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: 8045215
• 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/8045215
• 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新的，新型的CD22靶向，免疫 - 脂质体（IL）的药物，用于治疗非霍奇金淋巴瘤（NHL）。我们的最初研究使用了用抗CD22单克隆抗体（MAB）靶向NHL的Doxil，“ HB22.7”。通过使用后膜插入技术将MHB22.7掺入Doxil中，可以实现IL的NHL靶向，以形成免疫 - 脂质体 - 陶瓷（IL- Doxil）。目的是将脂质体的含量直接存放在NHL位置。 特异性靶向，MAB和协同作用与脂质体封装的药物的结合可能会导致更有效但毒性更少的治疗方案。 CD22在超过90％的B细胞NHL上表达。 HB22.7，抗CD22配体阻塞MAB具有独特的促凋亡和淋巴细胞化特性。作为NCI RAID计划的一部分，HB22.7已被人性化，资金已被批准用于GMP生产和I/II期人类临床试验。 IL在体外和体内显示NHL特异性与NHL的结合。与其母（Doxil）相比，IL-Doxil特别增加了NHL细胞中细胞内的阿霉素浓度。这与NHL特异性的细胞毒性相关。使用携带NHL异种移植的小鼠，与Doxil相比，我们证明了肿瘤生长显着减少，用IL-doxil治疗的小鼠的存活率显着增加。我们将首先优化IL-Doxil，并将其发展作为进一步改善IL并封装其他药物的范式。免疫纳米细胞也将开发。 基于此初步数据，我们假设基于HB22.7的IL将被证明是有效且安全的NHL治疗方法。我们建议使用IL策略通过创建可以针对CD22和CD20的IL来进一步改善脂质体递送系统。此外，我们将将硼替佐米或白藜芦醇封装到IL中，以创建其他针对NHL的有效新药。 血液药代动力学（PK）和使用免疫发射断层扫描（I-PET）的体内靶向分析将有助于表征新开发的IL。提出了以下目的：1）使用CD22-2arget的IL-Doxil作为范式来创建和开发含有硼替佐米或白藜芦醇的更新颖的NHL靶向构建体，以检查和3）检查paradigm和3）以抗cd2222-iL nhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhh Xenerogr。