CD206 Targeted Therapy for Kaposi Sarcoma and Tumor Associated Macrophages

Summary AbstractKaposi sarcomaKSis a potentially life threatening consequence of immunosuppression in patients that are infected with human herpes virusHHVMost KS occurs in patients with acquired immunodeficiency syndromeAIDSCurrent KS therapies have limited efficacy and serious off target toxicitiesNavidea has been developingmTc tilmanocepta wholly synthetic molecular construct that binds with very high affinity and specificity to the macrophage mannose receptorCDThe first commercial application formTc tilmanocept is as an intraoperative lymphatic mappingILMagent for identifying sentinel lymph nodesSLNsduring cancer surgeries to remove solid tumorsAfter a broad range of preclinical studies and highly successful clinical trialsthe FDA and European regulators approvedmTc tilmanocept for ILM and identification of SLNsNavidea has learned that KS tumor cells and also tumor associated macrophagesTAMsin most types of cancer highly express CDIn this grant applicationNavidea is seeking support to evaluate a tilmanocept like drug delivery constructMTwhich is intended to deliver doxorubicin to CDexpressing cellsDoxorubicin is an important therapy for KS in AIDS patientsbut its efficacy is limited due primarily to its off target cardiotoxicityHeart muscle cells do not express CDThe central concept of this proposal is that MTcould concentrate doxorubicin in CDexpressing cellssuch as KS cells and their TAMswhile sequestering away this cardiotoxic drug from other tissues and especially from heart musclesThis would enhance the effectiveness of the drug while reducing or virtually eliminating its cardiotoxicityAn important feature of CDs interactions with its ligands is that after CDligand bindingthe complex is internalized into endosomes inside the cellEndosomes become acidified causing CDto release its ligandallowing CDto recycle to the cell surfaceNavidea has developing acid labile linkerswhich are part of MTThese will permit MTto release its doxorubicin payload only once they are in the endosomes of the targeted cellsNavidea s has shown that a MTlike prototype molecule specifically kills CDexpressing cellsIt also kills KS cells and their TAMs in KS biopsy explants maintained in culturewhile sparing cells that do not express CDThis Fast Track SBIR application requests support to complete a series of in vitrocell culture based and preclinical animal studies to evaluate the likely safety and efficacy of MTfor the treatment of KSThe information from these studies will be combined with other information concerning chemical manufacturing controlsCMCand synthesis optimization in an investigational new drugINDapplication that will be submitted to the FDA requesting permission to begin testing MTin human KS patientsWe 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 treatmentWe also believe that given the data to datethis project will be a powerful gateway to a new class of anti TAM therapies directed at solid tumors generally