Structural and Pharmacological Characterization of Novel Potent and Selective Monoclonal Antibody Antagonists of Glucose-dependent Insulinotropic Polypeptide Receptor

Abstract

Background: GIPr mediates insulin secretion upon GIP stimulation.Results: Gipg013 is a highly specific and potent antagonist of GIPr with a fully characterized mode of action.Conclusion: Gipg013 antagonizes GIPr in vivo, as exemplified by inhibition of GIP-induced insulin secretion.Significance: This antagonizing antibody to the GIPr will be useful as a tool to further understand the biological roles of GIP.

Monoclonal anti-β1-adrenergic receptor antibodies activate G protein signaling in the absence of β-arrestin recruitment

“…A recent example of this has been the reporting of antagonist mAbs directed to the glucosedependent insulinotropic polypeptide receptor (GIP). 54 Similarly, orphan receptors (for which there are no known ligands) and GPCRs with emerging biology (such as the adhesion subfamilies) present a challenge in drug development. Attempts to identify small molecule agonists or antagonists for these generally fail; however, a functional mAb provides an alternative approach to identifying drugs to such targets.…”

Dual Targeting of the Chemokine Receptors CXCR4 and ACKR3 with Novel Engineered Chemokines

“…antagonism) or high affinity binding to a target, in vitro selection platforms such as phage display have proven extremely powerful (25)(26)(27). As chemokine affinity and pharmacology can be modified by minimal sequence changes in their N termini, they would seem an obvious scaffold for phage display.…”

Affinity maturation of a novel antagonistic human monoclonal antibody with a long VHCDR3 targeting the Class A GPCR formyl-peptide receptor 1

“…For example, a GPCR-specific neutralizing antibody has recently been identified by in vitro selection of a na€ ıve antibody library using reducing concentrations of the receptor N-terminus during rounds of selection to enrich the selected populations for higher affinity antibodies. 13 This approach should be equally applicable to the in vitro selection of antibody libraries for affinity optimization. In addition, the directed evolution of a single-domain camelid antibody fragment (nanobody) recognizing the b 2 -adrenoceptor (b 2 -AR) in its agonist-bound conformation has recently been described.…”

“…11 Other successful examples of the use of peptides as antigens include the isolation of single chain Fv fragment (scFv) antibodies that are able to recognize the native cholecystokinin-B receptor expressed on cells by panning of a phage display antibody library using a synthetic peptide corresponding to the second extracellular loop of the receptor, 12 and isolation of a competitive antagonistic antibody for the class B GPCR glucosedependent insulinotropic polypeptide receptor using phage display and ribosome display selections against a peptide comprising the receptor N-terminus. 13 In cases where the use of extracellular domains or peptides as surrogate GPCR immunogens is not feasible, approaches that avoid the need for a purified GPCR have been used, such as the immunization of animals with DNA encoding the GPCR of interest 14 or the use of GPCR overexpressing cell lines for the immunization of animals. The latter is a widely used solution to identify antibodies targeting GPCRs, and by this route neutralizing antibodies to the CXCR4 receptor, the rat sphingosine 1-phosphate receptor and the CCR5 receptor among others have been derived.…”