Antibody-Drug Conjugate (ADC) Technology

Fig.1 The Structure of Antibody-Drug Conjugate.

Fig.1 Antibody-drug conjugate.¹

Antibody-drug conjugates (ADCs) are novel targeted cancer treatments that combine the specificity of monoclonal antibodies with powerful cytotoxic drugs, delivering themselves to cancer cells without damaging healthy tissue. ADCs exploit the antibody's ability to go after tumor antigens, delivering cytotoxic drugs with accuracy, efficacy, and fewer side effects than traditional chemotherapy. The personalized strategy has yielded several approved ADCs, including brentuximab vedotin for Hodgkin's lymphoma and trastuzumab emtansine for HER2-positive breast cancer, with scores more on the drawing board. Creative Biolabs is the ADC research pioneer, offering comprehensive ADC solutions across the ADC development lifecycle, from antibody engineering to linker chemistry to cytotoxic payload optimization, to drive next-generation cancer therapies.

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Introduction

We must identify the complex building blocks of ADCs to make cancer therapies work. Both elements — antibody, cytotoxic payload, and linker — all help make ADCs effective and minimize off-target damage. From antibody specificity and payload power to linker stability, we can understand the delicate balance in ADC design by analyzing each part's detail. Creative Biolabs utilizes state-of-the-art technology and science to ensure that each element works perfectly with every other in order to make precise targeted cancer treatments.

Fig.2 The Antibody-Drug Conjugate Consists of Three Parts with Different Functions.

Fig.2 General structure of antibody-drug conjugate.²

Featured ADC Services

ADC Antibody Screening and Selection

Creative Biolabs offers comprehensive ADC antibody screening and selection services designed to identify antibodies with high specificity and optimal binding characteristics for ADC applications. By employing advanced techniques, including high-throughput screening and functional validation, our team ensures that selected antibodies meet the exacting standards needed for targeted cancer therapeutics, providing clients with customized solutions for diverse therapeutic targets.

ADC Conjugation Chemistry

Our ADC conjugation chemistry service focuses on innovative, site-specific conjugation techniques that enhance ADC homogeneity, stability, and efficacy. We utilize cutting-edge conjugation strategies such as cysteine re-bridging, enzymatic modification, and site-specific conjugation to achieve consistent drug-to-antibody ratios (DAR), optimizing ADC therapeutic performance across a range of indications.

Linker and Payload Synthesis

We specialize in linker and payload synthesis services, providing both conventional and proprietary linkers engineered for precise payload release. Creative Biolabs develops highly potent cytotoxic payloads that meet the safety and potency needs of advanced ADCs, ensuring efficient synthesis, purification, and integration of linkers and payloads tailored to specific therapeutic requirements.

Analytical Characterization and Validation

Our analytical characterization and validation services cover all aspects of ADC quality assessment, including mass spectrometry, HPLC, and stability testing. With state-of-the-art analytical platforms, Creative Biolabs provides comprehensive validation to ensure the homogeneity, stability, and bioactivity of ADCs, enabling safe and effective therapeutic products that comply with stringent regulatory standards.

Fill and Finish Services

Creative Biolabs offers complete fill and finish services to ensure ADC stability and consistency in the final formulation. Our experts oversee the final steps of ADC production, including aseptic filling, lyophilization, and packaging, providing tailored solutions that maintain ADC integrity, sterility, and readiness for clinical application.

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Get a Successful ADC Antibody

Creative Biolabs offers a suite of antibody selection and enhancement services and innovative strategies to tailor antibodies for ADCs, including:

Antibody Screening and Optimization

Isotype Screening: Evaluating various antibody isotypes to identify those best suited for ADC applications, considering factors like stability and immune response.
Affinity Maturation: Engineering antibodies to achieve higher binding affinity for target antigens, essential for effective payload delivery.
Functional Testing: Conducting rigorous preclinical tests to assess and ensure antibody compatibility with ADC requirements, including cellular uptake, stability, and effectiveness post-conjugation.

Tailored Modification

Humanization and Chimerization: Converting murine antibodies to human-compatible forms to enhance safety and reduce immunogenicity.
Site-Specific Engineering: Incorporating unique binding sites, like engineered cysteine residues, enables precise conjugation of cytotoxic agents, resulting in homogeneous ADC products with predictable pharmacokinetic properties.
Effector Function Modulation: Modifying the antibody Fc region to enhance antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC), increasing tumor cell death potential.

Find Best-fit Cytotoxic Payload

Payloads available at Creative Biolabs

The payload is the ADC's weapon, delivering a powerful cytotoxic effect directly to cancer cells. ADC payloads primarily disrupt mitosis or induce apoptosis through different mechanisms. Creative Biolabs actively explores innovative payloads that demonstrate high potency against resistant cancer types and novel pathways of cytotoxicity, aiming to expand ADC applications and overcome common resistance. We offer the following ADC payloads:

Tubulin Inhibitors
Agents like auristatins and maytansinoids interfere with microtubule formation, preventing cell division.

DNA-Targeting Agents
Molecules such as calicheamicins and duocarmycins bind DNA, causing irreversible damage and triggering cell death.

Protein Degraders
These emerging payloads can degrade essential proteins in cancer cells, offering a new mode of cell death. new!

RNA-Targeting Payloads
By binding to mRNA or other RNA molecules, these agents bypass conventional resistance mechanisms seen with DNA-targeting drugs. new!

Optimization of Drug-Antibody Ratio (DAR)

A critical determinant of ADC potency and safety, DAR represents the average number of drug molecules attached to each antibody. DAR optimization is essential; higher ratios may enhance cytotoxicity but could compromise stability and increase toxicity. Creative Biolabs employs advanced techniques to tailor DAR for various ADCs, ensuring a balance between efficacy and tolerability, thus maximizing therapeutic impact.

