Authors: Mark F. Maurer, Ursula Garrigues, Stephen R. Jaspers, Brent Meengs, Mark W. Rixon, Brenda L. Stevens, Kenneth B. Lewis, Susan H. Julien, Thomas R. Bukowski, Anitra C. Wolf, Nels B. Hamacher, Mark Snavely and Stacey R. Dillon

Mark F. Maurer

Department of Preclinical Research and Development; ZymoGenetics, Inc., a Bristol-Myers Squibb Company; Seattle, WA USA; These authors contributed equally to this work

Ursula Garrigues

Department of Preclinical Research and Development; ZymoGenetics, Inc., a Bristol-Myers Squibb Company; Seattle, WA USA; These authors contributed equally to this work

Stephen R. Jaspers

Department of Preclinical Research and Development; ZymoGenetics, Inc., a Bristol-Myers Squibb Company; Seattle, WA USA; Current address: Regeneron Pharmaceuticals; Tarrytown, NY USA

Brent Meengs

Department of Preclinical Research and Development; ZymoGenetics, Inc., a Bristol-Myers Squibb Company; Seattle, WA USA

Mark W. Rixon

Department of Preclinical Research and Development; ZymoGenetics, Inc., a Bristol-Myers Squibb Company; Seattle, WA USA

Brenda L. Stevens

Department of Preclinical Research and Development; ZymoGenetics, Inc., a Bristol-Myers Squibb Company; Seattle, WA USA

Kenneth B. Lewis

Department of Preclinical Research and Development; ZymoGenetics, Inc., a Bristol-Myers Squibb Company; Seattle, WA USA; Current address: CMC Biologics; Bothell, WA USA

Susan H. Julien

Department of Preclinical Research and Development; ZymoGenetics, Inc., a Bristol-Myers Squibb Company; Seattle, WA USA

Thomas R. Bukowski

Department of Preclinical Research and Development; ZymoGenetics, Inc., a Bristol-Myers Squibb Company; Seattle, WA USA; Current address: Immune Design; Seattle, WA USA

Anitra C. Wolf

Department of Preclinical Research and Development; ZymoGenetics, Inc., a Bristol-Myers Squibb Company; Seattle, WA USA; Current address: Novo Nordisk; Princeton, NJ USA

Nels B. Hamacher

Department of Preclinical Research and Development; ZymoGenetics, Inc., a Bristol-Myers Squibb Company; Seattle, WA USA

Mark Snavely

Department of Preclinical Research and Development; ZymoGenetics, Inc., a Bristol-Myers Squibb Company; Seattle, WA USA

Stacey R. Dillon

Corresponding author: Stacey.Dillon@bms.com
Department of Preclinical Research and Development; ZymoGenetics, Inc., a Bristol-Myers Squibb Company; Seattle, WA USA

Interleukin-21 (IL-21) is a type I four-helical bundle cytokine that exerts a variety of significant effects on many hematopoietic cells, including T and B lymphocytes and natural killer cells. IL-21 is produced predominantly by CD4+ T cells and natural killer T cells and, when aberrantly overexpressed, appears to play important roles in a wide variety of autoimmune disorders. To generate potential therapeutic reagents capable of inhibiting IL-21 for clinical use, we immunized human immunoglobulin transgenic mice with IL-21 and then identified and cloned a panel of human anti-human IL-21 binding monoclonal antibodies. IL-21 neutralizing and IL-21-binding, non-neutralizing antibodies were assigned to distinct epitope “bins” based on surface plasmon resonance competition studies. The most potent neutralizing antibodies had extremely high (sub pM) affinity for IL-21 and were able to block IL-21 activity in various biological assays using either an IL-21R-transfected pre-B-cell line or primary human B cells, and their neutralizing activity was, in some cases, superior to that of a soluble form of the high affinity heterodimeric IL-21 receptor. Characterization of this panel of IL-21 antibodies provided the basis for the selection of a therapeutic candidate antibody capable of inhibiting IL-21 activity for the treatment of autoimmune and inflammatory diseases.