HER3 Antibody-Drug Conjugates With Cleavable Linkers
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Solution Overview
Problem
Current anti-HER3 antibody-drug conjugates face challenges in effectively targeting HER3-expressing cancers due to limitations in specificity and efficacy, leading to adverse events such as hematological toxicity and limited progression-free survival, particularly in treating non-small cell lung cancer, metastatic breast cancer, and colorectal cancer.
Innovation Solution
Development of antibody-drug conjugates (ADCs) with specific antibody fragments that bind to HER3, utilizing various linker and cytotoxic drug combinations, including auristatin compounds and pyrrolobenzodiazepine, to enhance targeting and cytotoxicity while minimizing off-target effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional anti-HER3 antibody-drug conjugates are used, then treatment for HER3-expressing cancers is provided, but specificity and efficacy are insufficient leading to adverse events and limited progression-free survival
Solution Approach 1:
The patent modifies the linker structure by changing chemical parameters (using cleavable linkers with specific sequences like GGFG or TGFG) and adjusts the drug-to-antibody ratio parameter to optimize both specificity and efficacy while reducing adverse events. The linker cleavability parameter is changed to enable controlled drug release inside cells.
Solution Approach 2:
The patent creates composite antibody-drug conjugates combining specific antibody fragments (like anti-HER3 monoclonal antibodies) with cytotoxic drugs through engineered linkers. This composite structure integrates the targeting capability of the antibody with the cytotoxicity of the drug, achieving enhanced specificity and efficacy while controlling harmful effects through the linker's cleavable design.
2Productivity
If antibody-drug conjugates with higher cytotoxicity are developed, then cancer killing effectiveness is improved, but off-target effects and toxicity increase
Solution Approach 1:
The patent segments the ADC into distinct functional components: the antibody fragment for targeting, the cleavable linker for controlled release, and the cytotoxic drug for killing. This segmentation allows each component to be optimized independently - the antibody provides specific targeting to reduce off-target effects while the cytotoxic drug maintains high killing effectiveness against the intended target.
Solution Approach 2:
The cleavable linker acts as an intermediary between the antibody and the cytotoxic drug. It maintains the drug in a inactive or less toxic form while circulating in the blood, then cleaves to release the active cytotoxic drug inside the target cell. This intermediary function allows high cytotoxicity to be achieved only where needed, reducing off-target effects.
3Productivity
If existing ADC formulations are used, then treatment is provided for non-small cell lung cancer, metastatic breast cancer, and colorectal cancer, but objective response rates and progression-free survival are limited
Solution Approach 1:
The patent introduces dynamic cleavability to the linker, allowing it to transition from a stable state in circulation to an activated state inside target cells. This dynamic property enables the ADC to adapt its behavior based on location - remaining stable in blood to avoid premature release, then activating inside cells to maximize cytotoxicity, thereby improving response rates and extending progression-free survival.
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 ADCs demonstrate enhanced specificity and cytotoxicity against HER3-expressing cancers, improving objective response rates, disease control, and progression-free survival with reduced adverse events, making them effective for treating cancers like colon, gastric, breast, and non-small cell lung cancer.
Implementation Method 1
Ab is an antibody or antigen-binding fragment thereof that specifically binds to human epidermal growth factor receptor 3 (HER3, also known as Erbb3)
Implementation Method 2
The bioactive molecule is covalently conjugated to the antibody through the linker
Implementation Method 3
enable the ADC to enter the cancer cells through endocytosis effect
Implementation Method 4
the bioactive molecule is then released in the cancer cells to kill the cancer cells
Data Source
AI summary
The present application relates to an antibody-drug conjugate and its preparation methods and use, and specifically relates to an antibody-drug conjugate for treating HER3-positive cancers. The present application provides a fully human HER3 antibody, which has excellent binding activity to HER3-positive cells and can efficiently deliver drugs to HER3-positive cells. The present application also provides a drug-linker molecule coupled to the antibody, and the drug comprises a DNA topoisomerase inhibitor. The obtained antibody-drug conjugate has a better drug-to-antibody ratio, and has a good targeted killing effect on colon cancer, gastric cancer, breast cancer, and lung cancer (e.g., non-small cell lung cancer, specifically, lung adenocarcinoma). Therefore, the present application further provides a preparation method for the antibody-drug conjugate and application of the antibody-drug conjugate in the treatment of a HER3-positive cancer.