Introduction
Antibody–drug conjugates (ADCs) combine the tumor-targeting specificity of monoclonal antibodies with the cytotoxic potency of small-molecule payloads, connected by a chemical linker. Since 2020, the ADC field has undergone a profound transformation: from a handful of early-generation agents to a globally competitive ecosystem of more than 15 approved products spanning hematologic malignancies and solid tumors, with hundreds of programs in active development across the United States, European Union, China, and Japan 123. This narrative review synthesizes key 2020–2026 developments in ADC linker design, payload diversification, target biology, and clinical positioning for oncologists, hematologists, and clinical researchers.
Technology Evolution: How Next-Generation ADCs Differ
First-generation ADCs (approved 2013–2019) relied predominantly on heterogeneous lysine conjugation, non-cleavable or early protease-cleavable linkers, and potent microtubule inhibitors (e.g., trastuzumab emtansine/T-DM1) requiring low drug–antibody ratios (DAR; typically 2–4) to maintain tolerability. Next-generation ADCs (2020–2026) differ in several intersecting dimensions 12:
- Higher, more homogeneous DAR: Site-specific conjugation using engineered cysteine residues or unnatural amino acids yields consistent DAR 2–8, reducing batch-to-batch variability and off-target toxicity.
- Improved linker stability: Hydrophilic linker modifications (e.g., polyethylene glycol, polysarcosine-based platforms) mask the hydrophobicity inherent to high-DAR constructs, preserving pharmacokinetic (PK) profiles similar to unconjugated antibodies.
- Diversified payload classes: Topoisomerase I (Topo-I) inhibitors (e.g., deruxtecan/DXd) have supplanted microtubule inhibitors as the dominant next-generation payload, enabling higher DAR and robust bystander killing.
- Bystander effect exploitation: Membrane-permeable released payloads diffuse into neighboring antigen-negative cells, addressing antigen heterogeneity and resistance—a critical advantage in solid tumors 13.
Linker Innovation
The linker governs plasma stability, tumor-selective payload release, bystander killing potential, and systemic toxicity. Early maleimidocaproyl linkers were susceptible to premature deconjugation via retro-Michael reactions with plasma albumin; next-generation designs have substantially mitigated this liability 1.
Table 1. Linker Strategies in Next-Generation ADCs
| Linker Type | Release Trigger | Key Advantages | Key Limitations | Clinical Relevance/Examples |
|---|---|---|---|---|
| Protease-cleavable (Val-Cit-PABC; vedotin family) | Lysosomal cathepsin proteases | Efficient intracellular release; bystander potential with membrane-permeable payloads | Variable plasma kinetics; potential off-target protease cleavage | Enfortumab vedotin (Nectin-4–MMAE); tisotumab vedotin (TF–MMAE) |
| Protease-cleavable (peptide-based; deruxtecan family) | Enzymatic cleavage; self-immolative | Durable responses; activity in low-antigen/heterogeneous tumors | ILD/pneumonitis risk with DXd payloads | Trastuzumab deruxtecan (HER2); datopotamab deruxtecan (TROP2); ifinatamab deruxtecan (B7-H3) |
| Acid-labile (hydrazone) | Endosomal/lysosomal low pH | Simpler chemistry; can enable bystander effect | Greater off-tumor release risk | Earlier-generation hydrazone-linked ADCs (e.g., gemtuzumab ozogamicin) |
| Non-cleavable (SMCC) | Antibody lysosomal degradation | High plasma stability; defined catabolite; reduced systemic payload | Limited bystander effect; less suited to antigen-heterogeneous tumors | Trastuzumab emtansine (T-DM1); belantamab mafodotin (BCMA–MMAF) |
| Disulfide | Intracellular reducing environment | Tunable stability via steric hindrance | Risk of extracellular reduction; conjugation heterogeneity | Earlier-generation ADCs; less common in 2020–2026 programs |
| Hydrophilic/conditionally stable (polysarcosine, PEG-incorporating) | Enzymatic cleavage with hydrophilicity masking | Improved PK; reduced aggregation; supports high DAR; bystander-compatible | Complex synthesis; linker–payload optimization required | Emerging high-DAR platforms; peptide-based conjugates (e.g., zelenectide pevedotin/BT8009) |
Abbreviations: DAR, drug–antibody ratio; DXd, deruxtecan payload; ILD, interstitial lung disease; MMAE, monomethyl auristatin E; MMAF, monomethyl auristatin F; PABC, para-aminobenzyl carbamate; PEG, polyethylene glycol; PK, pharmacokinetics; SN-38, active metabolite of irinotecan; TF, tissue factor; Val-Cit, valine-citrulline.
