Enzyme therapy of gaucher disease: clinical and biochemical changes during production of and tolerization for neutralizing antibodies.

The clinical impact of neutralizing antibodies directed against the therapeutic enzyme was investigated in patients with Gaucher disease. Two patients with Gaucher disease type 1 were followed for their clinical progression during antibody development and clinical changes during tolerization. Patient 1 developed neutralizing antibodies to imiglucerase (GCase) at the 10th month of enzyme therapy. Tolerization was achieved within a 42-month period with a short course of cyclophosphamide and then higher dose enzyme (60 IU/kg/week) alone. Patient 1 continues to improve up to 100 months of enzyme therapy despite the presence of low level in vitro neutralizing antibodies. Patient 2 developed neutralizing antibodies to GCase at the 29th month of enzyme therapy that correlated with clinical deterioration. Clinical stabilization has been observed with increased enzyme therapy (60 IU/kg/week) even in the presence of the neutralizing antibodies. Patient 2 is the first to develop neutralizing antibodies after 12 months of enzyme therapy. Plasma chitotriosidase activities were not well correlated with the clinical course in either patient. The presence of neutralizing antibodies should be suspected in Gaucher disease patients on enzyme therapy who experience diminished response or deterioration. The persistence of minimal amounts of in vitro neutralizing antibodies does not interfere with the therapeutic effectiveness. Chitotriosidase is not a sensitive marker for the severity of disease or disease progression.