Characterization of alpha(4)beta(1) (CD49d/CD29) on equine leukocytes: potential utility of a potent alpha(4)beta(1) (CD49d/CD29) receptor antagonist in the treatment of equine heaves (recurrent airway obstruction).

This research explores the alpha(4)beta(1) receptor in horse leukocytes and the effectiveness of a particular antagonist, Compound B, in treating recurrent airway obstruction (also known as equine heaves) in horses.

Alpha(4)Beta(1) Receptor and Compound B

• Alpha(4)beta(1) also known as CD49d/CD29 or VLA-4, is a receptor present on horse leukocytes. This research aimed to characterize this receptor to study its properties and potential applications.
• The examination of the receptor’s antagonist, Compound B, was carried out to evaluate its effectiveness. An antagonist is a substance that interferes with or inhibits the physiological action of another, in this case, the alpha(4)beta(1) receptor.
• The objective is to see if by blocking alpha(4)beta(1), thus preventing the cellular recruitment of lymphocytes and neutrophils into the lung, could effectively treat RAO in horses.

Detailed Findings

• Researchers found that alpha(4)beta(1) receptor was present on horse lymphocytes and neutrophils, and could bind to the antagonists (Compounds A and B) with high potency.
• KD values, which represent the equilibrium between receptor and the agonist or antagonist, for the binding of Compound A to non-activated alpha(4)beta(1) on isolated horse PBMCs and activated neutrophils, were found to be 17 pM and 27 pM, respectively. This indicates high potential for stopping the receptor’s action.
• Compound B was selected for further study due to its high potency. It was determined that it possessed excellent potency in horse whole blood, with IC(50) and IC(90) values at 39 pM and 172 pM, respectively.
• Treatments with Compound B (5 mg/kg) in beagle dogs and rhesus monkeys showed rapid and sustained alpha(4)beta(1) receptor occupancy of over 80% which was maintained for a period of 24 hours. This suggests that Compound B could be an effective antagonist for alpha(4)beta(1).

Conclusion

• When Compound B was administered intravenously to the horse, by either a slow or rapid infusion, a receptor blockade of over 80% was observed within 24 hours with a corresponding leukocytosis (increase in the number of white blood cells).
• As a result of this study, Compound B has been identified as having a strong potential to be evaluated clinically as a treatment for horses affected by RAO, due to its potency and the sustained blockage of the alpha(4)beta(1) receptor it achieves.