Novel Human Anti-CD19 Antibodies for Lymphoma Therapy

描述(由申请人提供)： 非霍奇金淋巴瘤(NHL)是美国第五种最常见的癌症。美国目前约有30万人患有非霍奇金淋巴瘤，预计2002年将出现53,900例新病例。5%的年发病率增长速度是所有人类癌症中最快的。未经修饰的抗B细胞抗原CD20的单抗和放射性标记的单抗最近被FDA批准用于治疗复发和难治性B细胞NHL，证明了这些药物的治疗效果。虽然应答率很高，但完全治愈的情况很少见，有效时间的中位数只有1-2年。因此，迫切需要新的疗法来预防或抗击疾病复发。CD19是一种95kD的膜糖蛋白，几乎存在于所有B细胞淋巴瘤、慢性淋巴细胞白血病(CLL)和急性淋巴细胞白血病(ALL)中。CD19在成熟浆细胞、造血干细胞或B系以外的正常组织中不表达。CDI9蛋白不会进入循环，即使在抗CD20治疗后CD20的表达丢失，它仍被维持在肿瘤上。综上所述，CD19的表达谱使其成为B细胞肿瘤免疫治疗的一个极具吸引力的靶点。我们最近在人类淋巴瘤小鼠模型上的研究表明，CD19作为使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CD20具有明显的优势。在这些研究中观察到的深刻的抗肿瘤作用为CD19指导的治疗提供了令人信服的原则证据。然而，我们的研究使用了小鼠CD19单抗，这些单抗对人类的使用具有可预见的局限性。具有高亲和力和高特异性识别CD19的全人mAb将是治疗的理想候选者。我们建议利用人类免疫球蛋白基因座转基因的小鼠来开发新型的、完全人源性的抗CD19单抗。这些单抗将在体外进行特异性和抗肿瘤特性的评估，无论是在未标记的形式下，还是在标记了新的释放α和β辐射的治疗性同位素时。将使用最好的人类淋巴瘤动物模型对最有希望的免疫治疗剂的治疗潜力进行严格评估。该项目的成功将为迅速推动最有希望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.