Abstract 2518: A novel preclinical study in cynomolgus monkeys examining CCL2 production rate and kinetic profile after escalating dose administration of anti-CCL2 human monoclonal antibody carlumab (CNTO 888)
Authors: Puchalski Thomas , Han Chao , McIntosh Thomas , Brenner Erik , Fink Damien , Graham Kenneth , Jiao Qun , Seetharam Shobha , Takimoto Chris , Davis Hugh , Zhou Honghui 
Published: August 2012

Abstract
Purpose: Carlumab (CNTO 888) is a human IgG1α monoclonal antibody that binds CCL2 with high affinity in vitro. The objective of this study was to estimate the production rate and kinetic profile of CCL2 following escalating doses of carlumab with the goal of predicting the dose that would maintain suppression of free CCL2 throughout the dosing interval. Patients and methods: Eighteen male cynomolgus (cyno) monkeys were allocated to 3 treatment groups: low dose [LD], fixed dose [FD] or high dose [HD], (6 per group) and received various doses of carlumab weekly (qw) or every other week (q2w) over a 6-week study period. LD received a starting dose of 1 mg/kg qw for 3 weeks, followed by an increase to 5 mg/kg qw for 3 more weeks. FD received 15 mg/kg q2w. HD received a starting dose of 12.5 mg/kg qw for 2 weeks, increased to 25 mg/kg qw for 2 weeks and then increased to 50 mg/kg qw for the final 2 weeks. Serial serum samples were collected and analyzed using immunoassay methods to determine the concentrations of free CCL2, carlumab-CCL2 complex and carlumab. Results: Based on the slope of the carlumab-CCL2 complex concentration-time profile immediately after dosing, the production rate of CCL2 did not appear to significantly change as the dose of carlumab was increased from 1 to 50 mg/kg. Increasing the dose from 1 to 25 mg/kg resulted in a dose-proportional increase in the carlumab-CCL2 complex; however, increasing the dose from 25 to 50 mg/kg did not result in further increase of the carlumab-CCL2 complex, suggesting that a very high proportion of the CCL2 in the serum was bound by carlumab at a dose of 25 mg/kg. In LD, the concentration of free CCL2 was lower compared with the higher dose regimens. Free CCL2 increased after the carlumab dose increased from 12.5 to 25 mg/kg but decreased after a dose increase from 25 to 50 mg/kg. This finding suggested that a dose &gt;50 mg/kg would be required to maintain suppression of free CCL2 throughout the dosing interval due to the large amount of free CCL2 that continuously disassociates from the complex. After a dose of 15 mg/kg every 2 weeks, carlumab, free CCL2 and carlumab-CCL2 complex concentration-time profiles demonstrated similar results to those observed in cancer patients. Conclusions: In this novel comprehensive PK/PD study in cyno monkeys, the production rates of CCL2 did not appear to correlate with increasing doses of carlumab and suggested that a dose of &gt;50 mg/kg every week would be needed to continuously maintain suppression of free CCL2 below baseline levels. This study design demonstrated that the cyno monkey is a relevant species in which to examine the binding of carlumab on CCL2. This study methodology could be applied to test other therapeutic monoclonal antibodies targeting soluble ligands in cyno monkeys for which the cyno homolog demonstrates cross reactivity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2518. doi:1538-7445.AM2012-2518