Doxorubicin-Immunoconjugate Therapy of Non-Hodgkin's Lymphoma

非霍奇金淋巴瘤的阿霉素免疫结合疗法

• 批准号: 7365272
• 负责人: RHONA N STEIN
• 金额: $ 25.52万
• 依托单位: CTR FOR MOLECULAR MEDICINE/IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7365272
• 关键词: Abbreviations; Accounting; Acute Myelocytic Leukemia; Address; Age; Antibodies; Antigen Presentation; Antigens; Antineoplastic Agents; B-Lymphocytes; Binding; Biological; Biopsy Specimen; Bypass; Cardiac; Cardiotoxicity; Cell membrane; Cells; Cessation of life; Class; Clinical; Compatible; Complement; Cytotoxic agent; DNA; Disease; Doctor of Philosophy; Dose; Doxorubicin; Drug Delivery Systems; Drug resistance; Electrons; Fluorescence; Glycoproteins; HLA-DR Antigens; Hematopoietic Neoplasms; Histocompatibility Antigens Class II; Human; Immunoconjugates; In Vitro; Label; MCC protocol; Malignant Neoplasms; Manuscripts; Maximum Tolerated Dose; Mediating; Modeling; Molecular Chaperones; Monoclonal Antibodies; Multi-Drug Resistance; Multiple Myeloma; Mus; Nature; Non-Hodgkin' s Lymphoma; Normal Cell; Patients; Peptides; Pharmaceutical Preparations; Pharmacotherapy; Pre-Clinical Model; Proteins; Radioisotopes; Rate; Refractory; Relapse; Relative (related person); Renal Cell Carcinoma; Risk; Solid Neoplasm; Solutions; Structure; Surface; System; Testing; Therapeutic; Therapeutic Effect; Topoisomerase II inhibition; Toxin; Troponin T; United States Food and Drug Administration; Water; Xenograft Model; antibody conjugate; antibody-dependent cell cytotoxicity; aqueous; cancer cell; cytotoxicity; in vivo; intercalation; invariant chain; melanoma; neoplastic cell; novel; therapy development; tumor

Conjugates of monoclonal antibodies (MAbs) with drugs or toxins have been investigated for many years as a potential approach to delivering these agents more specifically to cancers. One such compound, Mylotarg¿, a conjugate of the anti-CD33 antibody with the highly potent cytotoxic drug, calicheamicin, has gained FDA approval for treatment of CD33-positive acute myeloid leukemia in patients over age 60 in first relapse. Other drug-MAb conjugates are currently in development for the treatment of various solid tumors. Although some have suggested that Mab conjugates of conventional anticancer drugs, such as doxorubicin (Dox) would not have adequate potency to elicit a significant therapeutic effect, we have accumulated a large body of evidence showing that the correct antigen-antibody targeting system can result in a highly effective Dox-immunoconjugate. CD74 is a type-ll transmembrane chaperone molecule that associates with HLA-DR, inhibiting binding of antigenic peptides to the class-ll antigen presentation structure. It is expressed on the surface of several types of tumor cells (e.g., NHL, MM, melanoma and RCC cells) and directs transport from the surface to an endosomal compartment within the cell. We have shown potent activity of antibody conjugates of radionuclides against CD74+ B cells, using the rapidly internalizing LL1 antibody to target CD74 labeled with Auger electron emitters. These results provided the impetus to test the LL1-anti-CD74 Mab for drug delivery. Doxorubicin, a key drug in the management of NH,L affords many advantages for drug-conjugate therapy including: (a) water-soluble nature and therefore readily compatible with aqueous protein solutions; (b) having several chemically reactive groups; (c) possessing several mechanisms of action, including inhibition of topoisomerase II, intercalation into DNA, and disrupting on cell membranes. Therapeutic results with LL1-Dox in a systemic NHL xenograft model have been outstanding (see preliminary results and appended manuscript). Non-Hodgkin's lymphoma (NHL) is the 5th most common cancer in the U.S. and accounts for 5% of all cancer- related deaths per year. The 5-year cure rate is only 50%. These tumors are known to express significant amounts of the CD74 antigen. NHL might best respond to a specific targeting approach using a drug-AB conjugate, due to its widely disseminated nature and the relative accessibility of cancer cells to systemically administered agents. In addition, the greater inherent sensitivity of hematopoietic tumors, the natural course of this disease with cells growing out of control and terminally outnumbering normal B cells, offers the chance of delivering a much higher . ratio of injected drug-Ab specifically to diseased cells, as compared to normal cells. This proposal will therefore address the utility of an LL1-Dox immunoconjugate for treatment of disseminated NHL using several established preclinical models and primary NHL biopsy specimens. We will also address several novel biological questions including (a) the possibility of overcoming multidrug resistance (typically expressed by ~60% of refractory NHL patients) by delivering Dox directly with an antibody, and (b) overcoming cardiotoxicity associated with the administration of free doxorubicin.

单克隆抗体（mAb）与药物或毒素的共轭物已被研究多年 将这些代理更具体地交付给癌症的潜在方法。 ， 抗CD33抗体与高效的细胞毒性药物Calicheamicin的结合已获得FDA批准 用于治疗CD33阳性的急性髓样白血病，在其他药物中60岁以上 目前正在开发各种实体瘤。 诸如阿霉素（dox）之类的章节剂药物的mab偶联物将没有足够的效力 为了产生重大的治疗作用，我们已经累积了大量证据 抗原 - 无抗体靶向系统可能会导致高效的DOX免疫缀合物。 CD74是一种与HLA-DR相关的型型跨膜伴侣分子，抗原的遗传结合 肽抗原表现结构的肽。 （例如，NHL，MM，黑色素瘤和RCC细胞），并指导从表面传输到andosomal室 在细胞中，我们已经显示 提供了用螺旋器电子发射器标记的靶标CD74的快速内在化抗体 测试LL1-ANTI-CD74 MAB的动力进行药物递送。 为药物结合疗法提供了许多优势，包括：（a）水溶性天然，因此很容易 与具有严格的化学反应性基团的水溶液兼容； 动作机制，无源拓扑异构体II，插入到DNA中以及细胞上的纪律处分 膜。 初步结果并附加了手稿）。 非霍奇金淋巴瘤（NHL）是美国第五大癌症，占所有癌症的5％ - 相关的死亡年份，五年治疗率仅为50％。 CD74抗原的使用可能最佳地响应特定的靶向方法 广泛传播的性质和癌细胞对系统的施用药物的相对辅助性 此外，造血肿瘤的固有灵敏度较高，这种疾病与细胞的自然病程 增强控制和终极的人数超过正常B细胞​​的数量，提供了更高的机会 与正常细胞相比，注射药物与患病细胞相比。 使用几个建立 临床前模型和主要的NHL活检标本。 包含（a）克服多药电阻的可能性（通常由约60％的难治性NHL表示 患者）直接用抗体熟食，（b）克服与该抗体相关的心脏氧毒素。 免费的阿霉素。