Structure Based Design of Humanized Monoclonal Antibodies that Recognize Bioactiv

基于结构的识别生物活性的人源化单克隆抗体的设计

• 批准号: 7749242
• 负责人: Jonathan Michael Wojciak
• 金额: $ 15.27万
• 依托单位: LPATH THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7749242
• 关键词: Affect; Affinity; Age related macular degeneration; Amino Acids; Anaphylaxis; Antibodies; Antigens; Applications Grants; Area; Autoimmune Diseases; Avastin; Binding; Biochemical; Biological; Biological Assay; Biomedical Research; Cell Adhesion; Cell Survival; Chemicals; Clinical Trials; Communities; Complementarity Determining Regions; Complex; Computer Simulation; Crystallization; Data; Disease; Drug Design; Drug Formulations; Engineering; Epitopes; Fab Immunoglobulins; Fibrosis; Funding; Generations; Grant; Heart; Human Pathology; Humira; Inflammatory; Investigation; Libraries; Ligands; Lipid A; Lipid Binding; Lipids; Lucentis; Lysophospholipids; Malignant Neoplasms; Marketing; Mediator of activation protein; Medical; Medicine; Metabolism; Methods; Mind; Molecular; Monoclonal Antibodies; Multiple Sclerosis; Mus; Mutate; Mutation; Neurites; Neurodegenerative Disorders; Pathogenesis; Pathologic Processes; Pathology; Pathway interactions; Phase; Phase I Clinical Trials; Physiological; Play; Porifera; Positioning Attribute; Process; Production; Proteins; Proteolysis; Research Personnel; Resolution; Roentgen Rays; Role; Safety; Science; Signal Transduction; Signaling Molecule; Small Business Innovation Research Grant; Specificity; Structural Models; Structure; Techniques; Technology; Testing; Therapeutic; Therapeutic Agents; Therapeutic Monoclonal Antibodies; Therapeutic antibodies; Time; Upper arm; Variant; X ray diffraction analysis; X-Ray Diffraction; absorption; angiogenesis; base; cancer therapy; cell motility; clinically relevant; commercialization; design; drug discovery; extracellular; human disease; humanized monoclonal antibodies; inflammatory neuropathic pain; infliximab; interest; lipid mediator; lysophosphatidic acid; news; novel; novel strategies; novel therapeutics; painful neuropathy; programs; public health relevance; response; scaffold; sphingosine 1-phosphate; success; therapeutic target; tool; tumorigenic; weapons

DESCRIPTION (provided by applicant): Currently, there are over 20 therapeutic antibodies on the market. It is the fastest growing segment of therapeutics largely because humanized mAbs have excellent safety profiles. The huge success of antibody molecular sponges like Avastin, Lucentis, Humira and Remicade have demonstrated that use of antibody therapeutics in this mode can be effective in the treatment of cancer, AMD, inflammatory and autoimmune disorders. Rather than directing antibodies against protein targets, Lpath has been successful in generating therapeutic monoclonal antibodies (mAbs) against a novel class of therapeutic targets, bioactive lipids. The first bioactive lipid target was sphingosine-1-phosphate (S1P) and our anti-S1P mAbs are in Phase I clinical trials for both cancer and age-related macular degeneration. We have recently humanized a mAb against lysophosphatidic acid (LPA) which is a validated tumorigenic bioactive lipid that also contributes to diseases of dysregulated fibrosis and neuropathic pain. We intend to use this Phase 1 SBIR grant to solve the crystal structures of our first two humanized mAbs in complex with their ligands, and we have promising preliminary data demonstrating feasibility of this approach. We hypothesize that we can use the Xray-derived structures to assemble a library of antibody framework scaffolds and complementarity determining regions (CDRs) that can be used to develop new therapeutic mAbs that will target novel bioactive lipids involved in inflammatory, heart and other disorders that will be of interest to the general medical community. Depending on the structures we obtain in the Phase 1 effort, we will propose for a Phase 2 SBIR using an in silico rational drug design method to design and produce novel therapeutic antibodies against valuable lipid targets without having to immunize mice, produce monoclonal antibodies and engage in a costly and time- consuming humanization effort. We have two bioactive lipids in mind for the Phase 2 effort but need the structural information that will be obtained in the Phase 1 activities to validate our new drug discovery platform. These techniques will be used to engineer monoclonal antibodies with specificities for other novel lipid targets as the platform grows. This technology will provide researchers a new tool for studying lipid pathways, metabolism and signaling and hopefully arms clinicians with powerful new weapons against lipid-based pathologies. As lipidomics emerges as an important field in medicine and as more bioactive lipids become implicated in human disease, antibodies that recognize lipids and other non-proteinaceous targets will likely play a significant role in biomedical research. PUBLIC HEALTH RELEVANCE: Biologically active lipids are now recognized by the scientific community to be important mediators of several physiologic and pathological processes. These signaling molecules have been implicated in a wide variety of human pathologies including cancer, inflammatory, neurodegenerative diseases, dysfunctional fibrosis and many other grievous illnesses. Lpath Inc. has developed two unique monoclonal antibodies (mAbs) which function as molecular sponges to bind and neutralize the bioactive lipids sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA). Considering the huge successes of Avastin, Lucentis and Remicade, this antibody-based therapeutic approach has become the focus of intense investigations in treatment of multiple diseases. An urgent need exists to understand how this novel class of anti- lipid mAbs can recognize their targets and neutralize their biological effects. The information gained from this project will be critical to design and develop new mAbs against the potentially thousands of additional clinically-relevant bioactive lipids.

