Modified Hinge Antibody Inhibiting c-Met Dimerization
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Solution Overview
Problem
Current antibodies targeting the c-Met receptor, such as the one-armed 5D5 antibody, lack significant inhibitory effects on ligand-independent c-Met activation and dimerization, which are crucial for treating cancers with aberrant c-Met signaling, and existing solutions fail to effectively inhibit c-Met dimerization.
Innovation Solution
A divalent, chimeric or humanized monoclonal antibody with a modified hinge region is developed, capable of specifically binding to the c-Met receptor and inhibiting its dimerization, both in ligand-dependent and ligand-independent manners, thereby impairing c-Met's signaling and interaction with partners.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a conventional monoclonal antibody is used to target c-Met receptor, then it can bind to the receptor, but it fails to effectively inhibit ligand-independent c-Met activation and dimerization
Solution Approach 1:
The patent applies parameter changes by modifying the antibody's structural parameters, specifically introducing a modified hinge region with altered amino acid sequences (such as PKSCDKTHTCPPCP or PRDCGCKPCPPCP) to change the antibody's conformational flexibility and valency expression. This structural parameter modification enables the antibody to effectively inhibit ligand-independent c-Met dimerization while maintaining receptor binding capability.
Solution Approach 2:
The patent employs dynamics by creating a divalent antibody configuration that can dynamically adapt its binding mode. The modified hinge region allows the antibody to switch between different conformational states, enabling it to effectively inhibit both ligand-dependent and ligand-independent c-Met activation pathways, thereby increasing adaptability to different activation mechanisms.
2Reliability
If a divalent antibody with modified hinge region is developed, then it can inhibit c-Met dimerization effectively, but the structural complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the antibody structure into distinct functional modules: variable regions for antigen binding, a modified hinge region for structural flexibility and valency control, and constant regions for effector functions. This modular segmentation allows the divalent configuration to achieve effective dimerization inhibition while managing structural complexity through organized functional domains.
3Adaptability or versatility
If existing antibodies are used, then they show limited therapeutic scope, but developing new antibodies requires extensive research and validation
Solution Approach 1:
The patent applies preliminary action by pre-engineering the divalent configuration with modified hinge region in the antibody design stage, rather than attempting to optimize it later. The amino acid sequences are predetermined (such as PKSCDKTHTCPPCP) to ensure proper folding, stability, and inhibitory function, thereby reducing the time required for subsequent validation and clinical development while expanding therapeutic scope.
Data Source
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AI summary
The present invention relates to a novel divalent antibody capable of binding specifically to the human c-Met receptor and/or capable of specifically inhibiting the tyrosine kinase activity of said receptor, preferably both in a ligand-dependent and in a ligand-independent manner as well as the amino acid and nucleic acid sequences coding for said antibody. More preferably said antibody comprises a modified hinge region and exhibits an improved antagonistic activity. More particularly, the antibody according to the invention is capable of inhibiting the c-Met dimerization. The invention likewise comprises the use of said antibody as a medicament for the prophylactic and/or therapeutic treatment of cancers, preferably for cancer characterized by a ligand- independent activation of c-Met,or any pathology connected with the over expression of said receptor as well as in processes or kits for diagnosis of illnesses connected with the over-expression of c-Met. The invention finally comprises products and/or compositions comprising such an antibody in combination with other antibodies and/or chemical compounds directed against other growth factors involved in tumor progression or metastasis and/or compounds and/or anti-cancer agents or agents conjugated with toxins and their use for the prevention and/or the treatment of certain cancers.