A notable example of linker-driven differentiation is the peptide-based Bicycle toxin conjugate zelenectide pevedotin (BT8009; Nectin-4–MMAE), which exhibits a short plasma half-life (<1 hour) and low rates of classical ADC toxicities (e.g., reduced neuropathy and ocular events). When combined with pembrolizumab in cisplatin-ineligible metastatic urothelial carcinoma (mUC), an objective response rate (ORR) of 65% (complete response [CR] 25%) was reported in first-line patients, with a differentiated safety profile 12.
Payload Evolution
The shift from microtubule inhibitors to Topo-I inhibitors has been the single most consequential payload transition of the 2020–2026 period 13.
Table 2. Payload Classes in Next-Generation ADCs
| Payload Class | Mechanism of Action | Bystander Potential | Common Toxicity Considerations | Representative ADCs/Programs |
|---|---|---|---|---|
| Topo-I inhibitors (DXd, SN-38) | Stabilize DNA–topoisomerase I complex; lethal DNA damage during replication | High (membrane-permeable metabolites diffuse to antigen-negative cells) | ILD/pneumonitis; myelosuppression (anemia, neutropenia); GI toxicity | T-DXd (Enhertu); sacituzumab govitecan (Trodelvy); datopotamab deruxtecan; ifinatamab deruxtecan; IBI354; DB-1303 |
| Microtubule inhibitors (MMAE/MMAF; DM1/DM4) | Disrupt microtubule dynamics; mitotic arrest and apoptosis | MMAE: moderate–high; MMAF/DM1: low–moderate | Peripheral neuropathy (MMAE); ocular events (MMAF); hepatotoxicity (DM1); cytopenias | Enfortumab vedotin; tisotumab vedotin; belantamab mafodotin; T-DM1 |
| DNA-damaging agents (calicheamicins, PBDs, duocarmycins) | DNA double-strand breaks; alkylation/crosslinking | High | Myelosuppression; hepatotoxicity; ocular toxicity (some duocarmycins) | Gemtuzumab ozogamicin (CD33); inotuzumab ozogamicin (CD22); loncastuximab tesirine (CD19); vobramitamab duocarmazine (B7-H3) |
| Immune-stimulatory (TLR7/8 agonists, STING agonists) | Innate/adaptive immune activation; inflammatory tumor microenvironment remodeling | Variable | Cytokine release; systemic inflammatory reactions | BDC-1001 (HER2–TLR7/8; ~29% response at RP2D; grade ≥3 TRAE 7.6%); SBT6050 (HER2–TLR8) |
| Emerging non-cytotoxic payloads (protein degraders, metabolic modulators) | Targeted protein degradation (PROTACs); metabolic disruption | Uncertain; program-dependent | Class-specific; emerging | ORM-5029 (HER2-targeted degrader payload); preclinical/early development |
Abbreviations: GI, gastrointestinal; PBD, pyrrolobenzodiazepine; PROTAC, proteolysis-targeting chimera; RP2D, recommended Phase 2 dose; TLR, Toll-like receptor; TRAE, treatment-related adverse event.
