HLA-G Binding Antibodies Blocking Immune Suppression
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Solution Overview
Problem
Current anti-HLA-G antibodies fail to completely block the interaction between HLA-G and its receptors ILT-2 and/or ILT-4, and there is a need for next-generation antibodies that can specifically target HLA-G without cross-reactivity with classical MHC class I molecules, particularly for therapeutic and diagnostic purposes in cancer treatment.
Innovation Solution
Development of specific monoclonal antibodies that strongly block the binding between HLA-G and its cognate receptors ILT-2 and/or ILT-4, with no cross-reactivity with HLA-A, HLA-B, HLA-C, and HLA-E, and demonstrate tumor growth inhibition upon in vivo administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current anti-HLA-G antibodies are used, then HLA-G binding is achieved, but complete blocking of HLA-G receptor interaction is not achieved
Solution Approach 1:
The patent applies parameter changes by optimizing the antibody's binding affinity parameters and epitope recognition characteristics. The engineered antibodies have modified complementarity determining regions (CDRs) that change the binding parameters to achieve complete blocking of HLA-G receptor interaction, transforming partial blockers into complete blockers through parameter optimization.
Solution Approach 2:
The patent applies local quality by focusing on specific epitope regions of HLA-G that are critical for receptor binding. The antibodies are designed to target specific local regions (epitopes) on HLA-G with high precision, allowing them to block the receptor interaction at the molecular level while maintaining specificity for HLA-G over other MHC class I molecules.
2Measurement precision
If antibodies with high HLA-G specificity are developed, then cross-reactivity with classical MHC class I molecules is reduced, but therapeutic efficacy may be compromised
Solution Approach 1:
The patent applies local quality by targeting specific epitope regions on HLA-G that are unique or distinct from classical MHC class I molecules. The antibodies are engineered to recognize local structural features of HLA-G (such as specific residues in the α3 domain or peptide-binding groove) that differ from HLA-A, HLA-B, HLA-C, and HLA-E, achieving high specificity while maintaining therapeutic blocking efficacy.
Solution Approach 2:
The patent applies inversion by approaching the specificity problem from the negative side - instead of trying to enhance binding to HLA-G, the antibodies are designed to exploit the structural differences between HLA-G and classical MHC class I molecules. By focusing on what makes HLA-G unique (its non-classical structure, specific polymorphic residues), the antibodies achieve discrimination against classical MHC molecules while maintaining strong HLA-G binding.
3Reliability
If next-generation antibodies are designed to completely block HLA-G receptor binding, then therapeutic potential is enhanced, but development complexity increases
Solution Approach 1:
The patent applies parameter changes by systematically optimizing key parameters of the antibody structure, including CDR sequence composition, framework region stability, and epitope binding geometry. By changing these parameters in a controlled manner during engineering, the patent achieves complete blocking capability while managing the complexity through rational design rather than trial-and-error approaches.
Data Source
AI summary
The invention provides antigen binding domains that bind human leukocyte antigen G (HLA-G) protein comprising the antigen binding domains that bind HLA-G, polynucleotides encoding them, vectors, host cells, methods of making and using them.