Dual-Specificity Polypeptide Structure for Stable TCR-Antibody Targeting
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Solution Overview
Problem
Existing bispecific molecules face challenges such as poor production yields, difficult purification processes, aggregation propensity, short serum half-life, and unspecific immobilization due to Fc-gamma receptor interactions, limiting their effectiveness in cancer therapy and other applications.
Innovation Solution
A dual specificity polypeptide molecule is designed with a first and second polypeptide chain, each comprising a binding region from a T cell receptor (TCR) and an antibody, stabilized by covalent and non-covalent bonds, capable of simultaneously binding to a cell surface antigen and an MHC-associated peptide epitope, and fused with human IgG hinge and Fc domains for enhanced stability and half-life.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If existing bispecific molecules are used for cancer therapy, then immune effector cells can be redirected to tumor sites, but production yields are poor and purification processes are difficult
Solution Approach 1:
The invention extracts and removes the Fc region from the bispecific antibody molecule, creating an Fc-free format. This extraction eliminates the problematic Fc-gamma receptor interactions that cause unspecific immobilization while simplifying the purification process and improving production yields by focusing on the essential antigen-binding and effector cell recruitment functions.
Solution Approach 2:
The Fc-free bisspecific molecule design adopts a simplified structure that is easier and more cost-effective to produce. By eliminating the Fc region, the molecule requires less complex purification steps and can be manufactured with higher yields, making it a more practical therapeutic option despite the reduced molecular complexity.
2Reliability
If existing bisspecific molecules are used, then dual binding specificity is achieved, but aggregation propensity increases and serum half-life is short
Solution Approach 1:
The invention changes the molecular parameters by removing the Fc region and adjusting the overall structure of the bispecific molecule. This parameter change reduces aggregation propensity by eliminating the Fc region that is prone to aggregation, while the retained variable domains maintain dual binding specificity. The simplified structure also improves pharmacokinetic properties and extends serum half-life.
3Stability of the object's composition
If Fc region is included in bispecific molecules, then stability is enhanced, but unspecific immobilization occurs due to Fc-gamma receptor interactions
Solution Approach 1:
The invention extracts and removes the Fc region from the bisspecific antibody, eliminating the source of unspecific immobilization through Fc-gamma receptor interactions. The extracted Fc-free format maintains sufficient stability through the retained variable domains and engineered structures, while avoiding the harmful interactions caused by the Fc region.
4Adaptability or versatility
If complex bispecific antibody formats are used, then multiple functions are achieved, but device complexity increases
Solution Approach 1:
The invention extracts only the essential functional components (variable domains with antigen-binding and effector cell recruitment specificities) while removing the non-essential Fc region. This creates a simplified Fc-free format that maintains multiple functions including dual binding specificity and immune effector cell recruitment, while reducing molecular complexity and facilitating easier production and purification.
Data Source
AI summary
The present invention relates to a bispecific polypeptide molecule comprising a first polypeptide chain and a second polypeptide chain providing a binding region derived from a T cell receptor (TCR) being specific for a major histocompatibility complex (MHC)-associated peptide epitope, and a binding region derived from an antibody capable of recruiting human immune effector cells by specifically binding to a surface antigen of said cells, as well as methods of making the bispecific polypeptide molecule, and uses thereof.