Strategy for specific delivery of antisense oligonucleotides to T cells

将反义寡核苷酸特异性递送至 T 细胞的策略

基本信息

批准号：
10547347
负责人：
Gaddiel Galarza-Munoz
金额：
$ 30.65万
依托单位：
AUTOIMMUNITY BIOLOGIC SOLUTIONS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-17 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10547347
关键词：
Address Antibodies Antisense Oligonucleotides Autoimmune Diseases Autoimmunity Binding Biological CD4 Positive T Lymphocytes Cell Surface Receptors Cell physiology Cells Cellular biology Clinical Communicable Diseases Development Disease Dose Ensure Exclusion Exons Eye Gene Expression Genes Genetic Diseases Goals Health Hepatic Hepatocyte Homeostasis Human IL2RB gene Immune Immunologic Deficiency Syndromes Immunologics Immunooncology Interleukin 2 Receptor Interleukin 7 Receptor Liver Maintenance Malignant Neoplasms Mediating Methods Monoclonal Antibodies Mus Muscle Nerve Degeneration Neuraxis Peptides Pharmaceutical Preparations Pharmacotherapy Phase Proteins Proteome RNA Splicing Role Safety Specificity Spleen T-Cell Immunologic Specificity T-Lymphocyte Testing Therapeutic Therapeutic Index Thymus Gland Tissues Toxic effect Transfection Tumor Suppression Vaccines Validation Visualization Work antibody conjugate base cancer cell cancer therapy cell type empowered fluorophore immunoregulation improved in vivo in vivo Model lymph nodes nanobodies nonhuman primate peripheral blood programmed cell death protein 1 receptor receptor mediated endocytosis response success tool tumor uptake vaccine development vaccine response

项目摘要

PROJECT SUMMARY Antisense oligonucleotides (ASOs) are promising drugs given their potential to modify expression of disease- related genes, including those previously considered ‘undruggable’. Despite their clinical potential, their success has been limited to hepatic, muscular and neurodegenerative conditions due to limitations with delivering ASOs to tissues other than liver, muscle and the central nervous system (CNS), which are tissues with either rich distribution of ASOs or specific delivery methods. Unfortunately, applications to immunological conditions or conditions that could benefit from immuno-modulation (e.g., cancer, vaccines) have been limited due to the lack of effective tools to deliver ASOs to immune cells in vivo, in particular to T cells. Accordingly, delivery tools that could enhance the efficiency and specificity of ASO delivery to T cells remain a critical unmet need. To address this critical need, ABS is developing a modular delivery platform to target ASOs specifically to T cells utilizing conjugated mono-specific monoclonal antibodies (mmAbs) against T cell-specific cell surface receptors. mmAbs are highly specific antibodies that have been screened against the human proteome and selected for their exclusive binding to the target protein. Such selectivity screen is not usually employed in the development of monoclonal antibodies, resulting in antibodies that bind to other proteins besides their intended target, thereby enhancing potentially toxic effects due to off-target binding. Accordingly, the mmAbs proposed here have the potential to enhance delivery of ASOs to T cells while reducing potential toxic effects of the antibody conjugate. ABS’ T cell-specific delivery platform takes advantage of the T cell-predominant expression of the Programmed Cell Death Protein 1 (PDCD1, PD1, CD279) and Interleukin 2 Receptor Subunit Beta (IL2RB, CD122). Besides their T cell-predominant expression, their biological roles in T cells make them attractive candidates. PDCD1 is highly expressed in tumor-infiltrating T cells and mediates suppression of these tumor-reactive T cells, thereby hindering their efficacy to kill cancer cells. Accordingly, -PDCD1 antibodies could have a dual role in enhancing tumor reactivity by directing immuno-modulatory ASOs to these critical cells, while also relieving the PDCD1- mediated suppression of tumor-reactive T cells. IL2RB promotes receptor-mediated endocytosis in T cells, and here we leverage this function to target and drive internalization of the conjugated ASO specifically in T cells. The goal of this Phase I proposal is to test the efficiency and specificity of -PDCD1 and -IL2RB mmAbs to deliver the conjugated ASOs to T cells ex vivo and in mice. Successful completion of this goal will validate the utility of ABS’ T cell-specific delivery platform to deliver ASOs to T cells in vivo. This modular delivery platform will have broad impact on human health given its wide applicability for treatment of cancers, immunodeficiencies, autoimmune and infectious diseases, and applications in vaccine development. In the ensuing Phase II proposal, we will create a mono-specific nanobody of the optimal mmAb to further improve its therapeutic index, and test its efficacy and safety to deliver ASOs to T cells in mice and nonhuman primates.

项目概要反义寡核苷酸（ASO）是有前途的药物，因为它们具有改变疾病表达的潜力。相关基因，包括那些以前被认为“不可成药”的基因，尽管它们具有临床潜力，但它们却取得了成功。由于提供 ASO 的限制，仅限于肝脏、肌肉和神经退行性疾病肝脏、肌肉和中枢神经系统（CNS）以外的组织，这些组织富含不幸的是，ASO 的分布或特定的递送方法不适用于免疫学条件或。由于缺乏免疫调节，可受益于免疫调节的疾病（例如癌症、疫苗）受到限制。将 ASO 递送至体内免疫细胞，特别是 T 细胞的有效工具的研究。可以提高 ASO 递送至 T 细胞的效率和特异性仍然是一个关键的未满足的需求。为了满足这一关键需求，ABS 正在开发一种模块化递送平台，以将 ASO 专门针对 T 细胞利用针对 T 细胞特异性细胞表面受体的缀合单特异性单克隆抗体 (mmAb)。 mmAb 是高度特异性的抗体，已针对人类蛋白质组进行筛选并选择用于它们与目标蛋白的排他性结合通常不会在开发中使用。单克隆抗体，产生的抗体可以结合除预期目标之外的其他蛋白质，从而增强由于脱靶结合而产生的潜在毒性作用。因此，本文提出的 mmAb 具有以下特点：增强 ASO 向 T 细胞的递送的潜力，同时减少抗体缀合物的潜在毒性作用。 ABS 的 T 细胞特异性递送平台利用了编程的 T 细胞主导表达细胞死亡蛋白 1（PDCD1、PD1、CD279）和白介素 2 受体亚基 Beta（IL2RB、CD122）。它们以 T 细胞为主的表达，在 T 细胞中的生物学作用使它们成为有吸引力的候选者。在肿瘤浸润 T 细胞中高表达并介导这些肿瘤反应性 T 细胞的抑制，从而阻碍其杀死癌细胞的功效因此，α-PDCD1 抗体可能具有增强作用的双重作用。通过将免疫调节 ASO 导向这些关键细胞来降低肿瘤反应性，同时还减轻 PDCD1- IL2RB 介导的肿瘤反应性 T 细胞抑制促进 T 细胞中受体介导的内吞作用，以及在这里，我们利用这个功能来靶向并驱动结合的 ASO 的内化，特别是在 T 细胞中。该第一阶段提案的目标是测试 α-PDCD1 和 α-IL2RB mmAb 的效率和特异性，以将缀合的 ASO 递送至体外和小鼠体内的 T 细胞将验证这一目标的成功完成。 ABS 的 T 细胞特异性递送平台可将 ASO 递送至体内 T 细胞。由于其广泛适用于治疗癌症、免疫缺陷、自身免疫性疾病和传染病以及在疫苗开发中的应用在随后的第二阶段提案中，我们将创建最佳mmAb的单特异性纳米抗体，进一步提高其治疗指数，并进行测试其将 ASO 递送至小鼠和非人灵长类动物 T 细胞的功效和安全性。