Multivalent Antibody Constructs With Orthogonal Chain Pairing
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Solution Overview
Problem
Existing multispecific antibody platforms face challenges in ensuring high fidelity pairing between heavy and light chain pairs, leading to issues such as poor stability, expression, folding, and inefficient manufacturing processes, limiting their applicability in therapeutic and research settings.
Innovation Solution
A novel multivalent antibody construct design with specific domain arrangements and orthogonal modifications, allowing for high fidelity pairing of polypeptide chains, enabling efficient expression and purification using conventional systems and a single-step CH1 affinity resin.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antibody engineering approaches are used to create multisspecific antibodies, then therapeutic control and target specificity are improved, but manufacturing complexity and purification difficulty increase
Solution Approach 1:
The antibody is divided into separate heavy and light chains that can be independently expressed and then assembled. This segmentation allows for simplified manufacturing of individual chains while achieving the complex multisspecific functionality through controlled assembly of the chains into the final antibody structure.
Solution Approach 2:
A domain exchange mechanism serves as an intermediary process between chain expression and final antibody formation. The domain exchange facilitates high-fidelity pairing between heavy and light chains, acting as a mediator that ensures correct assembly while simplifying the overall manufacturing process by enabling modular construction.
2Manufacturing precision
If domain exchange mechanisms are implemented for high fidelity pairing, then chain pairing accuracy is improved, but expression and folding efficiency deteriorate
Solution Approach 1:
The domain exchange mechanism is applied locally at specific interfaces between heavy and light chains rather than throughout the entire antibody structure. This localized approach maintains high pairing accuracy at the critical domain interfaces while minimizing disruption to the overall expression and folding processes of the antibody chains.
Solution Approach 2:
The patent modifies specific parameters of the domain interfaces through engineered mutations that enhance pairing fidelity. By changing local amino acid sequences at the domain interfaces, the patent achieves high-fidelity pairing without requiring global changes to the antibody structure that would compromise expression efficiency.
3Adaptability or versatility
If multiple antibody chains are assembled for multispecific functionality, then therapeutic versatility is improved, but stability and folding quality worsen
Solution Approach 1:
The patent creates a composite antibody structure by assembling multiple heavy and light chains with different specificities. The domain exchange mechanism acts as a bonding interface that ensures stable integration of these diverse chains into a single functional complex, maintaining structural stability while achieving therapeutic versatility through the combination of different antigen-specific chains.
4Ease of manufacture
If conventional purification methods are used for multisspecific antibodies, then manufacturing flexibility is maintained, but purification efficiency and time consumption increase
Solution Approach 1:
The patent extracts and utilizes the natural affinity of CH1 domains for specific resins to enable selective purification. By leveraging this inherent property, the patent simplifies the purification process into a single efficient step that separates the antibody chains from other cellular components, dramatically improving purification efficiency while maintaining manufacturing flexibility.
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 antibody constructs achieve high-level expression, stability, and efficient purification, making them suitable for high-throughput screening and therapeutic applications.
Implementation Method 1
purified in a single-step with CH1 affinity resins
Data Source
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AI summary
Multivalent antibody constructs, pharmaceutical compositions comprising the constructs, and methods of use thereof are presented.