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: Blocking antibody

Reliable risk assessment for biotherapeutics requires accurate evaluation of factors associated with immunogenicity. Immunogenicity tools were developed and applied to investigate the immunogenicity a fully human therapeutic monoclonal antibody, ATR-107 [anti-interleukin (IL)-21 receptor] that elicited anti-drug antibodies (ADA) in 76% healthy subjects Phase 1 study. Because target is expressed on dendritic cells (DCs), related engagement DC antigen presentation pathways was studied. Despite presence IL-21R DCs, did not bind DCs more extensively than control antibody (PF-1) had low clinical ADA incidence. However, ATR-107, but translocated late endosomes, co-localized intracellular antigen-D (HLA-DR) molecules presented dominant T cell epitope overlapping complementarity determining region 2 (CDR2) light chain. induced increased activation exemplified by up-regulation surface expression CD86, CD274 (PD-L1) CD40, expansion activated populations expressing CD86(hi), CD40(hi), CD83(hi), programmed death ligand (PD-L1)(hi), HLA-DR(hi) or CCR7(hi), as well elevated secretion tumour necrosis factor (TNF)-α DCs. exposed stimulated an autologous proliferative response donor cells, concert detection immunoglobulin (Ig)G-type anti-ATR-107 samples. Collectively, enhanced machinery suggested. The approaches findings described this study may be relevant identifying lower targets molecules.