Alpha Cancer Technologies, Inc.

偶联技术有多火？仅ADC（抗体偶联药物）领域，2017年之后就有超过10款新药获FDA批准上市，时至今日，全球进入临床阶段的ADC药物更是超过500余款，而万物偶联趋势下，这个数字还在无限扩大。 偶联药物有多卷？随着DS-8201获批上市，其突出的优势为ADC药物开发提出了更高的标准，也让“差异化偶联创新药”成为主要趋势，部分入局较晚的企业产品还在研就已丧失优势，不得不思考“偶联药物未来又将如何发展”？ 其实，与最初“魔术子弹概念”时代并没有太大的变化，尽管蛋白质基因工程、化学偶联等技术的持续进步，但偶联药物的发展方向仍主要围绕新的靶抗原、新作用机制的有效载荷、新的抗体和载体形式等方面进行，而最大的不同就在于，偶联药物方向更偏向于了靶向性，即更多具有特异定向作用的结构被用作了小分子毒素等有效载荷的载体。 数据来源：公开数据整理 在此环境之下，组合用药、精确递药的理念和应用场景进一步扩大，多种新兴偶联技术概念相继涌现，业界也掀起了新兴偶联技术药物研发热潮。 差异化之路 非抗体蛋白偶联的出现 原则上来讲，偶联药物或许并不存在最优组合。 “万物皆可偶联”的核心理念之下，对最优组合的不断探索反而促进了更多创新技术的出现，继ADC爆火之后，PDC、FDC、SMDC、ISAC、RDC、ARC等多种技术如雨后春笋般不断冒出。 多样化策略之下，各种创新偶联技术相较传统ADC技术，或多或少都存在自身的核心优势，如PDC较强肿瘤穿透性、更低的免疫原性与更低的生产成本；SMDC工艺简单、安全性较好与安全性较高。而除了抗体、多肽与小分子等常规的靶向分子，近来出现的“非抗体蛋白”也逐渐全新的研究领域。 非抗体蛋白偶联药物，即将靶向性蛋白分子与发挥药效的效应分子（比如细胞毒分子，siRNA等）连接在一起，递送效应分子到特定疾病部位发挥作用。其原理上与ADC的机理类似，最大区别就是靶向分子的不同，但相较前者却有着核心的四大优势： 免疫副作用更小：蛋白偶联药物的蛋白部分大都来源于人类蛋白，例如重组人甲胎蛋白、重组人转铁蛋白等，相较于抗体、多肽能对人产生较小的免疫副作用。 靶点灵活：对靶点的选择相对灵活，很多企业在蛋白部分做了很多创新，例如Aro Biotherapeutics的Centyrins蛋白经过设计后可以与不同肿瘤抗原相结合。原则上可以避开偶联药物较集中的hear2等领域，去尝试更新、更小众的靶点方向。 高效：如外泌体偶联药物，可控的、模块化的药物装载与递送，突破了抗体偶联药物（ADC）载药率低、安全性有限的瓶颈，实现了更高效的提升效率。 稳定：蛋白偶联药物的结构稳定性一般较高，且具有高效、可控的制药载荷数量。 依从性高：可以通过在蛋白中引入半胱氨酸来提高药物的结合率，提高了药物的依从性和便利性。 不过，由于蛋白偶联技术总体上处于研究早期阶段，某种程度上其优势性与局限性都尚未研究透彻，后续或可能存在系列变化，但无论如何，从目前市面上相继出现的非抗体蛋白偶联技术来看，其临床优势也可初见端倪。 外泌体+转铁蛋白 蛋白偶联的两大典型技术路线 外泌体偶联药物（EDC） 2021年7月26日，Nature子刊Nature Biomedical Engineering在线刊发了中科院魏炜教授团队联合首都医科大学陶勇教授团队和昆士兰大学余迪教授团队共同署名文章，开发出外泌体偶联VEGF单抗，利用Treg来源的外泌体（rEXS）为载体，通过基质金属蛋白酶（MMP）敏感肽段（cL）连接VEGF抗体（aV)，创建了rEXS-cL-aV体系。 后续通过外泌体化学偶联技术，在外泌体上进行可控、可调节的多功能化改造，如构建融合表达特定蛋白和外泌体膜蛋白的质粒，通过转染等方式，让该融合蛋白在外泌体来源细胞中大量表达，使得这些细胞分泌的外泌体能够会携目标融合蛋白。 图片来源：参考资料1 最终，将外源性小分子化学药物或生物大分子药物与外泌体偶联结合，形成外泌体偶联药物（EDC），实现高效、稳定、广谱、可控的外泌体模块化药物装载与递送，突破了抗体偶联药物（ADC）载药率低、安全性有限的瓶颈。 在该领域上，天津外泌体科技有限公司是国内掌握该技术商业化的领先公司，根据其以往公布的数据显示，其EDC药物装载率可达到92.3%、溶解性提高71.4倍、半衰期提高36.2倍、药峰浓度提高3倍、 口服相对生物利用度提升2.6倍；装载Herceptin抗体的外泌体呈现靶向效果相比对照组提升174.5倍，数据着实惊人。 至少就目前而言，EDC技术是外泌体领域最具商业化前景的技术，也是最为经典的非抗体蛋白偶联技术。 重组人转铁蛋白偶联药物 铁蛋白作为一种脱铁蛋白组成的具有大分子结构的糖蛋白，通常情况下是由蛋白质外壳和铁内核两部分组成，在维持机体铁代谢平衡和细胞抗氧化过程中起着关键作用，并且与炎症、血管增生和肿瘤有关。 而人工条件下的铁蛋白是具有空腔结构的笼形结构，外部的蛋白质外壳可通过基因和化学修饰增加靶向性，以达到提高递送效率的目的，而空腔机构则可以用于装载药物，实现药物的包载荷递送。 图片来源：参考资料2 2005年铁蛋白被成功用于包载递送阿霉素，开启药物递送领域新篇章，之后铁蛋白药物载体（FDC）的概念得以面世，相较ADC等常规偶联药物，其在安全性、渗透性、稳定性与靶向性等方面具有天然优势，尤其是靶向性方面。 