸激酶Syk的激活，而DAP10通过招募PI3K促进信号传播。TREM2可以结合DAP12或DAP10，并可能形成TREM2-DAP12-DAP10异二聚体。下游信号转导严重依赖于一些活动，例如，在小鼠巨噬细胞中，DAP12是Ca2+动员所必需的，而DAP10对丝氨酸/苏氨酸蛋白激酶（AKT1）和细胞外信号调节激酶（ERK）的激活至关重要。靶向TREM2信号转导过程（A）当TREM2与其一个配体相互作用时，信号通过衔接蛋白DAP10和DAP12传播，分别激活PI3K或Syk。ADAM10/17通过切割茎部区域的TREM2形成sTREM2并停止TREM2信号级联。（B） 靶向TREM2和信号级联不同阶段的可能治疗途径。02Trem2生理学作用在生理学上，TREM2的活性仅限于特定的组织部位：如在大脑、骨骼和毛囊干细胞部位；在这些部位中，TREM2在组织维持中的作用得到了实验证实。此外，TREM2在各种病理学中成为重要的组织损伤信号中枢：比如在AD和其他可能的神经退行性病变、代谢综合征相关肥胖、脂肪肝和动脉粥样硬化以及肿瘤中。在这些不同的疾病中，TREM2信号的激活会导致病理特异性结果（A）。根据人类细胞图景分析TREM2在人类细胞和组织中的表达水平显示，健康人、肾上腺和胎盘中可能存在TREM2激活并发挥功能的其它部位，而这其中TREM2的表达也仅限于巨噬细胞或单核细胞（B）。TREM2在特定组织中的生理学和病理学作用吉满生物根据市场需求和研究现状，推出构建TREM2过表达稳定细胞系/抗体的服务（详细数据见文末），可用于抗体筛选、表征、一致性评价, 充分满足药物研发的需求，助力抗体药物临床申报。03Trem2在癌症中的新角色此前已发现Trem2在阿尔茨海默病、肥胖、脂肪肝和动脉粥样硬化等疾病中的潜在角色。如今，越来越多的证据表明TREM2在肿瘤相关巨噬细胞（TAM）和髓源性抑制细胞（MDSCs）中发挥作用。已有多项研究表明，在癌症患者中TREM2表达显著上调，包括肺癌、胃癌、胶质瘤、肝细胞癌和食管癌等。与治疗AD等疾病的策略（通过激动剂化合物增强TREM2信号，以促进巨噬细胞和小胶质细胞的治疗活动）不同，治疗癌症像是一种相反的挑战。TREM2的抗炎和免疫抑制作用是有害的，这会促进肿瘤生长和免疫逃避。癌症的治疗方法是阻断TREM2信号或从肿瘤微环境中清除TREM2+髓样细胞，从而重新激活T细胞介导的抗肿瘤免疫反应。抗TREM2抗体依赖性细胞毒性（ADCC）或作为TREM2拮抗剂的单克隆抗体是逆转髓系免疫抑制环境的两种主要策略，也是癌症免疫治疗的潜力方向。对信号通路、其下游效应基因和TREM2表达调节器的进一步了解有望带来调控TREM2活性的新靶点和替代治疗策略。2020年8月11日，华盛顿大学医学院Marco Colonna团队在Cell发表的研究表明Trem2–/–小鼠比野生型小鼠对各种癌症的生长更有抵抗力，并且对抗PD-1免疫疗法的反应更强。此外，与抗PD-1结合使用抗TREM2 mAb可以抑制肿瘤生长并促进肿瘤消退。04在研药物目前针对Trem2的药物开发不多，主要集中于AD领域。艾伯维/Alector的AL002目前进展较快，是Trem2激动剂。预计2024年会获得2期顶线数据Denali/武田的DNL919也是Trem2激动剂，曾于去年1月被FDA拒绝进入临床，在补充提交资料后，于7月顺利开展。2023年1月，Denali/武田在“Nature Neuroscience”上介绍了一种高亲和力的新型抗体ATV: TREM2，是基于Denali专有的Transport Vehicle（TV）平台开发。研究表明ATV: TREM2可以改善大脑暴露、生物分布和活性，且显着优于标准IgG TREM2抗体。也进一步证明了激活TREM2受体在阿尔茨海默症中的潜在作用。此外，如Pionyr公司，已经开始探究Trem2在实体瘤中的作用，PY-314是一种人源化单抗，能特异性地结合TREM2，旨在通过抗体依赖性细胞介导的细胞毒性（ADCC）和/或抗体依赖性细胞介导的吞噬作用（ADCP）来消耗TREM2表达的肿瘤相关巨噬细胞（TAMs）。PY314在临床前模型中显示了单药和组合药的疗效，单独或与CPI联合使用进行治疗，可使多个小鼠共生肿瘤模型的肿瘤完全消退。在肿瘤治愈的小鼠中，通过重新植入相同的肿瘤细胞系，发现在无治疗期一个月后没有肿瘤生长，从而证实了长期的免疫力。在过去的20年里，被称为“天坑”的AD领域有百余款新药均研发失败，临床失败率高达97.3%，Biogen已上市的两款Aβ药物也备受争议，而Trem2无论在AD领域还是癌症的治疗上都体现了一定的潜力。用心做好细胞，为更好的靶向药吉满生物科技（上海）有限公司，是位于上海浦东的一家以创新为驱动的工程化细胞系研发公司，基于自有的国内最大报告基因平台、慢病毒平台以及最迅速的药研网资讯平台，目前已构建出500余株现货单克隆细胞系产品，覆盖ROR1/DLL3/SLC39A6/TROP2/BCMA/BDCA/TREM2……200余新药热门靶点，其中有90余靶点开发有对应luciferase reporter方法，更有国内独家/首家CCR8, BDCA, TREM2和GAPR等luciferase的assay平台。TREM2细胞系/抗体产品列表部分结果：GM-C25370：H_TREM2 CHO-K1 Cell Line使用Anti-H_TREM2 hIgG4 Antibody流式验证结果GM-C24478：H_TREM2 HEK-293 Cell Line使用Anti-H_TREM2 hIgG4 Antibody流式验证结果GM-C13261：H_TREM2 Reporter Jurkat Cell Line   使用Anti-H_TREM2 Rat_IgG2b Antibody包被激活GM-C13261：H_TREM2 Reporter Jurkat Cell Line   使用Anti-H_TREM2 Rat_IgG2b Antibody包被激活后，使用非包被抗体竞争性抑制吉满生物助力药物研发，紧随前沿靶点资讯，储备几百株现货细胞，覆盖GPCR、细胞因子、免疫检查点、TAA等多领域近200余个靶点。2020年底成立专业细胞系子品牌DDXCELL，同时已建立了DDXCELL现货查询小程序。截止当前已布局近200个热门靶向药靶点500余株细胞系，旨在助力、加速大分子早期研发，做到进口细胞的国产替代。同时可根据客户需求提供细胞系服务。细胞系现货查询请扫码👇1.DOI:10.3389/fimmu.2021.7167102. DOI：10.1016/j.cell.2020.07.013；3. DOI：10.1016/j.cell.2020.06.032；4. doi: 10.1126/scitranslmed.aba6006.；5. https://doi-org.libproxy1.nus.edu.sg/10.1016/j.pharmthera.2017.02.0436. https://doi-org.libproxy1.nus.edu.sg/10.1016/j.cell.2020.05.003；弗图医学译文：https://mp.weixin.qq.com/s/h8PVjmbGVUpgmJ0LKkAO8w；

