Humanized L1-CAM Antibodies With High-Affinity Tumor Selectivity
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Solution Overview
Problem
Existing CAR-modified T-cell therapies for cancer treatment face challenges such as bystander toxicity, immunosuppressive tumor microenvironments, cell exhaustion, and suboptimal survival and homing, along with side effects like ADCC and CDC due to L1-CAM expression in normal tissues, necessitating improved therapeutic antibodies with low KD and high affinity for tumor targeting.
Innovation Solution
Development of humanized antibodies with specific CDR sequences (e.g., SEQ ID NO.s 1-27) that exhibit enhanced affinity and stability for L1-CAM, reducing off-target binding and minimizing healthy tissue exposure.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR-modified T cells are used to target L1-CAM in tumors, then tumor targeting capability is improved, but bystander toxicity in normal tissues increases
Solution Approach 1:
The patent changes the binding parameters of the antibody by optimizing affinity (KD) to achieve high tumor targeting while maintaining safety. The antibody of the invention has a KD of approximately 10^-11 M to 10^-12 M, which is optimized to bind L1-CAM on tumor cells with high affinity while avoiding binding to L1-CAM on normal tissues, thus resolving the contradiction between tumor targeting capability and bystander toxicity.
2Reliability
If L1-CAM targeted therapy is administered, then cancer treatment efficacy is improved, but side effects due to L1-CAM expression in normal tissues increase
Solution Approach 1:
The patent optimizes the binding parameters of the antibody by achieving a KD of approximately 10^-11 M to 10^-12 M, which is optimized to bind L1-CAM on tumor cells with high affinity while avoiding binding to L1-CAM on normal tissues, thus resolving the contradiction between cancer treatment efficacy and side effects.
3Measurement precision
If high affinity antibodies are developed for L1-CAM, then binding affinity is improved, but manufacturing complexity increases
Solution Approach 1:
The patent achieves high binding affinity (KD of approximately 10^-11 M to 10^-12 M) by optimizing the antibody's binding parameters through careful selection of CDR sequences and framework regions, demonstrating that high affinity can be achieved without excessive manufacturing complexity.
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 antibodies demonstrate improved binding affinity and stability, effectively targeting L1-CAM-expressing cancers while minimizing side effects, offering potential therapeutic and diagnostic applications.
Implementation Method 1
an antibody or an antigen binding fragment thereof that specifically binds to L1-CAM (CD171)
Data Source
AI summary
The present invention relates to an antibody or an antigen binding fragment thereof that specifically binds to L1-CAM (CD171), to a polynucleotide encoding at least one variable heavy chain sequence and/or at least one variable light chain sequence as in the antibody or an antigen binding fragment thereof of the present invention, to a host cell comprising the polynucleotide of the present invention, to an immunoconjugate comprising an antibody or an antigen-fragment binding thereof of the present invention and an active agent, to a pharmaceutical composition comprising the antibody or the antigen-binding fragment thereof of the present invention, or the immunoconjugate of the present invention, and their use in treatment and/or diagnosis. The antibodies, antigen-binding fragments thereof, the immunoconjugates and the pharmaceutical compositions described herein are particularly useful in treatment or diagnosis of an L1-CAM (CD171) associated cancer.