Fc Region Variants for Longer Plasma Retention and Lower ADA Binding
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing therapeutic antibodies face challenges in plasma retention, immunogenicity, and antigen elimination, with limitations in binding to FcRn and FcγR, leading to high production costs and reduced efficacy.
Innovation Solution
Development of ion concentration-dependent antibodies with modified amino acid residues to increase isoelectric point (pI) and extracellular matrix binding, and Fc region variants with specific mutations to enhance plasma retention and reduce binding to pre-existing anti-drug antibodies, along with pH-dependent anti-IL-8 antibodies for rapid antigen elimination.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of stationary object
If amino acid residues in the constant region are substituted to improve antibody pharmacokinetics, then plasma retention is improved, but binding to pre-existing anti-drug antibodies may increase
Solution Approach 1:
The patent applies parameter changes by systematically varying amino acid substitutions at positions 252, 254, and 256 in the Fc region to optimize the balance between plasma retention and immunogenicity. Specific substitutions like M252Y/S254T/T256E (YTE) and M252Y/S254T (ST) were identified to enhance FcRn binding affinity while minimizing binding to pre-existing anti-drug antibodies, thus resolving the contradiction through precise parameter optimization.
2Reliability
If affinity maturation is used to enhance antigen-neutralizing ability, then antigen-binding activity increases, but production costs and dosage requirements may worsen
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid substitutions in the CDR regions to enhance antigen-binding affinity. Mutations such as H998/L63 and H998/L118 in the anti-IL-8 antibodies were designed to increase binding strength to the target antigen, thereby improving neutralizing ability while allowing for reduced dosage and production costs due to enhanced potency.
3Duration of action of stationary object
If FcRn binding is enhanced to improve plasma half-life, then antigen elimination is improved, but binding to effector receptors may increase causing unwanted immune activation
Solution Approach 1:
The patent applies local quality by making targeted amino acid substitutions specifically in the Fc region (positions 252, 254, 256) that selectively enhance FcRn binding affinity while maintaining or reducing binding to effector receptors like FcγR. This localized modification approach allows the antibody to achieve extended plasma half-life through improved FcRn interaction without triggering unwanted immune activation via effector receptors.
Data Source
AI summary
One nonexclusive aspect provides molecules further improved from antibodies that can bind to antigens in an ion concentration-dependent manner. An alternative nonexclusive aspect provides safe and more advantageous Fc region variants that have decreased binding to pre-existing ADA. An alternative nonexclusive aspect provides novel IL-8 antibodies that are superior as pharmaceuticals.