B7-DC Cross-linking antibody immunotherapy

B7-DC交联抗体免疫疗法

• 批准号: 7320592
• 负责人: SVETOMIR Nenad MARKOVIC
• 金额: $ 28.53万
• 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 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7320592
• 关键词: Admission activity; Aliquot; American Joint Committee on Cancer; Animals; Antibodies; Blood; Blood donor; Characteristics; Clinic; Clinical; Clinical Data; Clinical Research; Clinical Trials; Condition; Cytotoxic Chemotherapy; Cytotoxic T-Lymphocytes; Dendritic Cells; Dendritic cell activation; Development; Disease; Disease regression; Disseminated Malignant Neoplasm; Dose; Functional disorder; Guidelines; HLA-A2 Antigen; Helper-Inducer T-Lymphocyte; Homeostasis; Hospitals; Human; Immune; Immune System Diseases; Immune system; Immunoglobulin M; Immunotherapeutic agent; Immunotherapy; In Vitro; Interleukin-2; Intervention; Investigation; Laboratories; Lead; Malignant - descriptor; Malignant Neoplasms; Malignant lymphoid neoplasm; Mediating; Metastatic Melanoma; Mus; Patients; Pattern; Pharmacologic Substance; Phase I Clinical Trials; Plasma; Plasma Proteins; Production; Property; Purpose; Recombinants; Safety; Serum; Source; Staging; Surface; Survival Rate; T-Lymphocyte; Testing; Therapeutic; Time; Toxic effect; Transfusion; Translating; Tumor Immunity; Validation; Waldenstrom Macroglobulinemia; Week; Work; base; concept; cost; crosslink; cytokine; immunoregulation; in vivo; intravenous injection; melanoma; novel; pathogen; patient safety; pre-clinical; treatment effect; tumor; volunteer

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(申请人提供)：B7-DC Xab是一种患者来源的IgM抗体，能够将人和小鼠树突状细胞表面的B7-DC分子交联。这种人类抗体已经得到了充分的表征，并在临床前进行了作为免疫调节剂/癌症免疫治疗药物的效用测试。其特点之一是能够在荷瘤小鼠体内产生有效的细胞毒性T细胞介导的抗肿瘤免疫；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在体外以相似的方式激活人和小鼠的DC，我们将测试抗体将以类似于在小鼠身上观察到的方式调节人类免疫系统的假设，当抗体被注射给转移性黑色素瘤患者时。在此，我们提出了一项原则证明的I期临床试验，评估B7-DC Xab对转移性恶性黑色素瘤患者的安全性和免疫调节特性。除了评估这种有效的免疫调节剂治疗患者的安全性外，我们还将评估治疗对树突状细胞激活、肿瘤特异性T细胞功能和细胞因子产生的影响。抗体的来源是独一无二的，因为自然产生抗体的患者善意地捐赠了血浆用于这项研究。已经收集了患者的血浆，检测了与输血有关的病原体，并根据B7-DC Xab的数量和比活性按单位剂量等分。这一方法将使我们能够在人类身上测试B7-DC Xab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，而不需要制造GMP级抗体的成本。如果研究成功，结果将证明重组B7-DC Xab的合成及其作为新药的开发是合理的。在过去的几年里，我们已经能够在转移性癌症(如黑色素瘤)的动物研究中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，导致保护性抗肿瘤免疫。抗体(B7-DC Xab)是从一名患有低级别淋巴系统恶性肿瘤的健康患者的血液中分离出来的，该患者负责产生B7-DC Xab。目前提议的临床试验是将我们的实验室工作“转化”到临床的一种尝试，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“原则证明”临床试验将证明B7-DC Xab作为一种癌症治疗方法的进一步发展是合理的，具有潜在的普遍应用于所有恶性疾病的潜力。