Description
Belatacept is an immunosuppressive that was approved by the U.S. FDA
for prophylactic prevention of rejection in kidney transplant recipients.
Belatacept, which
selectively blocks T cell costimulation, provides an alternative to the
calcineurin inhibitors, which are associated with adverse effects on renal
function as well as cardiovascular and metabolic parameters. T-cell
activation by antigen-presenting cells (APCs) requires a costimulatory
signal in addition to the signal mediated by interaction of the T-cell
receptor and MHC-bound peptide antigen. Belatacept can block
that second signal by binding to APC costimulatory surface proteins
CD80 and CD86 to inhibit their interaction with the T-cell signaling
molecule CD28. Belatacept is a recombinant protein comprising a
hinge-region modified (to reduce Fc receptor binding) carboxylterminal
human IgG1 Fc domain fused to a modified extracellular
domain of human CTLA-4 that includes two amino acid substitutions
in the ligand-binding site. As a result of this modification, belatacept
binds more tightly to CD80 and CD86 than the parent molecule
abatacept (Orencia, FDA approved for treatment of adult RA and
juvenile idiopathic arthritis), from which its structure is derived. CTLA-4
is a T-cell negative signaling molecule that is structurally related to
CD28 and shares its two ligands. While belatacept incorporates CTLA-4
sequences to bind CD80 and CD86, the immunosuppressive activity of
the drug suggests that its principal mechanism of action is blockade
of CD28-mediated T-cell activation.
Originator
Bristol-Myers Squibb (United States)
Uses
Prevention of allograft rejection in recipients of solid
organ transplants; prevention of graft-vs-host disease
following bone marrow transplantation; treatment of
autoimmune diseases and conditions such as rheumatoid
arthritis and Type 1 diabetes.
Clinical Use
Prevents T-cell activation
Prophylaxis of renal transplant rejection
Drug interactions
Potentially hazardous interactions with other drugs
Vaccines: avoid concomitant use with live vaccines.
Metabolism
Because the drug is a protein, belatacept is degraded into
smaller peptides and amino acids by proteolytic enzymes.
