Validation of Siglec-6 as a novel target for cancer immunotherapy

验证 Siglec-6 作为癌症免疫治疗的新靶点

基本信息

批准号：
9751232
负责人：
Natarajan Muthusamy
金额：
$ 17.98万
依托单位：
SCRIPPS FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9751232
关键词：
Allogenic Antibodies Antibody titer measurement Antigens Attenuated Autologous B lymphoid malignancy B-Lymphocytes Binding Bispecific Antibodies CD3 Antigens Cell Surface Receptors Cell surface Cells Chronic Chronic Lymphocytic Leukemia Clinical Combination Drug Therapy Complementarity Determining Regions Data Development Drug Kinetics Drug Targeting Evaluation Fc domain Funding Opportunities Generations Geometry Goals Half-Life Hematopoietic Stem Cell Transplantation Human ITIM Immune system Immuno-Chemotherapy Immunotherapy Incidence Individual Joints Jupiter Laboratories Leukemic Cell Malignant - descriptor Mediating Methods Modality Monoclonal Antibodies Morbidity - disease rate Mus Newly Diagnosed Ohio Pathogenesis Patients Phage Display Placenta Play ROR1 gene Receptor Signaling Receptors, Antigen, B-Cell Refractory Relapse Reporting Research Research Institute Route Sampling Surface Antigens Synapses T-Lymphocyte Testing Therapeutic Time Tissues Toxic effect Transgenic Mice Transgenic Organisms Transplantation United States Food and Drug Administration Universities Validation Work Xenograft procedure anergy antibody engineering antibody libraries arm base cancer immunotherapy cancer therapy cell killing chronic lymphocytic leukemia cell curative treatments deep sequencing design exhaustion experience experimental study graft vs leukemia effect human monoclonal antibodies in vivo in vivo evaluation kinase inhibitor leukemia lifetime risk mast cell mortality mouse model novel preclinical development preclinical study receptor recruit response sialic acid binding Ig-like lectin small molecule targeted treatment

项目摘要

PROJECT SUMMARY In response to funding opportunity announcement PAR-16-176, this joint proposal by Drs. Christoph Rader from The Scripps Research Institute (Jupiter, FL) and Natarajan Muthusamy from The Ohio State University (Columbus, OH) proposes to validate a novel target for immunotherapy of chronic lymphocytic leukemia (CLL). As part of the proposed study, we will develop novel T-cell engaging bispecific antibodies (biAbs) and a novel transgenic mouse model to assess and initiate further preclinical development. Our research team will generate, validate, and deliver novel biAbs that are specifically designed to recruit and activate T cells for selective and potent eradication of malignant B cells in CLL patients. CLL is the most common leukemia in the U.S. with a lifetime risk of 0.6% and an annual mortality of ~5,000. Despite the advent of immunochemotherapy and small molecule kinase inhibitors, there remains a great need for potent and safe treatment options for newly diagnosed, refractory, and relapsed CLL patients. In fact, there are currently no Food and Drug Administration (FDA)- approved therapeutic modalities in CLL that allow for selective targeting of malignant B cells without harming healthy cells and tissues. Notably, allogeneic hematopoietic stem cell transplantation (alloHSCT) has remained the only potentially curative treatment of CLL, underscoring the unmatched capability of immunotherapy. Pursuing potential contributors of the powerful graft-versus-leukemia (GVL) response, we devised a concerted antibody drug and target discovery strategy by generating the first post-alloHSCT antibody library from a cured CLL patient and selecting it by phage display against primary CLL cells. We identified a panel of fully human monoclonal antibodies (mAbs) with a common antigen on primary CLL cells. In still undisclosed work presented for the first time in this proposal, we identified the new target as Siglec-6. In healthy individuals, the expression of Siglec-6 is highly restricted to the placenta, to mast cells, and to certain B-cell subpopulations. Its expression on leukemia cells in CLL has not been reported previously. Our proposed study, which builds on our combined strengths in antibody engineering and transgenic mouse models, on the availability of clinical samples from both untreated and treated CLL patients for ex vivo and in vivo preclinical studies, as well as on our extensive supporting data, has the objective to rigorously test the hypothesis that Siglec-6 can serve as a target for T-cell recruiting and activating biAbs to mediate potent and safe eradication of leukemia cells in CLL patients. The experimental execution of this objective will be based on two Specific Aims. In Aim 1, we will build and test a panel of Siglec-6 x CD3 biAbs for primary CLL cell killing by autologous T-cells ex vivo and in vivo. In Aim 2, we will develop a novel CLL mouse model expressing transgenic human Siglec-6 and employ it for the in vivo evaluation of surrogate Siglec-6 x CD3 biAbs in a native and competent immune system. Collectively, our study explores a unique route for targeted therapy of CLL by interrogating a novel target with novel agents and a novel mouse model to assess and initiate further preclinical development.

