Dual Constant Domain Fab Antibody Fragments for Extended Half-Life
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Solution Overview
Problem
Current antibody fragments, such as the Fab molecule targeting the hepatocyte growth factor receptor (HGFR/Met), have a short plasma half-life due to renal clearance, limiting their therapeutic use, and existing methods to enhance stability, like PEGylation or the 'One Armed' procedure, are cumbersome and reduce manufacturing yield.
Innovation Solution
Development of Dual Constant Domain Fabs (DCD-Fabs) with a light chain variable domain fused to two light chain constant domains and a heavy chain variable domain fused to two heavy chain CH1 constant domains, which are more stable in vivo and maintain high affinity for the HGFR/Met receptor, reducing renal clearance and extending half-life.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antibody fragments (Fab molecules) are used to target HGFR/Met, then they can effectively bind to the receptor and inhibit signaling, but they have a short plasma half-life due to renal clearance
Solution Approach 1:
The antibody is divided into separate heavy and light chain variable domains that can be expressed independently as single-chain variable fragments (scFv) or fused to constant domains to create stable antibody fragments with improved pharmacokinetic properties while maintaining target binding capability
Solution Approach 2:
The patent combines variable domains with constant domains in novel configurations (such as Fc-fusion proteins or engineered antibody fragments) to create composite molecular structures that retain high affinity binding while gaining extended half-life characteristics from the constant region components
2Stability of the object's composition
If PEGylation or 'One Armed' procedure is used to enhance antibody fragment stability, then in vivo stability is improved, but manufacturing complexity increases and yield decreases
Solution Approach 1:
The antibody fragment design incorporates self-stabilizing features through proper domain pairing and disulfide bond formation, allowing the molecule to maintain stability without requiring external modification processes like PEGylation, thereby simplifying manufacturing while preserving in vivo stability
Solution Approach 2:
The patent optimizes amino acid sequences, disulfide bond positions, and domain orientations to inherently enhance stability parameters of the antibody fragment, achieving improved in vivo stability through sequence engineering rather than post-translational modifications that complicate manufacturing
Data Source
AI summary
An isolated nucleic acid encoding a monovalent antibody fragment comprising a first polypeptide comprising a light chain variable domain and two constant domains and a second polypeptide comprising a heavy chain variable domain and two constant domains, wherein two chain constant domains are light chain constant domains and two constant domains are CH1 heavy chain constant domains.