Antibody-Drug Conjugates (ADCs) are reshaping modern cancer treatment by offering a more targeted and efficient way to fight tumorsĀ¹. Contrary to conventional chemotherapy, which moves to all parts of the body, damaging all healthy and cancerous cells, ADCs target the entire procedure in a surgically correct way. This has made them significantly less harmful to the normal tissues and has given them the ability to transport strong drugs to destroy cancer cells at their origins within the body.
Also known as biological missiles, ADCs are a result of merging the two worlds: the selectivity of monoclonal antibodies (mAbs) and the killing effect of the cytotoxic agent. The monoclonal antibody is the navigating system as it is able to identify and bind to the antigens usually present on the surface of cancer cells. After the antibody binds to its target, it infects the tumor cell with the burdensome cytotoxic component, causing a cell-lethal effect in the most relevant site, the cell.
One aspect of the ADC that is of great significance is the chemical linker, which binds the cytotoxic agent to provide the antibody with a payload until the antibody is brought to the destination. This linker needs to be robust to ensure that the drug can remain stable in circulation, but within a response range of releasing the drug when within the cancer cell. With this fine-tuning of the equilibrium, researchers will be able to make sure that the treatment causes maximum effects on the cancer cells and minimal side effects.
Through this clever integration of targeting antibodies, powerful payloads, and advanced linkers, ADC technology is redefining the future of targeted cancer therapy. Not only does it enhance the outcome of treatment, but it also helps the patients to have better lives after they are cured by treating the severe side effects, usually brought about by the conventional chemotherapy.
Fig.1. General structure of an Antibody Drug Conjugate.
What Are ADCs and Why Are They Important?
Antibody-Drug Conjugates (ADCs) are an innovation challenge in targeted cancer therapy due to the combination of precise treatment utilization of immunotherapy and efficient treatment using chemotherapy2. Rather than subject the entire body to harmful drugs, ADCs are meant to administer treatment only where it is needed: to the cancer cells, sparing most of the rest of the body. Such a specialized strategy can increase the efficacy of treatment and drastically lower the risks to which patients are exposed.
These three components are the building blocks of an ADC, which function similarly to a guided missile system:
- Monoclonal antibody (mAb): This is the guidance system of the ADC. The antibody would target and combine with certain antigens-special proteins that are found in abundance on the outside of cancer cells and not commonly in large amounts on normal cells. After finding its target, the mAb helps the drug payload to be delivered where it is required.
- Cytotoxic payload: This will be the warhead of the ADC. These medicines are highly active and cannot be administered on their own in large quantities because they would be very risky. Attached to the targeting antibody, however, they can be brought directly to the cancer cell, where they disrupt any critical processes (such as DNA replication or cell division), thus killing the tumor cell.
- Chemical linker: The linker is the connector that forms the connection between the drug and the antibody and determines the release of the drug in which way and when. A sufficient linker should be stable enough to ensure that the drug remains linked as the ADC is moving around the circulation in the bloodstream, but, upon reaching the interior of the cancer cell, should separate easily. This will allow damaging the tumor as much as possible and inflicting minimal damage to healthy tissues.
This imaginative construction is what makes ADCs so significant about ADCs. Using selective targeting in concert with potent drugs, they can enlarge the therapeutic window, the drug regimen in which the drug is effective but not too toxic. This implies that doctors will be able to offer patients treatments that will be powerful enough to fight the cancer yet less likely to produce serious side effects than those commonly experienced during traditional chemotherapy.
Figure 1. Structures of different linker groups used in ADCs. (a) A cleavable hydrazone linker and disulphide trigger as used in MylotargĀ®; (b) an MCāValāCitāPABC linker, combining the non-cleavable MC and dipeptide cleavable ValāCit linkers with a PABC spacer, as used in AdcetrisĀ®; (c) a non-cleavable MCC linker as used in KadcylaĀ®.
The Role of Glycosylation in ADC Technology
In biopharmaceutical innovation, glycosylation, the addition of sugar molecules (glycans) to proteins, is an essential post-translational process3. With antibody-drug conjugates (ADCs), glycosylation is no basic biochemical aside; it is a major determinant of the efficacy of a therapy. Glycosylation is central to the development of targeted cancer therapy by mediating the stability, force, and safety of therapeutic antibodies.
