Mutated CD47 Antibody Oncolytic Virus for Tumor Targeting
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Solution Overview
Problem
Current CD47-targeting antibodies for cancer therapy face challenges such as anemia, hyperbilirubinemia, thrombocytopenia, and insufficient affinity due to binding with red blood cells, and existing oncolytic viruses have limitations in targeting and efficacy, particularly for non-superficial tumors and metastases.
Innovation Solution
A recombinant oncolytic virus expressing a mutated CD47 antibody with high affinity and stability, specifically designed to target tumor cells while avoiding red blood cells, combined with a vaccinia virus Tian Tan strain to enhance anti-tumor effects and immune response.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a CD47-blocking antibody is used to target tumor cells, then anti-tumor effect is improved, but side effects such as anemia occur due to binding with red blood cells
Solution Approach 1:
The patent applies local quality by modifying specific amino acid residues in the Fc region of the antibody (e.g., L328, E330, L332, E334) to alter its binding properties. This localized modification enables the antibody to maintain high affinity for CD47 on tumor cells while reducing or eliminating binding to CD47 on red blood cells, thereby achieving tumor-specific targeting without causing anemia.
Solution Approach 2:
The patent employs parameter changes by systematically varying the amino acid sequence of the Fc region through multiple mutations. These parameter changes in the antibody structure fundamentally alter its interaction characteristics with different CD47 isoforms or conformations on various cell types, enabling selective binding to tumor cells while sparing red blood cells.
2Reliability
If a CD47 antibody with high affinity is developed, then anti-tumor efficacy is improved, but immunogenicity increases
Solution Approach 1:
The patent applies parameter changes by optimizing the amino acid sequence of the Fc region to achieve high affinity for tumor cell CD47 while maintaining low immunogenicity. Specific mutations in the Fc region fine-tune the antibody's binding characteristics and immune recognition properties, enabling high efficacy with reduced immunogenic response.
3Reliability
If an oncolytic virus is used to treat non-superficial tumors, then targeting capability is improved, but delivery efficiency decreases
Solution Approach 1:
The patent merges the oncolytic virus delivery system with the modified anti-CD47 antibody therapy. The virus serves as a delivery vehicle that can reach non-superficial tumors, while the antibody provides the specific anti-tumor mechanism. This combination leverages the strengths of both approaches: viral delivery efficiency and antibody targeting capability.
Solution Approach 2:
The oncolytic virus acts as an intermediary that facilitates the delivery of therapeutic agents to deep-seated tumors. The virus infects and replicates within tumor cells, enabling local accumulation of therapeutic effect while the modified antibody provides systemic anti-CD47 activity, together overcoming the limitations of delivering therapy to non-superficial tumors.
Data Source
AI summary
Provided is an antibody capable of specifically binding to CD47or an antigen binding fragment thereof. Also provided is a recombinant oncolytic virus, which is operably inserted with or comprises a gene coding sequence of an anti-CD47antibody or a CD47ligand, wherein the anti-CD47antibody comprises an Fc mutant having A330L/I332E mutations (ALIE antibody), i.e., the anti-CD47antibody is αCD47-Fc(ALIE). Also provided are a preparation method for the recombinant oncolytic virus, a use of the recombinant oncolytic virus in preparation of anti-tumor drugs, and a vaccinia virus Tiantan strain capable of efficiently expressing an αCD47-Fc(ALIE) gene.