Structure Based Design of Humanized Monoclonal Antibodies that Recognize Bioactiv

描述（申请人提供）：目前，市场上有20多种治疗性抗体。它是治疗学中增长最快的部分，主要是因为人源单克隆抗体具有出色的安全性。抗体分子海绵（如Avastin、Lucentis、Humira和Remicade）的巨大成功表明，在这种模式下使用抗体疗法可以有效治疗癌症、AMD、炎症和自身免疫性疾病。Lpath已经成功地产生了针对一类新的治疗靶点（生物活性脂类）的治疗性单克隆抗体（mab），而不是针对蛋白质靶点的直接抗体。第一个生物活性脂质靶点是鞘氨醇-1-磷酸（S1P），我们的抗S1P单克隆抗体正在癌症和年龄相关性黄斑变性的I期临床试验中。我们最近人源化了一种针对溶血磷脂酸（LPA）的单抗，LPA是一种经过验证的致瘤性生物活性脂质，也有助于失调纤维化和神经性疼痛疾病。我们打算利用第一阶段SBIR拨款来解决我们的前两个人源单克隆抗体及其配体的晶体结构，我们有很好的初步数据证明了这种方法的可行性。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域（cdr）库，可用于开发新的治疗性单克隆抗体，这些单克隆抗体将针对炎症、心脏和其他疾病的新型生物活性脂质，这将是一般医学界感兴趣的。根据我们在第一阶段工作中获得的结构，我们将提出第二阶段的SBIR，使用硅理性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，而无需对小鼠进行免疫，生产单克隆抗体并进行昂贵且耗时的人源化工作。我们有两种生物活性脂质用于第二阶段的工作，但需要在第一阶段活动中获得的结构信息来验证我们的新药发现平台。随着平台的发展，这些技术将用于设计具有其他新型脂质靶点特异性的单克隆抗体。这项技术将为研究人员提供一种研究脂质途径、代谢和信号传导的新工具，并有望为临床医生提供对抗基于脂质病理的强大新武器。随着脂质组学成为医学的一个重要领域，以及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靶点的抗体可能在生物医学研究中发挥重要作用。

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.