The Development of a Therapeutic Antibody for Equine Endocrinopathic Laminitis

Although therapeutic monoclonal antibodies (mAb) are used in human medicine, few are under development for small animals and none are available for horses.  Nor are there any registered medications to prevent or treat endocrinopathic laminitis, which is associated with hyperinsulinaemia.  Because insulin receptors are scarce in the hoof, it was proposed that high concentrations of insulin damage the lamellae by overstimulating IGF-1 receptors (IGF-1R). Anti-IGF-1R mAb have been used successfully in human cancer patients, with few adverse effects. Thus, they could provide a useful therapeutic option for laminitis. A recombinant human anti-IGF-1R mAb was re-engineered to avoid an immune response in the horse, and expressed in CHO cells. In vitro, the equinized mAb was highly selective for binding to equine IGF-1R over insulin receptors ( > 60-fold), as measured by radioligand binding studies using lamellar and liver cell membranes. However, the mAb blocked the stimulatory effects of both peptides on cell proliferation in lamellar explants (100%, P < 0.001), as measured by 3H-thymidine uptake. In vivo, when Australian Standardbred horses were subjected to a prolonged hyperinsulinaemic-euglycaemic clamp over 48 h (n = 6), pre-treatment with a low dose of the mAb reduced the sinking of the distal phalanx (47%, P < 0.05), measured radiographically, and markedly lessened the stretching of the secondary epidermal lamellae, as observed in histological sections (P < 0.05). The results confirm that insulin can induce laminitis via IGF-1R, and demonstrate the potential of an anti-IGF-1R mAb for preventing or treating this disease.