In 1982, human insulin was marketed as the first recombinant DNA-derived
protein for human use. Since then dozens of recombinant proteins have been
introduced and some of these products such as the interferons and the epoetins
are among the most widely used drugs in the world. And, although these proteins
were developed as close copies of human endogenous proteins, nearly all these
proteins induce antibodies, sometimes even in a majority of patients (Table 1).
In addition, most of these products are used in patients who do not have an
innate deficiency and can be assumed to have immune tolerance to the protein.
The initial assumption was that the production by recombinant technology
in nonhuman host cells and the downstream processing modified the proteins and
the immunological response was the classical response to a foreign protein.
However, according to the current opinion the antibody response to human
homologues is based on breaking B-cell tolerance. This phenomenon is not yet
completely understood but is clearly different from the vaccine type of
reaction seen with foreign proteins.
The clinical manifestations of both types of reaction are very
different. The vaccine-type response occurs within weeks and sometimes a single
injection is sufficient to induce a substantial antibody response. In general
high levels of neutralizing antibodies are induced and a rechallenge leads to a
booster reaction, indicating a memory response.
However, breaking B-cell tolerance takes in general 6 to 12 months of
chronic treatment and often only leads to the production of binding antibodies
with no biological effect. The antibodies often dis-appear shortly after
treatment has been stopped and sometimes even during treatment. This response
also appears to have no memory, because rechallenging patients in whom the antibody levels have declined does not induce a response.