We have developed immunoliposomes for targeted drug delivery, and will apply this approach to brain tumors in conjunction with novel regional targeting as well as systemic administration. The modular organization of immunoliposome constructs makes possible a combinatorial strategy for the generation of new therapeutics: monoclonal antibody (MAb) fragments, derived from available MAbs or newly selected from phage antibody libraries, can be coupled to an appropriate liposomal drug, chosen from a repertoire of liposomal drugs. We hypothesize that immunoliposomes can be developed for targeted treatment of brain tumor cells, such as by targeting EGFR or other tumor-associated antigens. We will therefore construct immunoliposomes that bind and internalize in brain tumor cells, enabling intracellular delivery of potent anticancer agents, including those with high inherent activity against glioma cells. These immunoliposome constructs can be further developed in conjunction with novel delivery strategies for central nervous system (CNS) tumors, such as convection-enhanced delivery (CED), as well as intra-arterial (i.a) and intravenous (i.v.) administration. This represents an integrated approach in which molecular targeting is combined with regional targeting to maximize therapeutic index.
Our specific aims are: 1) Construct immunoliposomes targeted to EGFR-associated brain tumors, using our established methods. 2) Optimize immunoliposomes in conjunction with regional delivery methods in preclinical glioma models. Immunoliposomes, already optimized for systemic administration, can also be optimized in conjunction with CED to integrate regional and molecular targeting of brain tumors. 3) Evaluate anti-EGFR immunoliposomes for targeted defivery of anticancer agents, immunoliposomes will be used to deliver potent small molecule drugs, including doxorubicin which is already available in an FDA-approved liposomal version, as well as novel compounds (e.g, ellipticine, breflate) with unique mechanisms, potent activity against brain tumor cells, and pharmacologic limitations as free drugs necessitating targeted delivery. 4) Construct new brain tumor-targeted immunoliposomes. We have developed novel selection methods to isolate new internalizing scFv from phage antibody libraries, including scFv against both known and novel antigens, and will employ these to rapidly derive new immunoliposomes against brain tumor cells. 5) Perform advanced preclinical studies and clinical development of best construct. Immunoliposome agents that appear the most promising based on studies in Aims 1-4 will be moved to a development track for clinical testing, including process scale up, GMP manufacturing, IND-enabling preclinical studies, and Phase I clinical trial.
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