Modified IgG4 Hinge Reduces Hemagglutination
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Solution Overview
Problem
Current therapeutic monoclonal antibodies (mAbs) targeting cancer cells often require combination therapy and may lead to incomplete responses due to cancer cell resistance, and CD47-blocking antibodies can cause undesirable hemagglutination and anemia by targeting cancer cells and red blood cells alike.
Innovation Solution
Development of immunoglobulin constant region polypeptides with a modified IgG4 hinge region that reduces hemagglutination by specifically binding to CD47 on red blood cells, using a truncated hinge sequence and a binding moiety that targets CD47, thereby minimizing agglutination while maintaining therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If anti-CD47 antibody is administered to block CD47 on cancer cells, then therapeutic efficacy is improved, but hemagglutination and anemia occur due to targeting of red blood cells
Solution Approach 1:
The patent applies local quality by modifying only the hinge region of the antibody while maintaining the rest of the antibody structure unchanged. The modified hinge region (with deletions of 1-5 amino acids) specifically reduces hemagglutination activity, while the variable regions and constant domains retain their cancer cell targeting and therapeutic functions. This localized modification allows the antibody to differentiate between cancer cells and red blood cells.
Solution Approach 2:
The patent employs parameter changes by altering the amino acid sequence of the hinge region (deleting 1-5 amino acids from positions 226-230). This structural parameter change in the hinge region modifies the antibody's interaction with CD47 on red blood cells, reducing hemagglutination while preserving therapeutic efficacy against cancer cells.
2Reliability
If conventional chemotherapy is combined with mAbs, then treatment coverage is improved, but patient quality of life deteriorates due to side effects
Solution Approach 1:
The patent applies parameter changes by modifying the hinge region structure (amino acid deletions) to reduce hemagglutination side effects. This structural modification allows the antibody to maintain its cancer cell targeting capability while reducing harmful interactions with red blood cells, potentially enabling better combination therapy with reduced side effects.
3Stability of the object's composition
If IgG4 antibody is used to reduce half molecule exchange, then stability is improved, but hemagglutination activity increases
Solution Approach 1:
The patent applies local quality by making a specific modification to the hinge region of IgG4 antibodies. The deletion of 1-5 amino acids in the hinge region specifically addresses hemagglutination activity while preserving the IgG4 characteristic of reduced half molecule exchange and improved stability.
Solution Approach 2:
The patent employs parameter changes by altering the hinge region amino acid sequence (deleting residues at positions 226-230). This structural parameter change reduces hemagglutination activity while maintaining the IgG4 antibody's stability properties and reduced half molecule exchange.
Data Source
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AI summary
Polypeptide compositions comprising a human immunoglobulin constant region with a modified IgG4 hinge region having an N-terminal deletion of 1, 2, 3, 4, 5 amino acids, relative to a native human IgG4 hinge sequence are provided. In some embodiments the hinge sequence further comprises the amino acid substitution S228P (Eu numbering). Polypeptides comprising the modified sequence optionally comprise a binding moiety specific for an epitope that is present on red blood cells; and can provide for reduced agglutination of hematopoietic cells compared to a comparable polypeptide with a native hinge region.