Engineered receptors for human cytomegalovirus and uses thereof
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Publication Number
US-12570720-B2
Publication Date
2026-03-10
Expiration Date
Abstract
Modified platelet-derived growth factor receptor alpha (PDGFRα) polypeptides are described. The modified polypeptides include at least one amino acid substitution that allows the polypeptide to retain the capacity to bind a cytomegalovirus (CMV) trimer comprised of glycoprotein H (gH), gL and gO, but leads to reduced binding to one or more platelet-derived growth factor (PDGF) ligands. Use of the modified PDGFRα polypeptides for inhibiting CMV replication and/or spread, or treating a CMV infection, is also described.
Core Innovation
The disclosure describes modified platelet-derived growth factor receptor alpha (PDGFRα) polypeptides, including a human PDGFRα or an extracellular fragment thereof, bearing at least one amino acid substitution relative to wild-type human PDGFRα of SEQ ID NO: 1. The modified polypeptides retain the capacity to bind a cytomegalovirus (CMV) trimer comprised of glycoprotein H (gH), gL and gO, while exhibiting reduced binding to one or more platelet-derived growth factor (PDGF) ligands compared to wild type PDGFRα.
The disclosed substitutions include a single amino acid substitution selected from the group consisting of L137K, L137Q, Y206S, V242K and V242T. The disclosure further includes residue sets associated with maintaining CMV trimer affinity under PDGF competition while impairing PDGF signaling, as well as soluble PDGFRα-Fc variants derived from the modified PDGFRα polypeptides and fusion protein embodiments that combine the modified receptor with heterologous polypeptides.
The soluble variants are described as neutralizing HCMV and maintaining stability and binding characteristics across CMV strains. The disclosure also includes nucleic-acid and vector embodiments encoding the modified PDGFRα polypeptides and the fusion constructs.
Claims Coverage
The independent claim coverage centers on a modified PDGFRα polypeptide that retains CMV gH/gL/gO trimer binding while showing reduced binding to PDGF ligands, with the core inventive selection of specific single amino-acid substitutions. Based on the provided claim text, the main independent claim is clm-00001; related dependent claims refine the substitution set, the extracellular fragment range, and cover fusion protein and pharmaceutical composition embodiments.
Modified PDGFRα retains CMV trimer binding and reduces PDGF ligand binding
A modified platelet-derived growth factor receptor alpha (PDGFRα) polypeptide comprising a human PDGFRα or an extracellular fragment thereof, wherein the polypeptide comprises at least one amino acid substitution relative to wild-type human PDGFRα of SEQ ID NO: 1, retains the capacity to bind a cytomegalovirus (CMV) trimer comprised of glycoprotein H (gH), gL and gO, but exhibits reduced binding to one or more platelet-derived growth factor (PDGF) ligands compared to wild type PDGFRα.
Single amino acid substitution selected from L137K, L137Q, Y206S, V242K and V242T
The modified polypeptide wherein the single amino acid substitution is selected from the group consisting of L137K, L137Q, Y206S, V242K and V242T.
The claims focus on modified human PDGFRα or extracellular fragments that preserve CMV gH/gL/gO trimer binding while reducing binding to PDGF ligands, with the modification defined by specific single amino-acid substitutions from the listed group.
Stated Advantages
Enables orthogonal inhibition of CMV replication/spread by retaining CMV trimer binding while exhibiting reduced binding to PDGF ligands.
Documented Applications
Neutralization of HCMV in vitro using soluble PDGFRα-Fc variants across CMV strains (AD169/TB40/E referenced).
Inhibition of CMV replication/spread associated with orthogonal inhibition enabled by retained CMV trimer binding and reduced PDGF ligand binding.
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