Transplant rejection - belatacept
For full T-cell activation to occur a co-stimulation interaction is required in addition to the interaction between the T-cell receptor and antigen-presenting cells. These co-stimulation requirements have received much attention in the search for agents that could inhibit transplant rejection, downregulate inflammatory reactions and control autoimmune diseases.
For full T-cell activation to occur a co-stimulation interaction is required in addition to the interaction between the T-cell receptor and antigen-presenting cells. These co-stimulation requirements have received much attention in the search for agents that could inhibit transplant rejection, downregulate inflammatory reactions and control autoimmune diseases.
The best characterised of these co-stimulation pathways is the CD28:B7 pathway. CD28 is a transmembrane immunoglobulin and is expressed on most naïve T-cells, while its homologue, CTLA4, is a negative regulator of T-cell activation and a negative co-stimulatory molecule. Both of these share common ligands, CD80 and CD86, and if the interaction between these molecules is blocked, immune tolerance can be achieved.
Fusion proteins have been developed using recombinant technology that will competitively inhibit these ligands with their receptors, including Bristol-Myers Squibb's belatacept - the first rationally designed immunosuppressive fusion protein that blocks a critical T-cell co-stimulatory pathway.1
It was compared with cyclosporin in a multicentre randomised parallel group Phase II trial in 218 subjects who had received kidney transplants.2 Subjects were given either an intensive belatacept regimen, a less intensive regimen or standard cyclosporin therapy. All were given induction therapy with basiliximab and adjunctive maintenance therapy with corticosteroids and MMF. After six months the incidence of acute rejection stood at 6-8% in all three groups. After 12 months the glomerular filtration rate was higher with belatacept than cyclosporin, and chronic nephropathy was lower in those given belatacept. It gave similar immunosuppressive efficacy to cyclosporin, with better risk profiles and improved preservation of kidney function.
It has also been investigated in patients with rheumatoid arthritis who had been unsuccessfully treated with disease modifying agents.3 A total of 214 patients in a randomised double-blind placebo-controlled study were given either intravenous infusions of 0.5, 2 or 10 mg/kg belatacept, similar doses of the older fusion protein abatacept or placebo on days one, 15, 29 and 57. The efficacy was dose-dependent, with 34, 45 and 61% of the patients given three doses experiencing a response higher than those given the older drug. Infusions were well tolerated at all levels, and the incidence of adverse events was similar across all treatment groups.