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: 8777038
• 负责人: Rodney Balhorn
• 金额: $ 74.89万
• 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 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8777038
• 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; Companions; Data; Diagnosis; Diagnostic; Disease; Dose; Drug Interactions; Drug Kinetics; Exhibits; Goals; 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; cost; cost effective; cytotoxic; cytotoxicity; design; drug structure; experience; genotoxicity; human tissue; improved; killings; leukemia/lymphoma; mouse model; neoplastic cell; novel therapeutics; outcome forecast; overexpression; preclinical study; public health relevance; 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）：本 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，并将一种有前景的非霍奇金淋巴瘤新疗法 SH7139 推进临床试验。 SH7139 是一种选择性高亲和力配体 (SHAL)，旨在靶向 HLA-DR10 上的独特位点，HLA-DR10 是 B 细胞淋巴细胞表面上发现的蛋白质受体，在许多 B 细胞衍生的淋巴瘤和白血病中过度表达。 SH7139 选择性结合，仅对表达 HLA-DR10 的肿瘤细胞具有高度细胞毒性（pM 浓度）。在 Raji 异种移植小鼠模型中，接受 5μg/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，并且在动物的余生中没有复发。此外，即使剂量增加2000倍，在动物身上也没有观察到不良副作用。本次SBIR II期提出的具体目标是：（1）确定SH7139代谢和代谢物对其功能和其他药物代谢的潜在影响； (2)确认SH7139的作用机制； (3)测定SH7139在啮齿动物和犬体内的药代动力学、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。该二期项目成功完成后，SHAL Technologies 将利用这些结果来确定需要进行的任何其他测试，准备和提交 IND 申请，启动一期临床试验，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，这项工作将为晚期 NHL 提供更有效的一线治疗。预计副作用会更少，因为只有那些过度表达 HLA-DR10 的细胞才会被靶向和杀死；正常细胞不受影响。 SH7129 是 SH7139 的生物素化类似物，可用作伴随诊断，以确定这种治疗最有可能有效的患者。放射性核素标记的 SH7139 也可能被证明可用作成像剂来监测患者疾病的进展。 SH7139 合成成本低廉，应可显着降低 NHL 治疗成本，并使所有诊断为 NHL 的患者都能获得该药物。