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: 8391572
• 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/8391572
• 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）：