Contribution of enhanced engagement of antigen presentation machinery to the clinical immunogenicity of a human interleukin (IL)-21 receptor-blocking therapeutic antibody

• DOI: 10.1111/cei.12711
• Publication Date: 2015-09-24T09:49:11Z
• Authors: L Xue; T Hickling; R Song; J Nowak; B Rup
• Keywords: 0301 basic medicine; Antigen Presentation; 0303 health sciences; Tumor Necrosis Factor-alpha; Interleukins; T-Lymphocytes; Antibodies, Monoclonal; Epitopes, T-Lymphocyte; Cell Differentiation; Dendritic Cells; Endosomes; HLA-DR Antigens; Antibodies, Monoclonal, Humanized; Lymphocyte Activation; 3. Good health; 03 medical and health sciences; Antigens, CD; Humans; Cells, Cultured; Cell Proliferation

SummaryReliable risk assessment for biotherapeutics requires accurate evaluation of risk factors associated with immunogenicity. Immunogenicity risk assessment tools were developed and applied to investigate the immunogenicity of a fully human therapeutic monoclonal antibody, ATR-107 [anti-interleukin (IL)-21 receptor] that elicited anti-drug antibodies (ADA) in 76% of healthy subjects in a Phase 1 study. Because the ATR-107 target is expressed on dendritic cells (DCs), the immunogenicity risk related to engagement with DC and antigen presentation pathways was studied. Despite the presence of IL-21R on DCs, ATR-107 did not bind to the DCs more extensively than the control therapeutic antibody (PF-1) that had elicited low clinical ADA incidence. However, ATR-107, but not the control therapeutic antibody, was translocated to the DC late endosomes, co-localized with intracellular antigen-D related (HLA-DR) molecules and presented a dominant T cell epitope overlapping the complementarity determining region 2 (CDR2) of the light chain. ATR-107 induced increased DC activation exemplified by up-regulation of DC surface expression of CD86, CD274 (PD-L1) and CD40, increased expansion of activated DC populations expressing CD86hi, CD40hi, CD83hi, programmed death ligand 1 (PD-L1)hi, HLA-DRhi or CCR7hi, as well as elevated secretion of tumour necrosis factor (TNF)-α by DCs. DCs exposed to ATR-107 stimulated an autologous T cell proliferative response in human donor cells, in concert with the detection of immunoglobulin (Ig)G-type anti-ATR-107 antibody response in clinical samples. Collectively, the enhanced engagement of antigen presentation machinery by ATR-107 was suggested. The approaches and findings described in this study may be relevant to identifying lower immunogenicity risk targets and therapeutic molecules.