Anti-CD47 Antibodies with Cell-Free Expression for Phagocytosis
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Solution Overview
Problem
Current therapies targeting CD47 lack effectiveness in blocking its interaction with SIRPα, leading to inadequate promotion of phagocytosis and potential adverse effects such as agglutination and Fc effector function, while existing antibody production methods result in low yields and glycosylation, limiting therapeutic potential.
Innovation Solution
Development of monoclonal anti-CD47 antibodies with specific amino acid modifications that block CD47 binding to SIRPα, reduce Fc effector function, and are produced using a cell-free expression system, resulting in higher titers and reduced glycosylation, thereby promoting phagocytosis without adverse effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If conventional antibody production methods are used, then antibodies can be produced, but the yield is low and glycosylation occurs
Solution Approach 1:
The patent replaces conventional cell-based antibody production systems with a cell-free expression system. This substitution eliminates the cellular machinery that performs glycosylation, thereby preventing unwanted glycosylation modifications while maintaining high antibody yield. The cell-free system uses purified cellular extracts to synthesize proteins without the complexity and limitations of living cells.
2Reliability
If anti-CD47 antibodies are designed to block CD47-SIRPα interaction, then phagocytosis is promoted, but Fc effector function and agglutination may occur
Solution Approach 1:
The patent applies local quality modification by introducing specific amino acid substitutions at targeted positions within the antibody structure. These localized changes in the Fc region (such as L234A and L235A substitutions) selectively modulate Fc effector functions while preserving the antigen-binding capability. This allows the antibody to promote phagocytosis through CD47 blocking without triggering unwanted Fc-mediated effects or agglutination.
3Ease of manufacture
If parental antibody sequences are used in cell-free expression, then production is feasible, but expression titer is low
Solution Approach 1:
The patent applies parameter changes by optimizing the amino acid sequence of the antibody for cell-free expression. This involves introducing specific mutations that enhance protein stability, solubility, and translation efficiency in the cell-free system. These sequence modifications increase the expression titer by improving the compatibility of the antibody protein with the cell-free production environment, while maintaining the original antigen-binding function.
Data Source
AI summary
Provided herein are compositions, methods and uses involving antibodies that specifically bind to human CD47. Also provided are uses and methods, such as therapeutic methods, diagnostic methods, and methods of making such antibodies.