Engineering the Next Generation of Antibody-Drug Conjugates: Key Insights from the 17th World ADC, San Diego 2026

Antibody–drug conjugates (ADCs) deliver potent anticancer drugs to tumor cells while limiting exposure to healthy tissues. In clinical practice, however, this selectivity is not absolute. ADCs can still damage healthy cells, causing adverse effects that may limit the dose patients can tolerate, interrupt treatment, or affect quality of life. A recommended dose therefore does not guarantee safety; it reflects a balance among antitumor activity, toxicity, and the ability to sustain treatment. To address this challenge, researchers are refining ADC design at multiple levels, including dual-targeting antibodies, conditional activation, Fc engineering, site-specific conjugation, and linker chemistry. These approaches aim to improve tumor selectivity and treatment tolerability, but clinical evidence must establish each construct’s benefits and limitations.

Data presented at 17th World ADC San Diego, held October 12–15, 2026, at the Town & Country, with more than 1,300 attendees from over 400 companies across seven scientific tracks, provided a timely view of how these strategies are being evaluated. This article examines how ADC design has evolved, how individual engineering choices may influence clinical performance, and what these developments mean for drug developers, clinicians, and patients.

Key takeaways

• ADC performance is now limited less by payload potency than by delivery biology: where the conjugate goes, how much of it reaches the tumor, and what normal, healthy tissues take up along the way.
• Antibody engineering (biparatopic and bispecific formats, masked or pH-switched binding, Fc silencing) is the main lever for tumor selectivity and for reaching tumors with low or uneven antigen expression.
• Stable, site-specific conjugation and tumor-selective release triggers such as β-glucuronide linkers reduce payload loss in circulation, and early clinical comparisons show markedly lower ocular and hematologic toxicity than older constructs with the same payload class.
• Resistance and treatment sequencing are increasingly important as ADCs are used across more disease settings. Researchers are investigating dual-payload and other nontraditional formats, but they must demonstrate comparative value in clinical settings.
• At the 17th World ADC San Diego, the clinical conversation shifted from single-payload potency to resistance (dual-payload ADCs after trastuzumab deruxtecan; Enhertu®; Daiichi Sankyo/AstraZeneca), selectivity (masked and bispecific ADCs), and patient selection, with each claim now expected to be backed by human data.

A century-old idea, a 25-year clinical history

The conceptual idea of antibody-drug conjugates predates oncology as a specialty. In the first decade of the twentieth century, Paul Ehrlich, MD, described a magic bullet: a compound that would seek out disease-causing cells while sparing the patient’s healthy cells. In 1958, French oncologist and immunologist Georges Mathé, MD, and colleagues explored linking methotrexate to antibodies raised against leukemia cells, one of the first attempts to make the metaphor physical, but the polyclonal antibodies of that era were too variable to build a medicine on.

The turning point came in 1975, when Georges Köhler, PhD, and César Milstein, PhD, reported the hybridoma technique, enabling the production of monoclonal antibodies with defined specificity and reproducible characteristics [1]. Their discovery transformed biological research and opened new possibilities for targeted medicine. However, an antibody that recognizes a tumor-associated antigen does not necessarily kill the cancer cell on its own. Researchers therefore began exploring whether an antibody could serve as a carrier, directing a cytotoxic drug toward cells expressing a selected target. The clinical history of ADCs as approved medicines came decades later, starting only in 2000, and their development has not been a straight line, illustrating that molecular design alone does not determine clinical value.

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This approach laid the foundation for antibody–drug conjugates (ADCs) by combining an antibody’s target-recognition properties with a drug’s cell-killing activity. The antibody provides targeting, while the cytotoxic payload provides pharmacological activity. A chemical linker joins the two and must remain stable enough during circulation while allowing the payload to become available at the right site.

A key milestone came in 1983, when researchers reported a clinical study of a vindesine–anti-carcinoembryonic antigen (CEA) antibody conjugate in eight patients with advanced metastatic carcinoma, including colorectal and ovarian cancers [2]. The study assessed the conjugate’s localization and safety. After radiolabeling, localization was demonstrated in five patients, was equivocal in one, and was undetectable in two. The investigators reported no obvious toxicity or hypersensitivity attributable to the conjugate at the doses administered. The findings demonstrated that an antibody linked to a cytotoxic drug could be prepared and administered to patients, although tumor localization was not consistent across the small study population. [2]

These early studies established feasibility, but they did not resolve the challenges that would shape subsequent ADC development. The initial conjugates used murine antibodies, which could elicit human anti-mouse antibody (HAMA) responses and limit repeat treatment. Conjugation chemistry also posed challenges, including maintaining antibody binding, preserving payload activity, controlling the drug load per antibody, and balancing linker stability with drug release. The 1983 study itself showed that conjugation could preserve antibody localization, while separate laboratory work demonstrated selective cytotoxic activity with a vindesine–monoclonal antibody conjugate against antigen-reactive tumor cells [2][3].

The transition from experimental conjugates to approved medicines took nearly two decades. Advances in antibody engineering, linker chemistry, and payload selection helped advance the field, culminating in the 2000 U.S. Food and Drug Administration (FDA) approval of gemtuzumab ozogamicin (Mylotarg®; Pfizer/Wyeth), an anti-CD33 antibody–drug conjugate (ADC) carrying the cytotoxic agent calicheamicin, for acute myeloid leukemia (AML). [4]

The drug’s subsequent withdrawal from the U.S. market in 2010, following an unsuccessful confirmatory trial, and its reapproval in 2017 at a lower, fractionated dose highlighted the complexity of establishing a favorable benefit–risk profile. Reapproval did not result from a change to the molecule itself, but from a reassessment of the clinical evidence, dosing strategy, and patient selection. The history of gemtuzumab ozogamicin illustrates that successful target engagement and initial regulatory approval do not, by themselves, establish clinical benefit. Rather, the therapeutic value of an ADC must be evaluated in the context of clinical trial outcomes, treatment regimen, patient population, and the overall balance of benefits and risks.

These lesson repeated with belantamab mafodotin (Blenrep®; GSK), which also had a complex regulatory history, including withdrawal in 2023 after a confirmatory study failed to meet its primary endpoint and subsequent reapproval in 2025 in a combination setting for multiple myeloma [5].

