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治疗有反应，但癌症复发率很高，患者无法耐受化疗。因此，迫切需要为这些患者提供比目前使用的药物更有效、耐受性更好的新疗法。Actinobac Biomed公司正在开发一种天然生物疗法，可以寻找并杀死一种白细胞（wbc）亚群。这种疗法，白细胞毒素（LtxA），是一种从口腔细菌中提取的天然蛋白质。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仅存在于白细胞上，恶性白细胞过度表达该分子，使其成为该药物的理想靶点。在STTR应用的I期，我们发现1)LtxA通过一种独特的作用机制杀死恶性b细胞，该机制涉及Fas死亡受体和caspase 8；2) b细胞淋巴瘤患者淋巴结组织中LFA-1表达水平较高；3) LtxA在人源化b细胞淋巴瘤小鼠模型中使肿瘤完全消退，长期存活；4)该药物耐受性良好，活性高，不会引起健康犬或自然发生淋巴瘤犬的中和性免疫反应，5)我们已经在cGMP药物生产设施中开始表达和生产重组LtxA，为研究新药（IND）研究和临床试验做准备。LtxA的重要药物特性包括：1)药物在体内迅速起效，在几分钟或更短的时间内；2)低至0.5 g/kg的剂量已被证明对动物具有高度活性；3)在健康或患病动物中，即使重复给药，也不会产生LtxA的中和抗体；4)该药物的高特异性允许靶向一部分白细胞，并且LtxA治疗从未观察到白细胞的完全消耗。在STTR II期提案期间，Actinobac将开展IND启用研究，这些研究将包含在向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.