Multispecific Dopamine Receptor D2 Binding Agents for Longer Circulation
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Solution Overview
Problem
Existing VHH-based therapeutics face challenges in achieving optimal therapeutic efficacy due to short half-life and potential immunogenicity, limiting their effectiveness in targeting tumor cells and immune cells.
Innovation Solution
Development of multispecific binding agents comprising antigen binding domains that target Dopamine Receptor D2 (DR2), Programmed Cell Death Protein 1 (PD-1), and Cluster of Differentiation 47 (CD47), which are derived from heavy chain antibodies, allowing for enhanced tissue penetration and prolonged half-life through specific polypeptide chain configurations and dimerization domains.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Speed
If VHH-based therapeutics are used to target tumor cells, then tissue penetration is enhanced, but half-life is shortened due to rapid renal clearance
Solution Approach 1:
The patent combines multiple VHH domains into bivalent or multivalent constructs, merging the advantages of small size (penetration) with increased molecular weight (reduced clearance). The bivalent format allows the therapeutic to maintain tissue penetration capabilities while achieving prolonged circulation half-life through reduced renal filtration.
Solution Approach 2:
The patent creates composite VHH structures by fusing multiple VHH domains with linker sequences, forming bivalent or multivalent constructs that combine the penetrative properties of small VHH molecules with the extended half-life characteristics of larger molecular assemblies.
2Duration of action of moving object
If conventional antibody formats are used to extend VHH half-life, then therapeutic efficacy is improved, but immunogenicity increases
Solution Approach 1:
The patent changes the molecular weight parameter of VHH constructs by creating bivalent or multivalent formats, which extends half-life without introducing foreign protein structures that would trigger immunogenic responses. This parameter change allows the therapeutic to achieve prolonged circulation while maintaining low immunogenicity.
Solution Approach 2:
The patent creates copies of the VHH domain and assembles them into bivalent or multivalent constructs, using repeated units of the same low-immunogenicity sequence rather than introducing entirely different protein structures, thereby extending half-life while minimizing immunogenic risk.
3Device complexity
If monovalent VHH constructs are used, then simplicity is maintained, but avidity is reduced compared to bivalent constructs
Solution Approach 1:
The patent merges multiple VHH binding domains into a single bivalent construct, combining the simplicity of VHH technology with enhanced avidity through multivalent binding. This approach maintains relative simplicity while achieving superior target binding strength compared to monovalent constructs.
4Duration of action of moving object
If PEGylation or carrier protein fusions are used to extend VHH half-life, then circulation time is improved, but immunogenicity or manufacturing complexity increases
Solution Approach 1:
The patent extracts and eliminates the need for PEGylation or carrier protein fusions by using endogenous VHH domain assemblies. Instead of adding external modifications or fusion partners, the patent achieves extended half-life through the intrinsic properties of bivalent or multivalent VHH constructs, thereby reducing manufacturing complexity and immunogenicity risks.
Data Source
AI summary
The present disclosure generally relates to binding agents that are capable of targeting tumor cells and immune cells. The binding agents of the present disclosure are multispecific and comprise antigen binding domains that are capable of binding to Dopamine Receptor D2 (DR2), to Programmed Cell Death Protein 1 (PD-1) and/or to Cluster of Differentiation 47 (CD47). The multispecific binding agents of the present disclosure may be used to treat subjects in need thereof.