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Discovery and characterization of potent IL-21 neutralizing antibodies via a novel alternating antigen immunization and humanization strategy

Interleukin-21 (IL-21), a member of the common cytokine receptor γ chain (γ(c)) family, is secreted by CD4(+) T cells and natural killer T cells and induces effector function through interactions with the IL-21 receptor (IL-21R)/γ(c) complex expressed on both immune and non-immune cells. Numerous st...

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Detalles Bibliográficos
Autores principales: Varkey, Reena, Du, Qun, Karnell, Jodi L., Xiao, Xiaodong, Casey, Kerry A., Woods, Rob, Rosenthal, Kim, Wilson, Susan, Dall’Acqua, William F., Wu, Herren, Herbst, Ronald, Ettinger, Rachel, Damschroder, Melissa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347146/
https://www.ncbi.nlm.nih.gov/pubmed/30682117
http://dx.doi.org/10.1371/journal.pone.0211236
Descripción
Sumario:Interleukin-21 (IL-21), a member of the common cytokine receptor γ chain (γ(c)) family, is secreted by CD4(+) T cells and natural killer T cells and induces effector function through interactions with the IL-21 receptor (IL-21R)/γ(c) complex expressed on both immune and non-immune cells. Numerous studies suggest that IL-21 plays a significant role in autoimmune disorders. Therapeutic intervention to disrupt the IL-21/IL-21R/γ(c) interaction and inhibit subsequent downstream signal transduction could offer a treatment paradigm for these diseases. Potent neutralizing antibodies reported in the literature were generated after extensive immunizations with human IL-21 alone and in combination with various adjuvants. To circumvent the laborious method of antibody generation while targeting a conserved functional epitope, we designed a novel alternating-antigen immunization strategy utilizing both human and cynomolgus monkey (cyno) IL-21. Despite the high degree of homology between human and cyno IL-21, our alternating-immunization strategy elicited higher antibody titers and more potent neutralizing hybridomas in mice than did the immunization with human IL-21 antigen alone. The lead hybridoma clone was humanized by grafting the murine complementarity-determining regions onto human germline framework templates, using a unique rational design. The final humanized and engineered antibody, MEDI7169, encodes only one murine residue at the variable heavy/light-chain interface, retains the sub-picomolar affinity for IL-21, specifically inhibits IL-21/IL-21R–mediated signaling events and is currently under clinical development as a potential therapeutic agent for autoimmune diseases. This study provides experimental evidence of the immune system’s potential to recognize and respond to shared epitopes of antigens from distinct species, and presents a generally applicable, novel method for the rapid generation of exceptional therapeutic antibodies using the hybridoma platform.