描述（由申请人提供）：目前，市场上有超过20种治疗性抗体。它是治疗学中增长最快的部分，主要是因为人源化mAb具有优异的安全性。抗体分子海绵如Avastin、Lucentis、Humira和Remicade的巨大成功已经证明，以这种模式使用抗体治疗剂可以有效治疗癌症、AMD、炎症和自身免疫性疾病。Lpath不是针对蛋白质靶点指导抗体，而是成功地产生了针对新型治疗靶点（生物活性脂质）的治疗性单克隆抗体（mAb）。第一个生物活性脂质靶点是鞘氨醇-1-磷酸（S1 P），我们的抗S1 P mAb正在进行癌症和年龄相关性黄斑变性的I期临床试验。我们最近已经人源化了针对溶血磷脂酸（LPA）的mAb，溶血磷脂酸是一种经验证的致瘤生物活性脂质，其也有助于失调的纤维化和神经性疼痛的疾病。我们打算利用这一SBIR第一阶段拨款来解决我们的前两个人源化mAb与其配体复合物的晶体结构，我们有很有希望的初步数据证明这种方法的可行性。我们假设，我们可以使用X射线衍生的结构来组装抗体框架支架和互补决定区（CDR）的文库，这些抗体框架支架和互补决定区（CDR）可用于开发新的治疗性mAb，这些mAb将靶向与炎症，心脏和其他疾病相关的新型生物活性脂质，这些疾病将引起一般医学界的兴趣。根据我们在1期研究中获得的结构，我们将提出2期SBIR，其使用计算机模拟合理药物设计方法来设计和生产针对有价值的脂质靶点的新型治疗性抗体，而无需免疫小鼠、生产单克隆抗体和进行昂贵且耗时的人源化研究。我们有两个生物活性脂质在第2阶段的努力，但需要的结构信息，将获得在第1阶段的活动，以验证我们的新药物发现平台。随着平台的发展，这些技术将用于工程化单克隆抗体，其对其他新型脂质靶点具有特异性。这项技术将为研究人员提供一种研究脂质通路、代谢和信号传导的新工具，并有望为临床医生提供强大的新武器来对抗基于脂质的病理学。随着脂质组学成为医学中的一个重要领域，并且随着越来越多的生物活性脂质与人类疾病有关，识别脂质和其他非蛋白质靶点的抗体可能会在生物医学研究中发挥重要作用。 公共卫生相关性：生物活性脂质现在被科学界认为是几种生理和病理过程的重要介质。这些信号分子已经涉及各种各样的人类病理学，包括癌症、炎症、神经退行性疾病、功能障碍性纤维化和许多其他严重疾病。Lpath Inc.已经开发了两种独特的单克隆抗体（mAb），其作为分子海绵来结合和中和生物活性脂质鞘氨醇-1-磷酸（S1 P）和溶血磷脂酸（LPA）。考虑到Avastin，Lucentis和Remicade的巨大成功，这种基于抗体的治疗方法已成为治疗多种疾病的密集研究的焦点。迫切需要了解这类新型抗脂质mAb如何识别其靶标并中和其生物学效应。从该项目中获得的信息对于设计和开发针对潜在的数千种其他临床相关生物活性脂质的新mAb至关重要。