PY314 was well tolerated over a range of doses both as a single agent and in combination with checkpoint inhibitor pembrolizumab at its label approved dose A recommended dose for study expansion both as a single agent and in combination with pembrolizumab was derived, and enrollment of patients with metastatic refractory solid tumors into individual expansion cohorts of five prespecified cancers is ongoing PY314 targets TREM2, a protein receptor highly expressed on the surface of immunosuppressive, pro-tumor myeloid cells SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)-- Pionyr Immunotherapeutics, Inc., a company developing first-in-class Myeloid TuningTM antibody therapeutics that enhance the body’s antitumor immunity by altering, or “tuning,” immune cells within the tumor microenvironment, announced today that PY314, a monoclonal antibody targeting TREM2 (triggering receptor expressed on macrophages 2), was safe and well-tolerated in a Phase 1a dose-escalation study as a single agent and in combination with pembrolizumab at its label-approved dose. A maximum tolerated dose (MTD) was not observed over the range of PY314 doses tested and a dose for study expansion was recommended based on an analysis of clinical data (including PK exposure) in the context of supportive preclinical data models. The study will be featured in a poster presentation at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 3-7 virtually and in Chicago. “Pionyr developed PY314 to precisely bind human TREM2 and retune the tumor microenvironment by driving the selective depletion of TREM2 positive tumor-associated macrophages. Removing these macrophages shifts the balance of myeloid cells towards more pro-inflammatory populations and is expected to increase and promote anti-tumor immune responses,” said Leonard Reyno, EVP and Chief Medical Officer of Pionyr Immunotherapeutics. “We have applied what we have learned from the Phase 1a study to identify a recommended dose for Phase 1b expansion studies. We have already begun enrolling patients in these studies and expect to have new data this year and into 2023.” Safety and Tolerability as a Monotherapy and in Combination with Pembrolizumab Support Additional Clinical Studies The Phase 1a dose-escalation study of PY314 was a non-randomized, open-label study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of PY314 as a single agent and in combination with checkpoint inhibitor pembrolizumab in 28 subjects with advanced solid tumors. Dosing was intravenous and administered once every three weeks. Four predefined dose levels of PY314 were delivered both as a single agent and in combination with pembrolizumab. No dose-limiting toxicities, drug-related serious adverse reactions, or high-grade treatment-related adverse events (TRAEs) that resulted in treatment discontinuance were seen. Twelve patients experienced at least one TRAE, and these were low-grade in all but one subject who experienced a treatment-related immune system disorder. Eight patients experienced serious adverse events, all unrelated to treatment. Linear Dose-Response Observed and Recommended Dose for Expansion Studies Determined PY314 pharmacokinetics were linear and dose-proportional, with a half-life of five to nine days and no evidence of interference by pembrolizumab. The best radiographic response was stable disease, observed in eleven subjects (39.3%), which ranged in duration from nine to 42 weeks. Ten mg/kg PY314 was determined to be the recommended dose for expansion. Five expansion cohorts in patients with metastatic refractory solid tumors (triple-negative or HR-positive HER2 negative metastatic breast cancer, non-small cell lung cancer, renal cell carcinoma, colorectal cancer, ovarian cancer) are enrolling. Information about the ongoing Phase 1b expansion study is available at . Poster Presentation at ASCO 2022 The poster titled, “A Phase 1a Dose Escalation Study of PY314, a TREM2 (Triggering Receptor Expressed on Myeloid Cells 2)-Targeting Monoclonal Antibody,” will be