T10B9 (MEDI-500) mediated immunosuppression: studies on the mechanism of action.
The murine IgM anti-human CD3/TCR mAb T10B9 is an effective agent for the reversal of acute cellular renal allograft rejection which offers several advantages over conventional OKT3 therapy. These include reduced morbidity and a more rapid decrease in serum creatinine levels. In the studies presented here comparing T10B9 and OKT3, soluble T10B9 is shown to be a nonactivating anti-T cell mAb. Evidence for its lack of activating potential includes in vitro failure to stimulate PBMC proliferation either alone or in the presence of nonmitogenic doses of phorbol ester, failure to induce the expression of early and late activation antigens and failure to induce IFN-gamma, TNF-alpha, IL-6 or IL-2 release. Analysis of acute renal allograft rejection patient plasma cytokine levels 2 h after the first dose support the hypothesis that T10B9 has reduced immunoactivation activity in vivo. Both TNF alpha and IFN gamma patient plasma levels are significantly reduced in T10B9 as compared to OKT3 therapy. However, T10B9 is capable of cellular signaling as demonstrated by its ability to induce apoptosis and IL-2 release in the human T cell line Sup-T13. Thus T10B9 retains the potent immunosuppressive activity of OKT3 with reduced immunoactivation.
Brown
S A
SA
Department of Medicine and Surgery, University of Kentucky, Lexington, USA.
Lucas
B A
BA
Waid
T H
TH
McKeown
J W
JW
Barve
S
S
Jackson
L R
LR
Thompson
J S
JS
D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D017209:Apoptosis / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D004353:Drug Evaluation, Preclinical; D006084:Graft Rejection / Q000276:immunology / Q000628:therapy; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016030:Kidney Transplantation / Q000276:immunology; D008213:Lymphocyte Activation; D016853:Muromonab-CD3 / Q000627:therapeutic use*; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction
D000911:Antibodies, Monoclonal; D016207:Cytokines; D007075:Immunoglobulin M; D007166:Immunosuppressive Agents; D016853:Muromonab-CD3; D017260:Receptor-CD3 Complex, Antigen, T-Cell