Glycosylation in ADC technology influences several performance variables:
- Enhanced Stability and Pharmacokinetics:
The glycans found in the Fc area of the antibody are useful in the preservation of the structural integrity of this antibody and make it functional enough in the blood. This enhanced stability enables ADCs to spend a longer period in the body, which means the ADCs have a longer duration in locating and binding to the cancer cells. A longer half-life is necessary so that several doses can be used, which will be convenient to the patients, and the costs are likely to drop.
- Increased targeting and Decreased Immunogenicity:
Warranted glycan formations enhance how therapeutic antibodies interface in the immune system. In particular, they increase attachment to Fc gamma receptors (Fc g2Rs), which is fundamental to antibody-dependent cellular cytotoxicity (ADCC), whose line of duty is to assist the immune system in destroying cancer cells. Simultaneously, optimised glycosylation patterns help to ensure that this so-called geometrical change is less likely to result in unanticipated immune effects, meaning that ADCs are safer and more efficacious for patients.
- Site-Specific Conjugation through Glycoengineering:
The development of glycoengineering allowed the creation of antibodies with specific glycan chains that act as specific anchor points for the cytotoxic payloads. Such site-specific conjugation gives a consistent drug-to-antibody ratio (DAR) and makes ADCs homogeneous with predictable pharmacodynamic (PD) properties in the body. Controlled DAR is important in balancing potency and safety, which is a mark of the next-generation cancer therapy that targets the formation of new drugs.
By combining glycosylation expertise with innovative ADC design, researchers are pushing the limits of biopharmaceutical innovation. The result is a new generation of antibody-drug conjugates that are more stable, better targeted, and safer for patients, offering real hope in the fight against difficult-to-treat cancers.
Glycoengineering Approaches for ADCs
Conventional methods of antibody-drug conjugate (ADC) production involve the random conjugation of cytotoxic drugs to the antibody at lysine residues or reduced cysteines. Although this technique is commonplace, it may lead to an irregular drug-to-antibody ratio, which can contribute to non-homogeneous qualities of ADCs that affect the course of ADCs, changing their potency, safety, and pharmacokinetics. This variability increases the difficulty in predicting how the therapy is going to behave in the patients, and it could be a limitation to its overall efficacy. A more specific and controlled alternative is glycoengineering. The site-specific conjugation that can be achieved by targeting the conserved N-glycan in the Fc region does not have an impact on the antigen-binding domain of the antibodies. This guarantees that the specificity of the therapeutic antibody is preserved, but then allows for the precision in locating the drug cargo.
Better homogeneity is also a primary advantage of conjugation to a glycan. This strategy provides ADC batches with homogeneous DAR values, which generate consistent therapeutic efficacy and longer-term batch-to-batch reproducibility, an aspect essential to clinical research and large-scale production.
Also, glycoengineering does not cause the loss of antibody functionality as the site of modification is distant from the area that recognizes cancer cell antigens. This implies that the ADC can bind with its target cells specifically and effectively in a manner that administers a powerful anti-cancerous drug.
Particularly, the approaches based on glycosylation can be combined with large-scale production. Enzymatic remodeling and chemoenzymatic synthesis are two examples of techniques that can be applied to large-scale production, and the idea of being able to have high-quality, repeated ADCs becoming widely used and applicable in targeted cancer treatment is workable.
Fig.1. Glycoengineering mAbs for enhanced sialylation and glycan-targeted ADC production. (A) Cells can be supplemented with ManNAc or analogs (e.g., Ac4ManNAc or 1,3,4-O-Bu3ManNAc), which intercept and increase flux through the sialic acid biosynthetic pathway with the indicated relative efficiencies (āR.E.ā values) increasing sialylation of recombinant glycoproteins, such as mAbs. (B) Alternatively, cells can be supplemented with analogs containing non-natural chemical moieties (e.g., Ac4ManNAz or 1,3,4-O-Bu3ManNAz to install azide groups or Ac46-Thio-Fuc to install thiols).
