Transferrin-Binding sdAbs Extend Protein Serum Half-Life
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Solution Overview
Problem
Current methods for extending the serum half-life of short-lived proteins and peptides are inefficient, costly, and often result in undesired functions, highlighting the need for a more effective and cost-effective approach to enhance their therapeutic and diagnostic potential.
Innovation Solution
Development of novel single domain antibodies (sdAbs) specifically binding to transferrin, which are fused with target proteins to increase their serum half-life by leveraging the long half-life of transferrin, using specific amino acid sequences for the complementarity determining regions (CDRs) to enhance binding affinity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of stationary object
If conventional methods (pegylation, Fc fusion, albumin fusion) are used to extend serum half-life, then the serum half-life of short-lived proteins is prolonged, but the manufacturing complexity and cost increase significantly
Solution Approach 1:
The invention extracts and utilizes the naturally occurring long half-life property of transferrin by fusing target proteins to transferrin or transferrin-binding proteins. This approach leverages the endogenous transferrin system rather than introducing complex external modifications like pegylation or Fc fusion, thereby extending serum half-life while avoiding the manufacturing complexity associated with these conventional methods
Solution Approach 2:
The transferrin fusion platform serves multiple functions: it extends serum half-life of target proteins, utilizes the existing transferrin recycling pathway between serum and cells, and maintains compatibility with various target protein types. This multi-functionality reduces the need for separate optimization processes for different protein therapeutics, simplifying overall manufacturing compared to method-specific approaches like pegylation
2Duration of action of stationary object
If Fc fusion or albumin fusion is employed to prolong serum half-life, then circulation time increases, but expression levels decrease and undesired functions are introduced
Solution Approach 1:
The invention introduces transferrin or transferrin-binding proteins as an intermediary carrier that mediates the extension of serum half-life for target proteins. This intermediary utilizes the natural transferrin recycling pathway, allowing target proteins to benefit from prolonged circulation without the expression problems and undesired functions associated with direct Fc or albumin fusion
Solution Approach 2:
The invention changes the fusion partner from conventional options (Fc, albumin) to transferrin or transferrin-binding proteins, thereby altering the pharmacokinetic parameters of target proteins. This parameter change achieves prolonged circulation time while maintaining higher expression levels and avoiding the functional issues associated with Fc or albumin fusion
3Adaptability or versatility
If short-lived proteins are used for therapeutic applications, then they can be designed with specific functions, but their short serum half-life limits their therapeutic potential
Solution Approach 1:
The invention merges the specific therapeutic function of short-lived proteins with the long circulation time of transferrin through genetic fusion. This combination allows the target protein to maintain its designed therapeutic function while gaining extended serum half-life through the transferrin recycling pathway, thereby realizing both functional specificity and prolonged therapeutic action
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 use of sdAbs against transferrin significantly prolongs the serum half-life of target proteins, improving their stability and potential for therapeutic and diagnostic applications by increasing their circulation time and reducing clearance rates.
Implementation Method 1
novel single domain antibodies (sdAbs) specifically binding to transferrin, which are fused with target proteins to increase their serum half-life by leveraging the long half-life of transferrin, using specific amino acid sequences for the complementarity determining regions (CDRs) to enhance binding affinity
Data Source
AI summary
Novel antibodies, such as single domain antibodies (sdAbs), or fragments thereof that specifically bind a transferrin are described. Compositions, methods and systems for increasing the half-life of a target protein in a serum using an antibody or fragment thereof against a transferrin are described.