Antibody-Drug Conjugate Linkers for Selective Cancer Payload Release
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Solution Overview
Problem
Existing antibody-drug conjugates (ADCs) face challenges in delivering toxic payloads selectively to cancer cells while minimizing non-specific binding to non-target cells, leading to unacceptable toxicity and lack of specificity.
Innovation Solution
Development of novel antibody-drug conjugates with specific linkers (R*-L1-LA-) that facilitate targeted delivery and internalization of cytotoxic agents, utilizing linkers such as —[CH2]1-3—C(O)NH— and —[CH2CH2O]p—(CH2)1-5—C(O)—XAA—, where XAA is an amino acid sequence, to enhance selective delivery and release of the payload within cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If traditional small-molecule chemotherapeutics are used, then cytotoxic effects are achieved, but non-specific binding to non-cancerous tissues causes unacceptable toxicity
Solution Approach 1:
The chemotherapeutic agent is segmented from the targeting component by using an antibody-drug conjugate structure. The antibody portion targets cancer cells specifically while the cytotoxic payload is delivered only after internalization, segmenting the functions to reduce non-specific toxicity.
Solution Approach 2:
The antibody serves as an intermediary that bridges the targeting function and the cytotoxic function. It binds specifically to tumor-associated antigens and mediates the delivery of the cytotoxic payload only to cancer cells that express the target antigen.
2Reliability
If antibodies against tumor-specific antigens are used for targeting, then specificity is improved, but therapeutic activity is lacking
Solution Approach 1:
The patent merges the targeting function of the antibody with the therapeutic function of the cytotoxic agent into a single conjugate molecule. This combination allows the ADC to both specifically target cancer cells and deliver a potent therapeutic payload upon internalization.
3Productivity
If ADCs are designed to deliver toxic payload, then cytotoxic effectiveness is improved, but selective delivery and internalization capabilities are insufficient
Solution Approach 1:
The patent optimizes parameters including the drug-to-antibody ratio (DAR), linker chemistry, and payload potency to achieve both high cytotoxic effectiveness and selective delivery. The specific linker design enables controlled internalization and payload release while maintaining stability in circulation.
Data Source
AI summary
The present disclosure provides antibody-drug conjugates (ADCs), linkers, and compounds thereof useful for treating cancer.