Dual-Target Antibody Conjugates for Wider Cancer Therapeutic Window
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Solution Overview
Problem
Current therapeutics, including antibody-drug conjugates (ADCs) and nucleic acid-based therapeutics, face challenges such as non-specificity, off-target effects, insufficient safety, efficacy, and poor targeting to diseased cells, leading to adverse side effects and limited therapeutic index.
Innovation Solution
A therapeutic combination comprising a first proteinaceous molecule covalently bound to saponin and a second proteinaceous molecule with a different binding site for a distinct cell-surface molecule, optionally with an effector moiety, to enhance specificity and targeting to tumor cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional chemotherapy is used, then cancer cells can be treated, but normal dividing cells are also affected causing side effects
Solution Approach 1:
The therapeutic system is segmented into two distinct components: a targeting molecule (antibody or ligand) that specifically binds to tumor cell markers, and a cytotoxic effector molecule that delivers the therapeutic action. This segmentation allows the cytotoxic agent to be delivered only to target cells, avoiding damage to normal cells while maintaining therapeutic efficacy.
Solution Approach 2:
A targeting molecule serves as an intermediary between the cytotoxic effector and the tumor cell. This intermediary specifically recognizes and binds to cell-surface molecules on tumor cells, directing the cytotoxic agent to the intended target and preventing off-target effects on normal dividing cells.
2Reliability
If highly potent cytotoxic payloads are used in ADCs, then therapeutic efficacy is improved, but therapeutic index is limited
Solution Approach 1:
The patent uses a targeting molecule as an intermediary to deliver potent cytotoxic payloads selectively to tumor cells. This mediation ensures that highly potent effector molecules (such as calicheamicin, duocarmycin, or ricin) are only released at the target site, maintaining high therapeutic efficacy while improving the therapeutic index by minimizing systemic toxicity.
Solution Approach 2:
The cytotoxic effect is concentrated locally at the tumor cell site through specific binding of the targeting molecule to tumor cell markers. This local concentration of potent effector molecules maximizes therapeutic efficacy at the target while limiting exposure to normal tissues, thereby improving the therapeutic index.
3Device complexity
If single-target ADCs are used, then simplicity is maintained, but specificity to tumor cells is insufficient
Solution Approach 1:
The patent merges multiple targeting mechanisms by combining a first targeting molecule that binds to a first cell-surface marker with a second targeting molecule that binds to a second cell-surface marker. This combination enhances targeting specificity by requiring dual recognition, ensuring that only tumor cells expressing both markers are targeted while maintaining a relatively simple therapeutic structure.
Solution Approach 2:
The therapeutic composition is structured as a composite system containing multiple targeting molecules with different specificities. This composite approach combines molecules with distinct binding specificities to achieve enhanced tumor cell targeting, improving reliability without excessive complexity.
Data Source
AI summary
The invention relates to a therapeutic combination, comprising a first proteinaceous molecule comprising a first binding site for binding to a first epitope of a first cell-surface molecule, the first proteinaceous molecule provided with at least one saponin covalently bound to an amino-acid residue of said first proteinaceous molecule, and comprising a second pharmaceutical composition comprising a second proteinaceous molecule different from the first proteinaceous molecule, the second proteinaceous molecule comprising a second binding site for binding to a second epitope of a second cell-surface molecule different from the first cell-surface molecule, and comprising an effector moiety, wherein the second epitope is different from the first epitope. An aspect of the invention is a composition comprising the first proteinaceous molecule and the second proteinaceous molecule of the invention. The invention also relates to a composition or therapeutic combination comprising an antibody—drug conjugate or antibody—oligonucleotide conjugate and the first proteinaceous molecule of the invention. An aspect of the invention relates to a pharmaceutical composition comprising the composition or the antibody—drug conjugate of the invention, and optionally further comprising a pharmaceutically acceptable excipient. The invention also relates to the therapeutic combination or the composition or the antibody—drug conjugate or the pharmaceutical composition of the invention, for use as a medicament. The invention also relates to the therapeutic combination of the invention for use in the treatment or prophylaxis of a cancer.