Peptide-Hinge-Free Flexible Antibody Molecules for Small-Target Binding
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Solution Overview
Problem
Existing antibodies lack the flexibility and extendibility needed to effectively bind to smaller targets such as proteins, as their hinge parts typically point Fab arms away from each other, making it difficult to grasp these targets with sufficient affinity.
Innovation Solution
A chemical synthesis method using native chemical ligation to create a flexible and extendible nonprotein hinge region in antibody-like molecules, allowing for two-handed binding by incorporating nonprotein chains between the Aβ and Fc moieties, resulting in a symmetroadhesin with improved target affinity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If a traditional peptide hinge part is used in antibody molecules, then the structure is stable and easy to manufacture, but the flexibility and extendibility are insufficient, making it difficult to bind to smaller targets with high affinity
Solution Approach 1:
The patent applies composite materials by combining peptide segments with non-peptide polymers (such as polyethylene glycol or polypropylene oxide) in the hinge region. This creates a hybrid structure that exhibits both the biocompatibility of peptides and the flexibility/extendibility of synthetic polymers, enabling the antibody to adapt to smaller targets while maintaining manufacturability through established conjugation chemistry
Solution Approach 2:
The patent changes the physical and chemical parameters of the hinge part by incorporating polymers with adjustable molecular weights, compositions, and architectures. This allows tuning of the hinge's flexibility and extendibility parameters to optimize binding affinity for specific target sizes, while the modular nature of polymer conjugation maintains ease of manufacture
2Reliability
If the hinge part is made rigid to maintain structural stability, then manufacturing is simplified, but the ability to grasp smaller targets with high affinity is compromised
Solution Approach 1:
The patent implements flexible shells by incorporating polymer chains in the hinge region that can dynamically adjust their conformation. These polymer segments act as flexible connectors that maintain structural stability at the macro level while providing the microm-level flexibility needed for the Fab arms to grasp smaller targets, thereby improving binding affinity without excessive structural complexity
Solution Approach 2:
The patent applies dynamics by creating a hinge part that transitions from a static, rigid structure to a dynamic, adaptable one. The polymer-containing hinge can change its conformational state in response to target size, providing rigidity when needed for stability and flexibility when needed for high-affinity binding, thus resolving the contradiction between reliability and complexity
Data Source
AI summary
The present invention provides an antibody that can bind to targets with greater affinity. A flexible antibody-like molecule having a nonpeptide hinge part comprising: a group having a nonpeptide hinge part represented by a general formula (I): XY-Asp-Lys-Thr-His-Thr (SEQ ID No. 1)—wherein X represents an amino acid or a peptide composed of 2 to 50 amino acid residues, and Y represents for a group having an alkyleneoxide; and an antibody Fc fragment bound to the group having a nonpeptide hinge part.