Abstract
Cattle produce a subset of antibodies (Abs) with unique architecture. These immunoglobulins feature an ultralong CDR‐H3 (uCDR‐H3) composed of up to about 70 amino acids that protrudes from the scaffold and folds into a distinct stalk‐and‐knob structure. The knob is a disulfide‐rich mini‐domain that contains all paratope residues for antigen recognition. Due to their vast structural diversity and low molecular weight, cattle‐derived knob paratopes have emerged as promising building blocks for engineering next‐generation Abs. In this review, we discuss the structural features of uCDR‐H3 Abs alongside engineering strategies of cattle‐derived knob architectures, including stand‐alone knob peptides and knob engraftments to generate bispecific antibodies (bsAbs).