ISVD Polypeptides for Haemophilia A via Factor IXa and Xa Binding
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Solution Overview
Problem
Current treatments for haemophilia A, such as those involving coagulation Factor VIII replacement therapy, face challenges due to the development of neutralizing antibodies and inconvenient intravenous administration, with existing bispecific antibodies like emicizumab also experiencing efficacy issues due to non-specific binding leading to reduced half-life and cumbersome dosing regimens.
Innovation Solution
Development of procoagulant immunoglobulin single variable domain (ISVD) polypeptides, specifically VHH polypeptide derivatives, that can bind coagulation Factor IX(a) and Factor X(a), featuring a linker and protraction moieties to extend half-life, allowing for effective subcutaneous and peroral administration, thereby mimicking the cofactor activity of Factor VIIIa.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional replacement therapy with exogenous FVIII is administered intravenously, then coagulation function is restored, but patients develop neutralizing antibodies (inhibitors) rendering therapy ineffective
Solution Approach 1:
The patent creates a simplified copy of the FVIIIa cofactor function using an ISVD domain that mimics the essential binding interface. This single domain copy retains the procoagulant activity while avoiding the immunogenicity of the full FVIII protein, thus preventing inhibitor development while maintaining therapeutic efficacy
Solution Approach 2:
The invention extracts only the critical antigen-binding and cofactor function from the complete FVIII protein structure. By isolating the minimal functional element (ISVD domain), the therapy achieves the necessary coagulation support without the problematic regions that trigger antibody formation
2Reliability
If full-length bispecific antibodies like emicizumab are used to mimic FVIII cofactor function, then procoagulant activity is achieved, but non-specific binding reduces half-life and requires cumbersome dosing
Solution Approach 1:
The patent extracts only the essential antigen-binding domain from the full-length antibody structure. This ISVD domain retains the ability to bind FIXa and FXa while eliminating the Fc region that causes non-specific binding and rapid clearance, thereby extending half-life while maintaining procoagulant activity
Solution Approach 2:
The ISVD domain creates a simplified copy of the antibody's antigen-binding function without including the problematic Fc portion. This minimal copy achieves the same procoagulant effect with improved pharmacokinetic properties including extended half-life and reduced immunogenicity
3Reliability
If conventional intravenous administration is used for FVIII replacement, then therapeutic effect is achieved, but patient convenience is significantly reduced
Solution Approach 1:
The patent fundamentally changes the administration route from intravenous to subcutaneous by modifying the molecular structure to a smaller ISVD domain. This parameter change enables absorption through subcutaneous tissue while maintaining therapeutic efficacy, dramatically improving patient convenience and quality of life
Data Source
AI summary
The present invention provides ISVD polypeptide derivatives capable of binding coagulation Factor IX(a) and Factor X(a) which are highly potent and provide a sufficiently long half-life such to allow for effective subcutaneous—as well as peroral administration. The ISVD polypeptides derivatives disclosed herein are thus suitable for treatment of haemophilia A, haemophilia A with inhibitors and acquired haemophilia A by various routes of administration including subcutaneous and peroral administration.