Targeting B-cell lymphoma with Leukothera-phase II

描述（由申请人提供）：B细胞淋巴瘤是B淋巴细胞的癌症，每年在美国造成2万多人死亡。虽然许多患者对目前可用的疗法有反应，但癌症复发率高，患者无法耐受化疗。因此，非常需要为这些患者提供比目前使用的药物更有效和更好耐受的新疗法。Actinobac Biomed，Inc.正在开发一种天然生物疗法，寻找并杀死一部分白色血细胞（WBC）。这种疗法，Leukothera（R）（LtxA;白细胞毒素），是一种来自口腔细菌的天然蛋白质。LtxA特异性结合淋巴细胞功能相关抗原-1（LFA-1）的活性形式并导致细胞死亡。LFA-1仅在白细胞上发现，恶性白细胞过度表达该分子，使其成为药物的理想靶点。在该STTR应用的I期阶段期间，我们显示1）LtxA使用独特的作用机制杀死恶性B细胞，其涉及Fas死亡受体和半胱天冬酶8; 2）来自B细胞淋巴瘤患者的淋巴结组织样品表达高水平的LFA-1; 3）LtxA在B细胞淋巴瘤的人源化小鼠模型中引起肿瘤完全消退并导致长期存活; 4）该药物耐受性良好，活性高，并且不会在健康狗或患有自然发生的淋巴瘤的狗中引起中和免疫应答，以及5）我们已经在cGMP药物制造设施中开始表达和生产重组LtxA，为研究性新药（IND）-使能研究和临床试验做准备。LtxA的重要药物特性包括：1）药物在体内迅速起作用，在数分钟或更短时间内; 2）低至0.5g/kg的剂量已显示在动物中具有高度活性; 3）即使在重复给药后，在健康或患病动物中也不产生针对LtxA的中和抗体;和4）药物的高特异性允许靶向WBC的亚群，并且用LtxA治疗从未观察到WBC的完全消耗。在STTR II期提案期间，Actinobac将进行IND使能研究，这些研究将包括在向FDA提交的IND申请中。

DESCRIPTION (provided by applicant): B-cell lymphoma is cancer of B-lymphocytes and accounts for more than 20,000 deaths in the U.S. each year. While many patients respond to currently available therapy, there is a high rate of cancer relapse and inability for the patients o tolerate chemotherapy. Thus, there is a significant need to make available to these patients newer therapies that are more effective and better tolerated than the drugs that are currently used. Actinobac Biomed, Inc. is developing a natural biologic therapy that seeks out and kills a subset of white blood cells (WBCs). This therapy, Leukothera(R) (LtxA; leukotoxin), is a native protein derived from an oral bacterium. LtxA binds specifically to the active form of lymphocyte function associated antigen- 1 (LFA-1) and causes cell death. LFA-1 is found exclusively on WBCs, and malignant WBCs overexpress the molecule, making them ideal targets for the drug. During the phase I stage of this STTR application, we showed that 1) LtxA kills malignant B-cells using a unique mechanism of action, which involves Fas death receptor and caspase 8; 2) lymph node tissue samples from B-cell lymphoma patients express high levels of LFA-1; 3) LtxA causes complete regression of tumors in a humanized mouse model for B-cell lymphoma and results in long-term survival; 4) the drug is well-tolerated, highly active, and does not cause a neutralizing immune response in healthy dogs or a dog with naturally-occurring lymphoma, and 5) we have initiated expression and production of recombinant LtxA in a cGMP drug manufacturing facility in preparation for Investigational New Drug (IND)-enabling studies and clinical trials. Important pharmaceutical properties of LtxA include: 1) the drug works rapidly in vivo, within minutes or less; 2) doses as low as 0.5 g/kg have been shown to be highly active in animals; 3) neutralizing antibody to LtxA is not generated in healthy or diseased animals, even after repeat dosing; and 4) the high specificity of the drug allows targeting of a subset of WBCs and complete depletion of WBCs has never been observed with LtxA treatment. During this STTR phase II proposal, Actinobac will carry out IND-enabling studies that will be included in the IND application to the FDA.