title: IL-7/anti-IL-7 mAb complexes augment cytokine potency in mice through association with IgG-Fc and by competition with IL-7R.
abstract: 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.
authors.affiliation: Kellogg School of Science and Technology Doctoral Program in Chemical and Biological Sciences, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Martin
authors.forename: Ester M M
authors.initials: EM
authors.lastname: van Leeuwen
authors.forename: Se Jin
authors.initials: SJ
authors.lastname: Im
authors.forename: Derry C
authors.initials: DC
authors.lastname: Roopenian
authors.forename: Young-Chul
authors.initials: YC
authors.lastname: Sung
authors.forename: Charles D
authors.initials: CD
authors.lastname: Surh
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000378:metabolism; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000378:metabolism; D001572:Benzofurans; D001667:Binding, Competitive / Q000276:immunology; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism; D007141:Immunoglobulin Fc Fragments / Q000276:immunology* / Q000378:metabolism; D007074:Immunoglobulin G / Q000276:immunology* / Q000378:metabolism; D015851:Interleukin-7 / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011804:Quinolines; D011961:Receptors, Fc / Q000276:immunology / Q000378:metabolism; D020395:Receptors, Interleukin-7 / Q000276:immunology* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: C576715:(3aS,4S,9bS)-N-(2-(8-cyano-1-formyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo(3,2-c)quinolin-4-yl)-2-methylpropyl)-4,6-difluorobenzofuran-2-carboxyamide; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D001572:Benzofurans; D015395:Histocompatibility Antigens Class I; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D015851:Interleukin-7; D011804:Quinolines; D011961:Receptors, Fc; D020395:Receptors, Interleukin-7; D011993:Recombinant Fusion Proteins; C100688:Fc receptor, neonatal