Marc H. V. van Regenmortel, Ph.D
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Biotechnology-derived therapeutic proteins are playing an ever-increasing role in the pharmaceutical market. These proteins
are mostly used in the treatment of life-threatening and severe diseases. The aim is to correct an acquired or inherited deficiency
of a native protein or to alter a disease process. Interestingly, most therapeutic proteins have been shown to be immunogenic,
despite the fact that the amino acid sequence is identical or nearly identical to endogenous proteins. The formation of antibodies
appears, in many cases, not to have a clinical effect.
There are cases, however, in which antibodies were found to be neutralizing, which can negate the effect of the therapy or
when cross-reacting with the endogenous protein, deplete the effect of this protein. The clinical effects of such cases are
significant, and can result in a more severe disease and a need for acute intervention. Several potential mechanisms can cause
immunogenicity of therapeutic proteins such as aggregates, molecular mimicry, adjuvants, neo-antigens, and modification of
the protein. Epoetin is an example of one display of this mechanism.
THERAPEUTIC PROTEINS
Over the past 20 years our understanding of immunology has grown exponentially, and there is no end in sight. Because of the
complexity of this field, any discussion related to the formation of antibodies requires simplification since there are multiple
potential routes for the production of antibodies against a therapeutic protein. In general, we focus on the most common pathways.
For a more detailed discussion, the book by Abbas and Lichtman serves as a good reference.1
The number of biotechnology-derived therapeutic proteins now available includes over 75 products representing 65 different
types of molecules.2 In spite of the fact that biopharmaceuticals currently have only a small share of the pharmaceutical market, their medical
impact is enormous. Examples of deficiency correction are recombinant human-insulin therapy for diabetes mellitus, therapy
with factor VIII in patients with hemophilia A, and recombinant human erythropoietin (epoetin) therapy for the treatment of
anemia. An example of a biopharmaceutical that alters disease processes is the use of recombinant interferons in patients
with multiple sclerosis, hepatitis, and cancer.
Figure 1. Development of Central and Peripheral Tolerance to Self Antigens
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The majority of therapeutic proteins have an identical or nearly identical amino acid sequence of endogenous proteins, and
may not be immunogenic if they are recognized as self through mechanisms of immune tolerance (Figure 1). Yet, nearly all of
the biopharmaceuticals currently approved for clinical use are known to be immunogenic.3 Subtle differences in protein structure, a lack of tolerance in the patient, or the presence of an adjuvant may result in
the generation of an antibody response. In many cases of antibody formation to biopharmaceuticals, there is no clinical effect.3-5
In some cases antibodies may be neutralizing, which can negate the effect of the therapy.6-16 Cross-reaction with the endogenous protein can deplete the effect of this protein.17-19 This effect has been observed in the management of anemia in chronic kidney disease patients, where cross-reactive neutralizing
antibodies were found to inhibit the activity of both the administered epoetin and the patient's own residual erythropoietin.18,19 This created a more severe anemia, called pure red-cell aplasia (PRCA), characterized by an almost complete absence of red-blood-cell
precursors in bone marrow.18,19 In the majority of reported cases of PRCA, the presence of anti-erythropoietin antibodies has been confirmed, resulting in
the condition named antibody-mediated PRCA (Ab+PRCA).
