Antibody-mediated depletion of lymphocyte-activation gene-3 (LAG-3(+))-activated T lymphocytes prevents delayed-type hypersensitivity in non-human primates

作者：Poirier N; Haudebourg T; Brignone C; Dilek N; Hervouet J; Minault D; Coulon F; de Silly R V; Triebel F; Blancho G^*; Vanhove B

来源：Clinical and Experimental Immunology, 2011, 164(2): 265-274.

DOI：10.1111/j.1365-2249.2011.04329.x

• delayed-type hypersensitivity
• LAG-3
• primate
• therapeutic antibodies

Lymphocyte-activation gene-3 (LAG-3, CD223) is a marker for recently activated effector T cells. Activated T lymphocytes are of major importance in many autoimmune diseases and organ transplant rejection. Therefore, specifically depleting LAG-3(+) T cells might lead to targeted immunosuppression that would spare resting T cells while eliminating pathogenic activated T cells. We have shown previously that anti-LAG-3 antibodies sharing depleting as well as modulating activities inhibit heart allograft rejection in rats. Here, we have developed and characterized a cytotoxic LAG-3 chimeric antibody (chimeric A9H12), and evaluated its potential as a selective therapeutic depleting agent in a non-human primate model of delayed-type hypersensitivity (DTH). Chimeric A9H12 showed a high affinity to its antigen and depleted both cytomegalovirus (CMV)-activated CD4(+) and CD8(+) human T lymphocytes in vitro. In vivo, a single intravenous injection at either 1 or 0.1 mg/kg was sufficient to deplete LAG-3(+)-activated T cells in lymph nodes and to prevent the T helper type 1 (Th1)-driven skin inflammation in a tuberculin-induced DTH model in baboons. T lymphocyte and macrophage infiltration into the skin was also reduced. The in vivo effect was long-lasting, as several weeks to months were required after injection to restore a positive reaction after antigen challenge. Our data confirm that LAG-3 is a promising therapeutic target for depleting antibodies that might lead to higher therapeutic indexes compared to traditional immunosuppressive agents in autoimmune diseases and transplantation.

• 出版日期2011-5