Targeting B-cell lymphoma with Leukothera-phase II

Leukothera-II 期靶向 B 细胞淋巴瘤

• 批准号: 8935763
• 负责人: Benjamin A Belinka
• 金额: $ 89.42万
• 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/8935763
• 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; 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; caspase-8; chemotherapy; immunogenic; in vivo; killings; leukotoxin; manufacturing facility; mouse model; neutralizing antibody; 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，每年在美国造成20,000多人死亡。尽管许多患者对当前可用的治疗有反应，但患者o耐受化疗的癌症复发率很高。因此，与当前使用的药物相比，这些新疗法更有效，更具耐受性的疗法非常有必要提供。 Actinobac Biomed，Inc。正在开发一种自然生物疗法，该疗法寻求并杀死了白细胞（WBC）的一部分。该疗法是列科瑟拉（R）（LTXA；白细胞毒素），是一种源自口服细菌的天然蛋白质。 LTXA专门与淋巴细胞功能相关的抗原1（LFA-1）的活性形式结合，并导致细胞死亡。 LFA-1仅在WBC上发现，而恶性WBC过表达了该分子，使其成为该药物的理想靶标。在此STTR应用的第一阶段，我们表明1）LTXA使用独特的作用机理杀死恶性B细胞，该机理涉及FAS死亡受体和caspase 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在人源化小鼠模型中导致肿瘤的完全消退，用于B细胞淋巴瘤，并导致长期生存。 4）该药物具有良好的耐受性，高活性，并且不会在健康狗或具有天然淋巴瘤的狗中引起中和免疫反应，5）我们已经在CGMP药物制造设施中启动和生产重组LTXA，以准备研究新药物（IND） - 开发研究和临床研究。 LTXA的重要药物特性包括：1）在几分钟或更短的时间内，药物在体内迅速起作用； 2）剂量低至0.5 g/kg的剂量在动物中具有高度活性； 3）即使在重复给药后，在健康或患病的动物中也不会产生对LTXA的中和抗体； 4）药物的高特异性允许靶向WBC的一部分和WBC的完全耗竭，从未通过LTXA处理观察到。在此STTR II阶段提案中，ActinoBac将进行辅助研究，这些研究将包括在IND申请中。