Anti-SIRPalpha Antibody Fc Region Engineering
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Solution Overview
Problem
Current anti-CD47 agents used to treat cancer and infections can cause dose-dependent anemia due to binding with red blood cells, limiting their therapeutic efficacy, and existing anti-SIRPα antibodies may have reduced activity when binding to Fc receptors on effector cells, leading to inter-individual variability in patient response.
Innovation Solution
Development of anti-SIRPα antibodies with modified Fc regions that have reduced binding to Fc receptors, allowing for increased phagocytosis of target cells by blocking the CD47-SIRPα pathway, which can synergize with other cell-targeting agents, and are designed to minimize non-responder populations by engineering the Fc region to reduce engagement with Fcγ receptors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If anti-CD47 agents are used to block CD47-SIRPα interaction to enhance phagocytosis of cancer cells, then therapeutic efficacy is improved, but dose-dependent anemia occurs due to binding with red blood cells
Solution Approach 1:
The patent applies local quality by modifying the Fc region of the antibody to have different binding properties - specifically, reduced binding to Fcγ receptors on phagocytes while maintaining or enhanced binding to CD47 on target cells. This localized modification in the Fc region creates differential interaction patterns that enhance therapeutic efficacy on cancer cells while reducing off-target effects on red blood cells, thereby resolving the contradiction between efficacy and anemia induction
2Productivity
If anti-SIRPα antibodies bind to Fc receptors on effector cells to mediate phagocytosis, then phagocytic activity is enhanced, but inter-individual variability in patient response increases
Solution Approach 1:
The patent applies parameter changes by systematically modifying the Fc region properties of the antibody - specifically altering amino acid sequences in the Fc domain to reduce binding affinity for Fcγ receptors. This parameter modification creates a more consistent interaction profile across different patients by reducing dependence on variable Fc receptor expression levels, thereby enhancing phagocytic activity while improving response consistency across inter-individual populations
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 modified anti-SIRPα antibodies enhance phagocytosis of target cells, including cancer cells, while minimizing anemia risks and improving therapeutic profiles by reducing Fc receptor binding, thus providing a more consistent and effective treatment response across individuals.
Implementation Method 1
Blocking the CD47-SIRPα pathway mediates phagocytosis of targeted cells
Implementation Method 2
activity of an anti-SIRPα antibody on effector cells may be substantially reduced when the antibody productively binds to an Fc receptor on the effector cell surface
Data Source
AI summary
Anti-SIRPα antibodies, including multi-specific anti-SIRPα antibodies, are provided, as are related compositions and methods. The antibodies of the disclosure bind to SIRPα and can block the interaction of CD47 on one cell with SIRPα on a phagocytic cell. The subject anti-SIRPα antibodies find use in various therapeutic methods. Embodiments of the disclosure include isolated antibodies and derivatives and fragments thereof, pharmaceutical formulations comprising one or more of the anti-SIRPα antibodies; and cell lines that produce the antibodies. Also provided are amino acid sequences of exemplary anti-SIRPα antibodies.