Designing immune-modulating multivalent protein agonists using a naturally-occurring short peptide sequence derived from the COMP to pentamerize ECDs of known immune surface antigens
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COMP stands for Cartilage Oligomeric Matrix Protein, an abundant extracellular matrix (ECM) protein that may play a role in the structural integrity of cartilage via its interaction with other ECM proteins such as the collagens and fibronectin. COMP can mediate the interaction of chondrocytes with the cartilage extracellular matrix through interaction with cell surface integrin receptors. A 44-amino acid α-helical peptide within COMP codes for its pentamerization function by forming stable 5-α-helix peptide bundles stabilized by disulphide bridges (Figure 1). This COMP domain is being used in our laboratory to create high valency forms of known immune extracellular domains (ECDs) with a view to create non-Fc containing, high avidity agonists that work as soluble factors in altering immune cell functions.
Figure 1. Upright, Side, and Top view of mouse COMP pentamerization crystal structure ribbon structure (PDB Id: 1MZ9)
What is our COMP construct strategy ?
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Targeting co-stimulatory and co-inhibitory immune ligands to their cognate receptors represents an attractive therapeutic strategy for the treatment of cancer and inflammatory disorders respectably. However, soluble monomeric forms of ligand's ECDs typically display a low affinity for their cognate receptor, requiring them to be presented in multiple copies on cell surfaces in order to trigger cellular signalling events on T cells and other immune cells.
We have recently fused the single IgV domain of VISTA (a new immune checkpoint ligand/receptor) to the short COMP pentameric domain which forms a pentameric α-helix bundle stabilized by disulfide bonds (Figure 2). The petamerization of this ligand resulted in its enhanced avidity towards its receptor. VISTA.COMP displays strong immunosuppressive activity as a soluble factor both in vitro and in vivo; a phenomenon that was not observed for the dimeric VISTA.Fc. Furthermore, COMP constructs differ significantly from traditional bivalent ECD.Fc constructs as they lack the cytotoxic or potentially competing immune functions associated with Fc domains. We have recently constructed a number of functional ECD.COMP fusion constructs including ICOS-L.COMP, that behave as strong agonists in stimulating or inhibiting immune cell functions.
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Figure 2. Upright, Side, and Top view of human VISTA.COMP ribbon structure as predicted using Deepmind Alphafold 2.0 under a Google Colab iteration (https://colab.research.google.com/github/sokrypton/ColabFold/blob/main/beta/AlphaFold2_advanced.ipynb#scrollTo=KAZj6CBZTkJM)
Selected publication from our group:
1. Prodeus A, Abdul-Wahid A, Sparkes A, Fischer NW, Cydzik M, Chiang N, Alwash M, Ferzoco A, Vacaresse N, Julius M, Gorczysnki RM, Gariépy J. (2017) VISTA.COMP - an engineered checkpoint receptor agonist that potently suppresses T cell-mediated immune responses. JCI Insight. 2(18):e94308
Last updated on Nov-4-2021