Divalent Anti-cMet Antibody with Modified Hinge
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Solution Overview
Problem
Current antibodies targeting c-Met receptor are either agonists or partial agonists, and lack the ability to inhibit c-Met dimerization effectively, particularly in ligand-independent activated cancers, due to their monovalent nature and immunogenic mutations.
Innovation Solution
Development of a chimeric and/or humanized divalent monoclonal antibody with antagonist activity that specifically inhibits c-Met dimerization, featuring a modified hinge region for enhanced efficacy and reduced immunogenicity, capable of targeting both ligand-dependent and ligand-independent c-Met activations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If monovalent antibodies are used to target c-Met receptor, then they can bind to the receptor, but they lack the ability to effectively inhibit c-Met dimerization
Solution Approach 1:
The patent combines multiple antibody binding sites into a single divalent antibody structure, enabling simultaneous binding to two c-Met receptors and effective inhibition of dimerization. This merging of binding functions resolves the contradiction by providing both receptor binding capability and dimerization inhibition without requiring multiple separate monovalent antibodies.
Solution Approach 2:
The antibody design incorporates a flexible hinge region that allows dynamic adaptation of the antibody structure to accommodate the dimerization interface of c-Met receptors. This dynamic flexibility enables the divalent antibody to effectively block dimerization while maintaining binding affinity, resolving the contradiction between binding capability and dimerization inhibition.
2Ease of manufacture
If conventional antibodies with immunogenic mutations are used, then they can be produced, but they exhibit immunogenicity that limits therapeutic use
Solution Approach 1:
The patent applies humanization techniques to modify the antibody sequence parameters, replacing immunogenic murine amino acid sequences with human equivalents while maintaining the binding capability. This parameter change in the molecular sequence reduces immunogenicity while preserving production feasibility, resolving the contradiction between ease of manufacture and harmful immunogenic effects.
3Reliability
If agonist or partial agonist antibodies are used to target c-Met, then they can bind to the receptor, but they cannot effectively inhibit ligand-independent activation in cancers
Solution Approach 1:
Instead of using agonist or partial agonist antibodies that activate or partially activate c-Met, the patent employs a divalent antagonist antibody that inverts the approach by blocking the dimerization interface. This inversion of the mechanism of action enables effective inhibition of ligand-independent activation while maintaining adaptability to different cancer types, resolving the contradiction between therapeutic efficacy and activity profile versatility.
Data Source
AI summary
The invention relates to a novel antibody capable of binding specifically to the human c-Met receptor and/or capable of specifically inhibiting the tyrosine kinase activity of said receptor, with an improved antagonistic activity, said antibody comprising a modified hinge region.The invention also relates to a composition comprising such an antibody antagonist to c-Met and its use as a medicament for treating cancer.