Abstract
Soluble ligands have commonly been targeted by antibody therapeutics for cancers and other diseases. Although monoclonal antibodies targeting such ligands can block their interactions with their cognate receptors, they can also significantly increase the half-life of their ligands by FcRn-mediated antibody recycling, thereby evading ligand renal clearance and requiring increasingly high antibody doses to neutralize the increasing pool of target. To overcome this issue, we generated a bispecific/biparatopic antibody (BiSAb) that targets two different epitopes on IL-6 to block IL-6-mediated signaling. The BiSAb formed large immune complexes with IL-6 that can bind Fcγ receptors on phagocytic cells and are rapidly internalized. In addition, rapid clearance of the BiSAb·IL-6 complex was observed in mice while the parental antibodies prolonged the serum half-life of IL-6. Intravital imaging of the liver in mice confirmed that the rapid clearance of these large immune complexes was associated with Fcγ receptor-dependent binding to Kupffer cells in the liver. The approach described here provides a general strategy for therapeutic antibodies with the ability to not only neutralize but also actively drive clearance of their soluble antigens.
Highlights
Soluble ligands have commonly been targeted by antibody therapeutics for cancers and other diseases
Anti-IL-6 antibodies show promise in neutralizing IL-6 activity in vitro, the serum levels of injected human IL-6 in mice treated with antiIL-6 antibody are much higher than in control mice injected with human IL-6 alone because of the anti-IL-6 antibody-mediated buffering effect [8]
Subsequent application of the same antibody to the chip did not show any additional binding to the rhIL-6 (Fig. 2, A and B)
Summary
Soluble ligands have commonly been targeted by antibody therapeutics for cancers and other diseases. Monoclonal antibodies targeting such ligands can block their interactions with their cognate receptors, they can significantly increase the half-life of their ligands by FcRn-mediated antibody recycling, thereby evading ligand renal clearance and requiring increasingly high antibody doses to neutralize the increasing pool of target To overcome this issue, we generated a bispecific/ biparatopic antibody (BiSAb) that targets two different epitopes on IL-6 to block IL-6-mediated signaling. A bispecific antibody (BiSAb) that targets two unique epitopes on a soluble antigen can alleviate this problem by binding the antigen and generating large immune complexes that can exploit clearance mechanisms such as com-.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
