Claudin 18.2 ADC Epitope Targeting for Better Internalization
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Solution Overview
Problem
Existing anti-claudin 18.2 antibodies, such as IMAB362, do not efficiently induce receptor-mediated antibody internalization, limiting their effectiveness in delivering drug moieties to cancer cells overexpressing claudin 18.2 protein.
Innovation Solution
Development of antibodies that selectively bind to the B3-β4 loop and β5 strand of claudin 18.2, with a drug moiety covalently attached, enhancing receptor-mediated internalization and targeting cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing anti-claudin 18.2 antibodies (such as IMAB362) are used, then they can bind to claudin 18.2 protein, but they do not efficiently induce receptor-mediated antibody internalization
Solution Approach 1:
The patent applies parameter changes by modifying the antibody structure to alter its binding characteristics. Specifically, the invention identifies and targets particular epitopes on claudin 18.2 (including conformational epitopes involving extracellular loops) that, when bound, trigger efficient receptor-mediated internalization. This involves changing the binding parameters of the antibody from those of existing antibodies (which bind but do not internalize efficiently) to new antibodies with optimized epitope recognition that couples binding with internalization activation.
2Productivity
If antibodies are designed to bind to specific epitopes for high internalization, then internalization efficiency improves, but binding specificity to other claudin isoforms must be maintained
Solution Approach 1:
The patent applies local quality by targeting specific local regions (epitopes) on the claudin 18.2 protein structure. The invention focuses on particular extracellular loops and conformational regions that are unique to claudin 18.2 or differently configured compared to other claudin isoforms. By designing antibodies that recognize these specific local structural features rather than generic claudin characteristics, the patent achieves both high internalization efficiency through proper epitope engagement and isoform selectivity through structurally-specific binding.
3Productivity
If drug moiety is covalently attached to antibody, then drug delivery capability increases, but complexity of conjugate structure increases
Solution Approach 1:
The patent applies the intermediary principle by introducing a linker moiety as an intermediate component between the antibody and the cytotoxic drug. This linker serves multiple functions: it covalently connects the drug to the antibody, positions the drug for optimal intracellular delivery, and may control the release kinetics of the cytotoxic agent. The linker acts as a mediator that manages the complexity of the conjugate structure while enabling efficient drug delivery, transforming two separate molecules (antibody and drug) into a functional unified conjugate system.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The new antibodies achieve significantly increased drug delivery into cancer cells, demonstrating superior binding and internalization capabilities compared to existing antibodies, effectively inhibiting cancer cell multiplication and inducing apoptosis.
Implementation Method 1
these antibodies are highly effective in inducing receptor-mediated antibody internalization
Data Source
AI summary
Provided are antibody-drug conjugates containing a drug moiety attached to an antibody or fragment thereof having binding specificity to the wild-type human claudin 18.2 (CLDN18.2) protein. The antibody or the fragment thereof binds to the β3-β4 loop (residues 45-63 of SEQ ID NO: 30, NYQGLWRSCVRESSGFTEC) and the β5 strand (residues 169-172 of SEQ ID NO: 30, YTFG) of CLDN18.2.