Humanized monoclonal antibodies to treat mucormycosis

人源化单克隆抗体治疗毛霉菌病

基本信息

批准号：
9759762
负责人：
ASHRAF S. IBRAHIM
金额：
$ 29.98万
依托单位：
VITALEX BIOSCIENCES, LLC
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-09 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9759762
关键词：
Adrenal Cortex Hormones Affinity Allergic Reaction Amino Acids Angioinvasion Animal Model Antibiotics Antibodies Antibody Therapy Antifungal Agents Antifungal Therapy Antigens Attenuated Binding Biological Sciences Blood Vessels Brain Cell Line Cell Surface Proteins Clinical Clinical Trials Cunninghamella Data Development Diabetes Mellitus Diabetic Ketoacidosis Diagnostic Disease Disease Progression Dose Endothelial Cells Enzyme-Linked Immunosorbent Assay Erythrocytes Excision Fc Immunoglobulins Feasibility Studies Funding Genes Goals Grant Heat shock proteins Heat-Shock Response Hematogenous Hematopoietic Stem Cell Transplantation Human Human Cloning IgG1 Immune system Immunocompromised Host Immunotherapy In Vitro Incidence Infection Inflammation Injury Intervention Invaded Investments Iron Laboratories Lead Life Mammalian Cell Mediating Molds Monoclonal Antibodies Mucor Mucorales Mucormycosis Mus Mycoses Necrosis Neutropenia Operative Surgical Procedures Organ Transplantation Organism Orphan Drugs Outcome Pathogenesis Pathway interactions Patients Penetration Peptides Phagocytosis Pharmaceutical Preparations Phase Positioning Attribute Prevalence Prevention strategy Privatization Process Proteins Reporting Research Resources Rhizomucor Rhizopus Risk Risk Factors Serum Small Business Innovation Research Grant Small Business Technology Transfer Research Soldier Stains Technology Testing Therapeutics for Rare and Neglected Diseases Thrombosis Tissues Toxic effect Trauma Umbilical vein United States National Institutes of Health Vaccines Virulence Work Zygomycosis base cGMP production cancer transplantation cell injury cell type clinical development clinically relevant combat cross reactivity driving force effective therapy glucose-regulated proteins human tissue humanized monoclonal antibodies immunoreaction improved in vitro activity in vivo injured lead candidate method development mortality mortality risk mouse model murine monoclonal antibody mutant novel novel therapeutics operation pharmacokinetics and pharmacodynamics polyclonal antibody posaconazole pre-clinical prevent primary endpoint programs secondary endpoint synergism treatment strategy

项目摘要

Mucormycosis, most commonly caused by Rhizopus oryzae, is a life-threatening infection that occurs in patients immunocompromised by diabetic ketoacidosis (DKA), neutropenia, corticosteroid use, increased serum iron and/or severe trauma. Because of the rising prevalence of these risk factors, the incidence of mucormycosis has risen. Despite disfiguring surgery and aggressive antifungal therapy, the mortality of mucormycosis ranges from ~ 50% to 100%. The obvious unmet need for new, effective treatments and preventive strategies has been the driving force of our research program for over seventeen years. We propose to develop a passive vaccine targeting mucormycosis (i.e., an antibody that can be administered to patients with mucormycosis). Data in the academic laboratory of our founder (Dr. Ibrahim) indicate that antibody-based therapy is a promising strategy to treat mucormycosis. This technology is based on the important discovery that the fungal cell surface proteins encoded by CotH facilitate disease progression by allowing R. oryzae to invade mammalian cells via binding to Glucose Regulated Protein 78 (GRP78), a heat shock conserved protein expressed on endothelial cells lining blood vessels during mucormycosis. Importantly, CotH proteins were found to be conserved among Mucorales (organisms that cause mucormycosis) and absent from any other cell type including mammalian. Our data also show that CotH proteins are key determinants of mucormycosis pathogenesis since R. oryzae coth null mutants have markedly reduced virulence in mouse models of mucormycosis. Further, polyclonal antibodies targeting CotH are highly protective against murine mucormycosis caused by R. oryzae, Mucor, Lichtheimia, Cunninghamella, Rhizomucor, and Apophysomyces. Importantly and highly relevant to this application, anti-CotH murine monoclonal antibodies (mAb) raised against a peptide predicted to be present in the binding domain to GRP78, prevent the ability of R. oryzae to invade and injure endothelial cells in vitro and protect mice from mucormycosis caused by several Mucorales to levels that exceed those seen with antifungal therapy. While these mAbs are a promising new therapy for mucormycosis, the feasibility of further clinical development will hinge upon successful humanization of the Abs. Mouse mAbs cannot be used to treat humans, because humans mount an immune reaction to mouse mAbs that can cause rapid removal of the mAbs, systemic inflammation, severe allergic reactions, and even a risk for death. The humanization process prevents these undesirable effects. Thus, we propose two AIMS: 1) Develop our lead murine mAb into a humanized version with retained/enhanced binding ability to CotH proteins; and 2) Determine the protective activity of the humanized Ab in vitro/in vivo and evaluate its toxicity to human tissues. We propose conservative feasibility milestones that are part of a standard, methodical development pathway for our unique mAbs as a novel treatment for mucormycosis. The proposed work will identify a lead humanized Ab that will go into further development to ultimately test in clinical trials as an adjunctive therapy.

