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。 80% 的患者就诊时已患有局部晚期或转移性癌症；中位生存期不到一年。尽管进行化疗（无论是否进行放疗），3A、3B 和 IV 期非小细胞肺癌 (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 是一种膜糖蛋白粘附分子，以前认为仅在 B 淋巴细胞和非霍奇金淋巴瘤 (NHL) 上表达。在这项提案中，我们提供了第一个强有力的证据，证明 CD22（令人惊讶地）也表达为肺癌细胞的表面受体。我们建议研究CD22对肺癌细胞的作用，并探索CD22靶向作为肺癌患者的新治疗方法。 CD22 通常被认为是 B 淋巴细胞相关糖蛋白粘附分子；我们在分子水平上剖析了 CD22 信号级联反应。我们鉴定出抗 CD22 mAb 能够结合 CD22 的两个氨基末端免疫球蛋白结构域，并特异性阻断 CD22 与其配体的相互作用。 HB22.7 是一种抗 CD22 配体阻断单克隆抗体，在诱导 NHL 信号转导和细胞凋亡方面非常有效。 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 计划将 HB22.7 人性化，然后资助 GMP​​ 生产。人源化 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 结合的研究中，我们偶然发现了大多数 NSCLC 细胞系（计划用作阴性对照）上的 CD22 表达。此外，HB22.7 针对患者样本中的 NSCLC 细胞。我们启动了 NSCLC 异种移植试验，HB22.7 作为裸 mAb 和 CD22 靶向免疫脂质体表现出了令人惊讶的良好活性。 由于大量新数据和 huHB22.7 的可用性，我们假设 HB22.7 将成为 NSCLC 的有效、无毒的新疗法。为了进一步开发这种令人兴奋的新疗法，提出了以下目标：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作用； 2)确定CD22是否促进NSCLC细胞系的生长和转移。还将评估 HB22.7 与已知可用于治疗 NSCLC 的化疗药物的潜在协同效应； 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，将创建靶向 CD22 的、含顺铂的纳米颗粒 (NP)。 NP 的药代动力学及其治疗肺癌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、CD22 靶向治疗 NSCLC 的潜力，并将允许 huHB22.7 快速转化为 NSCLC 患者。