Topo-I inhibitor ADCs achieve higher DAR (typically 8) because their lower individual cytotoxic potency is offset by greater payload quantity per antibody. This design yields superior bystander killing in antigen-heterogeneous solid tumors—an activity pattern demonstrated by trastuzumab deruxtecan (T-DXd) in HER2-low breast cancer (ORR 37.0%) and HER2-mutant non-small cell lung cancer (NSCLC; ORR 72.7%) 12. However, the DXd payload class carries a class-defining risk of interstitial lung disease/pneumonitis (ILD): across pan-tumor programs, any-grade ILD has been reported in approximately 10–11% of patients, including rare fatal cases, necessitating systematic baseline imaging, patient education, and early corticosteroid intervention 12.
Target Selection and Biology
Table 3. Selected ADC Targets and Clinical Differentiation
| Target | Major Tumor Types | Biological Rationale | Representative ADCs | Differentiating Clinical Considerations |
|---|---|---|---|---|
| HER2 | Breast, gastric/GEJ, NSCLC, pan-tumor HER2-mutant | Oncogenic amplification; robust internalization | T-DXd (Enhertu); T-DM1 (Kadcyla); disitamab vedotin; DB-1303; IBI354; JSKN003 | Activity in HER2-low and HER2-mutant; ILD risk (DXd); expanding earlier-line and neoadjuvant/adjuvant use (May 2026 FDA approval for early HER2+ breast) |
| TROP2 | TNBC, NSCLC, urothelial, gynecologic, GI | Broad epithelial overexpression; rapid internalization | Sacituzumab govitecan (Trodelvy); datopotamab deruxtecan; sacituzumab tirumotecan (MK-2870) | Bystander effect critical; mucosal AEs (stomatitis, nausea); NMPA approved sacituzumab tirumotecan for EGFR-mutant NSCLC (2025) |
| Nectin-4 | Urothelial, NSCLC, TNBC, HNSCC | Cell adhesion molecule; high expression in urothelial; internalization-competent | Enfortumab vedotin (Padcev); zelenectide pevedotin (BT8009); ADRX-0706; SKB-410 | Neuropathy and hyperglycemia (EV); NECTIN4 gene amplification enriches response (BT8009); lower neuropathy with novel auristatin payload (ADRX-0706, DAR 8) |
| B7-H3 (CD276) | SCLC, CRPC, NPC, NSCLC, HNSCC | Immune checkpoint-like; pan-tumor overexpression; internalizing | Ifinatamab deruxtecan (I-DXd); DS-7300; DB-1311; HS-20093; vobramitamab duocarmazine | SCLC ORR 52.4% (DS-7300); broad solid-tumor applicability; ILD at higher doses; hematologic AEs |
| CLDN18.2 | Gastric/GEJ, pancreatic | Tumor-restricted tight-junction isoform; tissue-selective | LM-302; AZD-0901/CMG901; IBI-343; JS-107 | LM-302: ORR 30.6%, median PFS 7.16 months in pretreated gastric cancer; predominantly China-focused Phase II–III programs |
| HER3 (ERBB3) | EGFR/HER-pathway tumors (NSCLC, breast, GI, prostate) | Heregulin-binding; contributes to TKI resistance; internalizing | Patritumab deruxtecan | DXd payload supports bystander effect; utility after HER-family TKI resistance |
| Tissue Factor (TF) | Cervical, HNSCC, pancreatic | Coagulation factor receptor (F3/CD142); overexpressed on tumor cells and tumor-associated vasculature | Tisotumab vedotin (Tivdak); MRG004A; XB002 | Ocular AEs (conjunctivitis, keratopathy) ~50% any-grade; MRG004A: ORR 33.3% in pancreatic cancer; XB002: free payload <1 ng/mL (low systemic exposure) |
| FRα (folate receptor alpha) | Ovarian, endometrial | Folate metabolism; high tumor expression; internalization | Mirvetuximab soravtansine (Elahere) | Traditional FDA approval March 2024 for platinum-resistant ovarian; keratopathy 30–40% any-grade |
| BCMA | Multiple myeloma | Plasma cell-specific marker | Belantamab mafodotin (Blenrep); CC-99712 | Ocular toxicity (MMAF); competitive positioning alongside TCE bispecifics and CAR-T |
