Antibody-drug conjugates (ADCs)

01Overview and value chain#

Markers EC: REACH | OECD: bio-pharma | Regulator: FDA (USA), NMPA (China), EMA (EU)

An antibody-drug conjugate pairs a monoclonal antibody that targets a tumor-surface antigen with a highly potent cytotoxic payload, joined by a chemical linker engineered to stay stable in circulation and release the payload only after the antibody carries it inside the target cell. The result is chemotherapy-grade cell killing delivered with antibody-level selectivity, and it has become one of oncology’s clearest recent commercial successes: Daiichi Sankyo and AstraZeneca’s Enhertu (trastuzumab deruxtecan) has expanded from HER2-positive breast cancer to a tumor-agnostic EU approval for any HER2-positive solid tumor. But the field’s core engineering trade-off — payload potency versus off-target toxicity — remains unresolved even in late-stage, efficacy-positive trials: ADC Therapeutics’ Phase 3 LOTIS-5 trial of Zynlonta plus rituximab hit its progression-free-survival endpoint in 2026 while showing roughly three times the treatment-emergent death rate of the control arm, concentrated in patients over 75.

The key directions are:

1. HER2-targeted ADCs: The field’s most commercially mature target, led by Enhertu and RemeGen/Seagen’s disitamab vedotin, expanding from breast and gastric cancer into a widening set of HER2-expressing solid tumors.
2. Novel payload chemistry: Topoisomerase-I inhibitor payloads (deruxtecan-class) delivering a strong “bystander effect” that kills neighboring antigen-low tumor cells, distinct from the older auristatin/maytansine payload classes.
3. Linker engineering: Cleavable linkers (protease- or pH-sensitive) that release the payload inside the target cell versus non-cleavable linkers designed for maximum circulating stability.
4. Combination regimens: Pairing an ADC with a checkpoint inhibitor or a bispecific antibody to raise response rates, which is also where some of the field’s sharpest safety trade-offs are surfacing.

Sectoral value chain#

[Antigen target validation] ──> [Antibody + linker-payload engineering] ──> [Conjugation & GMP manufacturing] ──> [Purification & DAR QC]
                                  │
                          (Clinical trials in target-expressing tumors)
                                  │
                                  ▼
[Combination-regimen development] <─── [Regulatory approval] <─────┘

Value chain levels#

Cross-cutting technologies of the sector:

• Bystander effect payloads: Membrane-permeable payloads (deruxtecan-class) that diffuse out of the targeted cell after release and kill neighboring tumor cells with lower antigen expression, widening the population an ADC can treat.
• Site-specific conjugation: Engineering defined attachment points on the antibody (rather than conjugating to random lysines) to produce a homogeneous drug-to-antibody ratio, improving both potency consistency and manufacturability.
• Cleavable vs. non-cleavable linker chemistry: The choice directly trades off payload release efficiency against circulating stability, and is a large part of why two ADCs against the same target can have very different toxicity profiles.

02US#

The United States hosts the field’s dominant commercial platform following 2023’s largest ADC-driven acquisition, alongside a second major ADC franchise built on an entirely different tumor-antigen strategy.

Post-acquisition portfolio consolidation, a second blockbuster franchise#

• Seagen (a Pfizer company): Pfizer’s $43 billion acquisition of Seagen closed in December 2023, bringing Adcetris (brentuximab vedotin) and Padcev (enfortumab vedotin) plus Seagen’s ADC development platform into Pfizer’s oncology portfolio; Seagen had separately in-licensed ex-Asia rights to RemeGen’s disitamab vedotin in 2021.
• Gilead Sciences: Trodelvy (sacituzumab govitecan), a Trop-2-targeted ADC, is Gilead’s ADC franchise sitting alongside its (separately tabled) antiviral and Kite Pharma CAR-T businesses — a distinct product line built through Gilead’s 2020 acquisition of Immunomedics.

03CN#

China moved from ADC licensor to genuine co-developer in this field faster than in most other biologics categories, anchored by the country’s first homegrown approved ADC.

First domestic ADC approval, an active Phase 3 combination programme#

• RemeGen: disitamab vedotin (marketed in China as Aidixi, known in trials as RC48-ADC) became China’s first domestically developed ADC approved for HER2-overexpressing gastric cancer in 2021; RemeGen out-licensed ex-Asia rights to Seagen for $200 million upfront the same year, and in May 2025 reported that a Phase 3 trial combining disitamab vedotin with the PD-1 inhibitor toripalimab as first-line therapy for HER2-expressing urothelial carcinoma hit both its progression-free-survival and overall-survival endpoints.
• No second China-headquartered company with an approved or late-stage novel ADC comparable to RemeGen’s was confirmed — the category here is currently a single strong producer rather than a broad domestic field.

