αCD47–αCD3 BiTE Oncolytic Vaccinia Virus for Solid Tumors
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Solution Overview
Problem
Current bispecific T-cell engagers and oncolytic viruses are not optimally suited for targeting and treating solid tumors, with existing CD47 antibodies facing safety issues due to red blood cell binding and limited efficacy in intravenous administration, and oncolytic viruses having incomplete tumor clearance and limited applicability.
Innovation Solution
A novel αCD47-αCD3 bispecific T-cell engager (BiTE) is combined with a recombinant vaccinia virus Tian Tan strain, expressing the BiTE in the thymidine kinase region, to specifically target and lyse tumor cells while minimizing red blood cell damage, enhancing tumor immunotherapy and viral replication.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CD47 antibody drugs or SIRPα-Fc fusion protein are used to block CD47 on tumor cells, then macrophage phagocytosis of tumor cells is enhanced, but red blood cells are damaged causing anemia
Solution Approach 1:
The patent applies local quality by directing the CD47 blocking activity specifically to the tumor microenvironment through BiTE-mediated T cell recruitment. The CD47 antibody component is localized to tumor sites where T cells are activated by CD3 binding, rather than systemically distributed. This localized action enhances anti-tumor phagocytosis while minimizing exposure to red blood cells, thereby reducing anemia risk.
2Ease of operation
If BiTE is administered intravenously to treat solid tumors, then T cell activation occurs, but the BiTE cannot effectively penetrate the tumor interior
Solution Approach 1:
The patent uses T cells as intermediaries to deliver the CD47 blocking function directly to the tumor interior. Intravenously administered BiTE first activates T cells at the tumor site through CD3 binding. These activated T cells then locally express or interact with the CD47 antibody component, effectively delivering the therapeutic action deep within the tumor microenvironment without requiring direct BiTE penetration.
3Productivity
If oncolytic viruses are used to lyse tumor cells, then tumor cell death is induced, but immune tolerance of the tumor microenvironment is not fully broken
Solution Approach 1:
The patent merges two distinct mechanisms: oncolytic virus-mediated tumor cell lysis and BiTE-mediated T cell activation with CD47 blocking. The oncolytic virus provides immediate tumor cell death, while the BiTE component simultaneously activates T cells and blocks CD47 to enhance macrophage phagocytosis. This combination breaks immune tolerance more effectively by engaging both direct viral oncolysis and adaptive immune responses, creating durable anti-tumor immunity.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The recombinant vaccinia virus with the αCD47-αCD3 BiTE effectively penetrates solid tumors, activates T cells, and enhances macrophage phagocytosis, improving tumor targeting and treatment efficacy compared to standalone therapies.
Implementation Method 1
A novel αCD47-αCD3 bispecific T-cell engager (BiTE) is combined with a recombinant vaccinia virus Tian Tan strain, expressing the BiTE in the thymidine kinase region
Implementation Method 2
BiTE consists of two single-stranded variable fragments (scFv) connected in series by a flexible linker. One scFv recognizes the T cell surface protein CD3εH, while the other scFv recognizes a specific tumor cell surface antigen. This structure of BiTE and the ability to specifically bind proteins allows it to physically bridge T cells to tumor cells to form T cell-BiTE-tumor cell complexes, induce immune synapse formation, stimulate T cell activation
Implementation Method 3
Oncolytic viruses are increasingly becoming the first choice for anti-tumor because of their ability to selectively infect and lye tumor cells locally
Implementation Method 4
CD47 is widely expressed on the surface of various cancer cells. It releases the 'don't eat me' signal by linking to signaling regulatory protein alpha (SIRPα) on the surface of tumor phagocytes, thereby preventing macrophage phagocytosis
Data Source
AI summary
Provided by the present invention are a bispecific T-cell engager, recombinant oncolytic virus thereof, and use thereof. The present invention provides an αCD47 and αCD3 bispecific T-cell engager. The present invention also provides an isolated nucleic acid molecule that encodes said bispecific T-cell engager. The present invention also provides an expression framework of said bispecific T-cell engager BiTE. The present invention also provides a recombinant oncolytic virus, and said oncolytic virus is operably inserted with or contains the expression framework of said bispecific T-cell engager BiTE. In the present invention, the bispecific T-cell engager is combined with the oncolytic virus, and in comparison with pure gene therapy or virotherapy, the oncolytic virus significantly enhances the inhibition capability on malignant tumors.