Antirejection agent — visilizumab

In many transplant patients, acute graft versus host disease (GvHD) remains a problem after transplantation, and systemic glucocorticoids prove a successful treatment in only around 40% of cases. But there is no cure for the remaining 60% of affected patients.

The condition is mediated by donor T cells, so inducing central and peripheral T cell tolerance with a specific antigen could solve the problem. Various monoclonal antibodies are being developed to treat autoimmune diseases such as psoriasis, rheumatoid arthritis and multiple sclerosis. One such MAb is visilizumab, being investigated by Protein Design Labs in the US.¹ Unlike the previously studied mouse antibody OKT3, it does not cause severe cytokine release syndrome because it avoids activating the T cells.

Several trials have been carried out to establish its safety and tolerability. A study was carried out in 11 patients who had undergone a bone marrow transplant and were suffering from acute GvHD.² Peripheral blood mononuclear cells were isolated and treated with visilizumab or the murine anti-CD3 antibody BC3 over a period of 24 hours. Visilizumab significantly increased lyphocyte apoptosis, and it appears to be more selective in inducing the deletion of those host reactive T cells that are responsible for the development of GvHD.

Its efficacy has been investigated in an open label multiple dose Phase I trial in 16 kidney transplant patients who were also receiving steroid treatment for acute rejection.³ After three doses of 0.045mg/kg every other day, significant CD³⁺ cell depletion was seen, and the levels took a median of 24 days to recover. Acute rejection was reversed in seven of the eight patients given the highest doses investigated, 0.030 and 0.045mg/kg.

A further Phase I trial was carried out in 17 patients with acute GvHD,4 who were given a range of doses, some as single doses of 3mg/m² and some as multiple doses of either 0.25 or 1mg/m². Six patients were given multiple doses, with one having a complete response and the other five a partial response, but all six died at a median of 87 days after starting the treatment. Six of the 11 patients given a single 3mg/m² dose had a complete response and three a partial response, and seven had significantly increased survival. No allergic reactions were seen, and no development of human antibodies against visilizumab was detected. Phase II trials are now under way, and there are also plans to investigate its use in ulcerative colitis, lupus and myelodysplastic syndrome.