Multivalent antibody-based conjugates as new tools for tailored modulation of G protein-coupled receptors.

The G protein-coupled receptor (GPCR) superfamily consists of the most common targets of approved drugs. Targeting GPCRs offers appealing avenues for therapeutic development. Antibodies and their fragments, such as single-domain antibodies (VHHs or nanobodies), have emerged as useful alternatives to small molecule pharmacophores as building blocks in multivalent conjugates. Antibodies and nanobodies bind targets through a binding surface that offers high affinity and specificity while facilitating engagement of GPCR epitopes not easily amenable to small molecule binding. Nanobodies, in particular, have proven valuable as tools to stabilize or selectively recognize GPCR conformations for use in structural or biosensing applications, respectively. Here, we focus on the application of antibodies and nanobodies in multivalent conjugates to address GPCR function in new ways. Such conjugates offer opportunities for highly potent and specific activation of GPCRs of interest, preferential engagement of receptor assemblies and the induction of tailored (biased) pharmacological responses. This review reports on case studies of peptide-antibody constructs, nanobody-nanobody fusions and small molecule-nanobody conjugate formats. We further discuss how emerging bioconjugation strategies and antibody engineering platforms will expand the utility of multivalent bioconjugates as next-generation therapeutic agents for GPCRs.