Novel formulations of therapeutic antibodies with hyaluronic acid (HA) in the treatment of colorectal cancer: a pre-clinical evaluation

Proc Amer Assoc Cancer Res, Volume 47, 2006 682 INTRODUCTION: Knowledge of the molecular basis for cancer has been used to develop a new generation of therapies designed to target specific molecular processes that are essential for tumor growth and survival. Two such therapies employ the monoclonal antibodies, bevacizumab (Avastin®) and cetuximab (Erbitux®,ERB), which are routinely used for the treatment of metastatic colorectal cancer. A novel generation of anticancer formulations based on the naturally occurring polysaccharide HA, is currently under development which exploit the unique physiochemical and biological properties of HA, enabling it to direct entrained anticancer agent(s) to over-expressed CD44 receptors. To date HA formulations have been used with standard cytotoxic drugs. The objective of this study was to evaluate if HA could provide the basis for improved formulations of Erbitux® (ERB) monotherapies and ERB/chemotherapy combinations. The assessment of the formulation HyERB™ comprising HA and Erbitux® and the combination therapy of HyERB™ with HyCAMP™ (comprising HA and Camptosar®) in colon cancer xenografts is described. METHODOLOGY: LIM1215 colon cancer xenografts were subcutaneously injected into the mammary fat pad of athymic nude Balb/c mice. Treatment groups ( n =8) commenced when tumors reached 50-100mm3. The four treatment groups were: 1) HyERB™(150/0.5), 2) ERB(0.5), 3) HA (150), and 4) saline [all dosage amounts shown in brackets are in mg/kg]. Therapies were delivered IV on day 1 and 4 for a total of 5-weeks. Combination therapies included: 1) HyERB™(150/0.5)/HyCAMP™(26.6/50) and 2) ERB(0.5)/CAMP(50). The dosing regimen for HyCAMP™ or CAMP was day 1 of a 7-day cycle for a total of 5-weeks. Mice were observed for 120 days for tumor regrowth. RESULTS: Mice receiving HyERB™ monotherapy displayed a significant reduction in tumor size, which by day 29 was circa -29% of the original measurement compared to mice receiving ERB therapy, where all tumors were ±1% of the original measurement. During the tumor rebound period, tumor progression was more evident in the ERB group where 86% of tumors were assessed as ‘stable disease’ while 50% of HyERB™-treated tumors demonstrated partial response or stable disease. In combination therapies, the tumor size for HyERB™/HyCAMP™ at days 8, 11 and 15 was significantly smaller than in animals treated with ERB/CAMP. No treatment toxicities were observed.CONCLUSIONS: The formulation of HA with cetuximab (HyERB™) produced a significant anti-tumor response, whereas the antibody alone produced a cytostatic response in the LIM1215 (CD44 positive, EGFR positive) colon xenograft model. This increased efficacy was also achieved when using HA formulations in combination ERB/chemotherapy treatment regimens.