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Blood, Vol. 93 No. 6 (March 15), 1999:
pp. 2081-2088
Immunosurveillance of Alglucerase Enzyme Therapy for Gaucher Patients:
Induction of Humoral Tolerance in Seroconverted Patients After
Repeat Administration
Mireille Rosenberg,
Wytske Kingma,
Mary Anne Fitzpatrick, and
Susan M. Richards
From Genzyme Corp, Framingham, MA.
Alglucerase, a macrophage-targeted enzyme replacement therapy for
Gaucher disease, has been successfully used for several years to
improve clinical symptoms and reverse disease progression. As part of
an immunosurveillance program, 1,122 Gaucher patients were monitored
for antibody response to glucocerebrosidase, the active component of
alglucerase. Seroconversion was detected in 142 patients (12.8%) by
enzyme-linked immunosorbent assay (ELISA) and confirmed by
radioimmunoprecipitation. The majority (75%) of the seroconverted
population had no detectable levels of circulating inhibitory antibody
as assessed by in vitro inhibition of enzymatic activity of the
therapeutic molecule. Of the remaining patients with putative
inhibitory antibodies, the majority had only low levels of serum
inhibitory activity, which was transient. A very small number of
patients were identified as developing true neutralizing antibodies, as
defined by the development of antibodies that impacted clinical
efficacy. Many of the patient antibody responses were also diminished
with time. Eighty-two of the 142 seroconverted patients have stopped
producing antibody to the molecule and appear tolerized. The mean time
for humoral tolerization was 28 months from initiation of therapy. Of
64 seroconverted patients followed for at least 30 months of therapy,
the tolerization rate was 93%. These results show that although 12.8%
of the patients on therapy developed antibodies to the molecule, 90%
of these patients became tolerized over time.
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