Anti-ILT4 Antibody Variable-Region Optimization for MDSC and TAM Inhibition
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Solution Overview
Problem
Current antibody drugs targeting ILT2 or ILT4, such as MK-4830 and NGM707, have limitations in effectively inhibiting MDSCs and TAMs in the tumor microenvironment, leading to suboptimal anti-tumor effects.
Innovation Solution
Development of an anti-ILT4 antibody with specific variable region sequences that enhance binding affinity and promote differentiation of macrophages to M1, improving antigen presentation and T cell killing of tumors, while also targeting MDSCs and TAMs to ameliorate immunosuppression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing antibody drugs targeting ILT2 or ILT4 (such as MK-4830 and NGM707) are used, then some anti-tumor effect is achieved, but the effectiveness in inhibiting MDSCs and TAMs in the tumor microenvironment is insufficient
Solution Approach 1:
The patent modifies the antibody structure by optimizing the variable region sequences (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3) to achieve higher binding affinity to ILT4. This parameter change in the antibody's molecular structure enables superior inhibition of MDSCs and TAMs compared to existing antibodies like MK-4830 and NGM707, directly resolving the contradiction between reliability and adaptability.
Solution Approach 2:
The patent focuses on optimizing specific local regions of the antibody molecule, particularly the complementarity determining regions (CDRs), to enhance binding affinity to ILT4. By improving the local quality of the antigen-binding sites while maintaining the overall antibody structure, the patent achieves both high reliability in anti-tumor effect and enhanced adaptability against different immune cell types in the tumor microenvironment.
2Object-generated harmful factors
If antibody drugs target ILT2 or ILT4, then immunosuppressive functions are inhibited, but the differentiation of macrophages to M1 phenotype and antigen presentation capability are not sufficiently enhanced
Solution Approach 1:
Instead of merely blocking the inhibitory receptor ILT4, the patent's optimized antibody actively promotes the differentiation of macrophages to the M1 phenotype, which has enhanced antigen presentation capabilities. This inverted approach transforms the antibody's function from simple inhibition to active promotion of anti-tumor immunity, simultaneously reducing harmful immunosuppression and enhancing protective immune responses.
Solution Approach 2:
The patent's anti-ILT4 antibody exhibits multi-functionality by simultaneously achieving: (1) inhibition of immunosuppressive functions of MDSCs and TAMs, (2) promotion of macrophage differentiation to M1 phenotype, and (3) enhancement of antigen presentation and T cell killing. This multi-functional capability resolves the contradiction by making the antibody effective across multiple immune mechanisms rather than relying on a single pathway.
Data Source
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AI summary
Disclosed in the present invention are an anti-ILT4 antibody as well as a preparation method therefor and the use thereof. The antibody comprises a heavy chain variable region and a light chain variable region, and is specifically described in the specification. The antibody of the present invention has the ability to bind to human ILT4, wherein part of the antibody has the activity of binding to both human ILT2 and human ILT4, and may also bind to crab-eating macaque ILT4. The affinity of the antibody of the present invention binding to the human ILT4 is superior to that of MK-4830 (Merck). The antibody of the present invention promotes the differentiation of macrophages to M1 so as to secrete TNF-α, and the differentiated M1 cells have a better antigen presentation function, thereby improving the killing effect of T cells on tumors. The antibody of the present invention acts on MDSCs and TAMs in tumor microenvironments, and improves the environment of immunosuppression in the tumor microenvironments. The anti-tumor effect of the antibody of the present invention in in-vivo pharmacodynamic experiments on mice is obviously superior to that of control antibody MK-4830 (Merck) and that of NGM707 (NGM).