NK Cell Monobody Binding for Higher Affinity and Specificity
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Solution Overview
Problem
Existing NK cell therapies face challenges in enhancing the affinity between the NK binding domain and target molecules on NK cell surfaces, leading to potential off-tumor effects due to non-specific binding.
Innovation Solution
Development of a monobody with specific amino acid sequences that stably bind to surface proteins on NK cells, such as NKp46, NKp30, and 2B4, by modifying the BC, CD, or FG loops of the human fibronectin type III domain.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If an scFv is used for the NK binding domain of the crosslinking structure, then the structure can be formed, but the affinity between the NK binding domain and the target molecule of NK cell surfaces is insufficient
Solution Approach 1:
The patent changes the molecular parameters of the binding domain by replacing scFv with a monobody having a human fibronectin type III domain scaffold. This parameter change results in improved binding affinity to NK cell surface molecules while maintaining structural feasibility through the well-characterized fibronectin type III domain framework
Solution Approach 2:
The patent creates a composite binding domain structure combining the fibronectin type III domain scaffold with specific loop region sequences (BC loop, CD loop, or FG loop) that are optimized for NK cell binding. This composite approach integrates the structural stability of the scaffold with the binding specificity of the loop regions
2Productivity
If an antibody drug binds to the antigen on tumor cells, then cancer treatment effect is achieved, but normal cells with target antigen experience off-tumor effects
Solution Approach 1:
The patent introduces a monobody as an intermediary component that selectively binds to NK cell surface molecules (such as NKp46, NKp30, or 2B4). This intermediary creates a crosslinking structure that connects the NK cell to the antibody drug, enabling the NK cell to mediate ADCC activity against tumor cells while preventing direct binding to normal cell antigens
Solution Approach 2:
The patent applies local quality by directing the binding activity to specific locations on the NK cell surface through the monobody's selective interaction with NK cell surface molecules. This localized binding ensures that the antibody drug is delivered specifically to NK cells that will then target tumor cells, rather than binding to antigens on normal cells
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The monobody provides stable binding to NK cells, enhancing the specificity and efficacy of NK cell therapies by reducing off-tumor effects and improving targeted cancer cell destruction.
Implementation Method 1
a monobody having a specific amino acid sequence stably binds to a surface protein expressed on NK cells
Data Source
AI summary
The present invention provides a novel substance that stably binds to a surface protein expressed on NK cells. The present invention provides a monobody that binds to a surface protein of an NK cell, wherein the monobody has an amino acid sequence of any one of (1) to (3): (1) an amino acid sequence represented by any one of SEQ ID NOs: A1 to A12; (2) an amino acid sequence given by deletion, substitution, and/or addition of one or more amino acids in an amino acid sequence represented by any one of SEQ ID NOs: A1 to A12 excluding arbitrary amino acids; and (3) an amino acid sequence having an identity of 80% or more with an amino acid sequence represented by any one of SEQ ID NOs: A1 to A12 excluding arbitrary amino acid sequences, wherein X1, X2, X3, X4, X5, and X6 in SEQ ID NOs: A1 to A12 each independently represent an arbitrary amino acid, and n1, n2, n3, n4, n5, and n6 each independently represent an arbitrary natural number.X1n1 X2n2 X3n3 (SEQ ID NO: A1)PIWGRYGTTVRGQTYYWWMLX1n1X2n2 X3n3 (SEQ ID NO: A2)WTWLGYEYYWWDSKPGAIGIX1n1 X2n2 X3n3 (SEQ ID NO: A3)TYWDWGFRWSWARRTHISWFX4n4X5n5 X6n6 (SEQ ID NO: A4)PGYYMWQRGVINGQERAYGHPEHFX4n4X5n5 X6n6 (SEQ ID NO: A5)RYKYHRRINGTQWYVFNEAGDVAGYX1n1X2n2 X3n3 (SEQ ID NO: A6)GPIVSYSWWYHWVGYVNEKYDAWQSYVQX1n1X2n2 X3n3 (SEQ ID NO: A7)QAYWFEYTWWLEVVYDDQWTSGX4n4X5n5 X6n6 (SEQ ID NO: A8)TSPWYNGYDQYKSWNLEEFHX4n4X5n5 X6n6 (SEQ ID NO: A9)TPPWIHKGWVTPYGRKWVGMNGWX1n1X2n2 X3n3 (SEQ ID NO: A10)LWHYYGDQYWWMYVPEYYFNPWX1n1X2n2 X3n3 (SEQ ID NO: A11)TDRNYDITYGMQYWWDGYSYSEEAWYYX4n4X5n5 X6n6 (SEQ ID NO: A12)WSWESYWHGTYTFMKDIPSYY