Latest research on LEA29Y

Belatacept is a soluble fusion protein, which links the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) to the modified Fc (hinge, CH2, and CH3 domains) portion of human immunoglobulin G1 (IgG1). Structurally, abatacept is a glycosylated fusion protein with a MALDI-MS molecular weight of 92,300 Da and it is a homodimer of two homologous polypeptide chains of 357 amino acids each. It is produced through recombinant DNA technology in mammalian CHO cells. The drug has activity as a selective co-stimulation modulator with inhibitory activity on T lymphocytes. It is approved for the treatment of rheumatoid arthritis. Belatacept selectively blocks the process of T-cell activation. It was developed by Bristol-Myers-Squibb. It differs from abatacept (Orencia) by only 2 amino acids. FDA approved on June 15, 2011.

Latest findings

LEA29Y, later named belatacept (Bristol–Myers Squibb, New York, NY), was tested in non-human primates and showed superior prolongation in renal allograft survival as monotherapy, when compared with the first-generation CTLA4-Ig, and led to a marked improvement in survival when used in combination with other immunosuppressive regimens such as Mycophenolate mofetil and steroids, or an Anti-IL-2 receptor antibody. [source, 2011]
Using a rational mutagenesis and screening strategy, a daughter molecule, LEA29Y (belatacept, Bristol-Myers Squibb, New York, NY, USA), with two amino acid substitutions (L104->E and A29->Y), was developed. [source, 2010]
The failure of abatacept was thought to be secondary to a fast off-rate from CD86; consequently, a second generation agent, LEA29Y or belatacept, was created by codon-based mutagenesis, and it did demonstrate superior binding to CD80 and CD86 than abatacept [98]. [source, 2008]
Two amino-acid substitutions in the binding domain (L104E and A29Y) were identified as potentially useful, leading to the development of a new molecule, LEA29Y or belatacept. [source, 2007]
In particular, the results obtained with LEA29Y in NHP models of kidney transplantation led investigators to combine it with conventional immunosuppressive reagents for clinical applications so as to minimize the risk of acute rejection (Larsen et al 2005; Vincenti et al 2005). [source, 2007]
A second-generation version of this molecule (LEA29Y), with two amino acid mutations, has been developed to have increased binding avidity for CD86 [2]. [source, 2005]
In a dose ranging pilot study of patients with active RA [2], both abatacept and LEA29Y produced dose dependent reductions in the clinical manifestations of disease. [source, 2005]
A total of 90 received abatacept at doses of 0.5 mg/kg, 2 mg/kg, and 10 mg/kg; 92 received LEA29Y at the same doses; and 32 received placebo infusions. [source, 2005]
The most common reason for discontinuation, worsening arthritis, led to the withdrawal of 32% of the placebo group, 13% of the patients treated with abatacept, and 4% of the patients treated with LEA29Y. [source, 2005]