Anti-Properdin MoAb as a novel therapeutics for arthritis

抗备解素单克隆抗体作为关节炎的新型疗法

• 批准号: 7271370
• 负责人: Rekha Bansal
• 金额: $ 41.1万
• 依托单位: NOVELMED THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-15 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7271370
• 关键词: Anaphylatoxin; Anaphylatoxins; Animals; Arthritis; Basophils; Biological Assay; Bone and Cartilage Funding; Carbohydrates; Cells; Cellular Infiltration; Chemotactic Factors; Classical Complement Pathway; Clinical; Clinical Trials; Complement; Complement 3 Convertase; Complement 3a; Complement 5a; Complement Activation; Complement Factor B; Complement Inactivators; Complement Membrane Attack Complex; Data; Development; Disease; Disease Progression; Disease model; Drug Kinetics; Event; Grant; Immune; In Vitro; Infection; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Inorganic Sulfates; Interleukin-1; Investigational Drugs; Investigational New Drug Application; Joints; Knee joint; Legal patent; Leukocytes; Mediating; Mediator of activation protein; Modeling; Molecular Weight; Monoclonal Antibodies; Oryctolagus cuniculus; Pathogenesis; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Polymers; Preparation; Process; Production; Properdin; Prophylactic treatment; Rattus; Research Personnel; Rheumatoid Arthritis; Rodent; Role; Safety; Screening procedure; Serum; Site; TNF gene; Testing; Therapeutic; Therapeutic Agents; Time; Toxic effect; United States Food and Drug Administration; Unspecified or Sulfate Ion Sulfates; base; cost; cytokine; eosinophil; fighting; in vivo; inhibiting antibody; inhibitor/antagonist; macrophage; monocyte; neglect; neutrophil; novel therapeutics; preclinical study; prevent; programs; therapeutic target

DESCRIPTION (provided by applicant): Current therapeutic approaches for treating rheumatoid arthritis (RA) are not adequate to prevent the devastating inflammation and joint destruction. Complement activation contributes significantly to the inflammatory process in arthritic joints. While complement activation is vital to the body's defenses in fighting infections, unregulated complement activation significantly contributes to the pathogenesis of many inflammatory diseases, including RA. With complement activation, the anaphylatoxins C3a and C5a are released at sites of inflammation and are potent chemoattractants and activators of neutrophils, basophils, eosinophils, leukocytes, monocytes and macrophages that orchestrate and perpetuate the inflammatory response by producing pro-inflammatory mediators, such as cytokines. Recently developed humanized anti- 5 antibodies for inhibiting the downstream events of the complement cascade have highlighted the complement fragment C5a as a therapeutic target, but have neglected the essential role of C3a. Based on our preliminary data, therapeutic approaches that inhibit production of C3a, C5a and thus the final complement protein, the membrane attack complex (MAC) will completely inhibit the amplification loop of the alternative pathway (AP) and prevent its augmenting effect on activation of the classical complement pathway (CP). Such inhibitors should have greater potency than those that target only C5a in preventing cellular infiltration of cells, which direct the joint inflammation and destruction and to inhibit their activation and release of inflammatory mediators, such as TNF and IL-1. Consistent with this, C3a is known to regulate TNF and IL-1 production. The objective of this Phase II application is to further evaluate the efficacy of NM001(a blocking monoclonal antibody against factor B) and NM3014 (synthetic low molecular weight inhibitor of properdin function) in two well established models of RA; AIA rabbit model and CIA rat model. Similar to anti-properdin monoclonal antibodies both NM001 and NM3014 target the C3 convertase and prevent C3a, C5a and C5b-9 formation. We expect that such inhibitors will dramatically inhibit inflammation and joint destruction and will be an effective therapeutic approach for treating RA. NovelMed's approach appears to be more promising than current therapies because our approach is expected to inhibit the production of TNF and IL-1 instead of targeting each one separately. NovelMed has filed a patent on such inhibitors and additional patents are in preparation.

描述(申请人提供)：目前治疗类风湿性关节炎(RA)的治疗方法不足以防止毁灭性的炎症和关节破坏。补体的激活在关节炎关节的炎症过程中起重要作用。虽然补体激活对机体抵抗感染的防御至关重要，但不受调节的补体激活在许多炎症性疾病的发病机制中起着重要作用，包括类风湿关节炎。随着补体的激活，过敏毒素C3a和C5a在炎症部位释放，是中性粒细胞、碱性粒细胞、嗜酸性粒细胞、白细胞、单核细胞和巨噬细胞的强大趋化剂和激活剂，通过产生细胞因子等促炎介质来协调和维持炎症反应。最近开发的用于抑制补体级联下游事件的人源化抗-5抗体突出了补体片段C5a作为治疗靶点，但忽略了C3a的重要作用。根据我们的初步数据，抑制C3a、C5a的产生从而抑制最终补体蛋白的治疗方法，膜攻击复合体(MAC)将完全抑制替代途径(AP)的扩增环，并阻止其对经典补体途径(CP)激活的增强作用。这类抑制剂应该比那些只针对C5a的抑制剂在防止细胞渗透方面具有更大的效力，C5a指导关节的炎症和破坏，并抑制它们的激活和炎性介质的释放，如肿瘤坏死因子和白介素1。与此一致的是，已知C3a可以调节肿瘤坏死因子和白介素1的产生。此二期应用的目的是进一步评价NM001(B因子的封闭性单抗)和NM3014(合成的低分子质量的备解素功能抑制剂)在两种已建立的RA模型：AIA兔模型和CIA大鼠模型中的疗效。与抗备解素单抗相似，NM001和NM3014都针对C3转换酶，并防止C3a、C5a和C5b-9的形成。我们预计这些抑制剂将显著抑制炎症和关节破坏，并将成为治疗类风湿关节炎的有效方法。NovelMed的方法似乎比目前的疗法更有希望，因为我们的方法预计会抑制肿瘤坏死因子和白介素1的产生，而不是分别针对每一个。NovelMed已经为这种抑制剂申请了专利，更多的专利正在准备中。