MPI

MTAC platform expands company’s protein degradation capabilities to wider set of targets and complements ATAC degrader technology WALTHAM, Mass.--(BUSINESS WIRE)-- Avilar Therapeutics, a biopharmaceutical company focused on extracellular protein degradation, today announced it will present preclinical proof-of-concept data for the company’s MTAC (M6PR Targeting Chimera) protein degrader platform at IMMUNOLOGY™ 2024, the American Association of Immunologists annual meeting taking place May 3-7 in Chicago, Illinois. MTACs are novel bifunctional molecules containing a proprietary Avilar ligand to the mannose 6‑phosphate receptor (M6PR) conjugated to a second ligand that binds to a protein of interest for degradation. MTACs represent an expansion of Avilar’s capabilities for extracellular protein degradation, building on the company’s ATAC (ASGPR Targeting Chimera) platform, which utilizes the asialoglycoprotein receptor (ASGPR) for degradation of proteins in the hepatocyte endolysosome. As a complementary approach, MTACs harness the M6P receptor and work by degrading pathogenic proteins in the endolysosome of M6PR-expressing cells, which include hepatocytes but also encompass multiple additional cell types. Avilar scientists invented novel high affinity ligands to both ASGPR and M6PR, and these ligands form the chemistry backbone for ATACs and MTACs, respectively. In both cases, Avilar’s chemistry enables the design of highly efficient degraders with more streamlined monovalent designs, lower molecular weight, and improved physicochemical properties versus previous approaches. While Avilar leverages ATACs for degrading circulating proteins and hepatocyte membrane proteins, MTACs offer a new and complementary technology for degrading non-hepatocyte membrane proteins involved in the pathogenesis of human diseases. “We are building multiple technologies for protein degradation and have successfully demonstrated in vivo proof-of-concept for ATACs as potent degraders of extracellular proteins,” said Effie Tozzo, PhD, Chief Scientific Officer of Avilar. “While our primary focus continues to be on ATACs as we advance a pipeline of first-in-class degrader medicines, MTACs represent an additional strategy with expanded target reach for extracellular protein degradation.” Highlights from the MTAC data to be presented at the conference include: Development of novel M6PR ligands with enhanced affinity for M6PR through structure-based computational design methods Demonstration that monovalent MTACs containing these high affinity M6PR ligands achieve robust ternary complex formation and efficient uptake and degradation Benchmarking the performance of monovalent MTACs versus tridentate and monodentate bifunctional molecules containing ligands with weaker affinity for M6PR Details of the poster presentation are as follows: Title: In Vitro and In Vivo Proof-of-Concept Studies of Extracellular Protein Degradation Using Novel M6PR-Targeting Chimeras (MTACs) Session Date and Time: Saturday, May 4, 2024, 3:15 p.m. – 4:30 p.m. CT Poster #: 848 Presenter: Lisa Molz, PhD, Vice President, Research The poster will be available on the publications page of the Avilar website following the presentation. About Avilar Therapeutics Avilar Therapeutics is a biopharmaceutical company pioneering the discovery and development of extracellular protein degraders, a new frontier in targeted protein degradation. Avilar develops ATACs (ASGPR Targeting Chimeras), a new class of protein degraders that shuttle disease-causing proteins from circulation to the endolysosome where the unwanted proteins are degraded. Avilar has built a proprietary discovery platform that includes novel, high-affinity, small molecule ASGPR ligands and advanced modeling of the biophysics, pharmacokinetics, and pharmacodynamics of ATAC mediated endocytosis and degradation. This platform enables the modular design and synthesis of ATACs extendable across the extracellular proteome to a wide range of proteins involved in the pathogenesis of human diseases. Avilar is leveraging its ATAC platform to create a broad and diverse pipeline of first-in-class extracellular protein degraders. Avilar is based in Waltham, MA. For more information, please visit and follow us on LinkedIn.

在哺乳动物中， 在哺乳动物中，甘露糖（Mannose）是一种对生命至关重要的单糖，它是通过糖酵解分支途径从葡萄糖重新合成的。甘露糖作为一种天然糖类，在许多水果和蔬菜中含量丰富。最近的一些研究表明，甘露糖可以有效地促进免疫耐受，抑制炎症性疾病，并通过抑制糖酵解有效地抑制肿瘤。然而，人们对甘露糖如何发挥其抗癌作用还不完全清除。 2023年7月18日，日本大阪国际癌症研究所的研究人员在 eLife 期刊发表了题为：Metabolic clogging of mannose triggers dNTP loss and genomic instability in human cancer cells 的研究论文。该研究揭示了甘露糖的抗癌机制，并表明了甘露糖可能是一种有前景的癌症复制治疗手段。 甘露糖具有抗癌活性，可以抑制细胞增殖，提高化疗效果。然而，甘露糖具体是如何发挥其抗癌活性的，目前仍然知之甚少。 100多年前，人们就已经知道甘露糖对蜜蜂是致命的，因为蜜蜂不能像人类一样处理甘露糖，从而导致致命的蜜蜂综合征。那么蜜蜂综合征与甘露糖的抗癌特性之间是否存在联系呢？ 研究人员使用从纤维肉瘤中提取的基因工程人类癌细胞，重建了蜜蜂综合征。他们发现，如果没有代谢甘露糖所需的酶，细胞复制就会缓慢，而且更容易受到化疗的影响。 在这项最新研究中，研究团队从纤维肉瘤中提取了人类癌细胞，并敲除了其甘露糖磷酸异构酶（MPI）基因，这种基因工程化人类癌细胞难以代谢甘露糖，从而构建了蜜蜂综合征细胞模型。超过这些基因工程癌细胞代谢能力的大量甘露糖流入会诱导代谢重塑，导致产生具有有限的脱氧核糖核苷三磷酸（dNTPs）的慢循环细胞。重要的是，对新生dNTP生物合成的药理学抑制，足以延缓癌细胞周期进程，使癌细胞对化疗药物顺铂敏感，并抑制休眠复制起始点激活，这表明dNTP丢失诱导的基因组不稳定性是甘露糖抗癌活性的核心机制。 甘露糖在甘露糖磷酸异构酶敲除（MPI-KO）的人类癌细胞中抗癌活性的机制模型 如果我们能找到代谢甘露糖的酶活性较低的癌症类型，那么甘露糖就能起到足够的推动作用，让化疗更有效。癌细胞内糖代谢的糖生物学是一个未被充分开发的前沿领域，可能是一个潜在治疗宝库，等待我们去发现。 研究团队表示，到目前为止，甘露糖最有希望的治疗用途是治疗先天性糖基化紊乱，这种疾病会导致全身范围的严重症状。而甘露糖还可能会给癌细胞带来额外打击，由于甘露糖天然存在于全身，它可以改善癌症治疗，而不会产生任何不良副作用。