Abstract 2851: Development of an alkalizing antibody-enzyme conjugate for NSCLC treatment that is in Phase I clinical testing.

Abstract

Many solid human tumors generate an acidic and hypoxic microenvironment as a result of altered metabolic pathways and aberrant tumor vasculature. In certain tumors, the chronic exposure to acidic extracellular conditions has been reported to promote invasiveness and metastatic behaviour. In addition, the lower pH may promote resistance to weakly basic chemotherapeutic agents by altering their partitioning coefficient between the extracellular and intracellular compartments. L-DOS47, an immunoconjugate cancer therapeutic, has been developed to target this unique tumor microenvironment. L-DOS47 is a conjugate of a lung adenocarcinoma specific single domain antibody and a urease enzyme. The antibody serves as a targeting agent to deliver the enzyme to the affected site while the urease enzyme coverts urea, an abundant metabolite, into ammonia and generates a local pH increase. The combined effect of ammonia toxicity and pH increase is cytotoxic to cancer cells as shown both in culture and in xenograft models. In vitro experiments showed that L-DOS47 also dramatically potentiated the cytotoxicity of a number of chemotherapeutics. Imaging studies using A549 xenografts and labelled L-DOS47 applied intravenously showed that the drug molecule preferentially accumulated and persisted at the tumor site. L-DOS47 has been studied in a number of tissue-cross reactivity studies to identify suitable animal species for toxicological studies. Cryosections of normal human, cynomolgus monkey, Sprague-Dawley rat, and CD-1 mouse tissues were compared. L-DOS47 produced specific staining to control material (BxPC-3 cells) and those tissues that are known to express CEACAM6 - an antigen for L-DOS47. Both cytoplasmic and membrane bound staining were observed. Results of these studies suggest that the primate and both rodent species are suitable for animal toxicological studies. Pivotal GLP compliant animal toxicological studies in cynomologus monkey and rat together with several non-GLP pilot animal studies were done. In the primate GLP study, L-DOS47 (0, 17, 26, and 35 μg/kg) was administered by IV infusion on Days 1, 8, 15 and 22, followed by a 28-day recovery period. Main study animals were sacrificed on Day 25 and recovery animals on Day 50. Standard toxicology parameters were evaluated. In addition, toxicokinetics, cytokine stimulation and immunogenicity were also evaluated. A separate cardiovascular safety pharmacology study was also conducted. No treatment related clinical signs were observed for the animals treated with 17 or 26μg/kg of L-DOS47. Adverse signs were observed in some but not all of the high dose (35 μg/kg) treated animals. Based on adverse clinical signs observed at 35μg/kg, the NOAEL was determined to be 26 μg/kg/day in this study. Currently L-DOS47 is approved for phase I/II studies in Europe and the U.S.A. Patient enrollment has begun in Poland and first patient has been dosed.

Citation Format: Heman Chao, Baomin Tian, Kim Gaspar, John Docherty, Wah Wong. Development of an alkalizing antibody-enzyme conjugate for NSCLC treatment that is in Phase I clinical testing. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2851. doi:10.1158/1538-7445.AM2013-2851