Targeting B-cell lymphoma with Leukothera

使用 Leukothera 靶向 B 细胞淋巴瘤

基本信息

批准号：
8451828
负责人：
Benjamin A Belinka
金额：
$ 20.26万
依托单位：
ACTINOBAC BIOMED, INC.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-27 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8451828
关键词：
Adverse effects Affect Antigens B lymphoid malignancy B-Cell Lymphomas Biological Models Biological Products Blood Platelets Bone Marrow Burkitt Lymphoma Cell Death Cell Line Cell surface Cells Collaborations Data Diagnosis Disease Dose Erythrocytes Follicular Lymphoma Hemoglobin Hodgkin Disease In Vitro Institutes Knowledge Leukocytes Liver Lymphoma Macaca mulatta Malignant - descriptor Malignant Neoplasms Mantle Cell Lymphoma Methods NOD/SCID mouse Newly Diagnosed Non-Hodgkin&apos s Lymphoma Organ Patients Refractory Relapse Sampling Screening procedure Specificity Spleen Testing Tissues Toxic effect Work base cancer cell efficacy testing humanized SCID mouse in vivo in vivo Model killings large cell Diffuse non-Hodgkin&apos s lymphoma leukemia leukemia/lymphoma leukotoxin lymph nodes mouse model novel novel therapeutics outcome forecast preclinical study research clinical testing research study

项目摘要

DESCRIPTION (provided by applicant): B-cell lymphomas include Hodgkin's, and non-Hodgkin's lymphoma (NHL) (eg. mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and Burkitt lymphoma). More than 70,000 people will be diagnosed with these B-cell malignancies in the U.S. this year and more than 19,000 will die from NHL alone. B-cell lymphomas can affect numerous organs including the lymph nodes, spleen, liver, and bone marrow. Many patients who receive treatment for B-cell lymphomas become refractory to all available therapies and often die from disease. Thus, there is a significant need to identify newer therapeutics with greater activity and fewer side effects. The novel biologic agent Leukothera(R) (leukotoxin; LtxA) specifically targets active leukocyte function antigen-1 (LFA-1) expressed on white blood cells (WBCs). Malignant WBCs constantly express high levels active LFA-1, allowing LtxA to target specifically diseased cells while minimally affecting healthy cells and tissue. LtxA employs several mechanisms of cell death to intoxicate susceptible WBCs. We have found that cell lines and primary cells from patients with newly diagnosed, relapsed, and refractory leukemia and lymphoma are highly sensitive to LtxA. In preclinical studies, LtxA shows significant efficacy using humanized mouse models for leukemia. In addition, single- dose LtxA administered intravenously into rhesus monkeys was active, highly specific for WBCs, and well-tolerated. No effect was seen on red blood cells, platelets, hemoglobin, or markers of organ toxicity. However, no studies have yet examined LtxA for the treatment of B- cell lymphoma. Thus, based on our encouraging preclinical studies for leukemia, we propose to test LtxA using in vitro and in vivo B-cell lymphoma model systems. The data that we generate from the work described in this application is necessary to provide proof-of-principle and mechanistic knowledge for subsequent clinical testing in lymphoma patients. PUBLIC HEALTH RELEVANCE: B-cell lymphomas kill thousands of people each year. We are developing a biotherapeutic agent (leukotoxin) that has targeted specificity for malignant white blood cells. Our studies will test the hypothesis that leukotoxin can be used for the treatment of B-cell lymphomas employing in vitro and in vivo models.

描述（由申请人提供）：B 细胞淋巴瘤包括霍奇金淋巴瘤和非霍奇金淋巴瘤 (NHL)（例如套细胞淋巴瘤 (MCL)、滤泡性淋巴瘤 (FL)、弥漫性大 B 细胞淋巴瘤 (DLBCL) 和伯基特淋巴瘤淋巴瘤）。今年，美国将有超过 70,000 人被诊断患有这些 B 细胞恶性肿瘤，仅 NHL 就会有超过 19,000 人死亡。 B 细胞淋巴瘤可影响许多器官，包括淋巴结、脾、肝和骨髓。许多接受 B 细胞淋巴瘤治疗的患者对所有现有疗法都产生耐药性，并且常常死于疾病。因此，迫切需要确定具有更大活性和更少副作用的新疗法。新型生物制剂 Leukothera(R)（白细胞毒素；LtxA）专门针对白细胞 (WBC) 上表达的活性白细胞功能抗原 1 (LFA-1)。恶性白细胞持续表达高水平的活性 LFA-1，使 LtxA 能够靶向特定的患病细胞，同时将对健康细胞和组织的影响降至最低。 LtxA 采用多种细胞死亡机制来毒害敏感的白细胞。我们发现新诊断、复发和难治性白血病和淋巴瘤患者的细胞系和原代细胞对LtxA高度敏感。在临床前研究中，LtxA 使用人源化小鼠模型治疗白血病显示出显着疗效。此外，单剂量LtxA静脉注射给恒河猴具有活性，对白细胞具有高度特异性，并且耐受性良好。对红细胞、血小板、血红蛋白或器官毒性标志物没有影响。然而，尚无研究检验 LtxA 治疗 B 细胞淋巴瘤的作用。因此，基于我们令人鼓舞的白血病临床前研究，我们建议使用体外和体内 B 细胞淋巴瘤模型系统来测试 LtxA。我们从本申请中描述的工作中生成的数据对于为淋巴瘤患者的后续临床测试提供原理证明和机制知识是必要的。公共卫生相关性：B 细胞淋巴瘤每年导致数千人死亡。我们正在开发一种对恶性白细胞具有靶向特异性的生物治疗剂（白细胞毒素）。我们的研究将通过体外和体内模型检验白细胞毒素可用于治疗 B 细胞淋巴瘤的假设。