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

描述(由申请人提供)：这项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，并将一种有前途的非霍奇金淋巴瘤新疗法SH7139推向临床试验。SH7139是一种选择性高亲和力配体(SHAL)，旨在针对人类白细胞抗原-DR10上的一个独特位点。人类白细胞抗原-DR10是一种存在于B细胞淋巴细胞表面的蛋白质受体，在许多B细胞来源的淋巴瘤和白血病中过表达。SH7139与肿瘤细胞有选择性结合，在PM浓度下具有高度的细胞毒作用，只与表达HLA-DR10的肿瘤细胞结合。在Raji异种移植小鼠模型中，接受5�g/kg SH7139治疗的动物中，69%的动物经历了永久治愈；即肿瘤在治疗后30天内消失，并在动物的剩余生命中不再复发。此外，在动物身上也没有观察到不良副作用，即使剂量增加了2000倍。这项SBIR第二阶段提出的具体目标是：(1)确定SH7139的代谢及其代谢产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)确定SH7139在啮齿动物和狗身上的药代动力学、毒理学和安全性；以及(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。在这个第二阶段项目成功完成后，SHAL Technologies将利用这些结果来确定任何需要进行的额外测试，准备并提交IND申请，开启一期临床试验，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细胞衍生形式癌症的新疗法的临床评估。如果成功，这项努力将为晚期非霍奇金淋巴瘤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的细胞才会被靶向并被杀死；正常细胞不会受到影响。SH7129是SH7139的生物素化类似物，可以作为辅助诊断来确定这种治疗最有可能对哪些患者有效。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合成的低成本应该会显著降低NHL的治疗成本，并使所有被诊断为NHL的人都能获得这种药物。

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.