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

项目总结/摘要 Antiger Therapeutics Inc.的使命是为移植受者开发新的免疫疗法， 改善移植物长期结果并使副作用最小化。抗体介导的排斥反应（Antibody-mediated rejection，AMR） 移植物丢失的主要原因，在美国每年有超过3000例新发病例，估计市场规模 9000万美元然而，这一估计可能低估了市场潜力，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最常见的驱动因素， 肾脏心脏或肺移植目前的治疗，如血浆交换和抑制所有B细胞或 在随机临床试验中，尚未证明浆细胞对AMR患者的益处。这些 治疗还非选择性地抑制免疫系统并增加严重感染的风险。到 为了解决这些未满足的需求，该SBIR将探索抗原特异性的DSA产生细胞耗竭， AMR治疗的新方法。在我们的初步工作中，我们产生了I类HLA融合蛋白， 在体外和体内有效且选择性地消除I类HLA特异性靶细胞。这项工作促使我们 开发针对II类DSA引起的AMR的靶向免疫疗法。该SBIR的产物将是可溶的 II类HLA生物制品，能够消耗独特且更精确的治疗靶点-B细胞， 针对移植物上表达的特异性II类HLA的抗体。该产品的技术创新点是 II类HLA的基于结构的工程化以稳定AMR中的高风险抗原用于生产， 临床翻译该产品将成为一流的生物制剂，使抗原特异性 AMR市场上的免疫疗法，具有延长移植物存活和保留其余部分的潜力 控制感染的体液免疫。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地生产，这些生物制剂应该证明 对相应特异性的B细胞杂交瘤的选择性细胞毒性。具体目标1： 产生单价II类HLA生物制品以耗尽产生特异性抗体的B细胞杂交瘤。在 具体目标2，我们将创建二价II类HLA生物制剂以耗尽靶细胞。到第一阶段结束时， SBIR，我们期望产生一个或多个候选蛋白，具有高产量，纯度和选择性， 对靶细胞的细胞毒性，以符合预先规定的验收标准。我们将进一步展示 在II期SBIR中对这些候选药物进行体内有效性和安全性研究，然后将产品许可给 制药合作伙伴的发展对FDA的批准。最终的治疗，作为这个项目的结果， 这将以前所未有的精确度将AMR治疗的范式转变为抗原特异性免疫抑制。

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.