Preclinical Development of PEG-TNF

描述（由申请人提供）：未配制的人肿瘤坏死因子（huTNF）在小鼠体内具有抗肿瘤活性，但有效剂量和致死剂量差别不大。未配制的huTNFalpha系统管理已在人体中进行了测试。所有研究表明，剂量限制毒性通常是低血压，循环半衰期< 20 min，抗肿瘤活性很小。最近对huTNFalpha长时间肢体灌注的研究结果表明，这种细胞因子在黑色素瘤患者中具有显著的抗肿瘤活性。这表明，如果能够克服毒性和较短的循环半衰期，huTNFalpha可能具有治疗作用。

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.