The 2010s brought brentuximab vedotin (Adcetris®; Pfizer/Takeda) in 2011 and trastuzumab emtansine (Kadcyla®; Roche/Genentech) in 2013, both built on better antibodies and more potent payloads but still on first-generation conjugation chemistry. The real acceleration began in 2019, when trastuzumab deruxtecan arrived with a cleavable linker, a membrane-permeable topoisomerase I payload and a drug-to-antibody ratio (DAR) of 8. Its success redrew HER2 testing. What was once a positive-or-negative result is now a spectrum running from HER2-ultralow and HER2-low through HER2-positive to ERBB2-mutant disease, each with its own eligibility rules [6].

By July 2026, the Beacon ADC Database [5][7] and the ADC Review Drug Map, which offers a complementary, openly accessible overview of approved and investigational conjugates, listed 15 US Food and Drug Administration (FDA) approved ADCs [5][7][8]. In 2026, the FDA approved pivekimab sunirine (Decnupaz™; AbbVie) for blastic plasmacytoid dendritic cell neoplasm and added an indication for datopotamab deruxtecan (Datroway®; Daiichi Sankyo/AstraZeneca) in unresectable or metastatic triple-negative breast cancer. [9][10]

Interest in ADC development has followed approvals: in breast cancer alone, ClinicalTrials.gov records 325 ADC trials registered between 2021 and 2026, compared with 104 in 2015-2020 and four in 2003-2008 [11].

Counting approvals outside the United States, more than 20 ADCs have now reached patients worldwide [12]. Yet the transformative results remain concentrated in a handful of tumor types, and the field has absorbed many clinical setbacks. A review by Pistilli and colleagues notes that most ADCs reached the clinic without a validated predictive biomarker, which is unusual for a class described as targeted therapy. [13] Target expression remains important, but it is only one part of the drug-tumor relationship.

Why the therapeutic index stays narrow

Only about 0.1% of an administered ADC dose is estimated to reach the tumor; the rest distributes to normal tissues and is cleared [5]. That single number explains most of what follows, but it shouldn’t be treated as a universal value across constructs. An ADC is not a guided missile but a systemically administered biologic whose distribution and activity depend on the antibody, linker, payload, target biology, dose, and the patient’s physiology.[11].

Three biological problems keep the window narrow.

Antigen heterogeneity. Tumor cells vary in how much target they display, within one lesion, between primary and metastasis, and over time under treatment. Cells with high antigen density are killed efficiently; cells with little or none can survive and repopulate the tumor, so the therapy itself selects for the cells it cannot reach [5].

Approved ADCs have largely targeted antigens present at 100,000 to 1,000,000 copies per cell, such as HER2, TROP2, and Nectin-4; below roughly 10,000 copies, too little payload may be delivered to kill [2].  Antigen density can influence uptake and response, but no universal copy-number threshold determines whether an ADC will work. Chapman and colleagues argue that resistance should therefore be expected as an evolutionary outcome rather than treated as an anomaly [11].

Normal-tissue expression and exposure. Many validated breast cancer targets are not tumor exclusive. HER2 and TROP2 line continuous epithelial surfaces in skin, lung, and gastrointestinal mucosa. Even at lower per-cell density, these large compartments absorb ADC, alter its pharmacokinetics, and compete with the tumor for drug, producing organ-specific toxicities that are easily blamed on the payload alone [11]. Expression in healthy tissues can drive on-target, off-tumor exposure, while systemic payload release or distribution can cause toxicity through other routes. Hence, antigen expression alone does not prove that a tissue will accumulate a clinically meaningful amount of a particular ADC; accessibility, internalization, and construct properties also matter.

Distribution inside the tumor. When the target is abundant, the first layer of cells around blood vessels can consume ADC, creating a binding-site barrier that leaves deeper regions untreated [5]. Metastatic sites add another layer of complexity to ADC delivery and activity. Liver, lung, bone, and brain metastases differ in vascular architecture, stromal composition, immune microenvironment, and other factors that can influence ADC penetration, cellular uptake, and intracellular payload release. In brain metastases, the blood–tumor barrier (the altered vascular barrier within a brain tumor or brain metastasis) remains a potential obstacle to drug delivery, although its disruption and permeability vary among lesions. Consequently, intracranial ADC exposure and activity depend on both tumor biology and ADC-specific properties, including antibody structure, linker chemistry, and payload characteristics. [11]

For patients, these mechanisms are not abstract. Depending on the ADC, adverse events can include neutropenia and anemia when membrane-permeable payloads diffuse beyond the tumor; interstitial lung disease with topoisomerase I payloads; and corneal damage that can make reading or driving difficult with some conjugates carrying monomethyl auristatin F (MMAF) [5]. These events should not be attributed to a payload class alone: the antibody, linker, DAR, dose, exposure, patient characteristics, and treatment context all contribute. A reduction in one adverse event does not, by itself, establish that the overall therapeutic index has improved.

Engineering the antibody for selectivity. The antibody decides where an ADC goes, and most current innovation in precision targeting starts there. Biparatopic antibodies bind two separate epitopes on the same antigen. Depending on the target and construct, the extra avidity promotes receptor clustering and faster internalization, so each antigen-positive cell takes in more payload. Anbenitamab repodatecan, also known as JSKN003 (Alphamab Oncology), is a biparatopic anti-HER2 ADC that binds domains II and IV of HER2. A presentation at the annual meeting of the American Society of Clinical Oncology (ASCO) reported a 64.4% response rate and a median progression-free survival of 7.1 months in 45 patients with heavily pretreated, platinum-resistant ovarian cancer, including patients whose tumors scored HER2 0 by immunohistochemistry [15]. These findings, while encouraging, come from an early clinical dataset and require interpretation in light of the study design, sample size, follow-up, and ongoing confirmatory work [15]. They do not establish that all biparatopic ADCs will overcome low target expression. Other biparatopic HER2 conjugates, such as zanidatamab zovodotin (ZW49; Zymeworks), rely on the same clustering effect [16].

