Fc Antibody Variants for Longer Half-Life Without ADCC Loss
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Solution Overview
Problem
Existing therapeutic antibodies and proteins have not achieved a significant increase in in vivo half-life despite efforts to enhance binding affinity for FcRn through mutations in the Fc domain, necessitating the development of optimally mutated antibodies to reduce the frequency of injections.
Innovation Solution
Substituting a portion of the amino acid sequence of the Fc domain with a different sequence to optimize the binding affinity of therapeutic proteins or antibodies for FcRn, particularly under acidic conditions, while maintaining neutral pH dissociation characteristics.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If mutations are introduced into the Fc domain to enhance binding affinity for FcRn, then the in vivo half-life is extended, but the ADCC activity may be compromised
Solution Approach 1:
The patent applies local quality by making specific localized mutations at particular amino acid positions (M252, M428, and combinations thereof) in the Fc domain rather than global modifications. This allows enhancement of FcRn binding affinity at specific locations while preserving the overall structure and ADCC functionality of the antibody. The targeted approach enables selective improvement of half-life without compromising effector functions.
Solution Approach 2:
The patent utilizes parameter changes by systematically varying amino acid substitutions at specific positions (M252, M428, and combinations) to optimize the balance between FcRn binding affinity and ADCC activity. Different amino acid parameters (various substitutions at these positions) are tested to achieve the desired half-life extension while maintaining therapeutic efficacy through preserved ADCC function.
2Reliability
If frequent injections are administered to maintain therapeutic effect, then the treatment efficacy is maintained, but the patient burden and treatment cost increase
Solution Approach 1:
The patent applies dynamics by creating antibody variants with tunable half-life characteristics through specific Fc domain mutations. This allows the therapeutic antibody to dynamically adapt its persistence in the body, enabling extended dosing intervals (such as every 2-4 weeks or longer) while maintaining effective drug levels. The dynamic optimization of pharmacokinetic properties reduces injection frequency without compromising treatment efficacy.
3Duration of action of moving object
If existing Fc mutations are used to extend half-life, then some binding affinity improvement is achieved, but significant half-life extension (10-fold or more) is not realized
Solution Approach 1:
The patent applies composite materials by combining multiple amino acid mutations (M252, M428, and their combinations with other residues) to create synergistic effects on FcRn binding. This composite approach, where multiple local modifications work together, achieves dramatically enhanced half-life extension (10-fold or more) that exceeds the effect of single mutations, creating a composite mutant Fc domain with superior pharmacokinetic properties.
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 Fc variants exhibit significantly increased binding affinity for FcRn under acidic conditions and prolonged half-life, achieving up to 10 times the half-life of wild-type Fc domains, with maintained or improved ADCC activity.
Implementation Method 1
The Fc interface between Cγ2 and Cγ3 domains mediates interactions with the neonatal Fc receptor (FcRn) and its binding recycles endocytosed antibody from the endosome back to the bloodstream
Data Source
AI summary
The present invention relates to a polypeptide including an Fc variant produced by substituting a portion of the amino acid sequence of the Fc domain of a human antibody with a different amino acid sequence. The present invention also relates to an antibody including the polypeptide. The Fc variant can find application in a wide range of antibodies and Fc-fusion constructs. In one aspect, the antibody or Fc fusion construct of the present invention is a therapeutic, diagnostic or laboratory reagent, preferably a therapeutic reagent. The Fc variant is suitable for use in the treatment of cancer because its in vivo half-life can be maximized by optimization of the portion of the amino acid sequence. The antibody or Fc fusion construct of the present invention is used to kill target cells that bear a target antigen, for example cancer cells. Alternatively, the antibody or Fc fusion construct of the present invention is used to block, antagonize or agonize a target antigen. For example, the antibody or Fc fusion construct of the present invention may be used to antagonize a cytokine or a cytokine receptor.