04EU#

Europe anchors one half of the field’s biggest commercial success and, separately, supplies the year’s sharpest cautionary data point on ADC safety.

Enhertu’s label expansion, a real mortality signal in a PFS-positive trial#

• AstraZeneca: co-develops and co-commercializes Enhertu with Daiichi Sankyo; in 2026 the companies secured EU approval of Enhertu as a tumor-agnostic monotherapy for previously treated HER2-positive solid tumors, and FDA priority review for use after neoadjuvant treatment in HER2-positive early breast cancer.
• ADC Therapeutics: the Swiss company’s Phase 3 LOTIS-5 trial of Zynlonta (loncastuximab tesirine) plus rituximab met its primary progression-free-survival endpoint in 2026, but treatment-emergent adverse-event deaths ran roughly three times higher than the control arm — 27 deaths, over half infection-related, 16 in patients 75 or older — prompting a protocol amendment adding upfront immune-status screening and prophylaxis to a concurrent trial ahead of a planned Q4 2026 regulatory filing.
• Regulatory pattern: the EMA’s willingness to grant Enhertu a tumor-agnostic (histology-independent) approval, a first for an ADC in the EU, signals how far regulatory confidence in the modality has grown even as the LOTIS-5 result shows the underlying toxicity risk has not gone away.

05Leading companies and research institutes#

06Tech stack and innovations#

The stack is dominated by the linker-payload chemistry that determines whether an ADC’s potency translates into a workable therapeutic window or into the kind of safety signal LOTIS-5 surfaced.

1. Topoisomerase-I Inhibitor Payloads:
   • Deruxtecan-class payloads are membrane-permeable after release, producing a bystander effect that kills neighboring tumor cells with lower target-antigen density — a major reason Enhertu-class ADCs work across a wider range of HER2 expression than earlier-generation ADCs required.
2. Site-Specific Conjugation Chemistry:
   • Engineered cysteine or unnatural amino acid attachment points produce a defined, homogeneous drug-to-antibody ratio (commonly DAR 4 for deruxtecan-class ADCs), versus the heterogeneous DAR distributions produced by conjugating to native lysine residues.
3. Cleavable Linker Design:
   • Protease-cleavable (valine-citrulline) and pH-sensitive hydrazone linkers are tuned to stay intact in systemic circulation and release payload specifically inside the acidic, protease-rich lysosomal environment of the target cell after antibody-mediated internalization.

07Value chains and production pipelines#

Industrial pipeline of ADC manufacturing (Commercial Grade)#

┌───────────────────────────┐      ┌───────────────────────────┐
│ 1. Antibody production    │ ───> │ 2. Linker-payload          │
│    (mammalian cell culture)│      │    synthesis                │
└───────────────────────────┘      └───────────────────────────┘
                                                 │
                                                 ▼
┌───────────────────────────┐      ┌───────────────────────────┐
│ 4. Purification & DAR QC   │ <─── │ 3. Conjugation reaction    │
└───────────────────────────┘      └───────────────────────────┘
              │
              ▼
┌───────────────────────────┐      ┌───────────────────────────┐
│ 5. Formulation & sterile   │ ───> │ 6. Release testing &       │
│    fill-finish             │      │    shipment                 │
└───────────────────────────┘      └───────────────────────────┘

Stage 1: Antibody production

The targeting monoclonal antibody is expressed in mammalian cell culture (typically CHO cells) and purified to the standard required for subsequent chemical conjugation.

Stage 2: Linker-payload synthesis

The cytotoxic payload (a topoisomerase-I inhibitor, auristatin, or maytansinoid, depending on the ADC) is chemically pre-attached to its linker molecule in a separate synthesis stream.

Stage 3: Conjugation reaction

The linker-payload construct is chemically attached to the antibody, either at engineered site-specific positions or at native reactive residues, under controlled reaction conditions targeting the desired drug-to-antibody ratio.

Stage 4: Purification and DAR QC

Chromatography removes unconjugated antibody, free linker-payload, and aggregates, and analytical methods (hydrophobic-interaction or reversed-phase chromatography, mass spectrometry) confirm the DAR distribution meets specification.

Stage 5: Formulation and sterile fill-finish

The purified conjugate is formulated into its final buffer and aseptically filled, since ADCs, like most biologics, cannot be terminally sterilized without degrading the antibody or payload.

Stage 6: Release testing and shipment

Each lot undergoes identity, potency, DAR and sterility release testing before cold-chain shipment, with ongoing pharmacovigilance monitoring for the kind of late-emerging safety signals seen in LOTIS-5.