HEPylated G-CSF: Drug with Safer, Enhanced Delivery for Neutropenia Treatment

描述(申请人提供)：聚乙二醇聚合物被制药公司广泛用于增强有希望的候选药物的物理、化学和/或生物性质。将聚乙二醇聚合物添加到药物货物中的过程被称为聚乙二醇化，已经产生了几种每年10亿美元的药物。聚乙二醇化可保护体内的货物，延长治疗作用。对于患者来说，这些属性转化为通过更少的注射和更少的副作用来改善药物输送。然而，聚乙二醇降解产物的毒性、可控聚合的大小上限以及免疫原性的增加(聚乙二醇抗体的发生率从1984年的~0.2%上升到2001年的~22%-25%，部分原因可能是由含有聚乙二醇的消费品产生的)仍然是问题所在。因此，制药公司对下一代药物的聚乙二醇类替代品感兴趣；我们已经收到了业界对我们新给药系统的支持信。创新：俄克拉荷马州的一家生物技术公司Caisson Biotech LLC和俄克拉荷马大学正在合作开发一种平台技术HEPylating(Tm)并将其商业化，将一种肝素聚合物添加到治疗货物中，作为聚乙二醇化的一种可行的替代方案。肝素多糖是一种新型的治疗性修饰剂，是一种与肝素相关的天然“自身”多糖。凯森的技术还允许合成具有非常窄的尺寸分布和明确的化学活性的糖聚合物，从而促进与治疗药物的选择性偶联。与聚乙二醇化相比，HEP化具有更好的特性，包括自然降解途径，易于合成更长的聚合物尺寸，以及更低的免疫原性潜力。方法：在这个SBIR第一阶段项目中，两个P.I.将专注于创造和测试当前药物的HEP化版本，这是一种用于治疗中性粒细胞减少症(异常低的白细胞计数)的粒细胞集落刺激因子(G-CSF)的长效版本。聚乙二醇化的G-CSF，Neulasta(2009年销售额为46亿美元)，通常被用来预防抗癌化疗或其他疾病后的感染，以及有望治疗阿尔茨海默氏症。与单独使用G-CSF相比，聚乙二醇化的G-CSF是一种改进的药物，但聚乙二醇化的抗体将越来越多地抵消其未来的好处。因此，P.I.s将构建一系列HEPylated G-CSF结合物，并评估它们作为现有药物Neulasta的替代品的适宜性。概念合成的证明、基于细胞和动物的可行性实验以及第一阶段的初步毒理学测试将导致对先导药物的选择。稍后的第二阶段研究将扩大动物功效和毒理学数据集。总体而言，SBIR生成的临床前信息将是以下方面的关键：(A)启动与FDA的研究前新药申请会议；(B)通过降低技术风险来加快商业化进程，以便制药合作伙伴将与凯森生物技术公司合作，并在第三阶段支持人类临床试验。此外，用这种原型药物验证HEP基化平台有望扩大药物输送技术，使其与其他所需药物一起使用。 与公众健康相关：该项目中开发的药物输送系统将提供一种改进的替代方案，以替代目前制药公司使用的人造聚乙二醇酯(PEG)系统，这些系统可能会受到包括牙膏、化妆品、加工食品和泻药在内的大量含有聚乙二醇酯的消费品的破坏，因此2001年约有22%-25%的美国人口(1984年为0.2%)制造针对聚乙二醇酯的抗体，从而潜在地使患者对聚乙二醇酯药物敏感。将天然“自身”肝素聚合物添加到治疗货物中的过程(Caisson Biotech的HEPylation Platform)与基于聚乙二醇的过程相比具有几个优势，包括更高的生物兼容性、更好的合成控制和更低的免疫原性潜力，这应该转化为减少药物注射的副作用；我们来自制药公司的支持信表明了他们对这种聚乙二醇替代品的渴望。在这一阶段的SBIR中，我们的目标是合成聚乙二醇类药物Neulasta的优良替代品，并在动物疗效和毒理学模型系统中进行初步测试(2009年销售额为46亿美元)，Neulasta通常用于预防抗癌化疗后由于白细胞水平低而导致的感染。

DESCRIPTION (provided by applicant): Poly[ethylene glycol] (PEG) polymers are widely used by pharma to enhance the physical, chemical, and/or biological nature of promising drug candidates. The process of adding PEG polymers to drug cargo is termed PEGylation and has resulted in several $Billion/year drugs. PEGylation protects the cargo when in the body and prolongs therapeutic action. For patients, these attributes translate to improved drug delivery via fewer injections with fewer side effects. However, the toxicity of PEG's degradation products, the upper size limit for controlled polymerization, and the rising occurrence of immunogenicity (occurrence of PEG-antibodies up from ~0.2% in 1984 to ~22-25% in 2001 which may in part be spawned by PEG-containing consumer products) are still problematic. Therefore, pharma is interested in PEG alternatives for next generation medicines; we have letters of support from industry for our new delivery system. INNOVATION: Caisson Biotech LLC, an Oklahoma biotech company, and The University of Oklahoma are collaborating to develop and commercialize a platform technology, HEPylation(tm), to add a heparosan polymer to therapeutic cargo as a viable alternative to PEGylation. Heparosan, a new type of therapeutic modifying agent, is a natural "self" polysaccharide related to heparin. Caisson's technology also allows for synthesis of sugar polymers with a very