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

HEPylated G-CSF：用于中性粒细胞减少症治疗的更安全、增强递送的药物

• 批准号: 8121665
• 负责人: PAUL L DEANGELIS
• 金额: $ 28.25万
• 依托单位: CAISSON BIOTECH, LLC
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8121665
• 关键词: Adverse effects; Alzheimer' s Disease; Amination; Animals; Antibodies; Benchmarking; Biological; Biological Assay; Biological Models; Biological Testing; Blood Cell Count; Blood Circulation; CSF3 gene; Cell Count; Cell Proliferation; Cells; Chemicals; Chemistry; Chemotherapy-Oncologic Procedure; Clinical Data; Clinical Trials; Cosmetics; Coupling; Data Set; Degradation Pathway; Development; Doctor of Philosophy; Dose; Drug Delivery Systems; Drug Kinetics; Effectiveness; Electrophoresis; Ethylene Glycols; Food Processing; Future; Generations; Goals; Granulocyte Colony-Stimulating Factor; Half-Life; Heparin; Human; Industry; Infection; Infection prevention; Injection of therapeutic agent; Intellectual Property; Investigational New Drug Application; Lead; Letters; Leukocytes; Measures; Medicine; Methods; Modeling; Molecular Sieve Chromatography; Nature; Neutropenia; Oklahoma; Patients; Pegfilgrastim; Performance; Pharmaceutical Preparations; Pharmacodynamics; Phase; Polymers; Polysaccharides; Population; Positioning Attribute; Probability; Process; Rattus; Recombinants; Regimen; Relative (related person); Research Infrastructure; Resources; Risk; Rodent; Rodent Model; Safety; Sales; Series; Small Business Innovation Research Grant; System; Technology; Testing; Therapeutic; Toothpaste; Toxic effect; Toxicology; Translating; Universities; White Blood Cell Count procedure; animal efficacy; base; biomaterial compatibility; chemotherapy; commercialization; consumer product; drug candidate; drug development; drug modification; ethylene glycol; good laboratory practice; immunogenic; immunogenicity; improved; interest; laxative; light scattering; meetings; milligram; neutrophil; next generation; nonhuman primate; phase 2 study; polymerization; pre-clinical; prevent; prototype; research study; success; sugar

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.

描述（由申请人提供）：聚[乙二醇]（PEG）聚合物被制药公司广泛用于增强有前景的候选药物的物理、化学和/或生物学性质。将PEG聚合物添加到药物货物的过程称为PEG化，并且已经产生了数十亿美元/年的药物。PEG化保护货物时，在体内和治疗作用。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，PEG降解产物的毒性、受控聚合的尺寸上限和免疫原性的发生率上升（PEG抗体的发生率从1984年的约0.2%上升到2001年的约22-25%，这可能部分地由含PEG的消费品产生）仍然是问题。因此，制药公司对下一代药物的PEG替代品感兴趣;我们收到了工业界对我们新的输送系统的支持信。 创新：俄克拉荷马州的一家生物技术公司Caisson Biotech LLC和俄克拉荷马州大学正在合作开发一种平台技术HEPylation（tm）并将其商业化，以将肝素原聚合物添加到治疗货物中，作为PEG化的可行替代方案。肝素原是一种与肝素有关的天然“自体”多糖，是一种新型的治疗修饰剂。Caisson的技术还允许合成具有非常窄的尺寸分布和限定的化学活化的糖聚合物，这有助于选择性地与治疗剂偶联。与聚乙二醇化相比，HEPylation具有上级属性，包括天然降解途径、易于合成更长的聚合物尺寸和更低的免疫原性潜力。 方法：在该SBIR I期项目中，两名PI将专注于创建和测试当前药物的HEPyylated版本，这是一种用于治疗中性粒细胞减少症（异常低白色血细胞计数）的粒细胞集落刺激因子（G-CSF）的长效版本。PEG化的G-CSF，Neulasta（2009年销售额为46亿美元），通常用于预防抗癌化疗或其他疾病后的感染，并有望为阿尔茨海默氏症带来希望。与单独的G-CSF相比，PEG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抵消其益处。因此，PI将构建一系列HEPylated G-CSF结合物，并评估其作为现有药物Neulasta替代品的适用性。 概念合成的证明、基于细胞的和动物的可行性实验以及第一阶段的初步毒理学试验将导致先导药物的选择。随后的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关键：（a）与FDA启动研究前新药申请会议，以及（B）通过降低技术风险加速商业化，以便制药合作伙伴与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平台有望扩展药物递送技术，用于其他所需药物。 公共卫生关系：该项目中开发的药物递送系统将为制药公司目前使用的人工聚乙二醇（PEG）系统提供一种改进的替代方案，这些系统可能会被过多的含PEG的消费品（包括牙膏，化妆品，加工食品，和泻药，2001年约22-25%的美国人口（从1984年的0.2%上升）产生针对PEG的抗体，因此可能使患者对PEG药物敏感。将天然“自身”肝素原聚合物添加到治疗货物的过程（Caisson Biotech的HEPylation平台）比基于PEG的过程具有几个优点，包括更高的生物相容性、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频率的副作用;我们来自制药公司的支持信陈述了他们对这种PEG替代物的期望。 在该I期SBIR中，我们的目标是合成PEG药物Neulasta（2009年销售额为46亿美元）的上级替代品，并在动物疗效和毒理学模型系统中进行初步测试，Neulasta通常用于预防由于抗癌化疗后低白色血细胞水平引起的感染。