Although rare, immune response to a therapeutic protein may lead to anaphylactic or allergic reactions that require immediate medical attention. Less severe but far more frequent consequences are local injection-site reactions. Neutralizing antibodies in effect reduce the dose of drug available to exert a therapeutic response. Nonneutral-izing antibodies may also reduce biological activity by increasing the size of the resulting protein-antibody complex, which may influence the tissue distribution and clearance of the pharmaceutical protein. Although both mechanisms reduce biological activity, neutralizing antibodies usually result in more severe loss of activity.
An indirect consequence of antibody formation against a therapeutic protein is inhibition of endogenous protein and its functions. For example, if antibody to inter-leukin-2, a T-cell growth factor, is elicited due to administered recombinant IL-2, the neutralizing antibody that blocks the activity of recombinant IL-2 may also neutralize endogenous IL-2 function, which is essential for fighting infections. Another consequence is that patients who have antibodies against a protein drug are not good candidates to receive similar protein products. Immunogenicity data and clinical consequences for some marketed protein products are summarized in Table 5.6.
The FDA advises manufacturers not only to evaluate immunogenicity of new protein products but also to reevaluate immunogenicity on any change in the manufacturing process or target patient population. Understanding of mechanisms leading to induction of immune responses against proteins and other bio-pharmaceuticals will allow the development of strategies appropriate for better control of unintended consequences of immunogenicity .
ITABLE 5.6. Immunogenicity of protein pharmaceuticals and clinical consequences
Frequency (in Humans) Potential or Observed Clinical Effects
Murine (n = 6)b Mouse-human chimeric (n = 3) Humanized Remicade Etanercept
Human urokinase or tissue plasminogen activator
Streptokinase (isolated from bacteria)
Epoetin and G-CSF (human recombinant)
15-45% in multiple sclerosis patients 0-25%
None in chronic granulomatous
Less than 1%
Human against mouse allergic reactions Human against mouse allergic reactions
Human against mouse allergic reactions
Myalgia, rash fever, polyarthralgia
Redness at the sites of previous injections
Neutralizing antibodies (higher incidence with subcutanous route of administration)
Rare antibody or allergic reactions
Allergic reaction; increased incidence of binding antibody with recent infection of streptococcus
Binding antibody and allergic reactions
Binding and neutralizing antibodies; allergic reactions
Binding antibodies; but rarely are they neutralizing
Binding antibody; not neutralizing; some local subcutaneous site reactions reported
"Protein products were tested using therapeutic dosing schedules. bNumber of different molecules for the same type of protein surveyed.
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