narrow size distribution and defined chemical activation that facilitates selective coupling to therapeutics. HEPylation has superior attributes over PEGylation including natural degradation pathways, ease of longer polymer size synthesis, and lower potential for immunogenicity. APPROACH: In this SBIR Phase I project, the two P.I.s will focus on creating and testing HEPylated versions of a current drug, a long acting version of granulocyte colony stimulating factor (G-CSF) used in the treatment of neutropenia (abnormally low white blood cell counts). PEGylated G-CSF, Neulasta ($4.6 Billion in sales in 2009), is commonly employed to prevent infection after anti-cancer chemotherapy or other maladies as well as promises hope for Alzheimer's. PEGylated G-CSF is an improved drug compared to G-CSF alone, but PEG antibodies will increasingly negate its benefit in the future. Therefore, the P.I.s will construct a series of HEPylated G-CSF conjugates and assess their suitability as replacements for the existing drug, Neulasta. The proof of concept syntheses, cell-based and animal feasibility experiments, and the initial toxicology test in Phase I will result in lead drug selection. Later Phase II studies will expand the animal efficacy and toxicology data set. Overall, the SBIR-generated pre-clinical information will be key for: (a) initiating a pre- Investigational New Drug application meeting with the FDA and (b) accelerating commercialization by reducing the technical risk such that a pharma partner will collaborate with Caisson Biotech and support human clinical trials in Phase III. Furthermore, validating the HEPylation platform with this prototype drug promises to expand the drug delivery technology for use with other needed medicines. PUBLIC HEALTH RELEVANCE: The drug delivery system developed in this project will provide an improved alternative to artificial poly[ethylene glycol] (PEG) systems currently used by pharma that are potentially being undermined by a plethora of PEG- containing consumer products including toothpaste, cosmetics, processed foods, and laxatives such that ~22-25% of the US population in 2001 (up from 0.2% in 1984) makes antibodies against PEG thus potentially sensitizing patients to PEG-drugs. The process of adding natural "self" heparosan polymers to therapeutic cargo (Caisson Biotech's HEPylation platform) has several advantages over PEG-based processes including higher biocompatibility, better synthesis control, and lower potential for immunogenicity which should translate into reduced side effects with less frequent drug injections; our letters of support from pharma state their desires for such a PEG substitute. In this Phase I SBIR, our goal is the synthesis and initial testing in animal efficacy and toxicology model systems of a superior replacement for the PEG- drug, Neulasta ($4.6 Billion sales in 2009), which is commonly employed to prevent infection due to low white blood cell levels after anti-cancer chemotherapy.