Cytokines are often therapeutic targets in autoimmune diseases. Administration of a therapeutic cytokine may induce circulating neutralizing antibodies, which upon reaching significant levels may render therapy ineffective. Induction of these neutralizing antibodies, however, may have a beneficial function in anti-cytokine therapies.
Monoclonal anti-cytokine therapy has limitations. Quick metabolism of antibodies often necessitates repeated administration, thus requiring generation and purification of large amounts of antibodies. Additionally, anti-idiotype antibody production can reduce the capacity of an anti-cytokine antibody to neutralize its target. An alternative anti-cytokine therapy involves the use of a synthetic receptor antagonist such as a mutated form of a cytokine that can bind a specific receptor but cannot induce a signal.
An IL-6 receptor antagonist can induce an antibody, that neutralizes native IL-6.1 Thus, administration of a cytokine receptor antagonist may overcome the need for repeated infusions of anti-cytokine antibodies and offer a reliable means of neutralizing the target cytokine. Induction of antibodies, thus becomes important in modulating anti-cytokine therapy. Neutralization of a multi-functional cytokine may have unwelcome side effects caused by loss of other functions associated with the cytokine. Neutralization of, or blocking responses to, the cytokine is only effective if no other cytokine can replace its activity.
Autoantibodies (naturally occurring antibodies) to cytokines have been identified in serum from healthy people and patients with inflammatory diseases.2 It is unclear whether these autoantibodies down-regulate cytokine activity by neutralization or up-regulate cytokine function by acting as a carrier in the circulation.3 Although uncommon (0.3% of plasma samples tested), a dominant anti-cytokine antibody against GM-CSF can be found in normal serum.4 This has potential clinical impact where normal human IgG preparations are used in therapy of autoimmune diseases.5
Normal IgG preparations exert their therapeutic effect in one of three ways: elimination of disease-specific autoantibodies by anti-idiotype recognition, neutralization of the endotoxin that stimulates release or excessive production of cytokine(s) responsible for the disease, or saturation of Fc receptors (FcR) allowing targets coated with autoantibodies to evade FcR-mediated attack.5
In patients receiving normal IgG therapy, GM-CSF-IgG complexes that are formed cannot bind to cellular GM-CSF receptors thus neutralizing the normal function of GM-CSF. A carrier function for the anti-GM-CSF antibodies is not suspected due to their high avidity and stability. Anti-GM-CSF antibodies are also able to block GM-CSF binding to receptors. Since GM-CSF modulates primary cytokine responses, anti-GM-CSF activity may down-regulate acute and chronic inflammatory disorders.4
References
- Ciapponi, L. et al. (1997) Nature Biotechnology 15:997.
- Bendtzen, K. et al. (1998) Immunol. Today 19:209.
- van der Meide, P.H. and H. Schellekens (1997) Biotherapy 10:39.
- Svenson, M. et al. (1998) Blood 91:2054.
- Dwyer, J.M. (1992) New Eng. J. Med. 326:107.