Recent Advances in Patient Treatment and Care (Track)




L-DOS47 - a Phase I/II lung cancer candidate that uses tumor alkalization as a therapeutic approach

Heman Chao
Helix BioPharma Corp, Aurora, Ontario, Canada

Abstract:

Many solid human tumors generate an acidic and hypoxic microenvironment due to altered metabolic pathways and aberrant tumor vasculature.  These acidic conditions reportedly activate proteases which digest the extracellular matrix and allow phagocytosis of non-tumor cells, leading to invasiveness and metastatic behaviour.  In has been suggested that tumor acidosis affects chemotherapy by promoting resistance to (i) weakly basic chemotherapeutic agents by altering their intracellular/extracellular partition coefficient and (ii) radiation therapy by suppressing early steps of apoptotsis and reducing the degree of radiation induced fixation.  L-DOS47, an immunoconjugate cancer therapeutic, targets this unique tumor microenvironment by localizing urease to lung tumor using a specific antibody. Urease coverts the abundant metabolite urea to ammonia, increasing the local pH and exerts a cytotoxic effect on cancer cells in culture and xenograft models. In vitro experiments showed L-DOS47 dramatically potentiated the cytotoxicity of a number of chemotherapeutics and tissue staining shows specific binding to human lung adenocarcinoma biopsy samples. Imaging studies using A549 xenografts and labelled L-DOS47 applied intravenously shows accumulation and persistence at the tumor for well over 72 hours. A complete preclinical pharmacology-toxicology program has been conducted and two parallel Phase I/II open-label studies are being planned subject to regulatory approval.