This proposal focuses on the delivery of immunoconjugates to a model of human central nervous system metastatis in the nude rat. we have characterized the LX- 1 small cell lung carcinoma human tumor xenograft model in the nude rat with regard to permeability, growth characteristics, and survival times. We now propose to expand our current intracerebral tumor model using clonal populations of LX- 1 cells that stably express high or low amounts of the Lewis-y antigen for binding of monoclonal antibody (mAb) BR96. We hypothesize that these tumors will have similar growth and permeability characteristics to the parental LX- 1 model, but will have markedly different responses in the imaging and efficacy studies. In addition, these cell lines will provide a unique model to examine issues of tumor heterogeneity in imaging and therapy with immunoconjugates. We propose to examine the potential for specific imaging and diagnosis of intracerebral tumors using paramagnetic iron oxide particles conjugated to mAbs or mAb fragments as a tumor-specific contrast agent for magnetic resonance imaging. Pancarcinoma mAbs BR96 and L6, and the L6-F(ab')/2 and recombinant L6-sFv and BR96-sFv fragments, which may show reduced levels of non-specific binding compared to intact mAb, will be conjugated to the monocrystalline iron oxide nanoparticles (MIONs). We will then determine whether tumor-speclfic imaging can be attained using these agents, when delivery to intracerebral tumor is optimized with osmotic blood-brain barrier disruption (BBBD). The use of these MION antibodies conjugates offer the possibility of noninvasive assessment of tumor type and extent by adding specificity to an already sensitive MR imaging modality. In addition to the imaging studies, we will investigate the potential for therapy of intracerebral tumors using Doxorubicin and Pseudomonas exotoxin conjugated to the BR96 mAb or BR96- sFv fragment, respectively. We have the possibility for chemotherapy specifically targeted to brain tumors. The combination of an effective drug such as doxorubicin with tumor-specific localization and increased tumor delivery using osmotic BBBD is an innovative approach to brain turnor therapy with true practical application in the clinic. Clinical trials, based on previous blood-brain barrier program R01 funding, are resulting in durable tumor responses with no cognitive loss, particularly in CNS lymphoma patients. The proposed studies will further enhance these positive clinical results.
Showing the most recent 10 out of 58 publications
