A novel sweeping antibody exhibits efficient clearance of the cancer- and autoimmunity-associated cytokine interleukin 16

Abstract

Targeting soluble antigens using conventional monoclonal antibodies is challenging due to high levels of antigen and limited antigen clearance per antibody molecule. Sweeping antibodies are engineered monoclonal antibodies that more efficiently clear soluble antigens than conventional antibodies. Sweeping antibodies contain two modifications: (1) pH-dependent antigen binding to facilitate lysosomal degradation of the targeted antigen while allowing antibody recycling and (2) enhanced neonatal Fc receptor (FcRn) engagement, resulting in 50-1,000-fold increased clearance of target antigen compared to conventional antibodies. The pleiotropic cytokine interleukin 16 (IL-16) has been proposed as a promising therapeutic target for monoclonal antibody therapy, due to its high expression and potential disease-promoting function in autoimmune diseases and cancer. Here, we develop the first fully human antibody as well as multiple sweeping antibodies targeting IL-16. We demonstrate that amenability to the introduction of pH-dependent binding into anti-IL-16 antibodies is correlated with epitope size and proximity to a positively charged IL-16 residue, informing future sweeping antibody development. We demonstrate that anti-IL-16 sweeping antibodies exhibit significantly increased antibody recycling and IL-16 degradation indicating that these molecules are a superior approach for the therapeutic targeting of IL-16 compared to conventional antibodies. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=77 SRC="FIGDIR/small/666814v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@108c34corg.highwire.dtl.DTLVardef@4defa1org.highwire.dtl.DTLVardef@af646corg.highwire.dtl.DTLVardef@e9fd2a_HPS_FORMAT_FIGEXP M_FIG C_FIG One sentence summary: Development of antibodies targeting IL-16 provides insights into sweeping antibody engineering and confers efficient clearance of the cancer- and autoimmunity-associated cytokine interleukin-16.