| CD19 / CD22 / CD33 | B-cell lymphomas, B-ALL, AML | Lineage-restricted; validated internalization | Loncastuximab tesirine; inotuzumab ozogamicin; gemtuzumab ozogamicin | Myelosuppression; hepatotoxicity/VOD (inotuzumab); positioning evolving with CAR-T and bispecifics |
| CD123 | AML, BPDCN | Myeloid/plasmacytoid dendritic-cell specific | Pivekimab sunirine (PVEK) | CR 63.3% (PVEK + venetoclax + azacitidine in AML); BPDCN monotherapy ORR 90.9% in high-risk subgroup (ASH 2025) |
Abbreviations: AML, acute myeloid leukemia; B-ALL, B-cell acute lymphoblastic leukemia; BPDCN, blastic plasmacytoid dendritic cell neoplasm; CAR-T, chimeric antigen receptor T cell; CRPC, castration-resistant prostate cancer; GEJ, gastroesophageal junction; HNSCC, head and neck squamous cell carcinoma; NPC, nasopharyngeal carcinoma; PFS, progression-free survival; SCLC, small-cell lung cancer; TCE, T-cell engager; TKI, tyrosine kinase inhibitor; TNBC, triple-negative breast cancer; VOD, veno-occlusive disease.
Target heterogeneity remains a central challenge. T-DXd has demonstrated activity in HER2-low (IHC 1–2+) breast cancer—a segment previously considered untreatable with HER2-directed therapies—principally because of its bystander-permeable DXd payload 12. Emerging genomic biomarkers (e.g., NECTIN4 gene amplification) correlate with higher ORR to Nectin-4 ADCs in TNBC and NSCLC beyond IHC-based selection, signaling a shift toward genomic companion diagnostics 12.
Clinical Differentiation and Therapeutic Positioning
Table 4. Clinical Differentiation Themes for ADCs, 2020–2026
| Differentiation Axis | What Changed vs. Earlier ADCs | Clinical Implication | Remaining Challenge |
|---|---|---|---|
| Payload shift to Topo-I inhibitors | Widespread adoption of DXd/SN-38 over tubulin-only payloads | Greater bystander effect; activity in heterogeneous and low-antigen tumors; cross-tumor scope | ILD/pneumonitis management; myelosuppression; sequencing after prior DXd ADC |
| Linker stability and selectivity | Hydrophilic, enzyme-tuned, and short-half-life designs | Improved therapeutic index; reduced off-tumor free drug | Ensuring adequate intratumoral release; managing rare systemic toxicities |
| Target expansion beyond HER2 and CD antigens | TROP2, Nectin-4, B7-H3, HER3, CLDN18.2, FRα, TF, CD123 | New options across UC, lung, HNSCC, gastric, ovarian, AML | Target-specific AEs (ocular for TF; skin/neuropathy for Nectin-4); standardized companion diagnostics |
| Earlier-line and combination use | Moving from salvage to first-line; combinations with PD-(L)1, anti-VEGF, taxanes | Higher ORR/CR in earlier lines; potential for curative intent (neoadjuvant/adjuvant) | Overlapping toxicity; optimal sequencing; additive ILD risk with IO combinations |
| Biomarker enrichment | Beyond IHC expression thresholds to genomic amplification, mutation status | Precision patient selection; improved response prediction | Assay standardization; prospective validation of cut-offs |
| Immune-modulating ADCs | Integration of TLR agonists and STING agonists as payloads | Tumor microenvironment remodeling; potential synergy with checkpoint inhibitors | Characterizing immune activation vs. toxicity balance; early-stage evidence |
| Novel formats and convergence | Short-half-life peptide conjugates; protein degrader payloads; bispecific ADCs | Differentiated safety; new mechanisms of action | Manufacturability complexity; regulatory/CMC challenges; emerging cross-resistance data |
Abbreviations: CMC, chemistry, manufacturing, and controls; IO, immuno-oncology; PD-(L)1, programmed death-(ligand) 1.
