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.
Non-Hodgkin's lymphoma (NHL) is the sixth most common cause of cancer-related death in the USA. The fastest growing population acquiring this disease is elderly males, a substantial population at the VA. Given this, and the fact that NHL is an agent orange-associated malignancy, the impact on veterans is substantial. Elderly patients tolerate chemotherapy poorly, a factor leading to reduced efficacy and less chance of cure. Many VA patients are elderly males with multiple co-morbidities so development of less toxic treatments is very relevant. This proposal lays the groundwork for development of new, effective, and non-toxic treatment approaches for NHL which is directly applicable to the VA patient population.