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）：该SBIR项目的目的是完成提交IND申请的临床前研究，以提供有希望的新的治疗性（SH7139）（SH7139），用于非霍奇金淋巴瘤，以便能够将此药物推向临床试验。 SH7139是一种选择性高亲和力配体（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。在许多B细胞衍生的淋巴瘤和白血病中，HLA-DR10过表达10-100倍。我们从先前资助的NIH/NCI计划项目赠款中获得的结果表明，SH7139的目标是具有很高亲和力（KD〜23 pm）的HLA-DR10受体，并且它选择性地杀死了过度表达HLA-DR-10的细胞。在Raji异种移植小鼠模型中，用55g/kg的SH7139治疗的动物中有69％得到了永久治愈的方法。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再发生。另外，即使剂量增加了2000倍，在动物中也没有观察到不利的副作用。该SBIR I期提出的具体目的是：（1）合成，化学表征和测试SH7139标准的生物学活性； （2）将SH7139的合成扩展到多克数量，并检查其纯度，物理特征和生物活性，以针对标准化合物的化合物； （3）确定在异种移植模型中提供最高固化速率的SH7139的剂量，并使用此信息来定义将在SBIR的II期中进行的临床前，毒理学和安全研究中使用的剂量。在完成I阶段SBIR研究之后，我们将提交一项II期SBIR建议，其中规模综合方案和I期获得的剂量信息将用于生产GMP SH7139，并完成其余的临时，典型，毒理学和安全研究，这些研究是提交IND应用所必需的。如果成功的话，这项工作将为晚期NHL开发更有效的一线疗法，这种治疗在系统上是无毒的，可以治愈癌症进展的延迟，而不是逐渐增加。 SH7139比FDA批准的NHL药物的优势和开发的其他许多药物是：（1）SH7139代表了与包括Rituxan在内的当前B细胞淋巴瘤治疗剂的急剧不同。除了仅在靶向和杀死肿瘤细胞方面高度具体外，在大多数处理的个体（带有异种移植物的小鼠）中还可以实现治疗方法（未完成反应），（2）预计副作用较少，因为只有那些过表达HLA-DR10的细胞靶向靶向HLA-DR10，并且不影响正常细胞。 （3）由于SH7139是靶向剂，因此它也可以用作伴侣诊断，以识别那些最有可能有效的患者，从而最大程度地减少与治疗相关的风险。 （4）该药物合成的低成本应大大降低NHL治疗成本，从而使治疗变得更加广泛和可用。 公共卫生相关性：公共卫生需要为高级癌症开发更有效，毒性较小，更具成本效益的治疗方法。该项目通过提出需要提高诊所的研究所需的研究来解决这些问题，这是一种有希望的新的靶向剂和治疗性的针对晚期非霍奇金淋巴瘤患者的治疗方法，我们的初步结果表明这是显着的，并且可能会改善患者的生存并降低副作用和治疗成本。