安全性：铁蛋白是来自生物体内的天然存在蛋白质，毒性低，具有良好的生物降解性和生物相容性，不容易引起排异反应。 渗透和滞留性：由于铁蛋白粒径较小，使其易于逃脱网状内皮系统的吞噬，半衰期较长，可在病变部位形成蓄积，增强药效。 稳定性：铁蛋白的环境要求低，部分情况分解成亚基后仍能重组恢复笼状结构，在制备和储存工艺上要求简便很多。 靶向性：该领域铁蛋白主要优势主要有两者，一者是肿瘤靶向性的基本要求，即肿瘤细胞对铁离子的需求远大于正常细胞，使得肿瘤细胞表面的转铁蛋白受体过度表达；二者是其脑靶向性，由于铁蛋白可跨越血脑屏障，同时转铁蛋白受体在血脑屏障中的表达水平明显高于正常细胞组织，被寄希望于多种中枢神经疾病的药物载体。 很明显，就算同属于蛋白偶联药物，在较EDC药物高效、稳定与免疫副作用等相同的优势，不同技术路线的蛋白偶联药物也有着差异化的优势（如FDC的脑靶向性），而随着生物医药基础研究水平的上升，未来也有望诞生更多非抗体蛋白偶联药物，进一步丰富领域优势性的同时，也可以拉高整个市场的天花板。 国内空白 蛋白偶联药物的蓝海市场 就蛋白偶联药物市场而言，尽管近年来受ADC大火所带动，但目前国内外对于该类型药物的研究尚不完善，领域内多项技术仍处于临床早期阶段，相关性报道并不多。 数据显示，全球活跃蛋白偶联类临床药物仅有20款，且绝大多数均处于临床前阶段，FutureChe的镥[177Lu]Ludotadipep是目前临床进度最快的管线产品。 而就在研药物适应症来看，实体瘤、肺癌、乳腺癌等热门疾病类型的集中度明显更高，但同时部分蛋白偶联药物管线也选择了自免、脓毒症、代谢疾病与神经系统疾病为主要突破点。 其中，Aro Biotheraputics的「ABX1100」与Alpha Cancer Technologies的「ACT-903」是目前在研药物中信息披露较全面的品种，也是蛋白偶联药物中具有代表意义的品种。 「ABX1100」 ABX1100由ARO利用其Centyrins专利平台技术开发的核心产品，其特色的Centyrin蛋白FF0C具有优异的稳定性和溶解度、包括体积较小、可大肠杆菌生产，免疫原性较低，化学偶联方法与生产方式相对比较简单等优势，特别适合靶向递送寡核苷酸。 图片来源：ARO官网 与抗体相比，Centyrins在早期内体中含量更高递送速度更快，这可能Centyrins分子量小具有强渗透性优势， 这样更多的药物分子能够实现内涵体逃逸从而发挥其作用。 作为ARO针对庞贝病的一种全新潜在治疗方法，ABX1100由结合CD71受体的Centyrin与特异性干扰Gys1 mRNA表达的小干扰RNA（siRNA）结合而成，从而降低肌肉组织中Gys1酶的水平和整体活性。在GLP毒理学研究中显示出良好的安全性，肌肉中Gys1 mRNA的持久减少，支持每月或每季度给药的潜力，目前已获得美国食品药品监督管理局颁发的孤儿药资格认定和儿科罕见病资格认定。 「ACT-903」 Alpha Cancer Technologies Inc. (ACT）是一家生物制药公司，专注于其特有的重组人α胎蛋白（AFP）平台开发和商业化靶向免疫肿瘤学和免疫调节疗法。 图片来源：ACT官网 ACT-903作为ACT公司下一代ADC技术靶向α胎蛋白受体治疗癌症新方法的重要管线，其在2023 ASCO大会上首次亮相，是一种新型甲胎蛋白（AFP)-美坦氨酸偶联物，在一项卵巢异种移植模型试验中，ACT-903四种给药方案下的临床数据进行了对照，并观察其细胞毒性，目前所有治疗组体积缩小与生存期增加上均有明显统计学意义。 ACT-903结合物对肿瘤体积的影响 图片来源：ACT官网 总研究结果显示，ACT-903在卵巢异种移植模型中的安全性和有效性，以及在患者来源的癌症类器官中观察到的细胞毒性，支持ACT-903进入临床研究。目前ACT已计划在2024年提交ACT-903的研究新药（IND）申请。 小结 随着ADC药物的越来越火、越来越卷，就连PDC、FDC、SMDC、ISAC、RDC等领域的竞争格局也同样开始不容乐观，稀有标的属性正在逐渐消失，如何在偶联领域形成更差异化的竞争成为行业后续主要的思考方向。 但同时，药物研发虽不能盲目跟风，但也不能为了差异化而差异化，应着重考虑临床优势与产业优势，而对于蛋白偶联药物而言，尽管目前各项研究都尚处于早期阶段，但其高效、稳定与特殊靶向性等特点也足够吸引人。 或许，随着未来研究的深入，蛋白偶联药物还真有望成为下一代更具潜力的ADC技术。 路漫漫其修远兮，吾等仍将上下而求索。 参考资料： 外泌体的五大商业应用（三）：外泌体偶联药物，精致颜容， 2024年01月14日 药物递送（八）——铁蛋白技术， 药物递送，2021年10月08日 双靶向Centyrin-siRNA偶联物ABX300及其siRNA平台分析， 洞见conjugates 2022年06月19日 ALPHA CANCER TECHNOLOGIES PRESENTS NEW DATA FROM ACT-903, AN AFP-MAYTANSINE CONJUGATE, IN ONLINE PUBLICATION AT THE 2023 AMERICAN SOCIETY OF CLINICAL ONCOLOGY (ASCO) ANNUAL MEETING，ACT官网 来源 | 博药（药智网获取授权转载） 撰稿 | 头孢 责任编辑 | 八角 声明：本文系药智网转载内容，图片、文字版权归原作者所有，转载目的在于传递更多信息，并不代表本平台观点。如涉及作品内容、版权和其它问题，请在本平台留言，我们将在第一时间删除。 商务合作 | 王存星 19922864877（同微信）  阅读原文，是昨天最受欢迎的文章哦

