Anti-cMet Antibody Hinge Modification for Dimerization Inhibition
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Solution Overview
Problem
Current strategies for targeting c-Met receptor in cancer treatment, such as antibodies and inhibitors, face limitations in effectively inhibiting c-Met dimerization and addressing ligand-independent activations, which are crucial for tumor progression and metastasis.
Innovation Solution
Development of a chimeric or humanized monoclonal antibody capable of inhibiting c-Met dimerization, featuring specific amino acid sequences in its heavy and light chains and a modified hinge region, which also impairs ligand-independent activations and interactions with c-Met partners, thereby blocking its signaling pathways.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antibodies or inhibitors are used to target c-Met receptor, then some level of c-Met activity is blocked, but they fail to effectively inhibit c-Met dimerization and ligand-independent activations
Solution Approach 1:
Instead of blocking the ligand binding site (conventional approach), the patent uses a Fab fragment that binds to a different epitope on c-Met, specifically preventing dimerization through steric hindrance. This inverted approach targets the dimerization interface rather than the ligand binding site, effectively blocking both ligand-dependent and ligand-independent activations.
Solution Approach 2:
The patent employs a Fab fragment as an intermediary molecule that binds to c-Met and physically prevents dimerization. This intermediary approach uses the Fab fragment's binding capability to sterically hinder the dimerization process, thereby blocking downstream signaling pathways without directly interfering with ligand binding.
2Reliability
If monovalent Fab fragments are used to block c-Met, then dimerization is inhibited, but effector functions like ADCC and CDC are lost
Solution Approach 1:
The patent merges the dimerization-blocking capability of the Fab fragment with the effector function capability of the Fc region by creating an IgG1 antibody format. This combined structure allows the antibody to simultaneously prevent c-Met dimerization through its variable region while maintaining ADCC and CDC functions through its Fc region.
Solution Approach 2:
The patent designs an antibody that performs multiple functions: blocking dimerization, preventing ligand binding, and activating effector functions. This multi-functional antibody addresses both the inhibition requirement and the effector function requirement in a single molecular entity.
3Object-generated harmful factors
If full-length IgG antibodies are used, then effector functions are maintained, but steric hindrance for dimerization blocking may be reduced
Solution Approach 1:
The patent optimizes the hinge region flexibility and the orientation of the Fab fragment to maximize steric hindrance while maintaining effector functions. By adjusting the structural parameters of the antibody (hinge flexibility, Fab orientation), the patent achieves effective dimerization blocking without sacrificing ADCC and CDC capabilities.
Data Source
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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.