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

描述（由申请人提供）：聚[乙二醇]（PEG）聚合物被广泛用于制药，以增强有前途的候选药物的物理，化学和/或生物学性质。将聚乙二醇聚合物添加到药物货物中的过程称为聚乙二醇化，并导致每年数十亿美元的药物。聚乙二醇化保护货物时，在体内和延长治疗作用。对于患者来说，这些特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，PEG降解产物的毒性、可控聚合的上限以及免疫原性的上升（PEG抗体的发生率从1984年的~0.2%上升到2001年的~22-25%，这可能部分是由含PEG的消费品产生的）仍然存在问题。因此，制药公司对下一代药物的PEG替代品感兴趣；我们收到了业界对我们新配送系统的支持信。创新：俄克拉何马州的一家生物技术公司casisson Biotech LLC和俄克拉何马大学正在合作开发一种名为HEPylation（tm）的平台技术，并将其商业化，该技术可以将肝磷脂聚合物添加到治疗货物中，作为PEGylation的可行替代品。肝素聚糖是一种与肝素相关的天然“自体”多糖，是一种新型的治疗改性剂。casisson的技术还允许合成具有非常窄的尺寸分布和确定的化学激活的糖聚合物，促进选择性偶联治疗。hepyation具有优于PEGylation的特性，包括天然降解途径，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 I期项目中，两家P.I.s将专注于创建和测试一种现有药物的HEPylated版本，这是一种用于治疗中性粒细胞减少症（白细胞计数异常低）的长效粒细胞集落刺激因子（G-CSF）。聚乙二醇G-CSF， Neulasta（2009年销售额46亿美元），通常用于预防抗癌化疗或其他疾病后的感染，以及对阿尔茨海默氏症的希望。与单独的G-CSF相比，聚乙二醇化的G-CSF是一种改进的药物，但PEG抗体在未来将越来越多地否定其益处。因此，P.I.s将构建一系列HEPylated G-CSF偶联物，并评估其作为现有药物Neulasta替代品的适用性。第一阶段的概念合成证明、细胞和动物可行性实验以及初步毒理学测试将导致先导药物的选择。后期的II期研究将扩大动物疗效和毒理学数据集。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速商业化，这样制药合作伙伴将与Caisson Biotech合作并支持III期人体临床试验。此外，用这种原型药物验证HEPylation平台有望扩大药物输送技术，用于其他所需药物。

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.