Chimeric IgG-IgA Fc Domains for Dual Receptor Binding
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Solution Overview
Problem
Current antibody therapeutics, primarily of the IgG subclass, have limitations in recruiting immune cells via Fc receptors, particularly failing to engage Fcα receptors, which are crucial for activating neutrophils and other granulocytes, leading to suboptimal efficacy in cancer treatment.
Innovation Solution
Development of chimeric polypeptides that bind to both Fcα and Fcγ receptors, combining sequences from IgG and IgA Fc domains to enhance affinity and specificity, thereby improving the recruitment of immune cells for targeted therapies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If IgG subclass antibodies are used as antibody therapeutics, then they can engage Fcγ class of receptors to activate immune cells for cancer treatment, but they cannot bind to Fcα receptors with optimal affinity, leading to reduced efficacy in recruiting neutrophils and granulocytes
Solution Approach 1:
The patent merges the Fc domain of IgG antibody with the Fc domain of IgA antibody to create a chimeric Fc region that combines the binding capabilities of both parent antibodies. Specifically, the chimeric Fc region includes the CH2 and CH3 domains of IgG combined with the CH2 and CH3 domains of IgA, enabling simultaneous binding to both Fcγ receptors and Fcα receptors while maintaining the structural integrity and functional properties of the parent antibody classes.
Solution Approach 2:
The chimeric Fc region is designed to perform multiple functions by binding to multiple types of Fc receptors (both Fcγ and Fcα) simultaneously. This multi-functional Fc region enables the antibody to recruit diverse immune cell types including neutrophils, granulocytes, and other Fc receptor-bearing cells, thereby enhancing the versatility and therapeutic efficacy compared to traditional single-specificity IgG or IgA antibodies.
2Adaptability or versatility
If IgA antibodies are used to bind Fcα receptors, then neutrophil recruitment is enhanced, but they cannot engage Fcγ class of receptors effectively for cancer treatment
Solution Approach 1:
The patent combines the Fc domain of IgG antibody with the Fc domain of IgA antibody to create a chimeric Fc region that combines the binding capabilities of both parent antibodies. Specifically, the chimeric Fc region includes the CH2 and CH3 domains of IgG combined with the CH2 and CH3 domains of IgA, enabling simultaneous binding to both Fcγ receptors and Fcα receivers while maintaining the structural integrity and functional properties of the parent antibody classes.
3Reliability
If traditional IgG or IgA antibodies are used, then they have well-characterized binding to their respective Fc receptors, but they cannot simultaneously engage multiple Fc receptor classes to broaden effector functions
Solution Approach 1:
The patent merges the Fc domain of IgG antibody with the Fc domain of IgA antibody to create a chimeric Fc region that combines the binding capabilities of both parent antibodies. Specifically, the chimeric Fc region includes the CH2 and CH3 domains of IgG combined with the CH2 and CH3 domains of IgA, enabling simultaneous binding to both Fcγ receivers and Fcα receivers while maintaining the structural integrity and functional properties of the parent antibody classes.
Solution Approach 2:
The chimeric Fc region is designed to perform multiple functions by binding to multiple types of Fc receivers (both Fcγ and Fcα) simultaneously. This multi-functional Fc region enables the antibody to recruit diverse immune cell types including neutrophils, granulocytes, and other Fc receiver-bearing cells, thereby enhancing the versatility and therapeutic efficacy compared to traditional single-specificity IgG or IgA antibodies.
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 chimeric polypeptides demonstrate increased affinity for FcαRI and FcγRI, while maintaining binding to FcγRIIa, thus enhancing the efficacy of antibody-based therapeutics by activating neutrophils and other immune cells, potentially leading to improved cancer treatment outcomes.
Implementation Method 1
the Fc region of an antibody is crucial for recruitment of immunological cells and antibody dependent cytotoxicity (ADCC). In particular, the nature of the ADCC response elicited by antibodies depends on the interaction of the Fc region with receptors (FcRs) located on the surface of many cell types.
Data Source
AI summary
Antibody Fc polypeptides are provided that efficiently bind to both Fcγ and Fcα receptors. In certain aspects, a Fc polypeptide comprises a chimeric IgG CH2 domain having a α1 loop from IgA and an IgA CH3 domain. Recombinant antibodies comprising Fc polypeptides of the embodiments and methods for making and using such antibodies are likewise provided.