Antibody Constant Region Hinge Editing to Minimize FcγR Effector Binding
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Solution Overview
Problem
Existing antibody therapies that rely on effector functions, such as cell killing or pathogen elimination, often cause undesired inflammation due to interactions with Fcγ receptors, while therapies that do not depend on these functions still suffer from unnecessary binding, affecting pharmacokinetics and immunogenicity.
Innovation Solution
Modifying the hinge region of immunoglobulin heavy chains at positions 233-236 with glycine residues or deletions to reduce binding to Fcγ receptors, particularly FcγRI, FcγRIIA, and FcγRIIIA, thereby minimizing effector functions like ADCC and ADCP.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If the heavy chain constant region is modified to reduce binding to Fcγ receptors, then inflammation is minimized and effector functions are reduced, but binding affinity to Fcγ receptors is reduced
Solution Approach 1:
The patent applies parameter changes by modifying specific amino acid residues in the hinge region (positions 233-236) of the heavy chain constant region. These sequence modifications alter the binding parameters of the Fc region to Fcγ receptors, reducing affinity and thereby minimizing inflammation while maintaining controlled binding properties.
Solution Approach 2:
The invention applies local quality by making targeted modifications specifically in the hinge region (positions 233-236) rather than throughout the entire heavy chain constant region. This localized approach allows reduction of FcγR binding and inflammation in specific areas while preserving other important functions of the antibody.
2Reliability
If the hinge region is modified with glycine residues or deletions, then binding to Fcγ receptors is reduced, but structural integrity may be affected
Solution Approach 1:
The patent uses parameter changes by introducing glycine residues or deletions at specific positions (233-236) in the hinge region. These modifications change the local structural parameters and flexibility of the hinge, reducing FcγR binding while maintaining overall structural integrity through controlled alterations.
Solution Approach 2:
The invention applies local quality by confining modifications to the specific hinge region positions 233-236. This localized modification strategy allows reduction of FcγR binding while preserving the structural integrity of the rest of the antibody molecule through targeted rather than global changes.
3Object-affected harmful factors
If effector functions are minimized, then inflammation is reduced, but pharmacokinetic properties may be affected
Solution Approach 1:
The patent applies parameter changes by modifying the hinge region sequence to alter FcγR binding parameters, which in turn modifies effector function parameters. These controlled parameter changes reduce inflammation while allowing optimization of pharmacokinetic properties through adjusted binding characteristics.
Solution Approach 2:
The invention applies local quality by making targeted modifications in the hinge region that selectively reduce effector functions and inflammation while preserving other important properties including pharmacokinetics through localized rather than global structural changes.
Data Source
AI summary
The invention provides antibody heavy chain constant regions with a hinge region modified to reduce binding to Fcγ receptors. The modification occurs within positions 233-236 by replacement of natural residues by glycine(s) and/or deletion(s). Such modifications can reduce binding of an antibody bearing such a constant region to Fcγ receptors to background levels. The constant regions can be incorporated into any format of antibody or Fc fusion protein. Such antibodies or fusion proteins can be used in methods of treatment, particularly those in which the mechanisms of action of the antibody or Fc fusion protein is not primarily or at all dependent on effector functions, as is the case when an antibody inhibits a receptor-ligand interaction or agonizes a receptor.