Immunoliposomal Therapy of non-Hodgkin's Lymphoma

描述(由申请人提供)： 这项建议的重点是开发新的，新的，CD22靶向，免疫脂质体(IL)为基础的药物治疗非霍奇金淋巴瘤(NHL)。我们最初的研究是用抗CD22单抗(MAb)“HB22.7”靶向NHL的Doxil。IL靶向NHL是通过膜后插入技术将mHB22.7掺入Doxil形成免疫脂质体-Doxil(IL-Doxil)而实现的。目的是将脂质体的内容物直接存放在非霍奇金淋巴瘤的部位。结合特异性靶向、单抗的生物活性以及与脂质体包裹的药物的协同作用，可能会产生更有效、毒性更低的治疗方案。CD22在90%以上的B细胞NHL上表达。HB22.7，抗CD22配体封闭型单抗具有独特的促凋亡和杀瘤作用。作为NCI Raid计划的一部分，HB22.7已经人性化，并已批准为GMP生产和I/II期人类临床试验提供资金。IL在体外和体内均显示与NHL特异性结合。与其亲本(Doxil)相比，IL-Doxil特异性地增加了NHL细胞内多柔比星的浓度；这与NHL的特异性细胞毒性有关。在携带NHL异种移植的小鼠身上，我们证明了IL-Doxil治疗的小鼠比Doxil治疗的小鼠肿瘤生长显著减少，存活率显著提高。我们将首先优化IL-Doxil，并将其开发作为进一步改进IL-Doxil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。根据这些初步数据，我们推测基于HB22.7的IL将被证明是治疗NHL的有效和安全的药物。我们建议使用IL策略来进一步改进脂质体递送系统，创建既可以针对CD22又可以针对CD20的IL。此外，我们将把Bortezomib或白藜芦醇封装到IL中，以创造出其他专门针对NHL的有效新药。血液药代动力学(PK)和免疫正电子发射断层扫描(I-PET)体内靶向分析将有助于新开发的IL的特征。提出了以下目标：1)优化IL-Doxil的靶向治疗；2)以CD22靶向IL-Doxil为范式，创建和开发更多含有Bortezomib或白藜芦醇的新型NHL靶向构建体；3)通过标准血PK和I-PET检测抗CD22-IL在NHL异种移植模型中的PK。

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.