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)： 在美国，肺癌是癌症致死的主要原因。80%的患者出现局部晚期或转移性癌症；中位生存期不到一年。3A期、3B期和IV期非小细胞肺癌(NSCLC)的5年生存率分别约为20%、8%和2%。非小细胞肺癌患者需要新的治疗方法！CD22是一种膜糖蛋白黏附分子，以前被认为只在B淋巴细胞和非霍奇金淋巴瘤(NHL)上表达。在这项提议中，我们提供了第一个强有力的证据，CD22(令人惊讶地)也作为肺癌细胞的表面受体表达。我们建议研究CD22在肺癌细胞中的作用，并探索CD22靶向治疗肺癌的新方法。CD22通常被认为是一种B淋巴细胞相关的糖蛋白黏附分子，我们已经在分子水平上剖析了CD22信号级联反应。我们鉴定了结合CD22的两个氨基末端免疫球蛋白结构域的抗CD22单抗，并特异性地阻断了CD22与其配体的相互作用。HB22.7是一种高效诱导NHL细胞信号转导和细胞凋亡的抗CD22配体封闭型单抗。HB22.7对非霍奇金淋巴瘤异种移植模型有显著疗效。根据这些数据，NCI通过Raid计划使HB22.7人性化，然后为GMP生产提供资金。人源化HB22.7(huHB22.7)可能成为一种令人兴奋的新癌症治疗方法。在研究抗CD22抗体与非霍奇金淋巴瘤结合的过程中，我们偶然发现CD22在大多数非小细胞肺癌细胞系(原计划用作阴性对照)上表达。此外，HB22.7靶向于患者标本中的非小细胞肺癌细胞。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，作为裸露mAb和CD22靶向免疫脂质体。由于大量的新数据和huHB22.7的可用性，我们假设HB22.7将成为治疗非小细胞肺癌的有效、无毒的新疗法。为了进一步开发这一令人兴奋的新疗法，提出了以下目标：1)研究CD22表达的广度以及CD22结扎对NSCLC细胞的生理和信号作用；2)确定CD22是否促进NSCLC细胞的生长和转移。还将评估HB22.7与已知对非小细胞肺癌治疗有用的化疗药物的潜在协同效应；3)验证和优化CD22靶向治疗非小细胞肺癌和转移；4)与我们的合作者合作，将创建CD22靶向、含顺铂的纳米粒(NP)。NP的药代动力学及其治疗肺癌的疗效将在体内进行测试。这项工作将研究CD22在非小细胞肺癌中的作用，CD22靶向治疗非小细胞肺癌的可能性，并将使huHB22.7快速翻译到非小细胞肺癌患者中。