B7-DC Cross-linking antibody immunotherapy

B7-DC交联抗体免疫疗法

• 批准号: 7485730
• 负责人: SVETOMIR Nenad MARKOVIC
• 金额: $ 28.56万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2010-04-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7485730
• 关键词: Aliquot; Animals; Antibodies; B7-DC antigen; Blood; Characteristics; Clinic; Clinical Data; Clinical Trials; Cytotoxic T-Lymphocytes; Dendritic Cells; Dendritic cell activation; Development; Disease; Disease regression; Disseminated Malignant Neoplasm; Dose; Helper-Inducer T-Lymphocyte; Human; Immune; Immune system; Immunoglobulin M; Immunotherapeutic agent; Immunotherapy; In Vitro; Laboratories; Malignant - descriptor; Malignant Neoplasms; Malignant lymphoid neoplasm; Mediating; Metastatic Melanoma; Mus; Patients; Pattern; Pharmacologic Substance; Phase I Clinical Trials; Plasma; Production; Property; Recombinants; Safety; Source; Surface; T-Lymphocyte; Testing; Therapeutic; Transfusion; Translating; Tumor Immunity; Work; base; cost; crosslink; cytokine; in vivo; melanoma; novel; pathogen; pre-clinical; treatment effect; tumor

DESCRIPTION (provided by applicant): B7-DC XAb is a patient derived IgM antibody capable of cross linking surface B7-DC molecules on human and murine dendritic cells. This human antibody has been fully characterized and pre-clinically tested for its utility as an immune modulator/cancer immunotherapeutic. Among its characteristics is the ability to generate effective cytotoxic T cell mediated anti-tumor immunity in tumor bearing mice; and to change the polarity of mouse helper T lymphocytes (HTL) from Th2 to Th1 in vivo (and in vitro) resulting in tumor regression. Because B7-DC XAb activates both human and mouse DC in vitro in a similar manner, we will test the hypothesis that the antibody will modulate the human immune system in a manner similar to the pattern observed in the mouse when the antibody is administered to patients with metastatic melanoma. Herein, we propose a proof-of-principle, phase I clinical trial evaluating the safety and immunomodulatory properties of B7-DC XAb administered to patients with metastatic malignant melanoma. In addition to evaluating the safety of treating patients with this potent immune modulator, we will evaluate the effects of treatment on dendritic cell activation, the function of tumor- specific T cells and the production of cytokines. The source of the antibody is unique in that the patient who naturally produces the antibody has kindly donated plasma to be used in this study. The patient's plasma has been collected, tested for transfusion-related pathogens and aliquoted in unit doses based on the quantity and specific activity of B7-DC XAb. This approach will allows us to test the safety/immunomodulatory activity of B7-DC XAb in humans and compare the results to our pre-clinical data, without the cost of GMP-grade antibody manufacturing. If the study is successful, the results will justify efforts towards synthesis of recombinant B7-DC XAb and its development as a novel pharmaceutical. Over the last several years we've been able to identify and fully characterize a unique, spontaneously occurring human antibody capable of human dendritic cell activation leading to protective anti-tumor immunity in animal studies of metastatic cancer (e.g. melanoma). The antibody (B7-DC XAb) was isolated from the blood of an otherwise healthy patient with a low grade lymphoid malignancy responsible for the production of B7-DC XAb. The currently proposed clinical trial represents an attempt to "translate" our laboratory work into the clinic and will evaluate the safety and immune modulatory properties of B7-DC XAb in patients with metastatic melanoma. If successful, this "proof-of-principle" clinical trial will justify further development of B7-DC XAb as a cancer therapeutic with potential universal application for all malignant disorders.

描述（由申请人提供）：B7-DC XAb 是源自患者的 IgM 抗体，能够交联人和鼠树突状细胞上的表面 B7-DC 分子。这种人类抗体作为免疫调节剂/癌症免疫治疗剂的实用性已得到充分表征和临床前测试。其特点之一是能够在荷瘤小鼠中产生有效的细胞毒性 T 细胞介导的抗肿瘤免疫；并在体内（和体外）将小鼠辅助 T 淋巴细胞 (HTL) 的极性从 Th2 改变为 Th1，从而导致肿瘤消退。由于 B7-DC XAb 在体外以类似的方式激活人类和小鼠 DC，因此我们将测试以下假设：该抗体将以与将抗体施用给患者时在小鼠中观察到的模式类似的方式调节人类免疫系统患有转移性黑色素瘤。在此，我们提出了一项原理验证 I 期临床试验，评估对转移性恶性黑色素瘤患者施用 B7-DC XAb 的安全性和免疫调节特性。除了评估使用这种强效免疫调节剂治疗患者的安全性之外，我们还将评估治疗对树突状细胞活化、肿瘤特异性 T 细胞功能和细胞因子产生的影响。该抗体的来源很独特，因为自然产生该抗体的患者慷慨捐赠了血浆用于本研究。患者的血浆已被收集，检测是否有输血相关病原体，并根据 B7-DC XAb 的数量和比活性分成单位剂量。这种方法将使我们能够测试 B7-DC XAb 在人体中的安全性/免疫调节活性，并将结果与​​我们的临床前数据进行比较，而无需 GMP 级抗体制造成本。如果研究成功，结果将证明重组 B7-DC XAb 的合成及其作为新型药物的开发的努力是合理的。在过去的几年中，我们已经能够识别并充分表征一种独特的、自发产生的人类抗体，该抗体能够激活人类树突状细胞，从而在转移性癌症（例如黑色素瘤）的动物研究中产生保护性抗肿瘤免疫。该抗体 (B7-DC XAb) 是从一名健康患者的血液中分离出来的，该患者患有低度淋巴恶性肿瘤，导致 B7-DC XAb 的产生。目前提出的临床试验代表了将我们的实验室工作“转化”到临床的尝试，并将评估 B7-DC XAb 在转移性黑色素瘤患者中的安全性和免疫调节特性。如果成功，这项“原理验证”临床试验将证明 B7-DC XAb 作为癌症治疗剂的进一步开发是合理的，具有潜在普遍应用于所有恶性疾病的潜力。