US28-Targeting Binding Molecules for HCMV Therapy
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current antiviral therapies for human cytomegalovirus (HCMV) are limited by poor bioavailability, toxic side effects, and the inability to target latent infections, with existing drugs facing challenges due to high polymorphism in viral targets like US28, leading to suboptimal specificity and off-target effects.
Innovation Solution
Development of binding molecules that specifically target the US28 protein's extracellular domain 3 (ECD3) with high specificity, minimizing off-target binding to healthy cells and being strain-agnostic, enabling effective targeting of HCMV-infected cells regardless of viral strain variations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing antiviral therapies are used to treat HCMV infections, then viral replication is inhibited, but the drugs exhibit poor bioavailability and toxic side effects
Solution Approach 1:
The patent uses the US28 protein as an intermediary target to deliver therapeutic effects. The binding molecules (antibodies) bind to US28, which is expressed on HCMV-infected cells, thereby mediating the therapeutic effect through a specific viral target rather than directly inhibiting viral enzymes, reducing off-target toxicity while maintaining efficacy
2Reliability
If existing antiviral therapies are used to treat HCMV infections, then viral replication is inhibited, but the drugs exhibit poor bioavailability
Solution Approach 1:
The binding molecules target the US28 protein which is accessible on the cell surface of HCMV-infected cells. This surface-targeting approach improves bioavailability by eliminating the need for drugs to penetrate cellular membranes and reach intracellular targets, allowing direct binding to the viral protein from the extracellular environment
3Reliability
If existing antiviral therapies are used to treat HCMV infections, then some viral activity is suppressed, but the therapies cannot target latent infections
Solution Approach 1:
The binding molecules are designed to recognize and bind to the US28 protein regardless of whether the infection is lytic or latent. Since US28 is expressed in both infection states, the same therapeutic agent can universally target both active and latent HCMV infections, providing multi-functional capability
4Reliability
If existing antiviral therapies are used to treat HCMV infections, then viral replication is inhibited, but high polymorphism in viral targets leads to suboptimal specificity
Solution Approach 1:
The patent focuses on a specific region of the US28 protein (extracellular domain 3, ECD3) that exhibits lower polymorphism compared to other regions like the N-terminal domain. By targeting this conserved local region, the binding molecules achieve high specificity across different HCMV strains, overcoming the polymorphism problem
5Reliability
If existing antiviral therapies are used to treat HCMV infections, then viral replication is inhibited, but off-target effects occur due to low specificity
Solution Approach 1:
The binding molecules use US28 as a highly specific intermediary target that is uniquely expressed on HCMV-infected cells. This specific targeting through the viral US28 protein prevents off-target effects by ensuring the therapeutic agent only binds to and affects infected cells, leaving healthy uninfected cells untouched
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 extracellular domain 3 (ECD3) of a US28 protein of human cytomegalovirus (HCMV), the third of the four extracellular domains presented by US28, corresponding to positions 167 to 183 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.