Generation and characterization of human anti-human IL-21 neutralizing monoclonal antibodies.
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.
Department of Preclinical Research and Development, ZymoGenetics, Inc., Seattle, WA, USA.
Mark F
MF
Maurer
Ursula
U
Garrigues
Stephen R
SR
Jaspers
Brent
B
Meengs
Mark W
MW
Rixon
Brenda L
BL
Stevens
Kenneth B
KB
Lewis
Susan H
SH
Julien
Thomas R
TR
Bukowski
Anitra C
AC
Wolf
Nels B
NB
Hamacher
Mark
M
Snavely
Stacey R
SR
Dillon
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis* / Q000276:immunology* / Q000494:pharmacology / Q000627:therapeutic use; D057134:Antibodies, Neutralizing / Q000096:biosynthesis* / Q000276:immunology* / Q000494:pharmacology / Q000627:therapeutic use; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D000939:Epitopes / Q000276:immunology; D006801:Humans; D007378:Interleukins / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D054448:Precursor Cells, B-Lymphoid / Q000276:immunology; D011817:Rabbits; D051381:Rats; D053655:Receptors, Interleukin-21 / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D000098546:Interleukin-21
D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000939:Epitopes; D007378:Interleukins; D053655:Receptors, Interleukin-21; D000098546:Interleukin-21