Bispecific antibodies bind two different antigens and can be tuned like a logic gate. An ‘AND-gated’ concept favors binding or activity only when both targets are present before internalization, sparing normal tissue with only one; the trade-off is that losing either antigen allows escape. In contrast, an ‘OR-gated’ design can engage either target and may broaden coverage across heterogeneous tumors at some cost to selectivity [5]. These labels simplify the concept, but actual selectivity depends on binding affinity, antigen density and co-expression, internalization, and expression in normal tissues. Losing one antigen may allow escape from an AND-gated approach; an OR-gated approach may retain coverage but can also increase binding to healthy tissue.

Izalontamab brengitecan (iza-bren, BL-B01D1; SystImmune with Bristol Myers Squibb) is the most advanced ‘OR-gated‘ example. It pairs EGFR and HER3 binding arms with a topoisomerase I inhibitor payload at a DAR of 8 [5]. These payloads are chosen deliberately because when EGFR signaling is blocked, tumors often switch to HER3 to keep growing; targeting both receptors in a single molecule addresses that compensatory route [16].

After a first-in-human study across solid tumors [17], izalontamab brengitecan produced a 48.1% response rate in extensive-stage small cell lung cancer [5], and Phase 3 interim results in previously treated triple-negative breast cancer have been reported as positive [6]. For women with that disease, who often run out of effective options quickly, a new mechanism that works after prior therapy matters. A third bispecific design pairs a slowly internalizing tumor antigen with a fast-cycling receptor, such as CD63, SORT1, or the prolactin receptor, that acts as a trafficking handle. [5][16]

Conditional activation adds another layer of selectivity to ADC design. Protease-masked antibodies limit target binding in healthy tissues until tumor-associated proteases remove the masking peptide. Varsetatug masetecan (CX-2051; Varseta-M; CytomX Therapeutics), an investigational EpCAM-directed PROBODY® antibody-drug conjugate (ADC) being developed for advanced colorectal cancer, illustrates this approach. EpCAM is expressed by many carcinomas but is also present in normal epithelial tissues, creating a potential risk of on-target toxicity with conventional EpCAM-directed therapies. Varsetatug masetecan addresses this challenge by masking the antibody’s EpCAM-binding region until proteolytic cleavage enables target binding. The ADC carries CAMP59, a camptothecin-derived topoisomerase I inhibitor in the same chemical class as other well-known camptothecin analogs like irinotecan (SN-38) and exatecan (DXd), and is attached through a separate, cleavable tripeptide linker designed to facilitate payload release and bystander killing of neighboring tumor cells.[18]

In dose escalation, CytomX reported no dose-limiting toxicities or interstitial lung disease; in heavily pretreated metastatic colorectal cancer, without selecting patients for EpCAM expression, response rates were 32% at 10 mg/kg and 20% at 8.6 mg/kg. [5]  In late-line colorectal cancer, where responses to any therapy are uncommon, those numbers stand out; CytomX presented the Phase 1 data at the 17th World ADC San Diego [18]. These are company-reported, nonrandomized data and should be identified as such [19]. However, the reported absence of dose-limiting toxicities at a particular cutoff does not necessarily imply an absence of clinically significant adverse events. Therefore, the program’s safety and efficacy profile requires further evaluation.

pH-switched antibodies take a different route, exploiting the slightly acidic tumor microenvironment (pH 6.4 to 7.0, versus 7.4 in blood). Binding preferences measured in experimental systems reflect a molecular property; they alone do not establish improved clinical selectivity or tolerability.

BioAtla’s BA3361, a conditionally and reversibly active biologic (CAB) anti-Nectin-4 antibody-drug conjugate (ADC), features a novel, ultra-stable, glycosidase-cleavable NextGen ADC linker system designed for tumor-specific payload release and lower off-target toxicity, and binds roughly 100-fold more tightly at pH 6.0 [5].

Fc silencing reduces uptake by immune cells that carry Fcγ receptors, a route to off-target toxicity that adds nothing to a payload-driven mechanism. Common approaches include the LALA and LALA-PG mutations and modification of the N297 glycan, as in the CLDN18.2 ADC arcotatug tavatecan (IBI343; Innovent Biologics) [5].

Truncating the N297 glycan sharply lowers Fcγ receptor binding, which may reduce side effects such as thrombocytopenia and interstitial lung disease linked to immune-cell uptake; clinical benefit still needs confirmation [20]. Some silenced variants retain measurable effector activity or lose stability, so each must be tested in its own format [5].

Keeping the payload on the antibody until it arrives

Releasing the payload in circulation can expose healthy tissues to a cytotoxic drug, but less predictable than conventional chemotherapy. Conjugation chemistry and linker design therefore seek to balance stability during circulation with release at the intended site. No single platform is optimal for every antibody and payload.

From random to site-specific conjugation. Early ADCs commonly used lysine residues, which are abundant on antibody surfaces and produce mixtures with different attachment sites and DAR values; for example, trastuzumab emtansine possesses around 40 different lysines that carry drug [5].

Cysteine conjugation through the four interchain disulfides provided tighter DAR control, but maleimide chemistry used for a decade can reverse in plasma under some conditions (retro-Michael elimination). In a seven-day human plasma comparison, a vinyl-pyridine (PermaLink®; Iksuda Therapeutics) conjugate retained 97% of its drug loading, while maleimide-linked brentuximab vedotin lost roughly 60% [5].

Several platforms now converge on shared goals, including a defined attachment site, a uniform DAR, and stability in circulation. The conserved N297 glycan has proven a particularly good anchor because it sits far from the antigen-binding arms, carries a stable glycosidic bond, and tucks the payload into a pocket between the two heavy chains, shielding its hydrophobicity [20].

Depending on the platform, glycan-based methods can provide defined attachment sites without changing the antibody’s amino-acid sequence. Each approach has process and analytical requirements that may affect yield, scale-up, cost, and product consistency [20]. For example, glycan remodeling (GlycoConnect™; Lonza) requires no change to the antibody sequence while also silencing Fc; as of July 2026, 17 such ADCs were in clinical studies, with two in Phase 3 [5]. Enzymatic prenylation of a C-terminal tag (ConjuAll™; LigaChem Biosciences) yields homogeneous DAR 2 conjugates. Engineered unnatural amino acids give full control over site and DAR but lower expression yields, typically under 1 g/L compared with 4-6 g/L for standard CHO antibodies [5]. Added enzymes, sugar nucleotides, and purification steps raise manufacturing costs, a trade-off the field is working to reduce [20].

Release where it counts. Nine of the 15 approved ADCs rely on peptide linkers cleaved by lysosomal proteases. These linkers exploit the difference between systemic circulation and the interior of the target cell: the antibody binds a tumor-associated antigen, the complex is taken up by receptor-mediated endocytosis, and the resulting endosome matures into a lysosome, an acidic compartment (pH ~4.5–5.0) in which hydrolytic enzymes — principally cathepsin B and cathepsin L — are active. The peptide sequence serves as a substrate for these cathepsins, which hydrolyze the amide bonds within it; cathepsin B, for example, cleaves at the C-terminal side of the citrulline residue in valine-citrulline (Val-Cit). Cleavage leaves an unstable intermediate, and a self-immolative spacer — typically p-aminobenzyloxycarbonyl (PABC) — then fragments spontaneously into carbon dioxide and p-aminobenzyl alcohol, liberating the unmodified payload, such as monomethyl auristatin E (MMAE) or deruxtecan (DXd). The design is not fully selective because these linkers also encounter proteases outside the tumor cell. Val-Cit is a substrate for human neutrophil elastase, a likely contributor to the neutropenia observed with Val-Cit-MMAE conjugates, and the glycyl-glycyl-phenylalanyl-glycine (GGFG) linker can be cleaved by cathepsin L secreted into the tumor microenvironment, releasing payload extracellularly — a mechanism associated with a bystander effect on neighboring tumor cells that do not express the target antigen. [5]

β-Glucuronidase-sensitive linkers offer a narrower trigger than peptide-based designs. Cleavage depends on β-glucuronidase (GUSB), a lysosomal enzyme that hydrolyzes the β-glucuronic acid glycosidic bond. GUSB is abundant in lysosomes and is frequently elevated in the tumor microenvironment and within necrotic cores. The enzyme is most active near pH 4 inside the lysosomal compartment and far less active at neutral pH, limiting premature cleavage in circulation. Once the glycosidic bond is hydrolyzed, the linker undergoes spontaneous self-immolative breakdown through a spacer — typically p-aminobenzyloxycarbonyl (PABC) or N,N′-dimethylethylenediamine (DMED) — releasing the unconjugated, active payload. Unlike peptide linkers, which cleave only in the lysosome, β-glucuronide linkers can also release payload in the extracellular tumor space, a property associated with a bystander effect on neighboring tumor cells. The glucuronide group also increases the linker’s water solubility, counteracting hydrophobic payloads that, at higher drug-to-antibody ratios, promote aggregation and accelerated clearance. [5]

Hydrophilic linker components — sugars, polyethylene glycol (PEG), and related water-soluble groups built into the linker — have become a standard tool for improving stability and safety by counterbalancing hydrophobic payloads that affect aggregation, pharmacokinetics, and tolerability. The problem they address is structural. Most cytotoxic payloads in clinical use, including MMAE, MMAF, the maytansinoids DM1 and DM4, and deruxtecan, are strongly lipophilic, and attaching several of them to a single antibody creates hydrophobic patches on the conjugate surface. Those patches drive three linked liabilities: the molecules associate in aqueous solution, forming aggregates that complicate manufacturing and raise immunogenicity concerns; non-specific binding to plasma proteins and uptake by the reticuloendothelial system shorten circulating half-life, consequently, less drug reaching the tumor; and the resulting off-target distribution narrows the therapeutic window. Incorporating hydrophilic moieties into the linker masks that lipophilicity, keeping the conjugate soluble and stable in plasma. In practice, this has made uniform high-DAR constructs feasible—for example, a PEG8 stretcher allows a DAR of 8 without the clearance penalty historically seen above DAR 2-4—and discrete hydrophilic linkers with defined reactive handles support site-specific conjugation and more homogeneous batches. These effects depend on the complete conjugate and should not be assumed to translate uniformly into clinical outcomes. [21]

The clinical consequence is visible when two ADCs share a payload class. Belantamab mafodotin, a stochastically conjugated MMAF conjugate with a non-cleavable linker, produced grade 3-4 keratopathy in 27% of patients and thrombocytopenia in 35% in DREAMM-2 (NCT03525678) [22]. Caxmotabart entudotin (also known as IKS014, FS-1502 or LCB14) (LigaChem Biosciences and Iksuda Therapeutics), which carries MMAF through a site-specific, glucuronidase-cleavable linker at DAR 2, reported grade 3 ocular adverse events in 2.7% and thrombocytopenia in 8%, with a 53.7% response rate in HER2-positive breast cancer [23].

Caxmotabart entudotin is an investigational HER2-directed ADC using an MMAF payload. A Phase 1 study reported an overall response rate of 53.7% among 67 HER2-positive breast cancer patients treated at the recommended Phase 2 dose, including confirmed and pending responses; the confirmed response rate was lower [23].

These figures describe outcomes in separate studies; they do not establish that site-specific conjugation or glucuronidase-mediated release alone caused the differences. And while the data are encouraging for further investigation, they are not a head-to-head comparison with belantamab mafodotin. The comparison crosses trials and populations, but for a patient weighing months of therapy against the risk of losing clear vision, a difference of that size matters.

When the tumor adapts: Payloads and resistance

Resistance to an ADC can arise through several mechanisms. Tumors may reduce or lose target expression, alter membrane trafficking or internalization, change intracellular processing, or become less sensitive to the payload. These mechanisms can occur together and may differ among metastatic sites. [25][26] For example, the success of topoisomerase I ADCs has created a new group of patients: people whose disease progressed on trastuzumab deruxtecan or sacituzumab govitecan. For them, a second ADC carrying a similar payload often helps less than hoped, because the tumor has already learned to survive that mechanism [25].

A systematic review of ADC sequencing in metastatic breast cancer quantified this. In HER2-low disease, median progression-free survival fell from roughly five to eight months on the first ADC to two to three months on the next, and switching payload classes between ADCs preserved more activity than repeating one [27]. Resistance is also rarely a single event. In patients progressing on sacituzumab govitecan, separate tumor sites had acquired changes in both the target antigen and the payload’s molecular target at the same time [25]. Such findings should be interpreted as pooled observations from the included studies, not as a universal prediction for an individual patient. Outcomes depend on tumor subtype, prior therapy, each ADC’s target and payload, and the patient population [20].

Resistance can arise even where the target looks intact. In urothelial carcinoma treated with enfortumab vedotin, one resistant population kept high Nectin-4 on its surface yet failed to take the conjugate in because altered membrane trafficking blocked internalization and pushed the drug back out in extracellular vesicles [26]. A biopsy showing plenty of antigen, in other words, does not guarantee the drug is getting inside.

Dual-payload ADCs respond to this by carrying two drugs with different mechanisms on the same antibody, a fixed-ratio combination delivered to the same cells. Honda and Zhu describe four pairing logics now in development [25]:

• Topoisomerase I inhibitor plus tubulin inhibitor, attacking DNA replication and cell division, the most advanced pairing.
• Topoisomerase I inhibitor plus a DNA damage response inhibitor (ATR or PARP), blocking repair of the damage the first payload causes. CLIO-8221 (Callio Therapeutics) pairs exatecan with the ATR inhibitor berzosertib.
• Cytotoxic plus immune-stimulating payload, such as a stimulator of interferon genes (STING) or Toll-like receptor 7/8 (TLR7/8) agonist, to recruit the patient’s immune system.
• Membrane-permeable plus non-permeable payload, to reach antigen-low neighbors while keeping the more potent drug inside target cells.

The first dual-payload ADC to enter human testing was KH815 (Chengdu Kanghong Pharmaceuticals), a TROP2-directed conjugate carrying a topoisomerase I inhibitor and an RNA polymerase II inhibitor at a combined DAR of about 7.5 [25]. Others include IBI3020 (Innovent), which combines EGFR/HER3 bispecific targeting with two payloads, and JSKN021 (Alphamab) and CAN016 (CanWell Pharma) for HER2-refractory disease [25].

The same review also points to an important limitation of dual-payload ADCs. Adding a second payload does not necessarily overcome resistance: if the tumor loses the target antigen, fails to internalize the ADC, or no longer processes it effectively in the lysosome, both payloads may lose their intended effect. The payload ratio is fixed during manufacturing, and adding two drugs increases analytical and manufacturing complexity [25]. Whether delivering both payloads in a single ADC offers an advantage over administering the drugs separately remains to be demonstrated in clinical trials.

Dose, distribution and the right patient

Some of the most useful gains in therapeutic index have come not from a new molecule but from smarter use of an existing one.

• Dose and potency. A safely administrable dose affects exposure and may influence tumor delivery, but dose alone does not explain differences between ADCs.  For example, trastuzumab deruxtecan and trastuzumab emtansine share an antibody, but they differ in linker, payload, DAR, payload permeability, and other design features, in addition to their dose regimens. The newer drug is given at 5.4 mg/kg with DAR 8 and a bystander-active payload; the older drug is dosed at 3.6 mg/kg with DAR 3.5. Higher tolerated antibody doses help the conjugate penetrate deeper into tumor tissue [5]; however, comparisons between trastuzumab deruxtecan and trastuzumab emtansine should account for the full constructs and the clinical settings in which they were studied. The contrasting lesson came from D6.5 (also known as SC-DR002 or SG3199), a highly potent synthetic pyrrolobenzodiazepine (PBD) dimer developed as a cytotoxic payload for ADCs. D6.5 was incorporated into rovalpituzumab tesirine (Rova-T; SC16LD6.5; AbbVie), an investigational DLL3-directed ADC developed for small-cell lung cancer (SCLC). Although DLL3 is expressed in more than 80% of SCLC tumors, the clinical development of rovalpituzumab tesirine was limited by a narrow therapeutic window and significant toxicities, including thrombocytopenia, pleural effusions, and skin reactions. The recommended phase 2 regimen was 0.3 mg/kg every six weeks, and clinical activity in the phase 2 TRINITY study (NCT02674568) was modest, with an objective response rate of 12.4% in the overall study population. Rovalpituzumab tesirine’s discontinuation shows that a potent cytotoxic payload and a prevalent tumor-associated target are not enough to ensure clinical success when tolerability and therapeutic exposure limit benefit. [5]
• Co-dosing with unconjugated antibody. IKS04 (Iksuda Therapeutics), a CA242-directed ADC carrying a Femtogenix-developed, sequence-selective DNA-interactive PBD prodrug activated through a β-glucuronidase-sensitive linker system, illustrates how antibody co-dosing may influence ADC distribution within solid tumors. Administering the ADC alongside an excess of unconjugated antibody can occupy antigen-binding sites near blood vessels, potentially allowing more of the conjugate to penetrate deeper into the tumor. In preclinical models, this strategy improved tumor penetration and efficacy in tumors with moderate-to-high antigen expression. However, in low-expressing tumors, the unconjugated antibody competed with the ADC and reduced activity, highlighting the importance of target expression and patient selection [28]. Professor Peng Guo, PhD, of the Hangzhou Institute of Medicine, Chinese Academy of Sciences, discussed a related strategy. His presentation, “Exploring ‘ADC + Antibody’ as an Emerging Combination Strategy for Solid Tumor Therapies,” examined combining a HER2-targeted ADC with unconjugated trastuzumab, including preclinical and clinical findings and the potential role of antibody co-dosing in overcoming the binding-site barrier and improving tumor penetration [14]. Although distinct from the IKS04 approach, Professor Guo’s presentation highlights the broader potential of combining an ADC with an unconjugated antibody to improve tumor penetration and antitumor activity in solid tumors.

Breast cancer as a test case. Chapman and colleagues use breast cancer to argue that target choice must become a delivery question: not only whether an antigen is on the tumor, but how fast it internalizes, whether it recycles, and where else in the body it lives [11].

Breast cancer is a useful setting for examining target selection because researchers study or use several ADCs directed at different antigens. Trial counts for HER2, TROP2, HER3, and other targets depend on the dataset, inclusion criteria, and cutoff date; they describe research activity rather than comparative efficacy [11]. Normal-tissue expression, internalization, recycling, and the broader tumor microenvironment all affect whether a target is suitable for a particular ADC. HER2 still dominates, at 61.8% of breast cancer ADC trials with a defined target, followed by TROP2 (28.4%) and HER3 (3.8%), with Nectin-4, folate receptor α, B7-H3, and B7-H4 among the next tier [11]. Folate receptor α is a telling example. It is limited in most normal adult tissue, yet found in about 60% of chemotherapy-resistant residual triple-negative tumors (TNBC), a group at high risk of relapse [11].

Beyond antigen expression. Pistilli and colleagues argue that ADC activity depends on more than target expression. Tumor cell features and the surrounding microenvironment also shape response, which is why they describe ADCs as therapies aimed at a tumor ecosystem rather than a single receptor [13].

At the 17th World ADC in San Diego, Abraham Apfel, Ph.D., Associate Director of Clinical Data Science at Eisai, presented an analysis combining genomic profiling with Tempus real-world data ** to investigate associations between somatic mutations and treatment outcomes in patients with metastatic breast cancer receiving trastuzumab deruxtecan (T-DXd). The analysis identified PIK3CA mutations as a candidate biomarker associated with improved outcomes in the HER2-low subgroup, including longer real-world progression-free survival (P = 0.007) and overall survival (P = 0.002). However, most models were no longer statistically significant after false-discovery-rate adjustment. The findings suggest that PIK3CA warrants further investigation as a potential biomarker of T-DXd outcomes in HER2-low metastatic breast cancer, but do not establish it as a validated predictor of treatment response [14].

Liyu Wu, Ph.D., Global Vice President of Business Development at LIDE Biotech, presented data from a translational platform for ADC evaluation and next-generation target discovery. The presentation, titled “Beyond the Antigen: Exploring a Translational Platform for ADC Evaluation & Next-Generation Target Discovery,” described findings from payload-resistant models indicating that resistance was associated primarily with the payload’s mechanism of action and was largely independent of the target antigen. The work highlights the importance of evaluating payload-specific resistance alongside target expression when assessing ADC activity and considering next-generation ADC candidates [14].

Trial design is catching up. TRADE-DXd (NCT06533826) gives patients one ADC and, at progression, mandates crossover to an ADC against a different antigen, tracking HER2 and TROP2 expression along the way. The NCI’s ADC MATCH (NCT06311214) assigns ADCs based on RNA and protein testing, and tracks changes in antigen expression and the tumor microenvironment during treatment [11]. Mosele and colleagues add a blunt observation: the pace of chemical innovation now outruns clinical trials’ capacity to test it, so frameworks that de-risk candidates before they reach patients have become as important as the chemistry itself [29].

Moving into earlier lines. As ADCs move toward curative-intent settings, the cost of toxicity changes. A patient with early breast cancer may live for decades after treatment; hence, long-term pulmonary, ocular, hematologic, or other adverse effects weigh differently than they do in last-line disease and may affect patients for years. Clinical evaluation should therefore consider not only the response rate, but also duration of response, progression-free and overall survival where appropriate, treatment discontinuation, cumulative toxicity, symptoms, and health-related quality of life. As such, the most relevant endpoints depend on disease setting and treatment intent.

At the 17th World ADC San Diego, Rita Nanda, MD, Associate Professor of Medicine and Director of the Breast Oncology Program at the University of Chicago, presented “Evaluating I-SPY2 Clinical Data & Toxicity Monitoring to Assess ADC Progression to Early-Stage Oncology Settings in TNBC & HER2+ Breast Cancer.” The presentation examined antibody–drug conjugates (ADCs) in earlier-stage breast cancer, including clinical data for trastuzumab deruxtecan and datopotamab deruxtecan. Particular attention was given to monitoring for interstitial lung disease (ILD), a potentially serious toxicity associated with these agents [14].

I-SPY2 (NCT01042379) is an ongoing, multicenter, phase 2 adaptive clinical trial platform that evaluates investigational treatments in patients with high-risk, early-stage breast cancer in the neoadjuvant (pre-surgery) setting. Its role in ADC development is particularly relevant as researchers investigate whether agents initially developed for advanced disease can be used earlier in treatment, where both treatment-related toxicity and the potential for long-term benefit require careful consideration.

Another presentation addressed how molecular residual disease (MRD) testing could inform ADC development. In her presentation, “From Residual Disease to Earlier Approval: Leveraging Molecular Residual Disease & ctDNA to Accelerate ADC Development,” Vikki Cerniglia, BS, Senior Director of Biopharma Business Development at Natera, examined the potential of circulating tumor DNA (ctDNA) analysis to track tumor burden, detect cancer-associated mutations, and assess molecular response through a minimally invasive liquid biopsy. In solid tumors, including non-small cell lung cancer (NSCLC), ctDNA-based approaches are being investigated for MRD assessment, risk stratification, and treatment monitoring. In ADC development, these measures may provide early evidence of biological activity and help inform clinical decisions before conventional endpoints such as progression-free survival (PFS) or overall survival (OS) have fully matured. However, their prognostic or predictive value, and their ability to serve as surrogate endpoints, depend on the cancer type, clinical setting, and supporting validation data. ctDNA-based measures therefore complement, rather than automatically replace, established clinical endpoints [14].

The clinical development of established ADCs was another focus, highlighting how treatment positioning can evolve as clinical evidence accumulates. Ronald Fleming, PharmD, Executive Director of Clinical Development at Daiichi Sankyo US, discussed “The Transition of an ADC From Late-Line to First-Line Therapy in HER2+ Breast Cancer & Earlier Line Gastric Cancer: The Trastuzumab Deruxtecan (T-DXd) Example.” His presentation examined trastuzumab deruxtecan’s clinical trajectory, from use in previously treated patients to expansion into earlier settings, including first-line therapy in combination with pertuzumab (Perjeta®; Genentech/Roche) for HER2-positive metastatic breast cancer. The discussion also addressed evaluating trastuzumab deruxtecan in earlier-line gastric cancer, where treatment sequencing and selecting appropriate combination partners remain important considerations [14]. This evolution illustrates how the clinical role of an ADC depends not only on its molecular design and antitumor activity, but also on comparative efficacy, tolerability, biomarker-defined patient selection, and its position relative to existing treatment options. As with other ADCs, monitoring for adverse events, particularly interstitial lung disease (ILD) and pneumonitis, remains important as T-DXd use expands across clinical settings. [14]

What the 17th World ADC, San Diego, further added 

At the 17th World ADC San Diego, many of the strategies discussed in this review appeared on the program with preclinical and clinical evidence.*[14]

• Masked and multispecific antibodies reached the clinic. CytomX chief executive Sean McCarthy, D.Phil, presented Phase I data for varsetatug masetecan in colorectal cancer, linking the masked design to the clinical profile [18]. Salubris Biotherapeutics presented expansion-cohort data for JK06 during Day Two of the 17th World ADC conference in San Diego. In his presentation, “Analyzing JK06 Phase I/II Expansion Cohort Data: Leveraging Biparatopic & Conjugation Design to Unlock Novel Activity & Safety Profile,” Samuel Murphy, PhD, Chief Executive Officer of Salubris Biotherapeutics, discussed the candidate’s biparatopic design, which enables binding to two epitopes, alongside stable, site-specific payload conjugation. Together, these design features were presented as contributing to JK06’s potential for robust antitumor activity and a favorable safety profile in lung and breast cancer cohorts. [18] SystImmune’s late-afternoon session featured izalontamab brengitecan. In his presentation, “Spotlighting the Clinical Performance of Izalontamab Brengitecan Bispecific ADC,” Jimmy Zhao, MD, Ph.D., Global Asset Lead for izalontamab brengitecan, reviewed the candidate’s clinical profile, its development strategy, and the potential advantages of bispecific targeting over conventional monospecific ADCs. Earlier that day, Dan Chen, MD, Ph.D., Partner at Genesis BioCapital, presented “Innovating the A of ADC: Breaking Down Mechanisms, Learnings & Clinical Prospect of Multispecific ADCs,” discussing masked and conditionally active ADCs and logic-gated designs, including AND-gated EGFR×c-MET ADCs.[18] Aarvik Therapeutics highlighted its MUTTA™ platform for engineering dual-targeting ADCs, reporting that screening more than 50 target pairs had yielded over 15 novel candidates, including AV-P138-ADC (ARR-002), a preclinical tetravalent ADC targeting MUC16 and NaPi2b for ovarian and endometrial cancers. The company also presented its AQUALINK™ platform, which uses sugar-based spacers and engineered antibody conjugation sites to improve ADC hydrophilicity and potentially address limitations associated with hydrophobic payloads. Separately, Patrick Zweidler-McKay, MD, PhD, Chief Medical Officer of NEOK Bio, presented “The Emerging Wave of Bispecific ADCs: Breaking Down Design & Rationale for NEOK001 & NEOK002.” He examined the design and rationale behind two bispecific ADC candidates: NEOK001 (ABL206), which targets B7-H3 and ROR1, and NEOK002 (ABL209), which targets EGFR and MUC1.[14]
• Resistance after trastuzumab deruxtecan became the defining clinical question.

  Several groups presented dual-payload ADCs that combine a topoisomerase I inhibitor with a second mechanism of action. One of them is Callio Therapeutics’ CLIO-8221, a HER2-targeted ADC that combines a topoisomerase I inhibitor with an ATR inhibitor to target DNA damage response pathways tumor cells may use to survive treatment. The Phase 1/2 study (NCT07300943) began dosing its first patient in March 2026 and enrolls patients previously treated with trastuzumab deruxtecan [30]. On October 14, Callio received the Best New ADC Drug Developer award at the 13th World ADC Awards, recognizing its modular linker technology and pipeline of dual-payload ADCs designed to address treatment resistance in difficult-to-treat tumors. [30] Sutro Biopharma presented plenary data on the early clinical safety and pharmacokinetics of STRO-004, its tissue factor-targeted ADC, alongside preclinical findings for STRO-227, a dual-payload conjugate evaluated in resistance models [31]. Henry Yu, PhD, Chief Executive Officer and President of CanWell Pharma, presented “Exploring the Preclinical Profile & IND Journey of Dual Payload ADC CAN016 for HER2 Refractory Patients.” The presentation covered CAN016’s preclinical profile, including nonhuman primate toxicology data, its pre-IND regulatory strategy, and its planned progression toward first-in-human testing in patients with HER2-refractory or trastuzumab deruxtecan-resistant solid tumors. [14].  Sonny Hsiao, Ph.D., Founder and CEO of Acepodia Biotech, presented the engineering-free dual-payload approach. He introduced the company’s proprietary Antibody-Dual-Drug Conjugation platform, which enables dual-payload conjugation without antibody engineering, unnatural amino acids, or enzymatic ligation. [18]. Resistance can also be addressed by changing linker chemistry, which affects payload stability, release, and an ADC’s therapeutic index. At the 17th World ADC San Diego, Noémie Luong, Ph.D., Associate Principal Scientist in Translational Pharmacology at Debiopharm, presented “Evaluating Preclinical Performance of Novel Linker-Payloads to Widen ADC Therapeutic Index,” and “Leveraging MultiLINK™ Technology to Optimize ADC Selection & Improve the Therapeutic Window of ADCs.” [18]. Her presentations covered Debiopharm’s MultiLINK™ technologies, including MLINK Select, designed to improve control of monomethyl auristatin E (MMAE) release in vedotin-based ADCs; MLINK Duo, a dual-payload linker approach intended to combine complementary mechanisms of action; and MLINK HiSol, a modular linker platform being investigated for payloads beyond conventional cytotoxic agents. Reported preclinical findings included antitumor activity in selected ADC-resistant models, synergistic effects with dual-payload designs, and approaches to incorporating less conventional payload classes. These findings illustrate how linker and payload engineering may help address resistance and therapeutic-index limitations, although their clinical relevance remains to be established [18].

• Payloads beyond topoisomerase I. The opening panel, with leaders from Amgen, Daiichi Sankyo, Iksuda, Pfizer and Regeneron, asked whether the field is innovating enough beyond topoisomerase I payloads [9]. The program offered several preclinical-stage answers. AstraZeneca described degrader (PROTAC) payloads aimed at an oncology target that small-molecule inhibitors had failed to control. Pfizer and Hexagon Bio presented payloads that block protein translation, and Iksuda introduced IKS073, a B7-H3 ADC built on a protein-alkylating payload [14]. AbbVie (a PI3K/mTOR inhibitor) and Byondis (an antifolate) added further mechanisms, while Pfizer’s GPNMB conjugate uses a modified auristatin intended to be better tolerated than vedotin constructs [14][18]. Genentech’s Gail Lewis, PH.D., received the Longstanding Contribution to the Field Award (also known as the Toshinori Agatsuma Memorial Award; named for Daiichi Sankyo’s late head of research) during the 13th Annual World ADC Awards in San Diego, and opened the second day on non-cytotoxic payloads as a route to a wider therapeutic index [18].
• Non-traditional formats. The organizers of the 17th World ADC, San Diego, counted 575 non-traditional ADCs in development, nearly double the number a year earlier, spanning degrader-antibody conjugates (DACs), immune-stimulating antibody conjugates (ISACs), antibody-oligonucleotide conjugates (AOCs) and bispecific and dual-payload formats [32]. Pyxis Oncology’s micvotabart pelidotin (MICVO; previously known as PYX-201) illustrates a stromal-targeting approach directed against fibronectin extradomain B (EDB+FN), a structural component of the tumor extracellular matrix rather than a tumor-cell surface antigen. At the 17th World ADC San Diego, Anthony B. Rodriguez, Ph.D., Associate Director at Pyxis Oncology, presented preclinical findings on micvotabart pelidotin, including its antitumor activity, immunostimulatory effects, and potential synergy with immunotherapy in sensitive and treatment-refractory tumor models. [14].
• Conjugation and manufacturing. The move away from random conjugation was visible across tracks: Abzena’s ThioBridge disulfide re-bridging, Genovis’ GlyCLICK and Lonza’s GlycoConnect glycan methods (the latter in more than 30 partnered ADCs), Ajinomoto’s AJICAP site-specific chemistry including DAR 1 constructs, and CatenaBio’s CysTyr platform [14][18]. On the manufacturing side, Genentech described automated process analytical technology (PAT) for real-time monitoring of conjugation, Immunome laid out a path from CDMO start to IND filing in about one year, and Callio argued that dual-payload ADCs can be made at costs comparable to single-payload conjugates [14]. Defense Therapeutics’ poster on intracellular trafficking won the meeting’s Best Poster award, and its main-stage session asked whether the next frontier lies between binding and payload release [33].
• A patient in the room. On the first evening, Kelly Shanahan, MD, president of the metastatic breast cancer organization METAvivor, spoke to an audience of chemists and drug developers about living with cancer and its treatment. Her point was simple: extra time without quality of life is not a victory, and trials shaped with input from patients are better trials [14]. Coming just before a session on lung toxicity in early breast cancer, it framed the therapeutic index in the terms patients use.

The themes echoed those reported from World ADC London in February 2026, where speakers emphasized designing antibody, linker, and payload as a single system and using membrane protein data, rather than RNA, to find antigen pairs for bispecific ADCs [34].

Researchers from Iksuda Therapeutics played a prominent role, with Jutta Deckert, Ph.D., Vice President of Research & Development, chairing the clinical track and Robert Lutz, Ph.D., Chief Scientific Officer, delivering the main program’s closing presentation [18].

Across the sessions, a central question remained: as ADCs compete in increasingly crowded indications, do advances in molecular design translate into meaningful improvements in efficacy, safety, tolerability, and ultimately, patients’ quality of life? For clinicians and payers, the value of innovation depends not only on the sophistication of the design, but on whether it delivers measurable benefits in clinical practice.

Discussion

Twenty-six years after the first approval, the ADC field has learned to make its molecules more stable, more uniform and more potent. The harder lesson, written into the withdrawals and re-approvals of the past two decades, is that precision belongs to the whole system: the antibody, the chemistry, the dose, the tumor’s biology, and the patient chosen to receive it. The strategies now reaching the clinic each answer a specific way earlier ADCs failed people, whether through blurred vision, dangerously low blood counts or a tumor that simply stopped responding.

For clinicians, the near-term priorities are increasingly practical: understanding how antigen selection, payload class, and prior ADC exposure influence treatment sequencing. Studies such as TRADE-DXd and biomarker-led trials like ADC MATCH aim to address these questions. As review teams have emphasized, ADCs remain among the most complex and costly biologics to manufacture, making equitable patient access an important measure of progress [11]. Researchers are now testing the same design principles beyond cancer, in autoimmune, infectious, and neurodegenerative diseases [12].

Beyond oncology, related conjugate-based approaches are being explored in other therapeutic areas. AC Immune’s morphomer-antibody drug conjugates (morADCs), for example, are a preclinical platform designed to facilitate delivery across the blood–brain barrier and target pathological proteins associated with neurodegenerative diseases, including tau, amyloid-beta, and alpha-synuclein; the platform has not yet entered clinical trials [9]. In metabolic disease, Amgen’s maridebart cafraglutide (MariTide; AMG 133) illustrates a different application of conjugate technology. Classified as an antibody-peptide conjugate rather than a conventional ADC, it combines GIP receptor antagonism with GLP-1 receptor agonism and is being evaluated in Phase 3 clinical trials for obesity and related conditions [10]. In cardiovascular research, researchers are also investigating antibody-mediated delivery of liver X receptor (LXR) agonists as a preclinical strategy to target macrophages, promote cholesterol removal from atherosclerotic plaques, and potentially limit the systemic adverse effects associated with LXR activation [19]. These approaches illustrate how antibody-based targeting and conjugation technologies may extend beyond cytotoxic drug delivery, although their mechanisms, development stages, and clinical evidence differ substantially.

Ultimately, if the next decade delivers what the last two decades have promised, success will depend not simply on developing more potent payloads, but on delivering targeted treatments that are effective, tolerable, accessible, and sustainable for the patients who need them.

Note

* Full data sets will follow later this year in select publications. In this review, the data reflect what was presented during the conference, including the companies’ own announcements and presentations.
** The same data and conclusions were presented at the annual meeting of the American Association for Cancer Research (AACR), held April 17-22, 2026 at the San Diego Convention Center in San Diego, California.

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Featured image: CH DO 17th World ADC San Diego, 2026. Used with permission

DOI: 10.14229/jadc.2026.20.10.002