Targeting B-cell lymphoma with Leukothera-phase II

Leukothera-II 期靶向 B 细胞淋巴瘤

• 批准号: 9353591
• 负责人: Benjamin A Belinka
• 金额: $ 14万
• 依托单位: ACTINOBAC BIOMED, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-27 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9353591
• 关键词: Accounting; Addendum; Animals; Antibodies; Authorization documentation; B-Cell Lymphomas; B-Lymphocytes; B-lymphocyte Cancer; Binding; Biological Products; Biological Response Modifier Therapy; Biotechnology; CASP8 gene; Cancer Relapse; Canis familiaris; Cell Death; Cessation of life; Clinical Trials; Cyclic GMP; Detection; Dose; Drug Kinetics; Drug Targeting; Escherichia coli; Evaluation; Genes; Human; Immune response; International; Investigational Drugs; Investigational New Drug Application; Leukocytes; Lymph Node Tissue; Lymphocyte Function-Associated Antigen-1; Lymphoma; Malignant - descriptor; Marketing; Methods; NOD/SCID mouse; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Plasma; Plasmids; Preparation; Production; Property; Proteins; Rattus; Recombinants; Regimen; Safety; Sampling; Small Business Technology Transfer Research; Specificity; Staging; Testing; Tissue Sample; Toxicology; Work; chemotherapy; humanized mouse; immunogenic; in vivo; killings; leukotoxin; manufacturing facility; mouse model; neutralizing antibody; novel therapeutics; oral bacteria; overexpression; phase 1 study; preclinical safety; preclinical study; public health relevance; receptor; scale up; symposium; tumor

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.

描述（由申请人提供）：B 细胞淋巴瘤是 B 淋巴细胞的癌症，每年导致美国超过 20,000 人死亡。虽然许多患者对目前可用的治疗有反应，但癌症复发率很高并且患者无法耐受化疗。因此，非常需要为这些患者提供比目前使用的药物更有效且耐受性更好的新疗法。 Actinobac Biomed, Inc. 正在开发一种天然生物疗法，可寻找并杀死白细胞 (WBC) 子集。这种疗法 Leukothera(R)（LtxA；白细胞毒素）是一种源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，使其成为该药物的理想靶点。在 STTR 应用的 I 期阶段，我们表明：1) LtxA 使用独特的作用机制杀死恶性 B 细胞，其中涉及 Fas 死亡受体和 caspase 8； 2) B细胞淋巴瘤患者的淋巴结组织样本表达高水平的LFA-1； 3) LtxA 导致 B 细胞淋巴瘤人源化小鼠模型中的肿瘤完全消退，并导致长期生存； 4) 该药物耐受性良好，活性高，不会在健康狗或患有天然淋巴瘤的狗中引起中和免疫反应，并且 5) 我们已在 cGMP 药物生产设施中开始表达和生产重组 LtxA为研究性新药 (IND) 启用研究和临床试验做准备。 LtxA 的重要药物特性包括：1) 药物在几分钟或更短的时间内在体内快速起效； 2) 低至 0.5 g/kg 的剂量已被证明对动物具有高活性； 3) 即使重复给药，健康或患病动物中也不会产生针对 LtxA 的中和抗体； 4) 该药物的高特异性允许靶向白细胞亚群，并且 LtxA 治疗从未观察到白细胞完全耗尽。在 STTR II 期提案中，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。