Conjugation Technologies in ADCs: Innovations, Challenges, Clinical Impact, and Future Directions

Antibody–drug conjugates (ADCs) have transformed targeted cancer therapy by enabling the selective delivery of cytotoxic agents to tumor cells, sparing healthy tissue. The design of ADCs allows for higher doses of the cytotoxic drug to be administered, potentially increasing efficacy. They are currently considered the most promising drug classes in oncology, with ongoing efforts to expand their use for non-oncological indications and in combination therapies.

The clinical success of ADCs such as brentuximab vedotin (Adcetris®; Pfizer) and trastuzumab emtansine (Kadcyla®; Genentech/Roche) has accelerated research and led to the approval of more than 15 ADCs worldwide*, with more than 70 in late-stage clinical trials. However, ADCs are complex engineered biopharmaceutical drugs that require in-depth knowledge of their components and properties to support synthesis or production.

Central to ADC performance—efficacy, pharmacokinetics, and safety—is the method of drug conjugation to the antibody, which determines the drug-to-antibody ratio (DAR) and shapes the therapeutic window. [1][2][3][4]

In this article, we provide a comprehensive review of current and emerging conjugation technologies, their advantages and limitations, and the future direction of ADC development.

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The Critical Role of DAR
The drug-to-antibody ratio (DAR) quantifies the number of drug molecules bound to each antibody. DAR directly impacts ADC potency, pharmacokinetics, and toxicity. Conjugation chemistry determines not only the average DAR but also the distribution—whether the ADC population is heterogeneous (e.g., DAR 0–8) or more homogeneous (e.g., DAR 2 or 4). An optimal DAR varies with each ADC, depending on the target antigen and cytotoxic payload, and is required to maximize efficacy while minimizing off-target toxicity and aggregation.

For example, a higher DAR significantly increases payload delivery to tumors, but it can also increase hydrophobic interactions, leading to aggregation, reduce solubility, rapid clearance, high off-target toxicity, and dose-limiting toxicities. In contrast, a low DAR may result in insufficient potency, failing to effectively kill target cancer cells.

ADCs are rarely uniform but typically include a mixture of species with different numbers of attached drugs. Hence, the reported DAR represents a population-average value, rather than a fixed stoichiometry for every molecule. To assess the impact and accurately confirm the DAR profile of an ADC, it is important to account for inherent heterogeneity. DAR directly determines the balance among efficacy, safety, and pharmacokinetics in ADCs. Hence, by using appropriate analytical methods and linking drug loading to biological performance, a better understanding leads to more optimized ADC development.

Conjugation Strategies
Linking or conjugation strategies to attach the payload to the antibody are critical to the nature of the ADC. While early generations of ADCs were primarily synthesized as heterogeneous mixtures, researchers found that they had suboptimal pharmacokinetics, stability, tolerability, and/or efficacy. Hence, ongoing development efforts have shifted towards generating homogeneous ADC constructs with precise drug loading and predetermined, controlled sites of attachment.

The reason for this shift is simple: results from preclinical studies and clinical development repeatedly show that homogeneous ADCs demonstrate superior overall pharmacological profiles compared to their heterogeneous counterparts. In the pursuit of homogeneity, a wide range of methods have been developed.  These conjugation technologies can be broadly divided into three categories: [4][5][6]

1. Random (Non-Specific) Conjugation

• Lysine Conjugation
  • Lysine-based conjugation is historically one of the most significant and widely used conjugation methods. IgG antibodies possess roughly 80 lysine residues, about 20 of which are solvent-accessible. Lysine conjugation involves reacting these residues with activated esters (such as N-hydroxysuccinimide [NHS] esters), yielding ADCs with DARs typically between 0 and 9, with an average DAR of ~3.5. While this method is robust and chemically straightforward, the resulting heterogeneity can affect pharmacokinetics and toxicity. Gemtuzumab ozogamicin (Mylotarg®; Pfizer/Wyeth), which uses lysine-based conjugation to attach the cytotoxic payload calicheamicin to the anti-CD33 monoclonal antibody (hP67.6), was, in 2000, the first ADC approved by the US Food and Drug Administration (FDA). The drug was voluntarily withdrawn due to safety concerns linked to its heterogeneous DAR, but later, in 2017, it was reapproved with revised dosing and payload strategies. Advances such as site-selective lysine conjugation (e.g., K-lock™) are improving DAR uniformity. [5][6][7]
• Cysteine Conjugation
  • Cysteine-based conjugation leverages the antibody’s interchain disulfide bonds. Human IgG1 contains four interchain disulfides, which can be partially reduced with reducing agents (like DTT or TCEP) to generate reactive thiols. These are then covalently attached to the antibody payload via maleimide linkers. Since antibodies have fewer cysteine sites suitable for conjugation than lysine residues, cysteine conjugation generally yields ADCs with a narrower, more controlled drug-to-antibody ratio (DAR), often targeting DAR values around 4. However, some heterogeneity remains, typically yielding a DAR of around 4, with a distribution ranging from 0 to 8. Compared with lysine conjugation, cysteine methods yield less heterogeneous populations and are now the predominant method for clinical ADCs (e.g., brentuximab vedotin). However, maleimide-thiol conjugates can undergo reverse-Michael addition, risking premature payload release. Innovations such as N-aryl or ortho-amino groups and novel linkers (e.g., KTHIOL™, P5™)** enhance stability and selectivity. Cysteine conjugation is now dominant in clinical ADCs, though some heterogeneity and stability challenges remain. Improved cysteine conjugation platforms (such as selective reduction techniques and disulfide re-bridging strategies) have been developed to further enhance the homogeneity and stability of ADCs. These methods can enrich specific DAR species or minimize unwanted side products, contributing to better therapeutic outcomes. [8]

