Background: Chemokines and their receptors regulate a variety of immune responses to infection, inflammation, and tissue repair. CXCR4 is a chemokine receptor that has one known natural ligand, CXCL12 also known as stromal derived factor-1(SDF-1). Binding of CXCR4 and CXCL12 activates a variety of intracellular signal transduction pathways and effectors that regulate cell survival, proliferation, chemotaxis, migration, adhesion, angiogenesis, homing, and stem cell mobilization. CXCR4 is expressed on both hematopoietic and non hematopoietic tumor cells and its expression plays a prominent role in a number of malignancies. Accordingly, it is a therapeutic target of interest for both primary and metastatic disease. Furthermore, CXCR4 antagonism has been used clinically to enhance stem cell mobilization in autologous transplant procedures. MSX-122 is an orally available, specific small molecule antagonist of CXCR4/CXCL12 currently being tested in preclinical cancer models.
 Methods: Male cynomolgus monkeys were dosed by oral gavage with 15, 150 and 500 mg/kg of MSX-122 after which plasma concentrations and total white cell counts were monitored for 12 hours. In a second experiment, female cynomolgus monkeys were dosed by oral gavage with 1, 5, and 10 mg/kg of MSX-122 after which plasma concentrations and white cell counts were again monitored for 18 hours. Differential counts of B-cell and T-cell counts were also monitored at the 10 mg/kg dose. GLP, 28-day toxicology studies were conducted in cynomolgus monkeys at doses of 20 mg/kg/day, 80 mg/kg/day and 600 mg/kg/day.
 Results: At all dose levels tested, leukocytosis was observed beginning at 4 - 6 hours with a peak total white cell count at 12 - 18 hrs that was 1.5 - 2 fold higher than baseline. Differential B-cell and T-cell counts for the 10 mg/kg dose also peaked at 12 - 18 hours with cell counts that were 2 - 3 fold higher than starting counts. The observed leukocytosis is an expected pharmacodynamic response from CXCR4 inhibition and has been reported for other CXCR4 antagonists. Subsequent 28-day toxicology studies in monkeys revealed no adverse drug related clinical findings, after electrocardiographic examinations, CBC/chemistry measurements and both gross and microscopic pathology. Plasma exposures in the toxicology study well exceeded those necessary to produce leukocytosis.
 Conclusion: In monkeys, MSX-122 demonstrated the expected biologic effect of leukocytosis consistent with a CXCR4 antagonist effect in vivo at doses that were well tolerated in the same species. Initial clinical evaluation in advanced solid tumor patients is underway.

99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA