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: 8125536
• 负责人: Rodney Balhorn
• 金额: $ 15万
• 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 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8125536
• 关键词: Address; Advanced Malignant Neoplasm; Adverse effects; Affect; Affinity; Aftercare; Animals; B-Cell Lymphomas; B-Lymphocytes; Binding; Biologic Characteristic; Biological Testing; California; Cell Surface Receptors; Cells; Clinic; Clinical; Clinical Trials; Companions; Development; Diagnostic; Dose; Dose-Rate; FDA approved; Funding; Future; Goals; HLA-DR Antigens; Human; In complete remission; Individual; Inhibitory Concentration 50; Life; Ligands; Lymphocyte; Malignant Neoplasms; Mus; Non-Hodgkin' s Lymphoma; Normal Cell; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Process; Program Research Project Grants; Protocols documentation; Public Health; Risk; Roche brand of rituximab; Safety; Site; Small Business Innovation Research Grant; Surface; Technology; Therapeutic; Therapeutic Agents; Time; Toxic effect; Toxicology; Translating; Treatment Cost; United States National Institutes of Health; Universities; Work; Xenograft Model; Xenograft procedure; clinical toxicology; cost; cost effective; cytotoxic; design; dosage; drug synthesis; experience; improved; killings; leukemia/lymphoma; man; meetings; milligram; mouse model; neoplastic cell; novel therapeutics; outcome forecast; pre-clinical; preclinical study; receptor; safety study; scale up; small molecule; success; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): The goal of this SBIR project is to complete the preclinical studies required to submit an IND application for a promising new therapeutic (SH7139) for non-Hodgkin's lymphoma so as to be able to advance this drug into clinical trials. 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. HLA-DR10 is over-expressed 10- 100 fold in many B-cell derived lymphomas and leukemias. The results we obtained from a previously funded NIH/NCI program project grant showed that SH7139 targets the HLA-DR10 receptor with very high affinity (Kd ~ 23 pM) and that it selectively kills only cells over-expressing HLA-DR-10. In a Raji xenograft mouse model, 69% of the animals treated with 55g/kg of SH7139 experienced a permanent cure; that is, the tumors disappeared within 30 days after treatment and did not reoccur during the remainder of the life of the animal. In addition, no adverse side effects were observed in the animals, even when the dose was increased by 2000- fold. The specific aims proposed in Phase I of this SBIR are to: (1) synthesize, chemically characterize and test the biological activity of a SH7139 standard; (2) scale up the synthesis of SH7139 to multi-gram quantities and check its purity, physical characteristics and biological activity against that of the standard compound; and (3) determine the dose of SH7139 that provides the highest cure rate in a xenograft model and use this information to define the doses used in the preclinical, toxicology and safety studies that will be performed in Phase II of the SBIR. Following the completion of the Phase I SBIR study, we will submit a Phase II SBIR proposal in which the scale-up synthesis protocol and dose information obtained in Phase I will be used to produce GMP SH7139 and complete the remaining pre-clinical, toxicology and safety studies that are necessary to submit the IND application. If successful, this effort will develop a more effective first-line therapy for advanced NHL, one that is systemically non-toxic and provides cures rather than incremental increases in the delay of cancer progression. The advantages of SH7139 over the FDA approved NHL drugs and many others in development are: (1) SH7139 represents a dramatic departure from current B-cell lymphoma therapeutics, including Rituxan. In addition to being highly specific in targeting and killing only tumor cells, cures (not complete responses) are achieved in the majority of the treated individuals (mice bearing xenografts), (2) Fewer side effects would be expected, because only those cells that are over-expressing HLA- DR10 are targeted and normal cells are not affected. (3) Because SH7139 is a targeting agent, it can also be used as a companion diagnostic to identify those patients for whom this treatment would be most likely to be effective, thereby minimizing the risks associated with therapy. (4) The low cost of synthesis of this drug should reduce NHL therapy costs significantly, enabling treatments to become more widely available and accessible. PUBLIC HEALTH RELEVANCE: There is a public health need to develop more efficacious, less toxic and more cost effective treatments for advanced cancers. This project addresses these issues by proposing studies needed to advance into the clinic a promising new targeting agent and therapeutic for patients with advanced Non-Hodgkin's lymphoma, which our preliminary results suggest is remarkable and is likely to improve patient survival and reduce side effects and treatment costs significantly.

描述（由申请人提供）：本SBIR项目的目标是完成一种有前景的新型非霍奇金淋巴瘤治疗药物（SH 7139）提交IND申请所需的临床前研究，以便能够将该药物推进临床试验。SH 7139是一种选择性高亲和力配体（SHAL），旨在靶向HLA-DR 10上的独特位点，HLA-DR 10是一种在B细胞淋巴细胞表面发现的蛋白受体。HLA-DR 10在许多B细胞来源的淋巴瘤和白血病中过表达10- 100倍。我们从先前资助的NIH/NCI计划项目资助中获得的结果表明，SH 7139以非常高的亲和力（Kd ~ 23 pM）靶向HLA-DR-10受体，并且它仅选择性地杀死过表达HLA-DR-10的细胞。在Raji异种移植小鼠模型中，用55 g/kg的SH 7139治疗的动物中有69%经历了永久治愈;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，即使剂量增加2000倍，在动物中也未观察到不良副作用。本SBIR第一阶段提出的具体目标是：（1）合成、化学表征和测试SH 7139标准品的生物活性;（2）将SH 7139的合成规模扩大到数克数量，并对照标准化合物检查其纯度、物理特性和生物活性;和（3）确定在异种移植模型中提供最高治愈率的SH 7139的剂量，并使用该信息来定义将在SBIR的II期中进行的临床前、毒理学和安全性研究中使用的剂量。在完成I期SBIR研究后，我们将提交II期SBIR提案，其中I期获得的放大合成方案和剂量信息将用于生产GMP SH 7139，并完成提交IND申请所需的其余临床前、毒理学和安全性研究。如果成功，这项工作将为晚期NHL开发一种更有效的一线治疗方法，这种方法是全身无毒的，并提供治愈，而不是延迟癌症进展的增量增加。与FDA批准的NHL药物和许多其他正在开发的药物相比，SH 7139的优势在于：（1）SH 7139代表了与当前B细胞淋巴瘤治疗方法（包括Rituxan）的巨大差异。除了在靶向和仅杀死肿瘤细胞方面具有高度特异性之外，在大多数治疗的个体（携带异种移植物的小鼠）中实现了治愈（不是完全应答）。（2）预期副作用更少，因为仅靶向过表达HLA-DR 10的那些细胞，而正常细胞不受影响。(3)由于SH 7139是一种靶向药物，它也可以用作伴随诊断，以确定这种治疗最有可能有效的患者，从而最大限度地减少与治疗相关的风险。(4)这种药物的合成成本低，应显着降低NHL治疗成本，使治疗变得更广泛和可获得。 公共卫生相关性：公共卫生需要为晚期癌症开发更有效、毒性更小和更具成本效益的治疗方法。该项目通过提出进入临床所需的研究来解决这些问题，这是一种有前途的新靶向药物和治疗晚期非霍奇金淋巴瘤患者的药物，我们的初步结果表明这是显着的，可能会提高患者的生存率并显着降低副作用和治疗费用。