Asymmetric Polypeptide Complexes for Monovalent Antigen Binding
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Conventional monoclonal antibodies, particularly IgGs, often activate target receptors due to their bivalent binding nature, which is undesirable in certain therapeutic applications, and their short half-life limits their effectiveness for chronic diseases, while stabilization through chemical modifications can compromise protein stability and manufacturability.
Innovation Solution
The development of a polypeptide complex comprising two antigen-binding domains linked via a disulfide bond, which restricts simultaneous binding and reduces receptor activation, and can include a thiol residue-containing peptide linker to enhance stability and prevent unwanted activation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional IgG antibodies are used for therapeutic application, then high binding affinity and specificity are achieved, but unwanted target receptor activation occurs due to bivalent binding
Solution Approach 1:
The antibody is divided into separate functional domains: a dimeric Fc portion for binding and a monovalent antigen-binding domain (such as scFv or Fab) for antigen recognition. This segmentation allows the antibody to maintain high affinity through the dimeric Fc while preventing receptor cross-linking activation by ensuring only one antigen-binding site is present per antibody molecule.
Solution Approach 2:
The antibody structure is made asymmetric by combining a dimeric Fc portion with a monovalent antigen-binding domain. This asymmetric configuration ensures that while the Fc portion can dimerize for stable binding, the antigen-binding portion remains monovalent, preventing the symmetric cross-linking that leads to unwanted receptor activation.
2Object-generated harmful factors
If antibody fragments such as scFv or Fab are used to achieve monovalent binding, then target receptor activation is reduced, but serum half-life is shortened due to small size
Solution Approach 1:
The invention merges the advantages of small monovalent antibody fragments (reduced receptor activation) with the advantages of large dimeric Fc structures (extended serum half-life). The dimeric Fc portion provides extended circulation time while the monovalent antigen-binding domain prevents unwanted activation, creating a hybrid molecule that combines both beneficial properties.
3Duration of action of moving object
If chemical modifications are applied to extend half-life of antibody fragments, then serum half-life is improved, but protein stability and manufacturability are compromised
Solution Approach 1:
The dimeric Fc portion serves its own function of extending serum half-life through natural dimerization, eliminating the need for external chemical modifications such as PEGylation or albumin fusion. This self-service approach maintains protein stability and manufacturability while achieving the desired pharmacokinetic properties through the inherent dimeric structure.
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 polypeptide complex achieves monovalent-like binding, reducing receptor activation and improving stability and manufacturability, with potential for extended serum half-life through strategic linker placement and domain configuration.
Implementation Method 1
The development of a polypeptide complex comprising two antigen-binding domains linked via a disulfide bond
Data Source
AI summary
Provided herein in certain embodiments are polypeptide complexes capable of binding to an antigen. Pharmaceutical compositions, method of using the polypeptide complexes are also provided.