Anti-CD47 Antibody Variable Region Design for Tumor Targeting
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Solution Overview
Problem
Current anti-CD47 antibodies used in tumor therapy often cause significant hemagglutination and anemia due to their interaction with red blood cells and platelets, limiting their therapeutic efficacy and safety.
Innovation Solution
Development of anti-CD47 antibodies or antigen-binding fragments with specific heavy and light chain variable regions, such as those defined by SEQ ID NOs, which have reduced hemagglutination activity while maintaining strong antitumor effects by selectively targeting CD47 on tumor cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If anti-CD47 antibody blocks the interaction between CD47 and SIRPα to eliminate immune suppression, then tumor cells can be effectively killed, but red blood cells and platelets lose protection and are subjected to phagocytosis causing hemagglutination and anemia
Solution Approach 1:
The patent applies local quality by designing an antibody with differentiated binding characteristics: the antibody binds to CD47 on tumor cells with high affinity to block SIRPα interaction, while through specific amino acid sequence design (particularly in the variable regions), it reduces or eliminates binding to CD47 on normal red blood cells and platelets. This creates different functional outcomes at different cellular locations - tumor cell targeting versus normal cell sparing.
Solution Approach 2:
The patent employs parameter changes by modifying the antibody's molecular structure through specific amino acid sequence variations in the heavy and light chain variable regions. These sequence changes alter the antibody's binding parameters - increasing affinity for tumor CD47 while decreasing affinity for normal cell CD47, thereby changing the therapeutic index to reduce hemagglutination and anemia.
2Productivity
If anti-CD47 antibody is used to target tumor cells, then tumor growth is inhibited, but significant side effects occur on red blood cells and platelets
Solution Approach 1:
The patent achieves local quality differentiation through the antibody's selective binding properties. The variable region sequences are designed to recognize specific epitopes on tumor cell CD47 that are either absent or structurally different from normal cell CD47 epitopes. This enables the antibody to locally target tumor cells for destruction while leaving normal red blood cells and platelets unaffected, thus generating tumor growth inhibition without significant adverse effects.
Solution Approach 2:
The patent utilizes parameter changes in the antibody's binding affinity and specificity parameters. By optimizing the amino acid sequences in the variable regions, the antibody's Kd value and epitope recognition parameters are tuned to achieve high binding to tumor CD47 (enabling tumor growth inhibition) while maintaining low binding to normal cell CD47 (avoiding hemagglutination and platelet depletion).
Data Source
AI summary
The present disclosure relates to the technical field of antibody drugs, and in particular, to an anti-CD47 antibody or an antigen-binding fragment thereof, a pharmaceutical composition comprising the anti-CD47 antibody or the antigen-binding fragment thereof, and applications thereof. The anti-CD47 antibody or the antigen-binding fragment thereof has significant antitumor activity and high affinity with human CD47 protein, can eliminate the capability of SIRPa to bind to CD47 on a surface of a cell, and does not have significant hemoagglutination activity and thus can be applied to the preparation of an anti-tumor drug.