Novel Human Anti-CD19 Antibodies for Lymphoma Therapy

描述（由申请人提供）： 非霍奇金淋巴瘤（NHL）是美国第五大常见癌症类型。美国目前约有30万人患有NHL，估计2002年将有53，900例新病例。每年5%的发病率增长是任何人类癌症中最快的。针对B细胞抗原CD 20的未修饰的单克隆抗体（mAb）和放射性标记的mAb的治疗效用通过最近FDA批准这些药剂用于治疗复发性和难治性B细胞NHL来证明。虽然反应率很高，但完全治愈是罕见的，反应的中位持续时间只有1-2年。因此，迫切需要新的疗法来预防或对抗疾病复发。CD 19是一种95-kD的膜糖蛋白，存在于几乎所有的B细胞淋巴瘤、慢性淋巴细胞白血病（CLL）和急性淋巴母细胞白血病（ALL）中。CD 19在成熟浆细胞、造血干细胞或B系以外的正常组织上不表达。CDI 9蛋白不会脱落到循环中，并且尽管抗CD 20治疗后CD 20表达丧失，但仍维持在肿瘤上。总之，CD 19的表达谱使其成为B细胞肿瘤免疫治疗的高度有吸引力的靶标。我们最近在人类淋巴瘤小鼠模型中的研究表明，CD 19作为采用传统和高度创新的放射性核素的放射免疫治疗的靶点，比CD 20具有明显的优势。这些研究中观察到的深远的抗肿瘤作用为CD 19定向疗法提供了令人信服的原理证明。然而，我们的研究采用了在人类中使用具有可预见的局限性的鼠CD 19 mAb。以高亲和力和特异性识别CD 19的全人mAb将是治疗的理想候选物。我们建议使用人免疫球蛋白基因座转基因小鼠开发新型全人源抗CD 19 mAb。将在体外评价mAb的特异性和抗肿瘤特性，包括未标记形式和用新型α和β发射治疗性同位素标记时。最有前途的免疫抑制剂将严格评估其治疗潜力，使用最好的人类淋巴瘤动物模型。该项目的成功将为快速推进最有前途的药物进入人类临床试验的开发提供强大的动力。

DESCRIPTION (provided by applicant): Non-Hodgkin's lymphoma (NHL) is the fifth most common type of cancer in the United States. Approximately 300,000 people are currently living with NHL in the U.S. and an estimated 53,900 new cases will occur in 2002. The 5% annual increase in incidence is the fastest for any human cancer. The therapeutic utility of unmodified monoclonal antibodies (mAbs) and radiolabeled mAbs against the B-cell antigen CD20 is demonstrated by the recent FDA approvals of these agents for the treatment of relapse and refractory B-cell NHL. Although response rates are high, complete cures are rare and the median duration of response is only 1-2 years. Consequently, there is an urgent need for new therapies to prevent or combat disease relapse. CD19 is a 95-kD membrane glycoprotein found on nearly all of B-cell lymphomas, chronic lymphocytic leukemias (CLL), and acute lymphoblastic leukemias (ALL). CD19 is not expressed on mature plasma cells, hematopoietic stem cells, or normal tissues outside the B-lineage. The CDI9 protein is not shed into the circulation and is maintained on tumors despite loss of CD20 expression following anti-CD20 therapy. Taken together, the expression profile of CD19 makes it a highly attractive target for immunotherapy of B-cell neoplasms. Our recent studies in mouse models of human lymphoma demonstrated that CD19 offers clear advantages over CD20 as a target for radioimmunotherapies that employ both traditional and highly innovative radionuclides. The profound anti-tumor effects observed in these studies provide compelling proof-of-principle for CD19-directed therapies. However, our studies employed murine CD19 mAbs that have foreseeable limitations for use in humans. A fully human mAb that recognizes CD19 with high affinity and specificity would be an ideal candidate for therapy. We propose development of novel, fully-human anti-CD19 mAbs using mice that are transgenic for the human immunoglobulin gene locus. The mAbs will be evaluated for specificity and anti-tumor properties in vitro in both unlabeled form and when labeled with novel alpha- and beta-emitting therapeutic isotopes. The most promising immunotherapeutic agents will be critically evaluated for their therapeutic potential using the best available animal models of human lymphoma. Success in the project would provide strong impetus to rapidly advance the most promising agents into development for human clinical testing.