Linker and payload featuring in ADCs determine both efficacy and safety, which influences the therapeutic window and minimizes off-target toxicity. ADCs deliver extremely potent drugs right to cells, and the linker and payload are the key ingredients to release at the specific target site. Creative Biolabs provides comprehensive linker and payload synthesis services for ADC therapeutic efficacy and stability. We're the leading partner for customized ADC solutions - from academic research to drug development, based on our knowledge and cutting-edge ADC Conjugation chemistry platforms.
Why Improve Linker and Payload in ADC Efficacy?
Enhancing ADC Stability and Targeting Through Linker Selection
The efficacy of an ADC is influenced heavily by the choice of linker, which must balance stability and targeted drug release. A linker that remains intact during circulation but cleaves upon reaching the cancerous tissue optimizes therapeutic outcomes. For example, the FDA-approved ADCs Kadcyla (trastuzumab emtansine) and Enhertu (fam-trastuzumab deruxtecan) exemplify success due to meticulous linker design that enhances drug stability and minimizes off-target effects.
Impact of Payload Selection on ADC Potency
The payload is the cytotoxic element of the ADC, which initiates cell death once transferred into the target cell. Creative Biolabs has cytotoxic payloads such as microtubule inhibitors (MMAE, MMAF) or DNA damage agents (DM1) and can customize the appropriate payload for each client depending on their target profile. These powerful agents are selected based on their mechanism of action and affinity for the linker, so that they reach their targeted site of action in their active state, delivering the most efficacy with the least systemic side effects.
Fig.1 Structure of FDA-approved ADCs: Mylotarg, Adcetris, and Kadcyla. (blue: linker, red: payload).1
Comprehensive Linker and Payload Modules at Creative Biolabs
Creative Biolabs provides highly specialized services, offering various linker and payload types categorized by release mechanisms and cytotoxic action. Below is an organized breakdown of the linker and payload modules available, each tailored to unique release and therapeutic profiles.
Linker Types for Optimal ADC Stability and Specificity
Module Type
Description
Application
pH-Sensitive Linkers
Linkers that release payload in acidic environments such as tumor tissue and lysosomes
Ideal for solid tumors with pH levels significantly different from healthy tissue
Disulfide Linkers
Cleavage occurs in response to high glutathione levels within cancer cells
Often used for hematologic cancers with elevated intracellular glutathione levels
Peptide Linkers
Cleavage is catalyzed by tumor-associated enzymes like cathepsins
Suitable for payload release in environments rich in specific proteolytic enzymes
β-Glucuronide Linkers
Cleavage triggered by β-glucuronidase, an enzyme overexpressed in certain tumors
Effective for ADCs targeting tumors with elevated enzyme expression levels
Non-Cleavable Linkers
Payload release is dependent on ADC degradation within the lysosome instead of linker cleavage
Provides prolonged action with reduced bystander toxicity, exemplified by Kadcyla
Payload Types for Targeted Cytotoxicity
Module Type
Description
Application
Microtubule Destabilizers
Disrupt cell division by binding to tubulin, leading to apoptosis
Effective in cancers dependent on cell division, using agents like MMAE and MMAF
DNA-Targeting Agents
Induce DNA damage to prevent cancer cell replication and proliferation
Commonly used agents include DM1, effective in rapidly proliferating cancer cells
Transcription Inhibitors
Halt cancer cell growth by inhibiting transcription processes
Effective in cancers that rely on rapid transcription for survival
Nanocarriers
Specialized carriers that deliver cytotoxic compounds directly to cancer cells
Useful for a broad range of cancers with unique delivery needs
Protein Toxins
Use proteins that are toxic to cancer cells for targeted destruction
Employed in various cancer types where high cytotoxicity is necessary
Toxic Enzymes/ADEPT
Enzyme systems designed to activate prodrugs at the tumor site
Provides localized toxicity, minimizing effects on healthy tissue
Inhibitors
Target specific cellular pathways essential for cancer cell survival
Provides localized toxicity, minimizing effects on healthy tissue
Innovative Linker-Payload Designs
Module Type
Description
Application
Fe(II)-Cleavable Linkers
Linkers activated by iron ions, allowing selective release in iron-rich tumor environments
Suitable for targeting solid tumors with enhanced selectivity and reduced off-target toxicity
Bioorthogonal Linkers
Achieve selective release via chemical reactions that occur only in the presence of specific biomolecules
Promising in preclinical studies, offering high control over payload release in complex biological environments
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Our End-to-end Linker/Payload Solutions
Based on a large in-house library of payloads, linkers and advanced synthetic chemistry platforms, Creative Biolabs offers one-stop solutions for our clients to meet your demand ultimately and save your time.
Fig.2 End-to-end Linker and Payload Solutions.
Why Choose Us?
Creative Biolabs' linker and payload synthesis process is engineered for flexibility and precision, ensuring each ADC is tailored to the specific requirements of our clients. Our services encompass in-house libraries, screening techniques, and advanced synthetic chemistry platforms.
In-House Libraries and Screening Techniques
Creative Biolabs utilizes extensive libraries containing a diverse range of linker and payload options, allowing rapid screening and selection. Our team optimizes the Drug-to-Antibody Ratio (DAR) for each ADC project, ensuring maximum payload efficacy with minimal toxicity. These libraries are a vital resource for rapidly identifying effective linker and payload combinations that align with therapeutic goals.
Our synthetic chemistry platform supports high customization levels, allowing for specific linker and payload conjugations based on client requirements. Equipped with advanced equipment, we utilize proprietary technology to synthesize complex linker structures, ensure payload compatibility, and maximize ADC efficacy. This customized approach enables us to adapt to each project's unique pharmacokinetic and pharmacodynamic challenges.
ADME (Absorption, Distribution, Metabolism, and Excretion) Considerations
Creative Biolabs emphasizes the ADME profile for each ADC, focusing on the pharmacokinetics and pharmacodynamics crucial for safe and effective drug delivery. Linker modifications, such as the inclusion of hydrophilic fragments or PEGylation, help improve ADC stability, reducing off-target toxicity while optimizing plasma clearance and tumor uptake. Our goal is to enhance ADC performance and expand therapeutic windows through precise linker and payload optimization.
Creative Biolabs offers tailored consultation services for researchers looking to develop ADCs for challenging targets or unique applications. Our experienced team of chemists and biologists collaborates closely with clients to design customized linker and payload systems that align with specific project requirements, ensuring optimal ADC performance. To explore custom linker and payload synthesis solutions, contact us for a consultation and benefit from our expertise in ADC innovation and development.
Reference
Tsuchikama, Kyoji, and Zhiqiang An. "Antibody-drug conjugates: recent advances in conjugation and linker chemistries." Protein & cell 9.1 (2018): 33-46. Distribute under Open Access license CC BY 4.0, without modification.
Fig.1 Structure of FDA-approved ADCs: Mylotarg, Adcetris, and Kadcyla. (blue: linker, red: payload).1
Fig.2 End-to-end Linker and Payload Solutions.
Antibody-Drug Conjugate (ADC) Technology 
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