Preclinical Development of PEG-TNF

PEG-TNF的临床前开发

• 批准号: 6855095
• 负责人: JOHN S BOMALASKI
• 金额: $ 40.76万
• 依托单位: PHOENIX PHARMACOLOGICS, INC.
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-11-01 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6855095
• 关键词: SDS polyacrylamide gel electrophoresis; biotherapeutic agent; cell mediated lymphocytolysis test; cytokine; drug design /synthesis /production; enzyme linked immunosorbent assay; gel electrophoresis; high performance liquid chromatography; laboratory mouse; laboratory rabbit; melanoma; perfusion; pharmacokinetics; pharmacology; polyethylene glycols; skin disorder chemotherapy; skin pharmacology; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Unformulated human tumor necrosis factor( (huTNF() has anti-tumor activity in mice, but there is little difference between the effective and lethal doses. Systemic administration of unformulated huTNFalpha has been tested in humans. All studies indicated the dose limiting toxicity was usually hypotension, the circulating half life was < 20 min and little anti-tumor activity was seen. Recent results from isolated limb perfusions with huTNFalpha for prolonged times indicated this cytokine to have marked anti-tumor activity in humans with melanoma. This suggests huTNFalpha may be therapeutically useful, provided the toxicity and short circulating half-life can be overcome. Formulation of other biologically active cytokines and proteins with polyethylene glycol (PEG) has significantly improved their safety and increases their circulating half-life. Examples include PEG-alpha interferon and PEG-GCSF, which are now approved by the FDA. The Phase 1 SBIR grant application proposed formulating huTNFalpha with PEG to increase its circulating half-life and increase its safety. An optimal formulation of huTNFalpha was found (termed huTNFalpha-SS PEG 20,000 mw). The circulating half-life, safety and efficacy of this formulation have been substantially increased compared with unformulated huTNFalpha in mice. In a Pre IND meeting with the FDA the final preclinical studies were identified and are the focus of this Phase 2 SBIR application. The specific aims are to: 1) produce cGMP huTNFalpha-SS PEG 20,000 mw; 2) finalize its pharmacological characterization; and 3) test the immunogenicity and its safety in animals according to GLP (Good Laboratory Practice). The data from these studies will provide the final information enabling the filing of an IND with the FDA to support human Phase I clinical testing.

描述（由申请方提供）：未配制的人肿瘤坏死因子（huTNF）在小鼠中具有抗肿瘤活性，但有效剂量和致死剂量之间几乎没有差异。已在人体中测试了未配制的huTNF α的全身施用。所有研究表明，剂量限制性毒性通常是低血压，循环半衰期< 20 min，几乎没有观察到抗肿瘤活性。最近用huTNF α长时间隔离肢体灌注的结果表明，这种细胞因子在患有黑色素瘤的人中具有显著的抗肿瘤活性。这表明huTNF α可能是治疗上有用的，前提是可以克服毒性和短循环半衰期。 其他生物活性细胞因子和蛋白质与聚乙二醇（PEG）的制剂显着提高了它们的安全性，并增加了它们的循环半衰期。例子包括PEG-alpha干扰素和PEG-GCSF，它们现在已被FDA批准。 1期SBIR资助申请提出用PEG配制huTNF α以增加其循环半衰期并增加其安全性。发现了huTNF α的最佳制剂（称为huTNF α-SS PEG 20，000 mw）。在小鼠中，与未配制的huTNF α相比，该制剂的循环半衰期、安全性和功效显著增加。 在与FDA的IND前会议上，确定了最终的临床前研究，并且是该2期SBIR申请的重点。具体目标是：1）生产cGMP huTNFalpha-SS PEG 20，000 mw; 2）完成其药理学表征; 3）根据GLP（药物非临床研究质量管理规范）测试动物免疫原性及其安全性。 这些研究的数据将提供最终信息，使IND能够提交给 FDA支持人类I期临床试验。