Abstract
Interleukin-21 (IL-21), a member of the common cytokine receptor γ chain (γc) 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)/γc 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/γc 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.
Highlights
Interleukin-21 (IL-21) belongs to a family of immune modulatory cytokines that includes IL-2, IL-4, IL-7, IL-9, and IL-15 and has a wide range of biologic activities
Despite the high sequence homology between human and cyno IL-21 (95.5% identical) [32] and cross-species interactions, the binding profiles of human and cyno IL-21 to hIL-21R-fragment crystallizable (Fc) were different (S1 and S2 Figs)
This observation suggests that discrete differences in the binding epitopes on human and cyno IL21 could be responsible for the divergent interactions with human IL-21 receptor (IL-21R)
Summary
Interleukin-21 (IL-21) belongs to a family of immune modulatory cytokines that includes IL-2, IL-4, IL-7, IL-9, and IL-15 and has a wide range of biologic activities. IL-21 is mainly produced by activated CD4+ T cells and natural killer (NK) T cells, whereas IL-21R is expressed on a broad array of cell types, including hematopoietic and nonhematopoietic cells [3,4,5]. IL-21 modulates various aspects of immune function, including differentiation of CD4+ T cells and B cells and upregulation of CD8+ T-cell and NK-cell cytolytic activity. IL-21 has widereaching actions in determining how B cells respond to their environment, as well as the potential to induce robust B-cell activation, class switch recombination, and plasma cell (PC) differentiation in concert with CD40 engagement [6]
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