A new small molecule targeting agent and therapeutic for non-Hodgkin's lymphoma

一种新的小分子靶向剂和非霍奇金淋巴瘤的治疗方法

• 批准号: 8930077
• 负责人: Rodney Balhorn
• 金额: $ 74.06万
• 依托单位: SHAL TECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8930077
• 关键词: Address; Advanced Malignant Neoplasm; Adverse effects; Affect; Affinity; Aftercare; Animals; Apoptosis; B lymphoid malignancy; B-Cell Lymphomas; B-Lymphocytes; Binding; Biological Testing; Biopsy Specimen; California; Canis familiaris; Cell Line; Cell Surface Receptors; Cells; Clinic; Clinical; Clinical Trials; Data; Diagnosis; Disease; Dose; Drug Interactions; Drug Kinetics; Exhibits; Goals; Health; Hepatocyte; Human; Image; In Vitro; In complete remission; Individual; Life; Ligands; Lymphocyte; Malignant Neoplasms; Metabolic; Metabolism; Mitochondria; Monitor; Mus; Necrosis Induction; Non-Hodgkin' s Lymphoma; Normal Cell; Normal tissue morphology; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phenotype; Predisposition; Preparation; Process; Public Health; Quality of life; Radioisotopes; Rattus; Reference Standards; Rodent; Safety; Site; Small Business Innovation Research Grant; Surface; Technology; Testing; Therapeutic; Therapeutic Agents; Therapeutic Index; Toxic effect; Toxicology; Translating; Treatment Cost; Tumor Cell Line; Universities; Work; Xenograft Model; Xenograft procedure; analog; cell growth; companion diagnostics; cost; cost effective; cytotoxic; cytotoxicity; design; drug structure; experience; genotoxicity; human tissue; imaging agent; improved; killings; leukemia/lymphoma; mouse model; neoplastic cell; novel therapeutics; outcome forecast; overexpression; preclinical study; receptor; research clinical testing; rituximab; safety study; safety testing; small molecule; success; tumor; tumor growth

DESCRIPTION (provided by applicant): The goal of this SBIR proposal is to complete the majority of the pre-clinical studies and testing needed to submit an IND application and advance a promising new therapeutic for non- Hodgkin's lymphoma, SH7139, into a clinical trial. SH7139 is a selective, high affinity ligand (SHAL) that was designed to target a unique site on HLA-DR10, a protein receptor found on the surface of B-cell lymphocytes and overexpressed in many B-cell derived lymphomas and leukemias. SH7139 binds selectively and is highly cytotoxic (at pM concentrations) only to tumor cells expressing HLA-DR10. In a Raji xenograft mouse model, 69% of animals treated with 5�g/kg of SH7139 experienced a permanent cure; that is, the tumors disappeared within 30 days after treatment and did not return during the remainder of the life of the animal. In addition, no adverse side effects have been observed in animals, even when the dose was increased 2000-fold. The specific aims proposed in phase II of this SBIR are to: (1) determine the potential impact of SH7139 metabolism and metabolites on its function and the metabolism of other drugs; (2) confirm the mechanism of action of SH7139; (3) determine the pharmacokinetics, toxicology and safety of SH7139 in rodents and dogs; and (4) confirm SH7139 selectivity for B-cell malignancies and identify the potential breadth of the SH7139 indication. Upon the successful completion of this Phase II project, SHAL Technologies will use the results to identify any additional tests that need to be conducted, prepare and submit an IND application, open a Phase I clinical trial, and move forward with the clinical evaluation of SH7139 as a new therapeutic for treating and potentially curing advanced non-Hodgkin's lymphoma and other B-cell derived forms of cancer. If successful, this effort will provide a more effective first-line therapy for advanced NHL. Fewer side effects would be expected, because only those cells that are overexpressing HLA-DR10 are targeted and killed; normal cells are not affected. SH7129, a biotinylated analog of SH7139, could be used as companion diagnostic to identify those patients for whom this treatment would be most likely to be effective. Radionuclide-tagged SH7139 may also prove useful as an imaging agent to monitor the progression of the patient's disease. The low cost of SH7139 synthesis should reduce the cost of NHL therapy significantly and make the drug available to all those diagnosed with NHL.

描述（由应用程序提供）：该SBIR提案的目的是完成提交IND应用所需的大多数临床前研究和测试，并为非霍奇金淋巴瘤（SH7139）提出新的新疗法，以进行临床试验。 SH7139是一种选择性的高亲和力配体（SHAL），旨在针对HLA-DR10上的独特位点，这是在B细胞淋巴细胞表面发现的蛋白质受体，并且在许多B细胞衍生的淋巴瘤和白血病中过表达。 SH7139选择性结合，高度细胞毒性（在PM浓度下）仅与表达HLA-DR10的肿瘤细胞。在Raji异种移植小鼠模型中，用5.g/kg SH7139治疗的动物中有69％经过永久治愈。也就是说，肿瘤在治疗后30天内消失，在动物的剩余时间内没有返回。此外，即使剂量增加了2000倍，也没有观察到动物的不利副作用。 SBIR第二阶段提出的具体目的是：（1）确定SH7139代谢和代谢物对其功能及其其他药物的代谢的潜在影响； （2）确认SH7139的作用机理； （3）确定啮齿动物和狗中SH7139的药代动力学，毒理学和安全性； （4）确认SH7139的B细胞恶性肿瘤的选择性，并确定SH7139指示的潜在广度。成功完成此II阶段项目后，Shal Technologies将使用结果来确定需要进行的任何其他测试，准备和提交IND应用程序，打开I期临床试验，并继续对SH7139进行临床评估，作为一种新的治疗方法，以治疗和潜在的治疗高级非Hodgkin的淋巴瘤和其他b-Cell的淋巴瘤和其他b-Cell orders carcer and Carlive carlive and carcer and carly of Carly。如果成功，这项工作将为高级NHL提供更有效的一线疗法。预期的副作用会更少，因为只有那些过表达HLA-DR10的细胞被靶向和杀死。正常细胞不受影响。 SH7129是SH7139的生物素化类似物，可以用作伴侣诊断，以识别那些最有可能有效的患者。放射线标签的SH7139也可能被证明是一种成像剂来监测患者疾病的进展。 SH7139合成的低成本应大大降低NHL治疗的成本，并使所有被诊断为NHL的人都可以使用。