Fluorolog: A Rapid-Acting Ultra-Concentrated Insulin Formulation

描述（由申请人提供）：在该2期SBIR申请中，我们寻求推进新型卤素基蛋白质设计的速效和超浓缩单体胰岛素类似物的人体临床试验。被命名为Fluorolog的这种类似物在I期研究中被发现表现出快速作用的PK/PD特性，而与0.6 - 3.0 mM范围内的蛋白质浓度无关，即，从U-100到U-500的强度。我们预计，U-500 Fluorolog制剂将特别有利于治疗明显胰岛素抵抗的2型糖尿病（T2 DM）。这些患者不成比例地来自贫困的少数民族社区，包括非洲裔美国人，西班牙裔美国人和土著美国人。T2 DM是美国社会医疗保健差距的主要组成部分。我们的I期研究验证了Fluorolog设计的关键假设：在胰岛素受体结合表面引入单个氟原子（对-F-PheB 24）可以同时（i）保护胰岛素单体免于降解和（ii）调节促有丝分裂性，从而减轻AspB 10对培养物中细胞增殖和与IGF受体交叉结合的不良影响。在第2阶段，我们寻求扩展这些研究，以获得IND申请所需的数据。为此，将扩大中试稳定性数据，以包括通过IND申请中通常提供的程序和条件对化学和物理降解（如二硫化物裂解、共价聚合物形成和原纤化）的各个方面进行的正式检测。同样，将试验性细胞培养数据扩展到裸鼠中肿瘤异种移植物生长率的分析和Sprague-Dawley大鼠中的正式毒性研究。因此，本II期申请的总体目标是提交适当且记录良好的IND申请。

DESCRIPTION (provided by applicant): In this Phase 2 SBIR application we seek to advance toward human clinical trials a rapid-acting and ultra- concentrated monomeric insulin analog of novel halogen-based protein design. Designated Fluorolog, this analog was found in Phase I studies to exhibit rapid-acting PK/PD properties irrespective of protein concentration in the range 0.6 - 3.0 mM, i.e., from U-100 to U-500 strengths. We anticipate that a U-500 formulation of Fluorolog will be of particular benefit to the treatment of Type 2 diabetes mellitus (T2DM) in the setting of marked insulin resistance. Such patients are disproportionately members of underprivileged minority communities, including African-Americans, Hispanic Americans, and Indigenous Americans. T2DM represents a major component of health-care disparities in American society. Our Phase 1 studies validated a key hypothesis underlying design of Fluorolog: that introduction of a single fluorine atom at the receptor-binding surface of insulin (para-F-PheB24) can at the same time (i) protect the insulin monomer from degradation and (ii) modulate mitogenicity such that untoward effects of AspB10 on cellular proliferation in culture and on cross-binding to the IGF receptor are each mitigated. In Phase 2 we seek to extend these studies to obtain data required in an IND application. To this end, pilot stability data willbe enlarged to include formal testing of the individual aspects of chemical and physical degradation (such as disulfide cleavage, covalent polymer formation, and fibrillation) by procedures and under conditions customarily provided in an IND application. Similarly, pilot cell-culture data wil be extended to analysis of tumor xenograft growth rates in nude mice and by formal toxicity studies in Sprague-Dawley rats. The overarching goal of this Phase 2 application is thus the submission of an appropriate and well-documented IND application.