Polymeric Linker Antibody-Drug Conjugates High DAR
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Solution Overview
Problem
Current antibody-drug conjugates (ADCs) are limited by low drug-to-antibody ratios (DARs), which restrict their therapeutic index and increase adverse reactions, and attempts to increase DAR result in aggregation, rendering them ineffective.
Innovation Solution
Development of an ADC with a specific polymeric linker that supports high DARs, enabling conjugation of multiple biologically active molecules to a single antibody, and controlling the release rate through covalent bond degradation, while maintaining stability and solubility.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the drug-to-antibody ratio (DAR) is increased to improve therapeutic index, then the therapeutic efficacy is improved, but aggregation occurs rendering the ADC ineffective
Solution Approach 1:
The invention uses a polymeric linker composed of multiple repeat units (at least 2, preferably at least 5) instead of a single conventional linker. This segmentation allows multiple drugs to be attached in a distributed manner along the polymer chain, preventing overcrowding at a single attachment point and thereby reducing aggregation while maintaining high DAR (4-20+ drugs per antibody).
Solution Approach 2:
The ADC comprises a composite structure combining an antibody, a polymeric linker with specific repeat units containing heteroatoms (O, NH, NRA, S) and carbonyl/imine groups, and multiple biologically active moieties. This composite polymeric linker design provides both high drug-loading capacity and structural stability, preventing aggregation even at high DAR levels.
2Reliability
If multiple drugs are conjugated to a single antibody to achieve combination therapy, then the therapeutic efficacy is improved, but the complexity of treatment protocol increases
Solution Approach 1:
The invention merges multiple biologically active moieties (different drugs) onto a single antibody molecule through a polymeric linker. This combining approach delivers multiple therapeutic agents simultaneously in a single administration, achieving combination therapy effects while simplifying the treatment protocol from multiple separate drug administrations to one unified ADC treatment.
Solution Approach 2:
The polymeric linker structure with its specific repeat units is designed to be universal and versatile, capable of conjugating different types of biologically active moieties (chemotherapeutic agents, cytotoxic drugs, etc.) through various linkage chemistries. This multi-functionality allows the same ADC platform to deliver different drug combinations for various cancer types and treatment needs.
3Ease of manufacture
If conventional linkers are used to attach drugs to antibodies, then the conjugation process is simple, but the drug release rate cannot be controlled and stability is reduced
Solution Approach 1:
The invention changes the chemical parameters of the linker by incorporating specific repeat units with heteroatoms (O, NH, NRA, S) and carbonyl/imine groups (C═O, C═NH). These parameter changes in the linker's chemical structure enable controlled drug release through hydrolysis under specific physiological conditions (pH, enzyme presence) while maintaining conjugation stability during circulation, achieving both stability and controlled release.
4Stability of the object's composition
If only one drug is attached per linker to maintain stability, then the ADC stability is preserved, but the therapeutic index is limited and adverse reactions increase
Solution Approach 1:
The polymeric linker acts as an intermediary structure between the antibody and multiple drugs. Rather than directly attaching each drug to the antibody (which would require multiple separate conjugation steps and reduce stability), the polymeric linker serves as a mediator that can hold multiple drugs in a stable configuration and release them in a controlled manner, thereby improving both stability and therapeutic index simultaneously.
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 solution allows for improved therapeutic index and targeted combination therapies with enhanced patient compliance and tolerance by enabling the conjugation of multiple drugs to a single antibody, preventing aggregation, and ensuring stability and controlled release.
Implementation Method 1
The specific polymer used in the ADCs of the present invention may also enable the release rate of the biologically active molecules from the conjugate to be controlled. This release rate depends on the degradation of the covalent polymer-drug or linker-drug bonds within the ADC. Different types of covalent linkage will hydrolyse under different conditions of (e.g.) pH, enzyme.
Data Source
AI summary
The present invention relates to antibody-drug conjugates comprising (i) an antibody or antigen-binding fragment thereof, (ii) a polymer comprising a particular repeat unit comprising an amino acid derivative, which is covalently bound to one or more biologically active moieties, such as small molecule drugs, optionally via a linker, and (iii) a polymer-antibody linker moiety which is covalently bound to both the polymer and the antibody or antigen-binding fragment thereof. Additionally, the present invention relates to pharmaceutical compositions comprising the antibody-drug conjugates and to use of the antibody-drug conjugates in medicine.