CD22-targeted Therapeutics for the Treatment of Lung Cancer

用于治疗肺癌的 CD22 靶向疗法

• 批准号: 8244390
• 负责人: JOSEPH M TUSCANO
• 金额: --
• 依托单位: VA NORTHERN CALIFORNIA HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8244390
• 关键词: Apoptosis; B-Cell NonHodgkins Lymphoma; B-Lymphocytes; Binding; CD22 gene; Cancer Patient; Cancer cell line; Cause of Death; Cell Adhesion Molecules; Cell Line; Cell Surface Receptors; Cells; Cisplatin; Clinic; Clinical Trials; Data; Development; Diagnosis; Disease; Disseminated Malignant Neoplasm; Dose; Drug Kinetics; Drug Targeting; Effectiveness; Engineering; Epidermal Growth Factor Receptor; Epithelial Cells; Event; Funding; Glycoproteins; Goals; Growth; Homing; Human; Immune; Immunoglobulin Domain; Immunoliposome; Intervention; Knowledge; Ligands; Ligation; Locally Advanced Malignant Neoplasm; Lung; Lymphocyte; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Membrane Glycoproteins; Molecular; Mus; N-terminal; Nature; Neoplasm Metastasis; Non-Hodgkin' s Lymphoma; Non-Small-Cell Lung Carcinoma; Pathogenesis; Patients; Pharmaceutical Preparations; Physiological; Population; Production; Radiation; Research; Research Design; Resistance; Role; Sampling; Signal Transduction; Specimen; Staging; Structure of parenchyma of lung; Surface; Survival Rate; Testing; Therapeutic; Toxic effect; Translations; Treatment Efficacy; United States; Work; Xenograft Model; Xenograft procedure; base; cancer cell; cancer therapy; carcinogenesis; chemotherapy; cytotoxicity; design; in vivo; innovation; nanoparticle; new therapeutic target; novel therapeutic intervention; older patient; particle; prevent; programs; public health relevance; receptor; therapeutic target; tumor; tumor growth

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of death from cancer in the United States. Locally advanced or metastatic cancer exists at presentation in 80% of patients; median survival is less than one year. The 5-year survival rates for Stages 3A, 3B and IV non-small cell lung cancer (NSCLC) are about 20%, 8% and 2%, respectively, despite chemotherapy, with or without radiation. NSCLC patients need new therapeutic approaches! CD22 is a membrane glycoprotein adhesion molecule previously thought to be expressed only on B-lymphocytes and non-Hodgkin's lymphoma (NHL). In this proposal, we provide the first strong evidence that CD22 is (surprisingly) also expressed as a surface receptor on lung cancer cells. We propose to study the role of CD22 on lung cancer cells, and to explore CD22-targeting as a new treatment for patients with lung cancer. CD22 is usually thought of as a B-lymphocyte associated glycoprotein adhesion molecule; we have dissected the CD22 signaling cascade at the molecular level. We identified anti-CD22 mAb that bound the two amino-terminal immunoglobulin domains of CD22 and specifically blocked the interaction of CD22 with its ligand. HB22.7 is an anti-CD22 ligand blocking mAb that is highly effective at inducing signal transduction and apoptosis in NHL. HB22.7 has significant efficacy in NHL xenograft models. Based on these data the NCI humanized HB22.7 through the RAID Program and then funded GMP production. Humanized HB22.7 (huHB22.7) could become an exciting new cancer therapy. During studies designed to examine the binding of anti-CD22 constructs to NHL, we serendipitously discovered the expression of CD22 on the majority of our NSCLC cell lines (which had been planned for use as negative controls). Furthermore, HB22.7 targeted NSCLC cells from patient specimens. We initiated NSCLC xenograft trials and HB22.7 demonstrated surprisingly good activity as a naked mAb and as CD22-targeted immunoliposome. Because of substantial new data and the availability of huHB22.7, we hypothesize that HB22.7 will be an effective, non-toxic, new treatment for NSCLC. In order to further develop this exciting new therapy, the following aims are proposed: 1) characterize the breadth of CD22 expression as well as the physiologic and signaling effects of CD22 ligation on NSCLC cells; 2) determine whether CD22 promotes the growth and metastasis of NSCLC cell lines. The potential synergistic effects of HB22.7 with chemotherapeutics known to be useful for therapy of NSCLC will also be assessed; 3) validate and optimize CD22-targeted therapy against NSCLC and metastasis; 4) along with our collaborators, CD22-targeted, cisplatin-containing nanoparticles (NP) will be created. The pharmacokinetics of the NP and their efficacy for treatment of lung cancer will tested in vivo. This work will study the role of CD22 in NSCLC, the potential for CD22-targeted therapy of NSCLC, and will allow for rapid translation of huHB22.7 to patients with NSCLC.

描述（由申请人提供）： 肺癌是美国癌症死亡的主要原因。在80％的患者中，局部晚期或转移性癌症存在；中位生存不到一年。尽管化学疗法，有或没有放射线，但第3A，3B和IV非小细胞肺癌（NSCLC）的5年生存率分别约为20％，8％和2％。 NSCLC患者需要新的治疗方法！ CD22是一种以前认为仅在B淋巴细胞和非霍奇金淋巴瘤（NHL）上表达的膜糖蛋白粘附分子。在此提案中，我们提供了第一个有力的证据，表明CD22（令人惊讶的是）也表示为肺癌细胞上的表面受体。我们建议研究CD22在肺癌细胞中的作用，并探索CD22靶向作为针对肺癌患者的新治疗方法。 CD22通常被认为是B-淋巴细胞相关的糖蛋白粘附分子。我们已经在分子水平上解剖了CD22信号级联。我们确定了抗CD22的两个氨基末端免疫球蛋白结构域的抗CD22 mAb，并特别阻止了CD22与配体的相互作用。 HB22.7是一种抗CD22配体阻断mAb，在诱导NHL的信号转导和凋亡方面非常有效。 HB22.7在NHL异种移植模型中具有显着疗效。基于这些数据，NCI通过RAID计划进行了人源化HB22.7，然后资助了GMP生产。人源化的HB22.7（HUHB22.7）可能成为一种令人兴奋的新癌症疗法。 在旨在检查抗CD22构建体与NHL的结合的研究中，我们偶然发现了CD22在大多数NSCLC细胞系上的表达（已计划用作阴性对照）。此外，HB22.7针对患者标本的NSCLC细胞。我们启动了NSCLC异种移植试验，HB22.7表现出令人惊讶的良好活性作为裸MAB和CD22靶向的免疫体。 由于大量的新数据和HUHB22.7的可用性，我们假设HB22.7将是NSCLC的有效，无毒的新方法。为了进一步发展这种令人兴奋的新疗法，提出了以下目的：1）表征CD22表达的广度以及CD22连接对NSCLC细胞的生理和信号传导效应； 2）确定CD22是否促进了NSCLC细胞系的生长和转移。 HB22.7与已知的化学治疗剂的潜在协同作用也将被评估为NSCLC治疗； 3）验证和优化针对NSCLC和转移的CD22靶向疗法； 4）与我们的合作者一起，将创建含有顺铂的纳米颗粒（NP）。 NP的药代动力学及其对肺癌治疗的功效将在体内进行测试。 这项工作将研究CD22在NSCLC中的作用，NSCLC的潜力是对NSCLC的CD22靶向治疗，并允许将HUHB22.7快速转换给NSCLC患者。