Antibody-Drug Conjugate with Moderate Binding Affinity for Cancer Tissue Penetration
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Solution Overview
Problem
Existing antibody-drug conjugates (ADCs) face limitations in delivering camptothecin-based drugs effectively to cancer tissues due to strong binding of antibodies to drug targets, leading to concentration of ADCs around blood vessels within cancer, rather than penetrating into cancer tissues.
Innovation Solution
The development of an immunoconjugate that binds a camptothecin-based drug degrading DDX5 protein through a linker to an antibody or antigen-binding site-containing fragment with a dissociation constant Kd value of 1*10^-8 to 1*10^-6 M, or an antibody that binds to cell surface proteins expressed in both normal and cancer cells with higher divalent binding affinity, to enhance penetration and distribution of the ADC within cancer tissues.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Strength
If an antibody with high antigen-binding affinity is used in ADC, then the ADC binds strongly to the target antigen, but the ADC concentrates around blood vessels within cancer tissue and fails to penetrate into the cancer tissue
Solution Approach 1:
The patent changes the binding affinity parameter of the antibody by selecting antibodies with moderate affinity (Kd = 1×10^-8 to 1×10^-6 M) instead of high affinity, thereby optimizing the balance between target binding and tissue penetration capabilities of the ADC
2Reliability
If an antibody with strong binding affinity is used, then the ADC binds effectively to the target, but the distribution of payload within cancer tissue becomes uneven
Solution Approach 1:
The patent modifies the binding affinity parameter to a moderate range that allows sufficient target binding while enabling adequate penetration and uniform distribution of the payload throughout the cancer tissue, avoiding the concentration effect around blood vessels
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
This approach allows for improved penetration of ADCs into cancer tissues, enhancing therapeutic efficacy while minimizing systemic side effects by ensuring even distribution of the payload within the cancer tissue.
Implementation Method 1
Camptothecin is a selective inhibitor of type I topoisomerase, which is an isomerase involved in DNA replication and recombination. This drug does not inhibit free enzymes, but stabilizes the covalent bonds of the topo-DNA complex and prevents the reconnection of cleaved DNA fragments.
Implementation Method 2
an antibody or an antigen-binding site-containing fragment (B-1) thereof having a dissociation constant Kd value of 1×10^-8
Data Source
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AI summary
The present invention relates to an immunoconjugate or a pharmaceutically acceptable salt thereof characterized in that a camptothecin-based drug (A) is bound, through a linker (C), to: an antibody or an antigen-binding fragment (B-1) thereof having a dissociation constant Kd value of 1*10-8 M to 1*10-6 M (exclusive of 1*10-6 M) with respect to an epitope of a cell surface protein; or an antibody or antigen-binding fragment (B-2) thereof which binds to a cell surface protein expressed in both normal cells and cancer cells and which has a higher binding affinity with respect to an epitope of the cell surface protein when binding divalently than when binding monovalently.