Biology Reference
In-Depth Information
The reasons why such antibodies appeared remain unclear. Clearly, their
appearance is due to treatment with rHuEPO. We obtained serum samples
from five patients before the onset of anemia and we did not detect anti-EPO
antibodies. Since, however, rHuEPO has been used safely during more than 10
years, these problems are not due to the molecule itself but to modifications
concerning either the patient population, medical practice, or the commercial
product. All patients developing anti-EPO neutralizing antibodies were treated
with rHuEPO for anemia associated with chronic renal failure of various eti-
ologies. They suddenly became refractory to rHuEPO treatment and developed
anti-EPO antibodies after three to 63 months of rHuEPO treatment during
which time they had a good response to the hormone. This pool of patients is
heterogeneous for all the tested parameters, except that all were treated with
rHuEPO for anemia associated with chronic renal failure. Careful examination
of the patient's medical history did not find any peculiar new medication intro-
duced before the appearance of the anti-EPO antibodies or a a viral infection.
The patients did not have HLA A, B, or DR in common. Moreover, we could
not find any evidence that this population of patients was different from those
previously treated with rHuEPO, patients who did not develop such antibod-
ies. Some of the patients who developed anti-EPO antibodies were previously
treated successfully with rHuEPO for years before developing anti-EPO anti-
bodies. The medical practices and especially those related to hemodialysis do
not seem to be correlated with the appearance of these antibodies. Although all
patients received rHuEPO subcutaneously, the route of injection, intravenous
route
versus
subcutaneous route, cannot simply be given as an explanation.
Indeed, the subcutaneous route introduced in 1991 has been widely used in
France since that time without induction of anti-EPO antibodies before these
cases were identified. We cannot, however, not exclude that the route of injec-
tion could favor the formation of antibodies. The most likely explanation
would be that slight modifications of the commercial product is responsible for
the induction of antibodies. Most patients (36/44 in the antibody cases detect-
ed in our laboratory and 78/82 patients with pure red cell aplasia in the FDA
report) were treated with a brand of epoetin alfa (Eprex) when they developed
antibodies. In our study, one patient received epoetin beta (NeoRecormon)
only and seven patients received both Eprex and NeoRecormon. Thus,
although we do not have definitive proof, we can hypothesize that subtle mod-
ifications concerning Eprex could be responsible for the appearance of anti-
bodies. To date, we have no indication concerning the possible modifications
of Eprex that could favor antibody development, but the appearance of anti-
body cases correlates with a modification of Eprex additives. Indeed, rHuEPO
was formulated with human serum albumin before 1998. For public health rea-
sons, human serum albumin was removed from Eprex preparations and
replaced by other additives after 1998. The frequency of appearance of such
antibodies remains relatively low compared with the number of patients treat-
ed with rHuEPO (one patient per 10,000 patients treated with rHuEPO devel-
ops pure red cell aplasia). Some characteristics of these patients combined