Recent Advances and Clinical Impact
Technology using glycoengineering to improve the therapeutic performance of antibody-drug conjugates (ADCs) has gone straight from an initial research concept to practical applications. Scientists are developing more consistent, potent, and safer to patient ADCs by optimising the glycosylation patterns that mediate the site-specific conjugation. Such inventions are not fantastical; they are rapidly changing the future of precision-based cancer treatments.
It has been demonstrated that glycosylation-guided ADCs can realize:
- Higher therapeutic index: Reduction in off-target effects and increased delivery.
- Improved pharmacokinetics: Longer half-life and low clearance rates.
- Increased effectiveness: Greater outcomes in tumor models and higher tolerability in preclinical experiments.
The fact that seven ADC-using glycoengineering candidates are already in clinical trials is demonstrative of increasing confidence in this approach.
Challenges and Future Perspectives
While ADC technology and glycoengineering have made significant progress, several challenges remain before these innovations in antibody-drug conjugates can reach their full potential in targeted cancer therapy. Addressing these issues is essential for advancing the next generation of therapeutic antibodies and driving long-term biopharmaceutical innovation.
- Intricate Glycan Chemistry: Instruments are required to generate repeatable glycan proficiencies.
- Production Uniformity:Ā The production of large-scale manufacturing has to maintain the uniformity of glycan patterns.
- Regulatory Approval:Ā New conjugation chemistries will need to undergo scientifically rigorous testing to establish safety and efficacy.
Future ADCs are likely to combine glycoengineering with novel payloads and linkers to further advance targeted cancer therapy.
Why GlycoDepot Supports Glycosylation-Based ADC Innovation
GlycoDepot offers the top-quality glycan building blocks and custom-made enzymatic tools, which propel innovation in the ADC technology. Our solutions are designed to support advanced glycosylation and glycoengineering methods, enabling researchers to perform precise glycan remodeling and achieve reliable site-specific conjugation. This level of control is essential for creating next-generation antibody-drug conjugates (ADCs) with improved stability, consistency, and safety. By empowering scientists and biopharmaceutical companies, GlycoDepot helps accelerate the development of smarter therapeutic antibodies that deliver real progress in targeted cancer therapy and advance the future of biopharmaceutical innovation.
Conclusion
The integration of glycosylation and ADC technology marks a powerful step forward in targeted cancer therapy. Through advanced glycoengineering, researchers can design therapeutic antibodies with greater stability, controlled drug attachment, and improved immune system interactions. Such a combination can not only increase precision, potency, and safety but also provide the grounds for further individualizing cancer treatment. As such innovations transition in-between the laboratory and clinical setting, they will present a genetic breakthrough in the field of biopharmaceuticals, and will provide patients with more efficacious options that come with reduced side effects.
Fig.1. Schematic diagram of the structure of an antibodyādrug conjugate, demonstrating the key components of the linker, payload, monoclonal antibody, and tumor target antigen; mAb, monoclonal antibody. Researchgate.
Reference:
Fu, Zhiwen, et al. “Antibody drug conjugate: the ābiological missileā for targeted cancer therapy.” Signal transduction and targeted therapy 7.1 (2022): 93.
Zhang, Meng, et al. “Antibodyādrug conjugates in urothelial carcinoma: scientometric analysis and clinical trials analysis.” Frontiers in Oncology 14 (2024): 1323366.
Fan et al., Review of conjugation technologies for antibody drug conjugates, AbT, 2025
Antibody drug conjugates for the treatment of multiple myeloma – Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/figure/Schematic-diagram-of-the-structure-of-an-antibody-drug-conjugate-demonstrating-the-key_fig1_364201357 [accessed 19 Aug 2025]
Recent developments in chemical conjugation strategies targeting native amino acids in proteins and their applications in antibodyādrug conjugates – Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/figure/General-structure-of-antibody-drug-conjugate_fig1_355319441 [accessed 18 Aug 2025]
Improving Immunotherapy Through Glycodesign – Scientific Figure on ResearchGate. Available from:https://www.researchgate.net/figure/Glycoengineering-mAbs-for-enhanced-sialylation-and-glycan-targeted-ADC-production-A_fig8_328701010 [accessed 18 Aug 2025]
