Structure-guided Discovery of Dual-recognition Chemibodies

Abstract

Small molecules and antibodies each have advantages and limitations as therapeutics. Here, we present for the first time to our knowledge, the structure-guided design of “chemibodies” as small molecule-antibody hybrids that offer dual recognition of a single target by both a small molecule and an antibody, using DPP-IV enzyme as a proof of concept study. Biochemical characterization demonstrates that the chemibodies present superior DPP-IV inhibition compared to either small molecule or antibody component alone. We validated our design by successfully solving a co-crystal structure of a chemibody in complex with DPP-IV, confirming specific binding of the small molecule portion at the interior catalytic site and the Fab portion at the protein surface. The discovery of chemibodies presents considerable potential for novel therapeutics that harness the power of both small molecule and antibody modalities to achieve superior specificity, potency, and pharmacokinetic properties.

Engineering NaV1.7 Inhibitory JzTx-V Peptides with a Potency and Basicity Profile Suitable for Antibody Conjugation To Enhance Pharmacokinetics

“…However, after significant molecular optimization, the high-exposure multiples required for small effect sizes in vivo with αDNP antibody–peptide conjugates in this report do not demonstrate a clear advantage in target access for these hybrids. Another potential path forward is to switch from a carrier to a targeting antibody that either binds to Na V 1.7 to increase potency or facilitates receptor-mediated delivery of the conjugate across the blood–nerve barrier using concepts that have been developed for crossing the blood–brain barrier …”

Chemical Diversification of Simple Synthetic Antibodies

“…60 Finally, Wang, Miranda, and coworkers reported the design and construction of bivalent small molecule-antibody "hybrids" based on a crystal structure of a dipeptidyl peptidase IV (DPPIV)-antibody complex. 61 Introduction of analogs of a known small molecule inhibitor of DPPIV into the noninhibitory antibody led to hybrid inhibitors with enhanced IC50 values in comparison to controls. Taken together, these studies indicate that there are several promising routes for diversifying the chemical groups that can be presented within antibody variable domains.…”

“…For example, Winter and co-workers reported a phage display antibody library encoding a cysteine in order to introduce fluorescent dyes; library screening against a model antigen led to a clone exhibiting both dye-dependent binding and changes in fluorescence properties upon antigen binding . Finally, Wang, Miranda, and co-workers reported the design and construction of bivalent small molecule-antibody “hybrids” based on a crystal structure of a dipeptidyl peptidase IV (DPPIV)–antibody complex . The introduction of analogs of a known small molecule inhibitor of DPPIV into the noninhibitory antibody led to hybrid inhibitors with enhanced IC 50 values in comparison to controls.…”

Activation of a G protein-coupled receptor through indirect antibody-mediated tethering of ligands

“…1 Ligands for cell surface receptors can also be linked to antibodies; however, such efforts often suffer from a lack of specificity or difficulties in producing active, stable conjugates in sufficient yield. [2][3][4][5][6] The use of single domain antibodies (VHHs or nanobodies) can overcome some of these complications. 7 Nanobodies are the recombinantly expressed variable regions of camelid heavy chain only antibodies.…”