GPCR therapeutics

Communication between cells is essential for a wide variety of physiological processes within the body. The largest superfamily of signal transduction proteins consists of G protein-coupled receptors (GPCRs), which pass through the cell membrane seven times (14). This large protein family of receptors is able to transfer an external signal into the cell by activating internal signal transduction pathways upon detection of certain ligands outside the cell. With this important regulatory function in mind, it is not surprising that GPCRs are involved in numerous types of human malignancies (15-16). Overexpression of these receptors has been shown in different tumor types and the expression of certain GPCR variants is linked to increased cancer risk (14, 16). Additionally, high levels of ligands are able to increase GPCR activity and thereby affect cell transformation, proliferation, antiogenesis, metastasis, and drug resistance (16). On the contrary, other members of the GPCR family were observed to have pro-apoptotic functions in various tumor cells (17).

Due to their substantial role in human pathophysiology and their accessibility on the cell membrane, GPCRs have been identified as extremely interesting drug targets. Approximately 34% of all modern medication approved by the US Food and Drug Administration (FDA) act on a variety of members of this receptor family (18). However, a large proportion of GPCRs has not been explored yet for their therapeutic potential (18). We are currently developing antibodies against a selected set of GPCRs, which we believe to be promising targets in novel pharmacological approaches for cancer patients.

GPCR Programs

metabotropic glutamate receptor 1 (mGluR1)

Using our phage-display libraries antibodies were identified with binding affinity to transiently expressed human mGluR1. Antibodies were expressed in human IgG1 format and tested for binding to mGluR1-transfected cells using flow cytometry and rat immunohistochemistry.

C-X-C chemokine receptor 4 (CXCR4)

Using our phage-display libraries antibodies were identified using CXCR4-functionalized virus-like particles (VLPs) and transiently CXCR4-expressing cells. CXCR4 isotype specific antibodies were identified that show inhibition of the interaction between the receptor and natural ligand (CXCL12).”

14. Lappano R,Maggiolini M. GPCRs and cancer. Acta Pharmacol Sin 2012, 33:351-62

15. Dorsam RT, Gutkind JS. G-protein-coupled receptors and cancer. Nature Rev Cancer 2007, 7:79–94

16. Lappano R, Maggiolini M. G protein-coupled receptors: novel targets for drug discovery in cancer. Nat Rev Drug Discov 2011, 10:47–6

17. Voisin T, El Firar A, Fasseu M, Rouyer-Fessard C, Descatoire V, Walker F, et al. Aberrant expression of OX1 receptors for orexins in colon cancers and liver metastases: an openable gate to apoptosis. Cancer Res 2011, 71:3341–51

18. Hauser AS,Attwood MM, Rask-Andersen M, Schiöth HB, Gloriam DE. Trends in GPCR drug discovery: new agents, targets and indications. Nat Rev Drug Discov 2017, 16:829-842