Anti-CD16 scFv Specificity for FcγRIIIA
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Solution Overview
Problem
Current anti-CD16 antibodies are unable to distinguish between the FcγRIIIA and FcγRIIIB isoforms, limiting their effectiveness in recruiting NK cells for therapeutic applications, as they bind to both forms, whereas a specific antibody targeting FcγRIIIA is needed to efficiently mediate NK-cell killing without being diverted by circulating FcγRIIIB or binding to neutrophils.
Innovation Solution
Development of anti-CD16 single-chain variable fragments (scFvs) that specifically bind to FcγRIIIA, excluding FcγRIIIB, and activate NK cells upon binding, recognizing both FcγRIIIA158V and FcγRIIIA158F alleles with equal affinity, enabling targeted recruitment and activation of NK cells for therapeutic purposes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If current anti-CD16 antibodies are used, then they can bind to CD16 on NK cells and macrophages, but they bind to both FcγRIIIA and FcγRIIIB isoforms, causing non-specific binding and reduced therapeutic efficacy
Solution Approach 1:
The patent applies local quality by designing scFvs with specific amino acid sequences in the variable regions that create differential binding characteristics. The scFv molecules have been engineered to recognize specific epitopes on FcγRIIIA that are distinct from those on FcγRIIIB, allowing selective binding to the desired target isoform while avoiding non-specific binding to other CD16 forms.
Solution Approach 2:
The patent utilizes parameter changes by modifying the binding characteristics of anti-CD16 antibodies through scFv engineering. The scFvs have been designed with specific affinity and selectivity parameters that enable discrimination between FcγRIIIA and FcγRIIIB isoforms, changing the binding profile from non-discriminatory to highly specific for therapeutic applications.
2Productivity
If anti-CD16 antibodies bind to circulating FcγRIIIB, then they can bind to CD16 on various cell types, but this diverts the antibody away from NK cell recruitment, reducing therapeutic effectiveness
Solution Approach 1:
The patent applies the extraction principle by selectively removing or excluding binding to FcγRIIIB from the antibody's target profile. The scFvs have been engineered to specifically recognize FcγRIIIA epitopes that are absent on FcγRIIIB, effectively extracting the unwanted binding interaction while preserving the desired NK cell recruitment function.
Solution Approach 2:
The scFv molecules serve as intermediaries that mediate specific binding to FcγRIIIA on NK cells without engaging FcγRIIIB. This intermediary role allows the antibody to selectively recruit NK cells for ADCC while avoiding diversion by circulating FcγRIIIB, improving therapeutic productivity.
3Reliability
If anti-CD16 antibodies bind to neutrophils, then they can bind to CD16 on multiple cell types, but this reduces their effectiveness in mediating NK-cell killing
Solution Approach 1:
The patent applies local quality by creating scFvs with highly specific binding characteristics that distinguish FcγRIIIA on NK cells from CD16 on neutrophils. The engineered variable regions recognize specific conformational epitopes on FcγRIIIA that are not present on neutrophil CD16, ensuring reliable NK cell targeting while eliminating harmful binding to neutrophils.
Data Source
AI summary
The present invention relates to binding molecules that specifically bind to the human Fc gamma receptor expressed on the surface of natural killer (NK) cells and macrophages (i.e. FcγRIIIA), and in particular binding molecules that specifically bind the A form FcγRIII but do not bind to the B form of FcγRIII, as well as to the use of such binding molecules in the diagnosis and treatment of disease. The invention further extends to polynucleotides encoding such binding molecules, host cells comprising such polynucleotides and methods of producing binding molecules of the invention using such host cells.