Lipocalin 2-Derived PSMA Binding Protein for Tissue Penetration
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Solution Overview
Problem
Current PSMA-specific imaging agents, such as murine monoclonal antibodies, suffer from poor tissue penetration and long circulation times, leading to significant background radioactivity and poor imaging contrast, highlighting the need for alternative binding proteins with high target specificity and tunable plasma half-life.
Innovation Solution
Development of a PSMA-specific binding protein derived from lipocalin 2 (Lcn2) with a dissociation constant (KD) of 10 nM or lower, which exhibits good tissue penetration and specific binding to PSMA, overcoming the limitations of existing antibodies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If murine monoclonal antibodies are used as PSMA-specific imaging agents, then target specificity is achieved, but tissue penetration is poor and circulation time is long
Solution Approach 1:
The patent segments the antibody structure into a smaller binding protein derived from lipocalin 2 that retains PSMA-specific binding capability while eliminating the size-related limitations of full antibodies, enabling faster tissue penetration
Solution Approach 2:
The patent changes the molecular size parameter by using a lipocalin 2-derived binding protein instead of a full monoclonal antibody, which reduces the molecular weight from typical antibody sizes (150 kDa) to much smaller dimensions, thereby improving tissue penetration kinetics while maintaining nanomolar affinity for PSMA
2Reliability
If murine monoclonal antibodies are used as PSMA-specific imaging agents, then target binding is achieved, but circulation time is prolonged leading to background radioactivity
Solution Approach 1:
The patent modifies the molecular size and structural parameters by employing a lipocalin 2-derived binding protein instead of a full antibody, which reduces circulation time and enables more rapid clearance from non-target tissues, thereby decreasing background radioactivity while preserving specific target binding
Solution Approach 2:
The patent creates a binding protein with dynamic pharmacokinetic properties that allow for optimized circulation time - small enough for rapid clearance from blood pool but maintaining sufficient stability to achieve and maintain specific binding to PSMA-expressing tissues
3Speed
If smaller binding proteins are used to improve tissue penetration, then penetration speed increases, but binding affinity may decrease
Solution Approach 1:
The patent optimizes the binding affinity parameter by engineering the lipocalin 2-derived binding protein to achieve nanomolar and picomolar KD values for PSMA, demonstrating that small size does not necessarily compromise binding strength when the binding interface is properly designed
Solution Approach 2:
The patent enhances the local binding quality at the PSMA interaction interface of the lipocalin 2-derived protein, concentrating binding energy at the critical contact points to achieve high affinity despite the overall small molecular size, thereby simultaneously enabling fast penetration and strong target binding
Data Source
AI summary
The present invention relates to a prostate-specific membrane antigen (PSMA)-specific binding protein, wherein the PSMA-specific binding protein is a lipocalin 2 (Lcn2)-derived binding protein and binds to PSMA with a KD of 10 nM or lower. The present invention also relates to a nucleic acid molecule encoding the PSMA-specific binding protein of the invention, a vector comprising said nucleic acid molecule of the invention and a host cell transformed with the vector. Furthermore, the invention relates to a method of producing the PSMA-specific binding protein of the invention, the method comprising culturing the host cell of the invention under suitable conditions and isolating the PSMA-specific binding protein produced. The present invention further relates to a protein conjugate comprising the PSMA-specific binding protein of the invention, or the PSMA-specific binding protein produced by the method of the invention. In addition, the present invention relates to a pharmaceutical or diagnostic composition; to the PSMA-specific binding protein of the invention, the nucleic acid molecule of the invention, the vector of the invention, the host cell of the invention or the PSMA-specific binding protein produced by the method of the invention, for use in therapy and/or diagnosis, and in particular for use in the therapy and/or diagnosis of tumors, Crohn's disease and/or neurological diseases.