Class II Human Leukocyte Antigen biologics for antibody-mediated graft rejection.

用于抗体介导的移植物排斥反应的 II 类人类白细胞抗原生物制剂。

• 批准号: 10598931
• 负责人: HONGJIE GUO
• 金额: $ 27.25万
• 依托单位: ANTIGER THERAPEUTICS INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10598931
• 关键词: Accounting; Address; Adverse effects; Antibodies; Antibody Therapy; Antibody-Producing Cells; Antigens; Automobile Driving; B-Cell Acute Lymphoblastic Leukemia; B-Lymphocytes; Binding; Biochemical; Biological; Biological Assay; Biological Products; Biological Response Modifier Therapy; C-terminal; Cell Culture System; Cells; Chimeric Proteins; Clinical Trials; Complement-Dependent Cytotoxicity; Complex; Development; Dialysis procedure; Dimerization; Dose; Effectiveness; Engineering; FDA approved; Funding; Goals; Graft Rejection; Graft Survival; Grant; HLA Antigens; Health Care Costs; Heart Transplantation; Histocompatibility Antigens Class I; Humoral Immunities; Hybridomas; Immune system; Immunity; Immunoglobulin-Secreting Cells; Immunoglobulins; Immunosuppression; Immunotherapy; In Vitro; Infection; Infection Control; Kidney Transplantation; Licensing; Link; Lung Transplantation; Mammalian Cell; Marketing; Measures; Mediating; Mission; Modification; Mutation; N-terminal; Organ; Orphan Drugs; Outcome; Patients; Peptides; Personal Satisfaction; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Plasma Cells; Plasma Exchange; Production; Proteins; Qualifying; Quality of life; Reporting; Rest; Risk; Safety; Small Business Innovation Research Grant; Specific qualifier value; Specificity; Structure; Therapeutic; Time; Transplant Recipients; United States; Work; antibody immunotherapy; antibody-mediated rejection; clinical translation; commercial application; cytotoxicity; disulfide bond; donor-specific antibody; graft failure; graft function; high risk; immunogenicity; improved; in vivo; infection risk; innovation; mortality; mouse model; novel; novel strategies; post-transplant; preservation; prototype; public health relevance; randomized, clinical trials; retransplantation; targeted treatment; technological innovation; therapeutic target

PROJECT SUMMARY/ABSTRACT The mission of Antiger Therapeutics Inc. is to develop novel immunotherapies for transplant recipients to improve long-term graft outcomes and minimize adverse effects. Antibody-mediated rejection (AMR) is a leading cause of graft loss, with over 3000 new cases per year in the United States and estimated market size of $90 million. However, this estimate is likely to underestimate the market potential as currently no FDA- approved drugs or treatments are available for AMR. Donor-specific antibodies (DSA) against class II human leukocyte antigens (HLA) are the most frequent driver of AMR, which was reported in 68-91% of AMR after kidney, heart, or lung transplants. Current therapies, such as plasma exchange and inhibition of all B cells or plasma cells, have not demonstrated benefits for patients with AMR in randomized clinical trials. These therapies also non-selectively suppress the immune system and increase the risk of severe infections. To address these unmet needs, this SBIR will explore antigen-specific depletion of DSA-producing cells as a novel approach to AMR treatment. In our preliminary work, we generated class I HLA fusion proteins that potently and selectively depleted class I HLA-specific target cells in vitro and in vivo. This work motivated us to develop targeted immunotherapies for AMR caused by class II DSA. The product of this SBIR will be a soluble class II HLA biologic, capable of depleting a unique and more precise therapeutic target—B cells producing antibodies against the specific class II HLA expressed on the graft. The technical innovation of this product is the structure-based engineering of class II HLA to stabilize a high-risk antigen in AMR for production and clinical translation. The product will be among the first-in-class biologics to enable antigen-specific immunotherapy on the AMR market, with the potential of prolonging the graft survival and preserving the rest of the humoral immunity for infection control. We hypothesize that functional class II HLA biologics can be efficiently produced through two distinct engineering approaches, and these biologics should demonstrate selective cytotoxicity against B cell hybridomas of the corresponding specificity. In Specific Aim 1, we will generate a monovalent class II HLA biologic to deplete specific antibody-producing B cell hybridomas. In Specific Aim 2, we will create a bivalent class II HLA biologic to deplete target cells. By the end of this phase I SBIR, we expect to generate one or more candidate proteins with high production yield, purity, and selective cytotoxicity against target cells to meet pre-specified acceptance criteria. We will further demonstrate the efficacy and safety of these candidates in vivo in a phase II SBIR and then pursue licensing the product to a pharmaceutical partner for development toward FDA approval. The ultimate therapy, as a result of this project, will shift the paradigm in AMR treatment to antigen-specific immunosuppression with unprecedented precision.

项目摘要/摘要 Antiger Therapeutics Inc.的使命是为移植受者开发新的免疫疗法 改善长期成绩的结果并最大程度地减少不良反应。抗体介导的排斥（AMR）是 年级损失的主要原因，美国每年有3000多个新病例和估计的市场规模 9000万美元。但是，该估计可能会低估市场潜力，因为目前没有FDA- 批准的药物或治疗可用于AMR。针对II类人的供体特异性抗体（DSA） 白细胞抗原（HLA）是AMR的最常驱动因素，在68-91％的AMR之后报告 肾脏，心脏或肺移植。当前疗法，例如血浆交换和所有B细胞的抑制作用或 在随机临床试验中，血浆细胞尚未显示出对AMR患者的好处。这些 疗法还非选择性抑制免疫系统并增加严重感染的风险。到 满足这些未满足的需求，该SBIR将探索抗原特定的DSA产生细胞的部署 新型AMR治疗方法。在我们的初步工作中，我们生成了I级融合蛋白 在体外和体内有潜在，有选择性地耗尽的I类HLA特异性靶细胞。这项工作使我们融合 由II类DSA引起的开发了针对AMR的靶向免疫疗法。该SBIR的产物将是可溶的 II类HLA生物学，能够耗尽独特，更精确的治疗靶标-B产生的B细胞 针对移植物上表达的特定II类HLA的抗体。该产品的技术创新是 II类HLA的基于结构的工程，以稳定AMR中的高风险抗原进行生产和 临床翻译。该产品将是启用抗原特异性的第一类生物制剂之一 AMR市场上的免疫疗法，有可能延长移植物生存并保留其余的 用于感染控制的体液免疫学。我们假设功能性II类HLA生物制剂可以是 通过两种不同的工程方法有效生产，这些生物制剂应证明 针对相应特异性的B细胞杂交瘤的选择性细胞毒性。在特定目标1中，我们将 产生单价II类HLA生物学，以复制特定的产生抗体的B细胞杂交瘤。在 具体的目标2，我们将创建一个双重II类HLA生物学来复制靶细胞。到本阶段I结束时 SBIR，我们希望产生一种或多种具有高产量，纯度和选择性的候选蛋白 针对靶细胞的细胞毒性符合预先指定的接受标准。我们将进一步证明 这些候选者在II阶段SBIR中在体内的功效和安全性，然后将产品许可为A 开发的制药合作伙伴，以实现FDA批准。由于这个项目的结果，最终的疗法 将以前所未有的精度将AMR处理中的范式转移到抗原特异性免疫抑制。