LILRB2 Binding Domains for Multispecific Antibody Assembly
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Solution Overview
Problem
There is a limited availability of stable and effective antibody fragments, such as scFvs, that can be used as universal building blocks for constructing multispecific antibodies to block the biological function of LILRB2, which is expressed on immune cells and mediates immunotolerance in cancer cells, allowing them to evade immune response.
Innovation Solution
Development of novel LILRB2-binding domains (LILRB2-BDs) with high stability and potency to block LILRB2 interactions with HLA-A3 and HLA-G, capable of activating T-cells and re-polarizing M2 macrophages to M1 state, and incorporated into multispecific antibodies like PRO4672, PRO5052, and PRO5055.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If conventional anti-LILRB2 antibodies are used, then LILRB2 binding function is achieved, but the availability of stable antibody fragments as universal building blocks is limited
Solution Approach 1:
The patent divides the antibody molecule into separate binding domains (scFv, Fab, Fv fragments) that can function independently as universal building blocks. These segmented antibody fragments specifically bind to LILRB2 while maintaining stability, allowing them to be incorporated into various multispecific antibody formats (bispecific, trispecific, tetraspecific antibodies) as modular components.
2Reliability
If LILRB2 blocking function is achieved, then immune response activation is enhanced, but the production efficiency and incorporability into multispecific antibodies is reduced due to instability
Solution Approach 1:
The patent optimizes the structural parameters of antibody fragments by selecting specific variable heavy chain (VH) and variable light chain (VL) combinations with proven stability characteristics. The binding domains are engineered with optimized amino acid sequences that maintain high affinity for LILRB2 while improving thermal stability and solubility, enabling high-yield production and successful incorporation into multispecific antibody formats.
3Object-affected harmful factors
If antibody fragments are used to block LILRB2-HLA-G interaction, then tumor immune escape is prevented, but the fragments require high stability for efficient production and incorporation
Solution Approach 1:
The patent employs stable antibody fragments as intermediary molecules that specifically bind to LILRB2 on immune cells, blocking the interaction between LILRB2 and HLA-G expressed on tumor cells. These intermediary binding domains transfer the blocking function from full-length antibodies to modular fragments that can be integrated into various multispecific antibody architectures, thereby preventing tumor immune escape while maintaining production efficiency.
Data Source
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AI summary
The present invention relates to an antibody binding domain, which specifically binds to LILRB2 (LILRB2-BD), to monospecific antibodies comprising two of said LILRB2-BDs and to multispecific antibodies comprising one or two of said LILRB2-BDs and at least one further binding domain, which specifically binds to a target different from LILRB2. The present invention further relates to nucleic acid sequences encoding said antibody binding domain, antibody or multispecific antibody, to vector(s) comprising said nucleic acid sequences, to host cell(s) comprising said nucleic acid sequences or said vector(s), and to a method of producing said multispecific antibody. Additionally, the present invention relates to pharmaceutical compositions comprising said antibody or multispecific antibody and methods of use thereof.