The Chemistry of Creating Chemically Programmed Antibodies (cPAbs): Site-Specific Bioconjugation of Small Molecules

Abstract

Small-molecule drugs have been employed for years as therapeutics in the pharmaceutical industry. However, small-molecule drugs typically have short in vivo half-lives which is one of the largest impediments to the success of many potentially valuable pharmacologically active small molecules. The undesirable pharmacokinetics and pharmacology associated with some small molecules have led to the development of a new class of bioconjugates known as chemically programmed antibodies (cPAbs). cPAbs are bioconjugates in which antibodies are used to augment small molecules with effector functions and prolonged pharmacokinetic profiles, where the pharmacophore of the small molecule is harnessed for target binding and therefore biological targeting. Many different small molecules can be conjugated to large proteins such as full monoclonal antibodies (IgG), fragment crystallizable regions (Fc), or fragment antigen binding regions (Fab). In order to successfully and site-specifically conjugate small molecules to any class of antibodies (IgG, Fc, or Fab), the molecules must be derivatized with a functional group for ease of conjugation without altering the pharmacology of the small molecules. In this Review, we summarize the different synthetic or biological methods that have been employed to produce cPAbs. These unique chemistries have potential to be applied to other fields of antibody modification such as antibody drug conjugates, radioimmunoconjugates, and fluorophore-tagged antibodies.

Chemical technology principles for selective bioconjugation of proteins and antibodies

“…28), activated esters (28a), anhydrides (117a), and activated lactams (118a). 266,[317][318][319] The NHS ester is the most widely used reagent for lysine conjugation in antibodies. 266,[320][321][322] The ease of synthetic manoeuvrability allows the installation of chemically orthogonal handles like alkyne, azide, aldehydes, and hydrazones to place a desired tag in the subsequent step.…”

Study of uricase-polynorbornene conjugates derived from grafting-from ring-opening metathesis polymerization

“…Bioconjugation of proteins is accomplished primarily through two approaches: grafting-to and grafting-from bioconjugation. [50][51][52][53][54] Grafting-to bioconjugation, notably employed in PEGylation of proteins, involves a covalent linkage of preformed polymers equipped with reactive end-group functionalities to complementary amino acid residues within the proteins. While the grafting-to technique allows for the synthesis of well-defined polymers and facilitates thorough characterization of the polymer component, it requires the addition of excess of polymers in the reaction.…”