2. Site-Specific but Non-Selective Conjugation

• Interchain Cysteine Conjugation Enhancements
  • IgG1 antibodies contain four pairs of interchain disulfide bonds. By carefully reducing these bonds, eight free thiol groups are generated at predictable locations, enabling targeted conjugation using thiol-reactive linkers (such as maleimide derivatives). This approach is site-specific because it exploits the antibody’s natural interchain cysteines, but it is not fully site-selective since all eligible cysteines may be modified. Standard interchain cysteine conjugation often produces ADCs with DAR values ranging from 0 to 8, with the most common target being DAR4. The distribution can remain heterogeneous, which may impact efficacy and pharmacokinetics. Enhancements to this technique—such as optimized reduction protocols, temperature adjustments, and metal-ion shielding—can significantly increase the proportion of molecules with the desired DAR.
  • To further reduce heterogeneity, platforms like WuXiDAR4™, a proprietary drug-antibody ratio technology platform developed by WuXi XDC to generate high-homogeneity ADCs, use metal-ion ‘hinge shielding’ to direct conjugation primarily to light-heavy chain interchain disulfides, dramatically increasing the proportion of DAR4 species (e.g., WuXiDAR4™ achieves >70% DAR4 species). [9]
  • Depending on the linker and conjugation conditions, disulfide ‘re-bridging’ with bifunctional linkers (e.g., disulfone, new maleimide, pyridazine diketone) enables even greater control, allowing DARs of 4, 8, or 16 while maintaining the antibody’s structural integrity and payload attachment. However, these methods can yield ‘half-antibody’ isomers affecting effector functions, and ongoing research aims to minimize these byproducts and optimize stability. Representing a pragmatic balance between simplicity and control, by refining reduction conditions and employing specialized linkers, interchain cysteine conjugation enhancements, a site-specific but non-selective strategy, achieves greater homogeneity and therapeutic performance, making it a cornerstone of modern ADC manufacturing. [10][11]

