title: Anti-CD25 monoclonal antibody Fc variants differentially impact regulatory T cells and immune homeostasis.
abstract: Interleukin-2 (IL-2) is a critical regulator of immune homeostasis through its non-redundant role in regulatory T (Treg) cell biology. There is major interest in therapeutic modulation of the IL-2 pathway to promote immune activation in the context of tumour immunotherapy or to enhance immune suppression in the context of transplantation, autoimmunity and inflammatory diseases. Antibody-mediated targeting of the high-affinity IL-2 receptor α chain (IL-2Rα or CD25) offers a direct mechanism to target IL-2 biology and is being actively explored in the clinic. In mouse models, the rat anti-mouse CD25 clone PC61 has been used extensively to investigate the biology of IL-2 and Treg cells; however, there has been controversy and conflicting data on the exact in vivo mechanistic function of PC61. Engineering antibodies to alter Fc/Fc receptor interactions can significantly alter their in vivo function. In this study, we re-engineered the heavy chain constant region of an anti-CD25 monoclonal antibody to generate variants with highly divergent Fc effector function. Using these anti-CD25 Fc variants in multiple mouse models, we investigated the in vivo impact of CD25 blockade versus depletion of CD25(+) Treg cells on immune homeostasis. We report that immune homeostasis can be maintained during CD25 blockade but aberrant T-cell activation prevails when CD25(+) Treg cells are actively depleted. These results clarify the impact of PC61 on Treg cell biology and reveal an important distinction between CD25 blockade and depletion of CD25(+) Treg cells. These findings should inform therapeutic manipulation of the IL-2 pathway by targeting the high-affinity IL-2R.
authors.affiliation: Biogen Inc., Cambridge, MA, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Huss
authors.affiliation: Biogen Inc., Cambridge, MA, USA.
authors.forename: Alex F
authors.identifier: 0000-0001-9562-3427
authors.initials: AF
authors.lastname: Pellerin
authors.affiliation: Biogen Inc., Cambridge, MA, USA.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Collette
authors.affiliation: Biogen Inc., Cambridge, MA, USA.
authors.forename: Arun K
authors.initials: AK
authors.lastname: Kannan
authors.affiliation: Biogen Inc., Cambridge, MA, USA.
authors.forename: Liaomin
authors.initials: L
authors.lastname: Peng
authors.affiliation: Biogen Inc., Cambridge, MA, USA.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Datta
authors.affiliation: Biogen Inc., Cambridge, MA, USA.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Wipke
authors.affiliation: Biogen Inc., Cambridge, MA, USA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Fontenot
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000494:pharmacology*; D000914:Antibodies, Viral / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D007074:Immunoglobulin G / Q000235:genetics / Q000494:pharmacology*; D007165:Immunosuppression Therapy; D007167:Immunotherapy; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism*; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015202:Protein Engineering; D051381:Rats; D017452:Receptors, IgG / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; C485701:Fcgr1 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007074:Immunoglobulin G; D007376:Interleukin-2; C584092:PC61 monoclonal antibody; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins
keywords: CD25; interleukin-2; regulatory T cells; therapeutic antibody