Statistically significant dose-dependent reduction in tumor volume across all treatment groups compared to control in an ovarian xenograft model. Complete elimination of tumor and 100% survival observed in the group receiving optimal treatment regimen. TORONTO--(BUSINESS WIRE)-- Alpha Cancer Technologies Inc. (ACT), a biopharmaceutical company focused on developing and commercializing targeted immuno-oncology and immunomodulation therapies based on its proprietary recombinant human Alpha Fetoprotein (AFP) platform, today announced details from the company’s abstract published as part of the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting. The ASCO meeting will take place in Chicago from June 2-6, 2023. “ACT continues to build upon the body of evidence supporting our novel approach of targeting alpha fetoprotein receptors for the treatment of cancer using our truly next-generation ADC technology,” said Dr. Igor Sherman, CEO of ACT. “By selectively targeting cancer cells and myeloid derived suppressor cells we can deliver toxins directly to the tumor, leading to enhanced therapeutic efficacy while mitigating many of the side effects associated with traditional ADC treatments. Now across multiple tumor models, we have observed high activity in treatment groups including statistically significant dose-dependent reduction in tumor volume and increased survival. With robust preclinical data demonstrating both safety and efficacy, we look forward to taking ACT-903 into the clinic next year.” The abstract, entitled “Efficacy and safety study of a novel Alpha-fetoprotein (AFP)-Maytansine conjugate in an ovarian xenograft model” was selected by the ASCO Scientific Program Committee for publication in the 2023 ASCO Annual Meeting Proceedings, a supplement to the Journal of Clinical Oncology. The research used an ovarian xenograft model compared to control with four dosing regimens of the AFP-maytansine conjugate, ACT-903. Tumor