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（由申请人提供）：该SBIR提案的目标是完成提交IND申请所需的大部分临床前研究和测试，并推进一种有前景的非霍奇金淋巴瘤新疗法SH7139进入临床试验。SH7139是一种选择性高亲和力配体（SHAL），被设计用于靶向HLA-DR10上的一个独特位点，HLA-DR10是一种在b细胞淋巴细胞表面发现的蛋白受体，在许多b细胞源性淋巴瘤和白血病中过表达。SH7139选择性结合，仅对表达HLA-DR10的肿瘤细胞具有高细胞毒性（pM浓度下）。在Raji异种移植小鼠模型中，用5 μ g/kg SH7139治疗的动物中有69%获得了永久性治愈；也就是说，肿瘤在治疗后30天内消失，并且在动物的剩余生命中没有复发。此外，即使将剂量增加2000倍，在动物身上也未观察到不良副作用。该SBIR二期研究提出的具体目标是：(1)确定SH7139代谢及其代谢物对其功能和其他药物代谢的潜在影响；(2)确认SH7139的作用机理；(3)确定SH7139在啮齿动物和狗体内的药代动力学、毒理学和安全性；(4)确认SH7139对b细胞恶性肿瘤的选择性，并确定SH7139适应症的潜在广度。在成功完成该II期项目后，SHAL Technologies将利用结果确定需要进行的任何其他测试，准备并提交IND申请，开展I期临床试验，并推进SH7139作为治疗和潜在治愈晚期非霍奇金淋巴瘤和其他b细胞衍生癌症的新疗法的临床评估。如果成功，这一努力将为晚期非霍奇金淋巴瘤提供更有效的一线治疗。预期副作用更少，因为只有那些过度表达HLA-DR10的细胞才会被靶向并杀死；正常细胞不受影响。SH7129是SH7139的生物素化类似物，可以作为辅助诊断来识别这种治疗最有可能有效的患者。放射性核素标记的SH7139也可能被证明是一种有用的显像剂，用于监测患者的疾病进展。SH7139合成的低成本将显著降低NHL治疗的成本，并使所有诊断为NHL的患者都能获得该药。