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

项目摘要/摘要 安提格治疗公司的使命是为移植受者开发新的免疫疗法，以 改善移植物的长期疗效并将不良反应降至最低。抗体介导排斥反应(AMR)是一种 腐败损失的主要原因，美国每年有3000多例新病例，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- 已批准的药物或治疗方法可用于AMR。抗人II类供体特异性抗体(DSA) 白细胞抗原(HL A)是AMR最常见的驱动因素，据报道68-91%的AMR发生在 肾、心脏或肺移植。目前的治疗方法，如血浆置换和抑制所有B细胞或 在随机临床试验中，浆细胞并未显示出对AMR患者的益处。这些 治疗还非选择性地抑制免疫系统，增加严重感染的风险。至 解决这些未得到满足的需求，这项SBIR将探索抗原特异性的DSA产生细胞的耗竭作为一种 治疗AMR的新方法。在我们的初步工作中，我们产生了I类人类白细胞抗原融合蛋白 在体外和体内有效和选择性地耗尽I类人类白细胞抗原特异性靶细胞。这项工作激励我们 开发针对II类DSA引起的AMR的靶向免疫疗法。这种丁苯橡胶的产物将是一种可溶的 II类人类白细胞抗原生物，能够耗尽一个独特的、更精确的治疗靶点-B细胞产生 移植物上表达针对特定II类人类白细胞抗原的抗体。该产品的技术创新之处在于 基于结构的第二类人类白细胞抗原工程以稳定AMR中的高危抗原生产和 临床翻译。该产品将是一流的生物制品之一，能够实现抗原特异性 免疫疗法在AMR市场上的应用，具有延长移植物存活和保存其余移植物的潜力 体液免疫用于控制感染。我们假设功能性II类人类白细胞抗原生物制品可能是 通过两种不同的工程方法高效生产，这些生物制剂应该证明 对相应特异性的B细胞杂交瘤具有选择性细胞毒作用。在具体目标1中，我们将 产生单价II类人类白细胞抗原生物以耗尽产生特异性抗体的B细胞杂交瘤。在……里面 具体目标2，我们将创造一个二价的II类人类白细胞抗原生物来耗尽靶细胞。到第一阶段结束时 SBIR，我们希望产生一个或多个具有高产量、高纯度和选择性的候选蛋白质 对靶细胞的细胞毒性，以满足预先指定的接受标准。我们将进一步展示 这些候选药物在体内的第二阶段SBIR的有效性和安全性，然后寻求将产品授权给 向FDA批准开发的药物合作伙伴。最终的疗法，作为这个项目的结果， 将以前所未有的精度将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.