Biparatopic antibodies: therapeutic applications and prospects

Abstract

Biparatopic antibodies (bpAbs) bind distinct, non-overlapping epitopes on an antigen. This unique binding mode enables new mechanisms of action beyond monospecific and bispecific antibodies (bsAbs) that can make bpAbs effective therapeutics for various indications, including oncology and infectious diseases. Biparatopic binding can lead to superior affinity and specificity, promote antagonism, lock target conformation, and result in higher-order target clustering. Such antibody-target complexes can elicit strong agonism, increase immune effector function, or result in rapid target downregulation and lysosomal trafficking. These are not only attractive properties for therapeutic antibodies but are increasingly being explored for other modalities such as antibody-drug conjugates, T-cell engagers and chimeric antigen receptors. Recent advances in bpAb engineering have enabled the construction of ever more sophisticated formats that are starting to show promise in the clinic.

A Biparatopic Intrabody Renders Vero Cells Impervious to Ricin Intoxication

“…Our study adds to the list of examples of engineered biparatopic antibodies that have biological properties ( e . g ., toxin neutralization) that exceed what is achieved by either of the variable elements alone, although V2A11-V9E1 may constitute the first reported biparatopic intrabody (Niquille et al, 2024). We postulate that the enhanced potency of V2A11-V9E1 is due to a combination of increased antibody avidity and simultaneous targeting of two sites of vulnerability of RTA.…”