growth, survival, and clinical observations were assessed 62 days following implantation. Separately, organoids were cultured from primary reprogrammed tumor cells from two different patients with high-grade serous ovarian carcinoma and treated with ACT-903 to observe cytotoxicity. The results in the ovarian xenograft models, consistent with prior research conducted by ACT using colorectal xenograft models, show a statistically significant dose-dependent reduction in tumor volume (p<0.001) and increase in survival (p<0.002) in all treatment groups when compared to the control group. All mice survived to the end of the study (day 62) in Groups 1, 3, and 4, and 6 out of 10 mice survived in the lowest dose group. In the control group, all animals were dead by day 38 due to excessive tumor burden. In the highest dose group, 100% of the mice had complete tumor regression with no regrowth at the end of the study. No signs of toxicity were observed in any treatment group. In the two ovarian organoids, ACT-903 demonstrated a cytotoxic effect over 72 hours similar to that of other known anti-cancer agents, such as paclitaxel and cisplatin. The results from this study demonstrating the safety and efficacy of ACT-903 in ovarian xenograft models and the cytotoxicity observed in patient-derived cancer organoids support advancement of ACT-903 into clinical studies. ACT plans to submit an Investigational New Drug (IND) application for ACT-903 in 2024. About Alpha Cancer Technologies, Inc. Alpha Cancer Technologies Inc., (ACT) is a private clinical stage biotechnology company with immuno-oncology, theranostics and immunomodulation platforms under development. The company’s drug products use ACT’s patented recombinant human alpha fetoprotein (ACT-101). ACT’s immuno-oncology products target AFP receptors uniquely expressed on almost all solid and liquid tumors and certain immune suppressor cells but are absent on normal cells. This approach utilizes next-generation ADC technology and offers the benefits of much lower toxicity and greater efficacy compared to conventional chemotherapy and other targeted therapies. ACT is based in Toronto, Ontario, Canada. For more information, please visit .

