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 更具体地将这些代理商交付给取消器的潜在方法。一个这样的化合物，mylotarg¿，一个 抗CD33抗体与高效的细胞毒性药物Calicheamicin的结合已获得FDA批准 为了治疗60岁以上的患者CD33阳性急性髓样白血病。其他药物 目前正在开发各种实体瘤。虽然有些人建议 传统抗癌药物（例如阿霉素（DOX） 为了引起显着的热效应，我们积累了大量证据，表明正确 抗原抗体靶向系统可以导致高效的DOX免疫缀合物。 CD74是一种与HLA-DR相关联的型typl跨膜链酮分子，抑制了抗原的结合 肽到类抗原表现结构的肽。它在几种类型的肿瘤细胞的表面表达 （例如，NHL，MM，黑色素瘤和RCC细胞）并指导从表面运输到内体隔室 在细胞内。我们已经显示了使用CD74+ B细胞的放射性抗体结合的抗体的潜在活性 靶向用螺旋钻电子发射器标记的CD74的快速内在化LL1抗体。提供了这些结果 测试LL1-ANTI-CD74 MAB进行药物输送的动力。阿霉素，NH管理中的关键药物 为药物轭疗法提供了许多优势，包括：（a）水溶性，因此很容易 与水溶液溶液兼容； （b）有几个化学反应性基团； （c）拥有几个 作用机制，包括抑制拓扑异构酶II，插入到DNA中，并破坏细胞 膜。在系统性NHL Xenograpon模型中使用LL1-DOX的治疗结果非常出色（请参阅 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％ - 每年相关死亡。 5年治疗率仅为50％。已知这些肿瘤表达大量 CD74抗原。 NHL可能会使用吸毒的结合物最好地对特定的靶向方法响应 广泛传播性质以及癌细胞对系统给药的药物的相对可及性。在 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 失控的生长和终端超过正常B细胞​​，提供了提供更高的机会 。与正常细胞相比，注射药物特异性药物的比率是特异性的。因此，该建议将 使用几种已建立 临床前模型和主要NHL活检标本。我们还将解决几个新颖的生物学问题 包括（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）通过直接用抗体传递DOX，（b）克服与该抗体相关的心脏毒性 免费的阿霉素。