PSMA Binding Proteins With Small-Format Tumor Targeting
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Solution Overview
Problem
Current PSMA-specific monoclonal antibodies for cancer diagnosis and treatment face challenges such as complex molecular structures, poor tissue penetration, short serum half-lives, and toxic side effects, limiting their effectiveness in diagnosing and treating PSMA-related cancers.
Innovation Solution
Development of novel PSMA binding proteins based on ubiquitin muteins, such as Affilin® molecules, with specific amino acid motifs and modifications, offering high affinity and ease of production, suitable for diagnostic and therapeutic applications.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If monoclonal antibodies are used for PSMA targeting, then diagnostic and therapeutic efficacy is improved, but molecular structure complexity and production difficulty increase
Solution Approach 1:
The patent segments the large monoclonal antibody structure into smaller binding proteins (e.g., nanobodies, single-domain antibodies) that retain PSMA targeting capability. This segmentation simplifies the molecular structure while maintaining diagnostic and therapeutic efficacy, and enables easier production through bacterial expression systems.
Solution Approach 2:
The patent extracts the essential PSMA-binding functional domain from the complex monoclonal antibody structure, isolating the minimal required elements (complementarity-determining regions, CDRs) to create simplified binding proteins. This extraction removes unnecessary structural complexity while preserving the core therapeutic and diagnostic functions.
2Reliability
If monoclonal antibodies are used for PSMA targeting, then PSMA binding affinity is improved, but tissue penetration capability deteriorates
Solution Approach 1:
The patent divides the large monoclonal antibody into smaller fragment structures (e.g., Fab fragments, Fv fragments, or complete single-domain antibodies) that can penetrate tumor tissue more effectively. These segmented structures maintain high PSMA binding affinity through optimized CDR regions while reducing overall molecular size for improved tissue penetration.
Solution Approach 2:
The patent changes the molecular size parameter by creating truncated or simplified antibody structures with reduced hydrodynamic radius. This parameter change enables better diffusion through the extracellular matrix and tumor vasculature while maintaining or enhancing PSMA binding affinity through rational design of the binding interface.
3Measurement precision
If monoclonal antibodies are used for PSMA imaging, then diagnostic capability is improved, but background signal increases due to long circulation time
Solution Approach 1:
The patent uses segmented, smaller binding protein structures that clear from the bloodstream more rapidly than full-sized monoclonal antibodies. This segmentation enables faster renal clearance, reducing background signal and improving tumor-to-background contrast ratio for diagnostic imaging applications.
Solution Approach 2:
The patent changes the circulation time parameter by designing binding proteins with optimized pharmacokinetic properties. The smaller molecular size and altered surface characteristics enable faster elimination from plasma, reducing the duration of background signal while maintaining sufficient time for tumor accumulation and imaging.
Data Source
AI summary
Binding proteins that are specific for prostate specific membrane antigen (PSMA), multimers thereof, and conjugates thereof are described. Also described are PSMA binding proteins that include a diagnostically or therapeutically active component and/or a pharmacokinetics-modulating moiety, as well as methods for using the described PSMA binding proteins in medicine, for example, in diagnosis and therapy of cancer associated with PSMA expression.