featured in a poster session at the ASCO 2022 Annual Meeting on Sunday, June 5, 2022, 8:00 AM-11:00 AM CDT. The abstract is currently available on the ASCO 2022 website here, and the poster will be available on the Pionyr company website here after the completion of the ASCO poster session. About Myeloid TuningTM Pionyr has developed a therapeutic platform called Myeloid Tuning, a process that rebalances the tumor microenvironment (TME) to promote anti-tumor immunity. Myeloid cells are a type of immune cell and are part of a family of cell types that play an important role in both the activation and suppression of the immune response to cancer. One such critical type of myeloid cell, tumor-associated macrophages (TAM), are a key component of the TME. TAMs are generally categorized into two functionally contrasting subtypes called M1-like and M2-like macrophages: M1-like typically exerts anti-tumor functions, including directly mediating antibody-dependent cell-mediated cytotoxicity (ADCC) to kill tumor cells; M2-like macrophages can promote the occurrence and metastasis of tumor cells, inhibit T cell-mediated anti-tumor immune response, promote tumor angiogenesis and lead to tumor progression. Myeloid Tuning TM effectively describes the mechanism of introducing agents that shift the balance of inhibitory myeloid cells – including M2-like TAMs – towards more inflammatory M1-like TAMs to promote anti-tumor immune responses in the TME and destroy solid tumors. About PY314 PY314 is a humanized IgG1 afucosylated monoclonal antibody, delivered by intravenous infusion, that binds Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) on the surface of immunosuppressive, pro-tumorigenic myeloid cells. It is designed to deplete TREM2-expressing TAMs, leading to productive anti-tumor immunity. Preclinical data generated by Pionyr suggest that when TAMs are depleted from tumors, pro-inflammatory, anti-tumorigenic immune cells such as CD8 T-cells, natural killer (NK), and M1-like macrophages become activated and penetrate tumors leading to tumor destruction. PY314 is currently being evaluated in a Phase 1b dose-expansion study as a single agent and in combination with pembrolizumab (Keytruda) as a treatment for refractory solid tumors and gynecologic cancer, colorectal cancer, lung adenocarcinoma, renal cell carcinoma, triple-negative breast cancer, hormone receptor/growth factor receptor-negative breast cancer, and ovarian cancer. About Pionyr Immunotherapeutics Pionyr is exploiting novel target discovery and antibody generation platform technologies to create the next generation of immuno-oncology therapeutics after checkpoint inhibitors. The company’s initial approach, termed “Myeloid TuningTM,” is designed to enhance the immune system’s anti-tumor response by specifically altering the cellular infiltrate of the tumor microenvironment. Pionyr’s lead programs PY314 and PY159, targeting TREM2 and TREM1 respectively, are designed to selectively deplete and in some cases reprogram certain tumor-associated macrophages responsible for immunosuppression. In July 2020, Pionyr entered into a transformational alliance with Gilead Sciences whereby Gilead acquired a minority interest in the company and has an exclusive option to acquire Pionyr upon completion of certain Phase 1b studies. Pionyr’s additional investors include New Enterprise Associates, OrbiMed, SV Health Investors, Sofinnova Ventures, Vida Ventures, Osage University Partners, Mission Bay Capital, and Trinitas Ventures. For more information, please visit .