Antagonism of chemokine receptor CCR8 is ineffective in a primate model of asthma
- Lin Wang1,2,
- Tracy J Jenkins1,3,
- Mingshi Dai1,4,
- Wei Yin1,5,
- Jacqueline C Pulido1,6,
- Elise LaMantia-Martin7,
- Martin R Hodge1,8,
- Timothy Ocain1,9,
- Roland Kolbeck1,10
- 1Department of Cellular Immunology and Pharmacology, Millennium Pharmaceuticals Inc. (Current: Millennium: The Takeda Oncology Company), Cambridge, Massachusetts, USA
- 2Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, Pennsylvania, USA
- 3Department of Medicinal Chemistry, Biogen Idec Pharmaceuticals, Inc, Cambridge, Massachusetts, USA
- 4World Financial Group, Inc., Lexington, Massachusetts, USA
- 5Aveo Oncology, Cambridge, Massachusetts, USA
- 6Westwood, Massachusetts, USA
- 7Charles River Laboratories Preclinical Services, Wilmington, Massachusetts, USA
- 8Immunoscience, Pfizer, Cambridge, Massachusetts, USA
- 9Seaside Therapeutics, Cambridge, Massachusetts, USA
- 10Department of Respiratory, Inflammation and Autoimmunity, MedImmune, LLC, Gaithersburg, Maryland, USA
- Correspondence to Dr Roland Kolbeck, Department of Respiratory, Inflammation and Autoimmunity, MedImmune, LLC, One MedImmune Way, Gaithersburg, MD 20878, USA;
- Received 17 November 2012
- Revised 29 January 2013
- Accepted 1 February 2013
- Published Online First 1 March 2013
Background Expression of the T-cell-associated chemokine receptor CCR8 and its ligand CCL1 have been demonstrated to be elevated in patients with asthma. CCR8 deficiency or inhibition in models of allergic airway disease in mice resulted in conflicting data.
Objective To investigate the effects of a selective small molecule CCR8 inhibitor (ML604086) in a primate model of asthma.
Methods ML604086 and vehicle were administered by intravenous infusion to 12 cynomolgus monkeys during airway challenge with Ascaris suum. Samples were collected throughout the study to measure pharmacokinetics (PK) and systemic CCR8 inhibition, as well as inflammation, T helper 2 (Th2) cytokines and mucus in bronchoalveolar lavage (BAL). Airway resistance and compliance were measured before and after allergen challenge, and in response to increasing concentrations of methacholine.
Results ML604086 inhibited CCL1 binding to CCR8 on circulating T-cells>98% throughout the duration of the study. However, CCR8 inhibition had no significant effect on allergen-induced BAL eosinophilia and the induction of the Th2 cytokines IL-4, IL-5, IL-13 and mucus levels in BAL. Changes in airway resistance and compliance induced by allergen provocation and increasing concentrations of methacholine were also not affected by ML604086.
Conclusions These results clearly demonstrate a dispensable role for CCR8 in ameliorating allergic airway disease in atopic primates, and suggest that strategies other than CCR8 antagonism should be considered for the treatment of asthma.