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

The LEA-tg pigs generated in this study express high levels of LEA29Y, specifically in the β-cells, with no signs of β-cell dysfunction or systemic immunosuppression, such as increased susceptibility to opportunistic infections. [source, 2012]
These findings, together with the strong, colocalized graft staining for insulin and LEA29Y, indicate that LEA29Y expression in β-cells does not interfere with β-cell development and function. [source, 2012]
Previous transplantation studies in rats and nonhuman primates using high doses of belatacept for systemic immunosuppression also have shown that costimulatory blockade by LEA29Y does not exert any adverse effects on β-cell function (5,11). [source, 2012]
Thus, our study shows for the first time that local expression of LEA29Y results in a prolonged islet xenograft function, supporting the hypothesis that inhibition of costimulation is able to modulate allo- and xenoimmunity (6,7). [source, 2012]
LEA29Y serum concentrations in recipients of LEA-tg ICCs were ~100–150 times lower as compared with systemic LEA29Y treatment in clinical trials (belatacept, BMS-224818), suggesting that graft protection is primarily mediated by local and not systemic LEA29Y immunomodulatory effects. [source, 2012]
In conclusion, the present proof-of-principle study demonstrates that the availability of transgenic pigs expressing LEA29Y in β-cells may represent a major step forward to overcome the immunological barrier to islet xenotransplantation. [source, 2012]
Additional transplantation studies using larger groups of mice with a stably transferred human immune system (22) will be conducted to investigate the long-term effects of LEA29Y transgenic islets on xenogeneic graft rejection. [source, 2012]
The immunity was not observed when animals were under immunosuppression with either Mycophenolate mofetil plus Prednisone for 3 weeks, or LEA29Y, a mutant of CTLA4-Ig which blocks costimulatory signaling through CD28 pathway that is required for optimal T cell activation (Toromanoff et al., 2008, 2010). [source, 2011]
Here, LEA29Y was expressed from AAV vector delivered intravenously to ensure therapeutic level. [source, 2011]
When LEA29Y was delivered intramuscularly, it did not eliminate immune responses to transgene product. [source, 2011]