3. Site-Specific Conjugation

• Enzymatic-Tag Conjugation
  • Site-specific enzymatic conjugation uses specific enzymes (e.g., Sortase A, formylglycine-generating enzyme, farnesyltransferase, microbial transglutaminase) that recognize engineered peptide tags or natural residues. This approach involves attaching payloads to specific amino acid sequences or functional groups on the antibody, offering high homogeneity and precise site control. Depending on the enzyme and the recognition sequence, it can be highly site-specific. However, this approach requires antibody engineering and careful CMC management to address immunogenicity and process complexity. Ongoing advances in enzyme engineering and tag design continue to improve efficiency and reduce immunogenic risk.
  • Enzymatic-Tag Conjugation is a powerful tool for producing next-generation ADCs with improved pharmacokinetics, safety, and efficacy.
  • One example, the SMARTag technology developed by Catalent (Rewood Bioscience), achieves site-specific conjugation through the use of an aldehyde tag comprising a six-amino acid sequence that is a substrate for the naturally occurring human enzyme formylglycine-generating enzyme (FGE). In this approach, the FGE enzyme oxidizes a cysteine residue in the tag sequence to a formylglycine residue, which contains an aldehyde functionality. The aldehyde chemical reactivity is bioorthogonal to other reactive groups within an antibody, and thus serves as the handle for site-specific bioconjugation. The technology was conceived in Carolyn Bertozzi’s laboratory as part of the suite of bioorthogonal chemistry innovations that earned her the 2022 Nobel Prize in Chemistry. [12][13]
• Glycan Remodeling
  • Glycan-based conjugation modifies the conserved N-glycan at the Fc region (primarily at the N297 site) of IgG antibody, either by chemical oxidation (e.g., NaIO4) or enzymatic remodeling (e.g., Endo S2, galactosyltransferase). Through enzymatic or chemical modification, the glycan is remodeled to introduce reactive groups that serve as anchor points for payload attachment. Technologies like Lonza‘s GlycoConnect™ enable efficient, site-specific payload attachment via click chemistry by modifying the antibody’s native glycan rather than engineering the antibody sequence.*** This approach supports rapid, stable ADC generation while preserving antibody structure and delivering highly consistent drug attachment. Glycan remodeling achieves high homogeneity (often DAR2 species) and can preserve or modulate Fc-mediated functions, though process complexity and cost remain challenges. This achieves high homogeneity (often DAR2) and preserves antibody structure, though the process can be more complex.
  • Just like Enzymatic-Tag Conjugation, glycan remodeling conjugation is a powerful tool for producing next-generation ADCs with improved pharmacokinetics, safety, and efficacy. By enabling precise, site-specific attachment of payloads, Enzymatic-Tag Conjugation and Glycan remodeling overcome many limitations of traditional random conjugation, though they introduce new considerations regarding manufacturing complexity and process control. As these methods continue to evolve, they are expected to play an increasingly central role in the development of novel, clinically effective ADCs. [14][15]
• Affinity Peptide Conjugation
  • This approach is a site-selective strategy for attaching cytotoxic payloads to antibodies, using specially designed peptides that exhibit strong, specific binding to defined regions on the antibody, typically the Fc region. It utilizes peptides derived from protein A or G, which naturally bind to the Fc portion of IgG antibodies, to direct payloads to specific Fc lysine residues. In this method, a linker or linker–payload is attached to an affinity peptide. When this modified peptide binds to the antibody, it positions the linker’s reactive group in close proximity to specific lysine residues (often K248, K288, or K337) on the Fc region. Under mild conjugation conditions, the payload is selectively transferred to these lysines, enabling site-selective conjugation without genetic engineering of the antibody.[1][16]
  • Technologies such as AJICAP™, a site-specific, Fc-affinity peptide-mediated conjugation technology developed by Ajinomoto Bio-Pharma Services, and AbClick™, a third-generation, site-selective antibody-drug conjugate (ADC) linker platform developed by AbTis, enable traceless, efficient, and site-selective conjugation with minimal impact on antibody structure or function. Both AJICAP™  and AbClick™ use cleavable linkers (e.g., disulfide or thioester bonds) that can be broken, releasing the affinity peptide after conjugation is complete. While promising, the risk of interfering with FcRn binding and effector functions necessitates careful optimization. [17] 
  • The affinity peptide conjugation strategy is a flexible, efficient method for site-selective ADC construction. By leveraging natural antibody-binding peptides and traceless linker strategies, it offers enhanced control over conjugation site and DAR. In turn, this supports the development of more homogeneous and effective ADCs.
• Fully Site-Specific and Selective Conjugation:
  • Engineered Cysteine (ThioMab)
    • By genetically introducing one or more cysteine residues at predetermined sites while replacing non-essential native amino acids, researchers can achieve site-specific conjugation and highly homogeneous ADCs (e.g., DAR2, with one payload per engineered cysteine on each antibody chain). These engineered cysteines serve as unique, reactive sites for thiol-specific conjugation chemistries, such as maleimide- or disulfide-based linkers. In this approach, the location of cysteine insertion is carefully selected to avoid disrupting antibody folding, stability, or antigen binding. After reduction and re-oxidation steps to ensure proper disulfide bond formation and expose the engineered cysteines, payloads are conjugated via thiol-specific chemistry. [18]
  • Non-Canonical Amino Acids (ncAAs)
    • Using genetic code expansion (GCE) technologies allows the incorporation of unique chemical handles (e.g., ketones, azides, alkynes), not found in natural proteins, at specific sites within the antibody sequence for bioorthogonal conjugation via chemoselective ‘click’ reactions (e.g., oxime ligation, strain-promoted azide-alkyne cycloaddition). By introducing an orthogonal tRNA/tRNA synthetase pair that recognizes a specific nonsense (stop) codon and inserts the desired ncAA during translation, the ncAAs approach provides unmatched precision, enabling the attachment of payloads at virtually any desired site. The site of ncAA incorporation can be chosen anywhere in the antibody, enabling unparalleled control over conjugation site and DAR. Since only the engineered position(s) are modified, this approach yields highly uniform ADCs. However, current limitations include lower antibody yield and the need for sophisticated expression systems. Cell-free platforms and ongoing optimizations are addressing these hurdles, with early-stage clinical candidates showing great promise. While highly precise, this method is technically complex and less mature in manufacturing. [19]

