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In this work we have generated cattle-derived chimeric ultralong CDR-H3 antibodies targeting tumor necrosis factor α (TNF-α)  via  immunization and yeast surface display. We identified one particular ultralong CDR-H3 paratope that potently neutralized TNF-α. Interestingly, grafting of the knob architecture onto a peripheral loop of the CH 3  domain of the Fc part of an IgG1 resulted in the generation of a TNF-α neutralizing Fc (Fc knob ) that did not show any potency loss compared with the parental chimeric IgG format. Eventually, grafting this knob onto the CH 3  region of adalimumab enabled the engineering of a novel TNF-α targeting antibody architecture displaying augmented TNF-α inhibition.

biological chemistry

Bovine ultralong CDR-H3 derived knob paratopes elicit potent TNF-α neutralization and enable the generation of novel adalimumab-based antibody architectures with augmented features