Optimized Engineering Platform for the Generation of Recycling Therapeutic Antibodies
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A new modality in antibody engineering has emerged in which the antigen affinity is designed to be pH dependent (PHD). In particular, the combination of high affinity binding at neutral pH with low affinity binding at acidic pH leads to a novel antibody that can more effectively act on its target through a pH dependent recycling mechanism. We have studied how the in vivo pharmacokinetics of the soluble superantigen, Staphylococcal enterotoxin B (SEB), is affected by an engineered therapeutic antibody with pH dependent binding. PHD anti-SEB antibodies were made by introducing mutations into a high affinity anti-SEB antibody using rational design and directed evolution. This same two-step engineering approach was applied in another antibody therapy to further highlight the utility of this approach. The second study was towards the generation of anti-tumor antibodies with pH dependent binding to a well studied tumor cell surface receptor (HER2). The effect of using PHD anti-tumor antibodies was an overall increase in antibody internalization and subsequent increase in tumor cell cytotoxicity. Therefore, these novel antibodies can be generated using this platform approach in a robust and efficient manner, which may be applied to a wide variety of diseases.