Chemically programmed antibodies

Abstract

Due to their unlimited chemical diversity, small molecules can rival monoclonal antibodies (mAbs) with respect to specificity and affinity for target molecules. However, key pharmacological properties of mAbs remain unmatched by small molecules. Chemical programming strategies have been developed for site-specific and covalent conjugation of small molecules to mAbs with unique reactivity centers. In addition to blending favorable features of small molecules and mAbs, chemically programmed antibodies (cpAbs) are economically attractive because they utilize the same mAb for a virtually unlimited number of target molecule specificities, reducing manufacturing costs and shortening drug discovery and development time. Preclinical studies and clinical trials have begun to demonstrate the broad utility of cpAbs for the treatment and prevention of human diseases.

Emerging formats for next-generation antibody drug conjugates

“…The CovX-body approach utilises a specific lysine residue buried in a hydrophobic pocket (Lys-99) making it super-reactive, which can be used to couple a variety of ligands from peptides, to drugs (Figure 1) [59].…”

Chemically Programmed Bispecific Antibody Targeting Legumain Protease and αvβ3 Integrin Mediates Strong Antitumor Effects

“…22 In some cases, the linker is replaced with an antigen of circulating Abs such that the latter can be recruited to a target of the organics used. 23 Upon chemical programming, plasma half-life of a small molecule increases, and the cpAb can discern Ab-dependent cell-mediated cytotoxicity, which we have shown earlier with the anti-integrin cpAbs.…”

Antibody Conjugates: From Heterogeneous Populations to Defined Reagents

“…In contrast to any conjugation technology previously described, the antibody acts here solely as a carrier protein and has no targeting properties. By fusing a small molecular weight payload (SMWP, e.g., peptide) with a catalytic antibody, it is possible to generate antibody conjugates that combine the highly specific targeting properties of the SMWP and the pharmacokinetic characteristics of an antibody [168][169][170]. The conjugation is based on the derivatization of the pharmacophore with either a diketone, vinylketone or azetidinone functional group that forms a covalent bond with a specific lysine residue in the active site of the catalytic antibody ( Figure 8B).…”