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: 7192572
• 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 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7192572
• 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; Gemtuzumab Ozogamicin; 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

DESCRIPTION (provided by applicant): 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 NHL 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.

描述（由申请人提供）：多年来，已经研究了与药物或毒素的单克隆抗体（mAb）的缀合物，这是一种潜在的方法，可以使这些药物更具体地将这些药物交付给癌症。一种这样的化合物mylotarg（，抗CD33抗体与高有效的细胞毒性药物calicheamicin的抗体抗体，已获得FDA批准，用于治疗CD33阳性急性髓样白血病，患者60岁以上的患者中有60岁以上的其他药物。目前正在开发各种实体瘤，尽管有些人建议使用的传统抗癌药物（例如阿霉素（DOX））具有足够的效力来引起大量的治疗效果，但我们已经积累了大量的身体证据表明，正确的抗原抗体靶向系统可以导致高效的dox-rumunoconjugate CD74。它在几种类型的肿瘤细胞（例如NHL，MM，黑色素瘤和RCC细胞）的表面上表达，并指导从表面运输到细胞内的内体隔室。我们使用快速内在化的LL1抗体靶向用螺旋电子发射器标记的CD74，显示了放射性核素对CD74+ B细胞的抗体结合物的有效活性。这些结果提供了测试LL1-ANTI-CD74 MAB进行药物输送的动力。阿霉素是NHL管理的关键药物，在药物偶联治疗中具有许多优势，包括：（a）水溶性，因此与水溶液蛋白溶液易于兼容； （b）有几个化学反应性基团； （c）具有多种作用机理，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异种移植模型中使用LL1-DOX的治疗结果非常出色（请参阅初步结果并附加手稿）。非霍奇金的淋巴瘤（NHL）是美国第五大癌症，占每年与癌症有关的所有死亡的5％。 5年治疗率仅为50％。已知这些肿瘤表达大量的CD74抗原。 NHL可能最能使用药物缀合物对特定的靶向方法响应，这是因为其广泛传播性质以及癌细胞对系统施用剂的相对可及性。此外，造血肿瘤的固有敏感性较高，这种疾病的自然病程因细胞而失控而超过正常B细胞​​的生长，它提供了向注射药物的特定注射药物比例更高的比例，因为它是针对患病细胞的更高比例的，因为与正常细胞相比。因此，该提案将解决LL1-DOX免疫偶联物使用几种已建立的临床前模型和原发性NHL活检标本来处理传播NHL的实用性。我们还将解决几个新的生物学问题，包括（a）通过直接用抗体传递DOX来克服多种耐药性（通常由约60％的难治性NHL患者表达），以及（b）克服与无用的无用的心脏毒性相关的心脏毒性阿霉素。