Linker Chemistry
The linker choice significantly impacts systemic stability, payload-release kinetics, and toxicity, influences the ADC’s stability, pharmacokinetics, safety, and therapeutic efficacy, and must be tailored to each ADC construct. The linker chemistry is broadly categorized as cleavable or non-cleavable based on how the payload is released from the antibody inside target cells. Cleavable linkers (hydrazone, cathepsin B-responsive, disulfide, pyrophosphate diester) exploit intracellular conditions to release the payload, while non-cleavable linkers rely on complete antibody degradation within the cell.[20][21]

Cleavable Linkers

• Designed to release the drug in response to intracellular triggers (acidic pH, enzymes, or reducing agents). Examples include hydrazone, cathepsin B-cleavable peptides, and disulfide linkers. They allow efficient payload release but may risk premature cleavage in circulation. [22]

Non-Cleavable Linkers

• Stable bonds that release the drug only after antibody degradation in the lysosome. These provide superior stability but require the payload to remain active when conjugated to an amino acid or linker fragment.

Challenges and Future Directions
Despite remarkable advances, selecting optimal conjugation sites and chemistries remains complex due to the interplay of binding, internalization, payload release, PK, and effector functions. Although site-specific methods offer improved homogeneity and potentially better clinical outcomes, they can also introduce new challenges in manufacturing, analytical control, and immunogenicity. The gap between preclinical promise and clinical reality underscores the need for continued research, especially as more clinical data on advanced conjugation technologies become available.

Looking ahead, the paradigm of ADC design will continue to evolve. As our understanding of ADC biology, chemistry, and clinical performance deepens, the integration of novel conjugation methods—tailored for specific antibody-linker-payload combinations—will unlock new therapeutic opportunities and address unmet clinical needs.

Conjugation technology and the site of conjugation are at the heart of ADC innovation, dictating product quality, safety, stability, efficacy, and manufacturability. From traditional lysine and cysteine methods to cutting-edge genetic code expansion and enzymatic techniques, the field is rapidly advancing toward ever more precise, homogeneous, and effective therapeutics. While preclinical profiles are often superior, clinical translation must consider potential immunogenicity and toxicity (e.g., ocular events and other adverse responses observed in clinical trials). Hence, continued interdisciplinary collaboration among chemists, biologists, engineers, and clinicians will be essential to fully realize the potential of ADCs to transform cancer therapy and beyond.[23]

__

Note:* Not all approved ADCs are approved by the U.S Food and Drug Administration (USA).
** KTHIOL™ and P5™ are proprietary, novel linker technologies developed by Kelun-Biotech that offer enhanced thiol selectivity and resistance to retro-Michael reactions. They enable stable, site-specific conjugation to optimize ADC safety and efficacy. These linker technologies are part of the company’s OptiDC technology platform to create ADCs with high drug-to-antibody ratios (DAR, e.g., 7.4) and superior pharmacological properties. [1]
*** When combined with GlycoConnect® technology, HydraSpace® technology, and the hydrophilic spacer technology developed by Lonza that improves ADC solubility and stability, enhancing the therapeutic index, the result is improved tolerability and more predictable pharmacokinetics compared with conventional ADC architectures.

Highlights of prescribing information
Brentuximab vedotin (Adcetris®; Pfizer) [Prescribing Information]
Trastuzumab emtansine (Kadcyla®; Genentech/Roche) [Prescribing information]
Gemtuzumab ozogamicin (Mylotarg®; Pfizer/Wyeth)[Prescribing information]
Inotuzumab ozogamicin (Besponsa®; Pfizer/Wyeth)[Prescribing Information]
Polatuzumab vedotin (Polivy®; Genentech/Roche)[Prescribing Information]
Enfortumab vedotin (Padcev®; Pfizer/Astellas)[Prescribing Information]
Trastuzumab deruxtecan (Enhertu®; Daiichi Sankyo/AstraZeneca)[Prescribing Information]
Sacituzumab govitecan (Trodelvy®; Gilead Sciences) [Prescribing Information]
Belantamab mafodotin (Blenrep®; GSK) [Prescribing Information]
Loncastuximab tesirine (Zynlonta®; ADC Therapeutics) [Prescribing Information]
Tisotumab vedotin (Tivdak®; Pfizer/Genmab) [Prescribing Information]
Disitamab vedotin (Aidixi®; RemeGen)
Mirvetuximab soravtansine (Elahere®; AbbVie) [Prescribing Information]
Sacituzumab tirumotecan (Jiatailai®; Kelun Biotech/Merck & Co)
Datopotamab deruxtecan (Datroway®; Daiichi Sankyo/AstraZeneca) [Prescribing Information]
Telisotuzumab vedotin (Emrelis®; AbbVie) [Prescribing Information]

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DOI: 10.14229/jadc.2026.16.04.001