IL-7/anti-IL-7 mAb complexes augment cytokine potency in mice through association with IgG-Fc and by competition with IL-7R.

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Adoptive Transfer, Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Benzofurans, Binding, Competitive, Female, Histocompatibility Antigens Class I, Immunoglobulin Fc Fragments, Immunoglobulin G, Interleukin-7, Male, Mice, Mice, Transgenic, Quinolines, Receptors, Fc, Receptors, Interleukin-7, Recombinant Fusion Proteins, T-Lymphocyte Subsets

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Blood 2013 May 30; 121(22):4484-4492




Interleukin-7 (IL-7) is essential to T-cell survival as well as homeostatic proliferation, and clinical trials that exploit the mitogenic effects of IL-7 have achieved success in treating human diseases. In mice, the in vivo potency of IL-7 improves dramatically when it is administered as a complex with the anti-IL-7 neutralizing monoclonal antibody clone M25. However, the mechanism whereby M25 augments IL-7 potency is unknown. We have analyzed the discrete contributions of the antibody constant (Fc) and IL-7-binding (Fab) domains to the mechanism. By engaging the neonatal Fc receptor the Fc domain extends the in vivo lifespan of IL-7/M25 complexes and accounts for the majority of their activity. Unexpectedly, the IL-7-neutralizing Fab domain provides an additional, albeit smaller, contribution, possibly by serving as a cytokine depot. This study is the first to demonstrate that the neutralizing aspect of the monoclonal antibody is directly involved in enhancing the potency of a cytokine with a single form of receptor. Lessons from the mechanism of IL-7/M25 complexes inform the design of next-generation cytokine therapeutics. Blood 2013 May 30; 121(22):4484-4492