Optimize YourLinker Design

Linker Stability and Release Mechanisms

The linker is the backbone of ADC stability, determining where and when the payload is released. Linkers are carefully designed to remain stable in the bloodstream and release the cytotoxic agent precisely in the target cells. Common linker types include cleavable linkers and non-cleavable linkers:

Know more about the differences between cleavable linkers and non-cleavable linkers

	Cleavable Linkers	Non-Cleavable Linkers
Release Mechanism	Payload released in response to specific conditions (e.g., acidic pH, enzymatic activity) within tumor cells.	Payload released only after full antibody degradation within lysosomes.
Common Linker Types	Acid-sensitive linkers, enzyme-sensitive linkers (e.g., cathepsin-cleavable linkers).	Thioether linkers or other stable chemical bonds that are not cleavable by tumor-specific factors.
Advantages	Enhanced selectivity due to environmental triggers that activate only in tumor cells, reducing off-target effects.	More controlled, relies on degradation in specific cells, but less dependent on environmental factors.
Applications	Suitable for ADCs targeting tumors with unique microenvironments, like acidic or enzyme-rich areas, enhancing delivery.	Ideal for situations where stable, systemic drug presence is critical; suited for drugs that benefit from lysosomal release.

Innovative Linker Technologies

Creative Biolabs has developed several proprietary linker technologies, including:

PtLnX Technology: Utilizing a platinum-based bis(ethylenediamine) chloride core for controlled release at tumor sites, maximizing cytotoxic impact while sparing healthy cells.
Reversible Conjugation Mechanisms: These linkers enable payload release only in specific conditions, reducing the risk of systemic toxicity and improving overall therapeutic safety.

Novel conjugation strategies

Conventional Conjugation - Native cysteine conjugation, Lysine conjugation;
Site-specific Conjugation - Engineered cysteine conjugation, Enzymatic conjugation, Unnatural amino acids as conjugation sites, Glycan conjugation;
Amino-terminal engineered serine conjugation - The aldehydes reacted from serines are used for oxime ligation.
Fab nucleotide-binding site conjugation - By conjugated indole-based 5‑difluoro‑2,4‑dinitrobenzene linker.
Native cysteine re-bridging - Using bis-alkylation conjugation at reduced interchain disulfides;
Avoiding retro-Michael deconjugation - Michael addition of a thiol to a maleimide used for bioconjugation of drugs to antibodies.

Next-Generation ADCs

Next-generation ADCs promise significant improvements over their predecessors, addressing some of the key challenges faced in early ADC designs. These include advancements in antibody engineering, linker stability, and payload optimization. The following table compares the key attributes of the first-, second-, and third-generation ADCs:

Feature	First-Generation ADCs	Second-Generation ADCs	Third-Generation ADCs
Conjugation Chemistry	Random conjugation (e.g., lysine/cysteine)	Improved random and some site-specific methods	Site-specific conjugation, providing uniformity and controlled DAR
Linker Stability	Poor stability, leading to premature drug release	Improved stability with enzyme-cleavable linkers	Highly stable linkers with tailored release mechanisms
Payload Potency	Limited to low-to-moderate potency agents	Potent payloads like auristatins, maytansinoids	Next-gen payloads, including protein degraders and dual-drug systems
Target Specificity	Lower specificity, increased off-target effects	Enhanced targeting with optimized antibody selection	High specificity with engineered antibodies for unique antigens
Therapeutic Window	Narrow, often resulting in significant side effects	Moderate, better balance between efficacy and safety	Broad, offering improved efficacy with minimal systemic toxicity
Example Drugs	Early trials, limited commercial success	Brentuximab vedotin, Trastuzumab emtansine	Ongoing research on dual-drug ADCs, bispecific ADCs

Focus on Third-Generation ADCs

Third-generation ADCs bring advanced features like site-specific conjugation and innovative linker-payload combinations. These technologies improve homogeneity in drug-antibody ratios (DARs) and reduce the likelihood of off-target toxicity. For example, Creative Biolabs is actively developing next-generation linkers that offer more precise drug release. Furthermore, site-specific conjugation methods such as enzymatic conjugation ensure consistent ADC structure, resulting in predictable pharmacokinetics and improved therapeutic outcomes.

More Innovate ADCs

Dual-Drug ADCs

These ADCs co-conjugate two different payloads, offering synergistic effects that combat drug resistance. They provide a potent combination approach, delivering multiple cytotoxic mechanisms within a single molecular construct.

Bispecific ADCs

By targeting two different antigens (e.g., HER2/EGFR), bispecific ADCs enhance tumor selectivity, ensuring that cytotoxic drugs are delivered more accurately to malignant cells. This dual-targeting mechanism holds promise for treating heterogeneous tumors.

Creative Biolabs's ADC technology combines the specificity of antibodies, novel linker systems, and powerful cell-killing agents to fight cancers and improve the prognosis of patients. Through our proprietary methods, new linkers have been synthesized and highly potent cytotoxic payloads have been created for optimized ADC products to potentially offer treatment options at clinical stages. If there is any query, please contact us for more details.

References

Image retrieved from https://en.wikipedia.org/wiki/Antibody%E2%80%93drug_conjugate#/media/File:Antibody-drug_conjugate_structure.svg, Bioconjugato, 2017, used under Open Access license CC BY-SA 4.0, without modification.
Cheng-Sánchez, Iván, et al. "Antibody-drug conjugates containing payloads from marine origin." Marine Drugs 20.8 (2022): 494. Distributed under Open Access license CC BY 4.0, without modification.