title: Contribution of enhanced engagement of antigen presentation machinery to the clinical immunogenicity of a human interleukin (IL)-21 receptor-blocking therapeutic antibody.
abstract: Reliable 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 CD86(hi), CD40(hi), CD83(hi), programmed death ligand 1 (PD-L1)(hi), HLA-DR(hi) or CCR7(hi), 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.
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism- NBE, Pfizer Inc., Andover, MA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Xue
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism- NBE, Pfizer Inc., Andover, MA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Hickling
authors.affiliation: Drug Safety R & D, Pfizer Inc., Andover, MA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Song
authors.affiliation: Clinical Pharmacology, Pfizer Inc., Andover, MA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Nowak
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism- NBE, Pfizer Inc., Andover, MA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Rup
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D017951:Antigen Presentation / Q000187:drug effects; D015703:Antigens, CD / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D011992:Endosomes / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000378:metabolism; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D007378:Interleukins / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D013601:T-Lymphocytes / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000098546:Interleukin-21
chemical_list: C000591157:ATR-107; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D018984:Epitopes, T-Lymphocyte; D006684:HLA-DR Antigens; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha; D000098546:Interleukin-21
keywords: IL-21 receptor; T cell epitope; T cell proliferation; antigen processing and presentation; immunogenicity