Immunoliposomal Therapy of non-Hodgkin's Lymphoma

非霍奇金淋巴瘤的免疫脂质体治疗

• 批准号: 8597357
• 负责人: ROBERT T O'DONNELL
• 金额: --
• 依托单位: VA NORTHERN CALIFORNIA HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-10-01 至 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8597357
• 关键词: Animals; Antibodies; Antineoplastic Agents; Apoptosis; Apoptotic; B-Cell NonHodgkins Lymphoma; B-Lymphocytes; Binding; Blood; Bortezomib; CD22 gene; Cancer Etiology; Cell Adhesion Molecules; Cells; Cessation of life; Clinical Trials; Comorbidity; Data; Deposition; Development; Disease; Doxorubicin; Doxorubicin Hydrochloride Liposome; Drug Kinetics; Elderly; Encapsulated; Event; Funding; Generations; Glycoproteins; Goals; Half-Life; Hematologic Agents; Human; Image; Immunoglobulin Domain; In Vitro; Intervention; Knowledge; Lead; Ligands; Liposomes; MS4A1 gene; Malignant Neoplasms; Mediating; Membrane; Monoclonal Antibodies; Mus; N-terminal; Non-Hodgkin' s Lymphoma; Parents; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phosphorylation; Population; Positron-Emission Tomography; Production; Property; Resveratrol; Roche brand of rituximab; Signal Transduction; Site; Specificity; Surface; System; Techniques; Toxic effect; Treatment Protocols; Veterans; Xenograft procedure; agent orange; base; cancer cell; chemotherapy; cytotoxicity; drug development; improved; in vivo; male; mouse model; neoplastic; novel; older patient; patient population; programs; rituximab; tumor; tumor growth

DESCRIPTION (provided by applicant): This proposal focuses on the development of new, novel, CD22-targeted, immuno- liposome (IL)-based drugs for the treatment of non-Hodgkin's lymphoma (NHL). Our initial studies used Doxil targeted to NHL with an anti-CD22 monoclonal antibody (mAb), "HB22.7". NHL targeting by IL has been accomplished by incorporating mHB22.7 into Doxil using a post membrane insertion technique to form immuno-liposomal-Doxil (IL- Doxil). The goal is to deposit the contents of the liposome directly at the site of NHL. The combination of specific targeting, biologic activity of the mAb and synergy with liposome-encapsulated drugs may lead to more effective yet less toxic treatment regimens. CD22 is expressed on more than 90% of B-cell NHL. The HB22.7, anti-CD22 ligand blocking mAb has unique pro-apoptotic and lymphomacidal properties. As part of the NCI RAID program, HB22.7 has been humanized and funding has been approved for GMP production and for a Phase I/II human clinical trial. The IL display NHL-specific binding to NHL in vitro and in vivo. When compared to its parent (Doxil), IL-Doxil specifically increased the intracellular doxorubicin concentration in NHL cells; this correlated with NHL-specific cytotoxicity. Using mice bearing NHL xenografts, we demonstrated a dramatic reduction in tumor growth and a significant increase in survival of mice treated with IL-Doxil compared to Doxil. We will first optimize IL-Doxil and use its development as a paradigm for further improving the IL, and encapsulating other drugs in them. Immuno-nanomicelles are also going to be developed. Based on this preliminary data we hypothesize that HB22.7-based IL will prove to be effective and safe treatment for NHL. We propose to use the IL strategy to further improve the liposome delivery system by creating IL that can target both CD22 and CD20. In addition, we are going to encapsulate bortezomib or resveratrol into IL to create other efficacious new drugs that specifically target NHL. Blood pharmacokinetics (PK) and in vivo targeting analysis using immuno- positron emission tomography (i-PET) will aid in the characterization of the newly developed IL. The following aims are proposed: 1) to optimize targeted therapy with IL- Doxil, 2) to create and develop more novel NHL-targeted constructs containing bortezomib or resveratrol, using CD22-targeted IL-Doxil as the paradigm, and 3) to examine the PK of anti-CD22-IL in a NHL xenograft mouse model by standard blood PK and i-PET.

描述（由申请人提供）： 该提案的重点是开发用于治疗非霍奇金淋巴瘤（NHL）的新型CD22靶向免疫脂质体（IL）药物。我们的初步研究使用 Doxil 与抗 CD22 单克隆抗体 (mAb)“HB22.7”靶向 NHL。通过使用膜后插入技术将 mHB22.7 掺入 Doxil 中以形成免疫脂质体-Doxil (IL-Doxil)，已完成 IL 靶向 NHL。目标是将脂质体的内容物直接沉积在 NHL 部位。 mAb 的特异性靶向、生物活性以及与脂质体封装药物的协同作用相结合，可能会产生更有效但毒性更小的治疗方案。 CD22 在 90% 以上的 B 细胞 NHL 上表达。 HB22.7 抗 CD22 配体阻断单克隆抗体具有独特的促凋亡和淋巴瘤特性。作为 NCI RAID 计划的一部分，HB22.7 已经人性化，并已批准用于 GMP 生产和 I/II 期人体临床试验的资金。 IL 在体外和体内表现出与 NHL 的 NHL 特异性结合。与其母体 (Doxil) 相比，IL-Doxil 特异性增加 NHL 细胞内阿霉素的浓度；这与 NHL 特异性细胞毒性相关。使用携带 NHL 异种移植物的小鼠，我们证明与 Doxil 相比，使用 IL-Doxil 治疗的小鼠肿瘤生长显着减少，存活率显着增加。我们将首先优化 IL-Doxil 并将其开发作为进一步改进 IL 的范例，并将其他药物封装在其中。免疫纳米胶束也将被开发。 基于这些初步数据，我们假设基于 HB22.7 的 IL 将被证明是治疗 NHL 的有效且安全的方法。我们建议使用 IL 策略通过创建可以同时靶向 CD22 和 CD20 的 IL 来进一步改进脂质体递送系统。此外，我们还将把硼替佐米或白藜芦醇封装到IL中，以创造其他专门针对NHL的有效新药。 血液药代动力学 (PK) 和使用免疫正电子发射断层扫描 (i-PET) 的体内靶向分析将有助于表征新开发的 IL。提出以下目标：1）优化 IL-Doxil 的靶向治疗，2）以 CD22 靶向 IL-Doxil 为范例，创建和开发更多包含硼替佐米或白藜芦醇的新型 NHL 靶向构建体，以及 3）检查通过标准血液 PK 和 i-PET 检测 NHL 异种移植小鼠模型中抗 CD22-IL 的 PK。