Targeting B-cell lymphoma with Leukothera

描述(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Burkitt淋巴瘤。今年，美国将有超过7万人被诊断出患有这种B细胞恶性肿瘤，仅非霍奇金淋巴瘤就有超过1.9万人死亡。B细胞淋巴瘤可累及许多器官，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可用的治疗方法都无效，往往死于疾病。因此，有必要确定活性更强、副作用更少的新疗法。新型生物制剂Leukthera(R)(白毒素；LtxA)特异性针对表达在白细胞(WBC)上的活性白细胞功能抗原-1(LFA-1)。恶性WBC持续表达高水平的活性LFA-1，使LtxA能够针对特定的病变细胞，同时最大限度地减少对健康细胞和组织的影响。LtxA利用几种细胞死亡机制使易中毒的WBC中毒。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使用人源化的小鼠模型治疗白血病显示出显著的疗效。此外，恒河猴静脉注射单次给药是有效的，对白细胞有高度的特异性，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，目前还没有研究检查LtxA用于治疗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产生的数据对于为随后的淋巴瘤患者的临床测试提供原则证明和机制知识是必要的。 与公共卫生相关：B细胞淋巴瘤每年导致数千人死亡。我们正在开发一种生物治疗剂(白毒素)，它具有针对恶性白细胞的靶向性。我们的研究将通过体外和体内模型来验证白毒素可以用于治疗B细胞淋巴瘤的假设。

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.