Sweeping antibody as a novel therapeutic antibody modality capable of eliminating soluble antigens from circulation

Abstract

Monoclonal antibodies have become a general modality in therapeutic development, and a variety of monoclonal antibodies targeting soluble antigens have been developed. However, even with infinite binding affinity to an antigen, a conventional antibody can bind to the antigen only once and results in an increase in total plasma antigen concentration in vivo. This antibody-mediated antigen accumulation generally occurs because the clearance from circulation of an antibody-antigen complex is much slower than that of a free antigen. This limitation has recently been overcome by sweeping antibodies, which are capable of actively eliminating soluble antigens from circulation. A sweeping antibody incorporates two antibody engineering technologies: one is variable region engineering to enable the antibody to bind to an antigen in plasma and dissociate from the antigen in endosome (after which the antigen undergoes lysosomal degradation), and the other is constant region engineering to increase the cellular uptake of the antibody-antigen complex into endosome. By enhancing the elimination of soluble antigens from circulation, sweeping antibodies can therapeutically target soluble antigens that conventional antibodies cannot. This review discusses the features, engineering technologies, advantages, and applications of sweeping antibodies that target soluble antigens.

Characterizing a pH‐switch anti‐C5 antibody as a tool for human and mouse complement C5 purification and cross‐species inhibition of classical and reactive lysis

“…Here we took advantage of a recently described anti‐C5 therapeutic mAb, RO7112689, that was selected to recycle in vivo by shedding its cargo when exposed to acidic pH (~ pH5·5) in the endosome . Such antibodies have been engineered to reduce therapeutic dose; pH‐dependence to release soluble antigen in the endosome is an essential property . Importantly, the mAb had also been engineered in the Fc region to ablate C1q binding and hence complement‐activating capacity .…”

Engineered clearing agents for the selective depletion of antigen-specific antibodies

“…Naturally occurring IgGs have substantially higher affinity for FcRn at acidic pH than at near neutral pH, and this property is essential for the recycling and transcytosis of IgG within FcRn-expressing cells8. By contrast, gain of binding affinity of an Fc (or IgG) for FcRn at pH 7.4 results in receptor-mediated internalization into cells and lysosomal delivery1910. In the current study, we demonstrate that Fc-antigen fusions, or Seldegs, containing such affinity-enhanced Fc fragments selectively capture antigen-specific antibodies and direct them into degradative lysosomal compartments in FcRn-expressing cells.…”

Pharmacokinetic and Pharmacodynamic Considerations in the Design of Therapeutic Antibodies

“…Fukuzawa and colleagues have developed recycling antibody or antibody with pH‐dependent antigen binding through variable region engineering to improve the PK/PD profile of IgG by increasing the clearance of the antigen but not the antibody. When coupled with sweeping technology (through constant region engineering), which has increased FcRn binding at neutral pH, an enhanced FcRn‐mediated uptake of the antibody–antigen complex into the endosome can be achieved and, thereby, an increase in the number of cycles of antigen binding and lysosomal degradation . Igawa et al .…”

“…When coupled with sweeping technology (through constant region engineering), which has increased FcRn binding at neutral pH, an enhanced FcRnmediated uptake of the antibody-antigen complex into the endosome can be achieved and, thereby, an increase in the number of cycles of antigen binding and lysosomal degradation. 26 Igawa et al 27 generated a sweeping antibody variant of tocilizumab, an antibody against the soluble and membranous interleukin-6 receptor (IL-6R). This increased the number of cycles of antigen binding and lysosomal degradation, which, coupled with Fc engineering to increase binding to FcRn, significantly improved both PK and PD in cynomolgus monkeys.…”