Targeting B-cell lymphoma with Leukothera

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）。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)。今年，美国将有超过7万人被诊断出患有这些b细胞恶性肿瘤，超过1.9万人将死于NHL。b细胞淋巴瘤可以影响许多器官，包括淋巴结、脾脏、肝脏和骨髓。许多接受b细胞淋巴瘤治疗的患者对所有可用的治疗方法都难以治愈，往往死于疾病。因此，有必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) （leukotoxin; LtxA）特异性靶向白细胞（wbc）上表达的活性白细胞功能抗原-1 （LFA-1）。恶性白细胞不断表达高水平的活性LFA-1，使LtxA特异性靶向病变细胞，同时对健康细胞和组织的影响最小。LtxA利用几种细胞死亡机制使易感白细胞中毒。我们发现来自新诊断、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在人源化白血病小鼠模型中显示出显著的疗效。此外，恒河猴静脉注射单剂量LtxA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，尚无研究证实LtxA治疗B细胞淋巴瘤。因此，基于我们令人鼓舞的白血病临床前研究，我们建议在体外和体内b细胞淋巴瘤模型系统中测试LtxA。我们从本应用程序中描述的工作中产生的数据对于为淋巴瘤患者的后续临床试验提供原理证明和机制知识是必要的。

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.