Class-defining toxicities increasingly guide clinical positioning. DXd-class ADCs require baseline chest imaging and serial monitoring for ILD/pneumonitis, with early corticosteroid intervention for any-grade ILD 12. TF-directed ADCs (tisotumab vedotin: ocular AEs in ~52.5% of patients; conjunctivitis, dry eye) mandate ophthalmology surveillance and ocular prophylaxis 12. MMAE-class ADCs (enfortumab vedotin: neuropathy ~50% any-grade; hyperglycemia ~20%) require baseline neuropathy assessment, glucose monitoring, and dose adjustment algorithms 1. Belantamab mafodotin (BCMA–MMAF) demands structured keratopathy/corneal monitoring 3.
Combination strategies are reshaping clinical positioning. T-DXd combined with taxanes plus trastuzumab and pertuzumab is being evaluated in neoadjuvant HER2-positive early breast cancer (DESTINY-Breast11, ESMO 2025); EV paired with pembrolizumab in the perioperative muscle-invasive bladder cancer setting is under investigation in KEYNOTE-905; and sacituzumab tirumotecan versus platinum chemotherapy in EGFR-mutated NSCLC post-TKI was presented at ESMO 2025 (OptiTROP-Lung04) 3. In China, three ADCs received NMPA approval in 2025, including sacituzumab tirumotecan for EGFR-mutant advanced NSCLC 3.
Future Outlook and Unresolved Challenges
Despite remarkable progress, several challenges define the next frontier 123:
- Resistance mechanisms: Antigen downregulation or loss (e.g., HER2-negative escape after T-DM1), upregulation of drug efflux transporters (MDR1/P-gp), altered lysosomal function (cathepsin B downregulation impairing cleavable linker processing), and payload-target resistance (tubulin mutations; upregulated DNA repair) all contribute to treatment failure. Evidence suggests that ADCs with distinct payload classes (e.g., Topo-I after microtubule inhibitor ADC) can partially overcome resistance, but cross-resistance between payload classes after the same target remains incompletely characterized clinically 1.
- Optimal sequencing: Prospective sequencing data after prior ADC exposure—particularly within the same target—are limited. Clinical decisions currently rely on mechanistic rationale and retrospective analyses rather than randomized evidence 12.
- Biomarker standardization: Companion diagnostics remain largely IHC-based; genomic biomarkers (gene amplification, mutation status) are not yet uniformly validated. Defining reliable expression thresholds for emerging targets (e.g., CLDN18.2, B7-H3) across platforms and regions is an ongoing priority 23.
- Manufacturability: Site-specific conjugation and complex linker–payload systems increase manufacturing complexity and cost, creating regulatory and commercial scale-up challenges 12.
- Next-generation modalities: Bispecific ADCs (e.g., izalontamab brengitecan targeting EGFR/HER3), dual-payload ADCs, and immune-modulating ADCs (BDC-1001; SBT6050) represent promising directions for overcoming heterogeneity and resistance; early clinical signals are encouraging, but evidence remains early-stage 123. Convergence with protein degrader payloads (e.g., ORM-5029) signals an expansion of ADC utility into non-cytotoxic mechanisms.
Conclusion
From 2020 to June 2026, next-generation ADCs have redefined targeted oncology through deliberate engineering of linker stability, payload diversification toward Topo-I inhibitors with high bystander potential, and intelligent expansion of targets beyond HER2 to include TROP2, Nectin-4, B7-H3, CLDN18.2, HER3, and TF. Clinical differentiation now hinges on payload mechanism, linker release kinetics, DAR homogeneity, target biology, and toxicity profile—not antibody platform alone. Approved agents demonstrate superior efficacy in expanding settings, with emerging data from ASCO 2025, ESMO 2025, and ASH 2025 reinforcing earlier-line use and rational combination strategies. Key unresolved challenges—resistance mechanisms, optimal sequencing after prior ADC, standardized companion diagnostics, and toxicity management—will determine how the field harnesses the next wave of bispecific, dual-payload, and immune-modulating ADCs for broader and more durable clinical benefit 123.