CD206 Targeted Therapy for Kaposi Sarcoma and Tumor Associated Macrophages

DESCRIPTION provided by applicant Kaposi sarcoma KS is a potentially life threatening consequence of immunosuppression in patients that are infected with human herpes virus HHV Most KS occurs in patients with acquired immunodeficiency syndrome AIDS Current KS therapies have limited efficacy and serious off target toxicities Navidea has been developing mTc tilmanocept r a wholly synthetic molecular construct that binds with very high affinity and specificity to the macrophage mannose receptor CD The first commercial application for mTc tilmanocept is as an intraoperative lymphatic mapping ILM agent for identifying sentinel lymph nodes SLNs during cancer surgeries to remove solid tumors After a broad range of preclinical studies and highly successful clinical trials the FDA and European regulators approved mTc tilmanocept for ILM and identification of SLNs Navidea has learned that KS tumor cells and also tumor associated macrophages TAMs in most types of cancer highly express CD In this grant application Navidea is seeking support to evaluate a tilmanocept like drug delivery construct MT which is intended to deliver doxorubicin to CD expressing cells Doxorubicin is an important therapy for KS in AIDS patients but its efficacy is limited due primarily to its off target cardiotoxicity Heart muscle cells do not expres CD The central concept of this proposal is that MT could concentrate doxorubicin in CD expressing cells such as KS cells and their TAMs while sequestering away this cardiotoxic drug from other tissues and especially from heart muscles This would enhance the effectiveness of the drug while reducing or virtually eliminating its cardiotoxicity An important feature of CD andapos s interactions with its ligands is that after CD ligand binding the complex is internalized into endosomes inside the cell Endosomes become acidified causing CD to release its ligand allowing CD to recycle to the cell surface Navidea has developing acid labile linkers which are part of MT These will permit MT to release its doxorubicin payload only once they are in the endosomes of the targeted cells Navideaandapos s has shown that a MT like prototype molecule specifically kills CD expressing cells It also kills KS cells and their TAMs in KS biopsy explants maintained in culture while sparing cells that do not express CD This Fast Track SBIR application requests support to complete a series of in vitro cell culture based and preclinical animal studies to evaluate the likely safety and efficacy of MT for the treatment of KS The information from these studies will be combined with other information concerning chemical manufacturing controls CMC and synthesis optimization in an investigational new drug IND application that will be submitted to the FDA requesting permission to begin testing MT in human KS patients We anticipate that this project will bring an effective and life sparing new therapy to KS patients who are in desperate need for such a new treatment We also believe that given the data to date this project will be a powerful gateway to a new class of anti TAM therapies directed at solid tumors generally PUBLIC HEALTH RELEVANCE Kaposi sarcoma KS is a serious and potentially life threatening illness in persons infected with the human immunodeficiency virus HIV the causative agent of acquired immunodeficiency syndrome AIDS Tumor associated macrophages TAMs constitute an important tumor component for most types of cancer including KS that contributes to tumor growth and protection from immune responses Navidea is developing a receptor targeted drug construct that may be able to effectively treat KS and could contribute to effective immunotherapy for a wide variety of cancers generally