项目摘要为了回应筹资机会公告16-176，这项由Drs的联合提案。克里斯托夫·拉德（Christoph Rader）来自Scripps研究所（佛罗里达木星）和俄亥俄州立大学的Natarajan Muthusamy （俄亥俄州哥伦布）提议验证慢性淋巴细胞白血病（CLL）免疫疗法的新靶标。作为拟议研究的一部分，我们将开发新型的T细胞引人入胜的双特异性抗体（BIAB）和一种新颖转基因小鼠模型评估和启动进一步的临床前发展。我们的研究团队将产生验证并提供专门设计的新型BIAB，以募集和激活T细胞以进行选择性和 CLL患者的恶性B细胞有效地消除。 CLL是美国最常见的白血病终身风险为0.6％，年死亡率约为5,000。尽管免疫化学疗法和小分子激酶抑制剂，对于新诊断的有效和安全的治疗方案仍然非常需要难治性和复发性CLL患者。实际上，目前没有食品药品监督管理局（FDA） - CLL中批准的治疗方式，可以选择性靶向恶性B细胞而不会损害健康的细胞和组织。值得注意的是，同种异体造血干细胞移植（AlloHSCT）仍然存在 CLL的唯一潜在治疗方法强调了免疫疗法无与伦比的能力。追求强大的移植物 - 白血病（GVL）的潜在贡献者，我们设计了一个协调一致的抗体药物和靶标发现策略通过从固化的第一个后AllOHSCT抗体库中产生 CLL患者并通过针对原代CLL细胞的噬菌体显示。我们确定了一个完全人类的小组单克隆抗体（mAb）在原代CLL细胞上具有共同的抗原。在仍然未公开的工作中在本提案中，我们第一次将新目标确定为Siglec-6。在健康的个体中，表达 SIGLEC-6的高度仅限于胎盘，肥大细胞以及某些B细胞亚群。它的表达以前尚未报道过CLL中的白血病细胞。我们提出的研究，基于我们的总和抗体工程和转基因小鼠模型的优势，涉及两者的临床样品的可用性未经治疗和治疗的CLL患者进行了体内和体内临床前研究，以及我们广泛的支持数据的目标是严格检验SIGLEC-6可以作为T细胞目标的假设招募和激活BIAB，以介导CLL患者中白血病细胞的有效和安全根除。这该目标的实验执行将基于两个具体目标。在AIM 1中，我们将构建和测试 Siglec-6 X CD3 BIAB的面板，用于自体T细胞杀死t-t-cells ex Vivo和In Vivo。在AIM 2中，我们将开发一种表达转基因人Siglec-6的新型CLL小鼠模型并将其用于体内在本地和称职的免疫系统中评估替代Siglec-6 x CD3 BIAB的评估。总体而言，我们的研究通过用新颖的代理和一种新颖的新目标询问新目标，探索针对CLL的靶向治疗的独特途径小鼠模型评估和启动进一步的临床前开发。