最常见的粘膜细胞增多是根瘤菌引起的，是一种威胁生命的感染，发生在患者中通过糖尿病酮症酸中毒（DKA），中性粒细胞减少症，皮质类固醇使用，血清铁增加的免疫功能和/或严重的创伤。由于这些危险因素的患病率上升，粘膜细胞增多的发生率已有复活。尽管手术和侵略性抗真菌疗法毁容，但粘膜菌病的死亡率范围从〜50％至100％。对新的有效治疗和预防策略的明显未满足的需求一直是我们的研究计划的驱动力已有十七年。我们建议开发一种被动疫苗靶向粘膜菌病（即，可以是一种可以是的抗体给予粘膜细胞增多患者）。我们的创始人学术实验室的数据（易卜拉欣博士）表明基于抗体的疗法是治疗粘胶细胞增多的有前途的策略。这项技术基于重要发现，即通过COTH编码的真菌细胞表面蛋白促进了疾病的进展允许R. oryzae通过与葡萄糖调节的蛋白78（GRP78）结合，热量侵袭哺乳动物细胞休克保守的蛋白质在粘膜细胞增多期间在血管内衬里的内皮细胞上表达。重要的是，发现Coth蛋白在粘膜中是保守的（引起粘胶菌病的生物），并且不存在来自包括哺乳动物的任何其他细胞类型。我们的数据还表明，Coth蛋白是粘膜菌病发病机理，因为R. oryzae coth null突变体显着降低了小鼠的毒力粘膜细胞增多模型。此外，靶向COTH的多克隆抗体对鼠具有高度保护性由R. oryzae，Mucor，Lichtheimia，Cunninghamella，Rhizomucor和apophysomyces引起的粘膜病。重要的是，与此应用高度相关，抗菌鼠单克隆抗体（MAB）预计将存在于与GRP78结合结构域中的肽，以防止R. oryzae侵入和在体外损伤内皮细胞，并保护小鼠免受多种粘膜造成的粘膜菌病的侵害，达到水平超过抗真菌治疗的人。尽管这些mAb是一种有希望的粘膜菌病疗法，但进一步临床发展的可行性将在成功人性化的情况下取决于ABS。鼠标mabs 不能用来治疗人类，因为人类对可能引起的小鼠mab进行免疫反应快速清除mAb，全身炎症，严重的过敏反应，甚至有死亡的风险。这人性化过程阻止了这些不良影响。因此，我们提出了两个目标：1）发展我们的领导鼠mab变成人源化版本，具有保留/增强的蛋白质结合能力； 2）确定人源化AB在体外/体内的保护活性，并评估其对人体组织的毒性。我们提出了保守的可行性里程碑，这些里程碑是标准，有条理的发展的一部分我们独特的mab作为粘胶细胞增多的新型途径。拟议的工作将确定潜在客户人性化的AB将进一步发展，最终在临床试验中测试作为辅助疗法。