US28 Binding Molecules for Strain-Agnostic HCMV Targeting
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Solution Overview
Problem
Current antiviral therapies for human cytomegalovirus (HCMV) are limited by drug resistance, off-target effects, and inability to target latent infections, while existing US28-targeting antibodies like VUN100 face challenges with strain-specific binding and high off-target activity, making them less effective against diverse HCMV strains.
Innovation Solution
Development of binding molecules that specifically target conserved epitopes in the N-terminus (ECD1) and extracellular domain 3 (ECD3) of the US28 protein, ensuring high specificity and strain-agnostic binding to HCMV-infected cells, minimizing off-target effects and maintaining efficacy across various HCMV strains.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If existing US28-targeting antibodies like VUN100 are used, then binding activity against US28 is achieved, but strain-specific binding limits effectiveness against diverse HCMV strains
Solution Approach 1:
The patent applies universality by designing binding molecules that recognize conserved epitopes across all HCMV strains. The binding molecules target highly conserved regions of the US28 protein that are identical or similar across diverse HCMV strains, enabling a single antibody candidate to effectively bind and neutralize multiple strains without requiring strain-specific customization.
2Reliability
If existing US28-targeting antibodies are used, then HCMV-infected cells can be targeted, but high off-target activity reduces therapeutic efficacy
Solution Approach 1:
The patent applies local quality by focusing the binding molecules on highly specific, conserved epitopes within the US28 protein structure. By targeting specific local regions (conserved amino acid sequences) rather than broader structures, the binding molecules achieve high specificity for HCMV-infected cells while minimizing cross-reactivity with host cells or other viral proteins, thereby reducing off-target effects.
3Reliability
If current antiviral therapies are used, then viral replication can be controlled, but drug resistance and inability to target latent infections limit their effectiveness
Solution Approach 1:
The patent applies inversion by shifting the therapeutic strategy from targeting viral replication machinery (which leads to resistance) to targeting the US28 receptor on infected cells. This alternative approach targets the host cell surface receptor that HCMV uses for entry and persistence, including latent infections. By inverting the target from viral to host-derived, the therapy can address both lytic and latent phases of infection while reducing resistance development.
Data Source
AI summary
The present invention provides binding molecules having one or more of (preferably all of) highly specific binding to the US28 protein of human cytomegalovirus (HCMV), very low levels of non-specific binding to healthy (non-infected) cells, and/or a strain-agnostic binding ability, as well as nucleic acid molecules encoding the said binding molecules. The binding molecules are designed to bind to a newly-identified epitopic region within extracellular domain 1 (ECD1) of a US28 protein of human cytomegalovirus (HCMV), the first of the four extracellular domains presented by US28, corresponding to positions 1 to 37 of the US28 protein sequence as defined by SEQ ID NO:5. The binding molecules of the present invention have been demonstrated to have excellent binding properties, including particular binding specificity for aggressive and/or metastasizing HCMV-infected cancers, including breast cancers. In certain preferred embodiments, the binding molecule is selected from an antibody (including, for example, a BiTE antibody) and a chimeric antigen receptor (CAR), or functional variants, fragments, fusion proteins, and/or conjugates thereof. Also provided are cells expressing said binding molecules, such as CAR-expressing cells, including CAR-T cells, CAR-NK cells, and CAR-M cells.