Repurpose an FDA‐Approved Antibody Using DARPin‐Scaffolded Bridge Protein

The cell line and scalable upstream/downstream process development needed for every new monoclonal antibody are both highly expensive and time‐consuming, significantly increasing the cost of new antibody therapeutics. By contrast, the production of many synthetic binders can be accomplished rapidly and with lower production costs. Unfortunately, the clinical efficacy of these synthetic binders is hampered by the lack of antibody Fc effector functions. We report a synthetic modular platform, Bridge Protein (BP), capable of permanently repurposing an FDA‐approved antibody to new therapeutic targets. BP is a bispecific designed ankyrin repeat protein (DARPin) that binds an antibody paratope and a new target of interest. As proof of concept, we created a BP for redirecting ofatumumab, an anti‐CD20 antibody, to HER2 + cells and demonstrated its ability to induce antibody‐dependent cellular cytotoxicity (ADCC). Incorporation of p ‐benzoyl‐L‐phenylalanine (BPA) in BP enables its covalent photocrosslinking to ofatumumab without compromising target binding or ADCC. This plug‐and‐play platform enables straightforward and cost‐effective antibody retargeting and opens the door to rapidly repurposing stockpiled antibodies for pandemic preparedness and biotherapeutic development.