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: 8762389
• 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 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8762389
• 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; 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; imaging system; improved; in vivo; male; mouse model; neoplastic; novel; older patient; patient population; programs; rituximab; targeted treatment; 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）： 该提案集中于开发用于治疗非霍奇金淋巴瘤（NHL）的新型、新型、CD 22靶向、基于免疫脂质体（IL）的药物。我们最初的研究使用Doxil靶向NHL与抗CD 22单克隆抗体（mAb），“HB22.7”。通过使用后膜插入技术将mHB22.7并入Doxil中以形成免疫脂质体-Doxil（IL-Doxil），已经实现了IL的NHL靶向。目的是将脂质体的内容物直接存款在NHL的部位。 特异性靶向、mAb的生物活性和与脂质体包封的药物的协同作用的组合可能导致更有效但毒性更小的治疗方案。CD 22在超过90%的B细胞NHL上表达。HB22.7抗CD 22配体阻断mAb具有独特的促凋亡和杀淋巴瘤特性。作为NCI RAID计划的一部分，HB22.7已被人源化，并已批准用于GMP生产和I/II期人体临床试验。 IL在体外和体内显示NHL特异性结合NHL。当与其亲本（Doxil）相比时，IL-Doxil特异性地增加NHL细胞中的细胞内多柔比星浓度;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，我们证明了与Doxil相比，用IL-Doxil治疗的小鼠的肿瘤生长显著减少并且存活率显著增加。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出来。 基于这些初步数据，我们假设基于HB22.7的IL将被证明是NHL的有效和安全的治疗。我们建议使用IL策略，通过产生可以靶向CD 22和CD 20的IL来进一步改善脂质体递送系统。此外，我们将把硼替佐米或白藜芦醇封装到白细胞介素中，以创造其他专门针对NHL的有效新药。 使用免疫正电子发射断层扫描（i-PET）的血液药代动力学（PK）和体内靶向分析将有助于表征新开发的IL。提出了以下目的：1）优化用IL-Doxil的靶向治疗，2）使用靶向CD 22的IL-Doxil作为范例，创建和开发更多新的含有硼替佐米或白藜芦醇的NHL靶向构建体，和3）通过标准血液PK和i-PET检查抗CD 22-IL在NHL异种移植小鼠模型中的PK。