TORONTO--( BUSINESS WIRE )--Alpha Cancer Technologies Inc. (ACT), a biopharmaceutical company focused on developing and commercializing targeted immuno-oncology and immunomodulation therapies based on its proprietary recombinant human Alpha Fetoprotein (AFP) platform, today announced the publication of pre-clinical study results in Cancer Cell International highlighting the company’s recombinant human AFP (ACT-101) conjugate with maytansine in mouse xenograft models of colorectal cancer. Results from the study demonstrate the exceptional safety profile and potent anti-tumor activity of multiple ACT-101 conjugates through the successful targeting of the alpha fetoprotein receptor uniquely located on cancerous cells and myeloid-derived suppressor cells (MDSCs). The AFP receptor has been found on the surface of cancer cells and MDSCs exclusively, making it an attractive target for the delivery of toxins selectively to tumor cells and MDSCs. Human AFP acts as a shuttle protein, transporting a variety of molecules including targeted anti-cancer agents inside the cell via the AFP receptor. ACT-101 is a recombinantly produced non-glycosylated form of human AFP, which will carry and deliver maytansine and other chemotherapy payloads to tumor cells via the AFP receptor. The selection of maytansine was based on its prior efficacy in clinical studies when incorporated into ADCs. The AFP receptor has emerged as a novel target for cancer therapeutics given the expression of AFP on most cancers and MDSCs, and lack of presence on normal tissues. Studies were performed to investigate the use of ACT-101 conjugated with maytansine for targeted toxin delivery to cancer. Four structurally different ACT-101-maytansinoid conjugates containing cleavable glutathione sensitive linkers were initially investigated in a mouse xenograft model of colorectal cancer (COLO-205). Reduction in tumor volume was seen for all four conjugates compared to control (p < 0.05). The anti-tumor effects of the conjugate selected for further development, ACT-903, persisted after treatment discontinuation, with tumors becoming undetectable in 9 of 10 mice, and all 10 mice surviving through Day 60 with no obvious signs of toxicity. A follow-up study performed in the same model compared the effects of single intravenous doses of ACT-903 (10–50 mg/kg) to control groups receiving vehicle or ACT-101. A significant reduction of tumor burden compared to control was achieved in the 40 and 50 mg/kg dose groups. Survival was also significantly prolonged in the 40 mg/kg and 50 mg/kg cohorts. Free maytansine blood levels at 4 hours were 0.008% of the dose, indicating stability in circulation as was expected based on in vitro plasma stability studies. No obvious signs of toxicity were seen in any of the treated groups. The observed efficacy and excellent tolerability of ACT-903 in these xenograft models support advancing the development of ACT-903 into clinical studies. “Based on the evidence we continue to observe in our pre-clinical studies, we believe ACT-903 has the potential to address the limitations of current-generation antibody drug conjugates through a targeted delivery exclusively to cancer and immune suppressor cells, allowing for greater efficacy with minimal toxicity,” said Dr. Igor Sherman, CEO of ACT. “Given the broad range of cancer cells expressing the AFP receptor, we believe our technology offers a potential pan-cancer opportunity and we look forward to continuing the development of this program to bring it to cancer patients in the shortest possible time.” The manuscript, titled “High anti-tumor activity of a novel alpha-fetoprotein-maytansinoid conjugate targeting alpha-fetoprotein receptors in colorectal cancer xenograft model,” was published in Cancer Cell International on April 5, 2023 and the full manuscript can be accessed here . About Alpha Cancer Technologies, Inc. Alpha Cancer Technologies Inc., (ACT) is a private clinical stage biotechnology company with immuno-oncology, theranostics and immunomodulation platforms under development. The company’s drug products use ACT’s patented recombinant human alpha fetoprotein (AFP or ACT-101). ACT’s immuno-oncology products target AFP receptors uniquely expressed on almost all solid and liquid tumors and immune suppressor cells but are absent on normal cells. This approach utilizes next-generation ADC technology and offers the benefits of much lower toxicity and greater efficacy compared to conventional chemotherapy and other targeted therapies. ACT is based in Toronto, Ontario, Canada. For more information, please visit www.alpha-cancer.com