Antibody-drug conjugates (ADCs)

Mechanism of Action

• Class mechanism: Monoclonal antibodies targeting tumor antigens linked to cytotoxic payloads (calicheamicins, auristatins, maytansinoids). Antibody delivers toxin; resistance via ↓ antigen expression or altered internalization.

ADC Structure (three components)

• Antibody: chimeric, humanized, or fully human IgG (mostly humanized IgG1; brentuximab is chimeric) against a tumor-associated surface antigen; provides target specificity and, for naked-antibody activity, can add ADCC. After binding the antigen the ADC is internalized.
• Linker: joins antibody to payload. Cleavable (enzyme, low pH, or glutathione sensitive) releases free payload and permits a bystander effect; non-cleavable releases payload only after lysosomal antibody degradation. Linker stability governs off-target release.
• Payload (warhead): a highly potent cytotoxic released intracellularly. Naming suffixes map to payload class:
  • Microtubule inhibitors: auristatins = "vedotin" (MMAE) or "mafodotin" (MMAF); maytansinoids (DM1, DM4) = "emtansine"/"soravtansine".
  • DNA-damaging: calicheamicins = "ozogamicin"; pyrrolobenzodiazepine (PBD) dimers (DNA crosslinkers) = "tesirine".
  • Topoisomerase I inhibitors: deruxtecan (exatecan derivative) and govitecan (SN-38, the active irinotecan metabolite).
  • Bacterial toxin: Pseudomonas exotoxin A fragment PE38 = "pasudotox" (blocks protein synthesis).
• Drug-to-antibody ratio (DAR) and bystander effect: membrane-permeable payloads (deruxtecan, govitecan) diffuse out of the targeted cell to kill neighboring antigen-low cells, giving activity in heterogeneous or antigen-low tumors.

CD33-Targeting ADCs

Gemtuzumab ozogamicin (Mylotarg)

• Mechanism: anti-CD33 linked to calicheamicin.
• Indications: Newly diagnosed CD33+ AML (adults and children ≥1 month, with daunorubicin/cytarabine induction, or single agent in adults; benefit mainly favorable/intermediate-risk) and relapsed/refractory CD33+ AML (adults and children ≥2 years) (note: not all AML expresses CD33; CD34+ and CD117+ are blasts).
• Toxicities: Veno-occlusive disease (VOD).

CD30-Targeting ADCs

Brentuximab vedotin (Adcetris)

• Mechanism: anti-CD30 linked to monomethyl auristatin E (MMAE, "vedotin") → disrupts microtubule networks. Dose IV 1.8 mg/kg q3wk for monotherapy and CHP-combination indications; 1.2 mg/kg q2wk with AVD (frontline cHL); 1.2 mg/kg q3wk (max 120 mg) with lenalidomide + rituximab (R/R LBCL).
• Indications: classical Hodgkin lymphoma (frontline stage III/IV with AVD [ECHELON-1]; pediatric high-risk frontline; post-ASCT consolidation [AETHERA]; relapse after ASCT or ≥2 prior regimens if not ASCT candidate), systemic ALCL and other CD30+ PTCL (frontline with CHP [ECHELON-2]; relapsed sALCL), primary cutaneous ALCL (pcALCL), CD30+ mycosis fungoides, and R/R LBCL with lenalidomide + rituximab (ECHELON-3).
• Toxicities: Peripheral neuropathy (hallmark); also tumor lysis syndrome, myelosuppression, hepatotoxicity, dermatologic reactions (SJS). Progressive multifocal leukoencephalopathy (JC virus) has been reported.

CD22-Targeting ADCs

Inotuzumab ozogamicin (Besponsa)

• Mechanism: anti-CD22 linked to calicheamicin.
• Indications: Relapsed/refractory CD22+ B-cell precursor ALL.
• Toxicities: VOD, hepatotoxicity.

BCMA-Targeting ADCs

Belantamab mafodotin (Blenrep)

• Mechanism: anti-BCMA (B-cell maturation antigen) linked to maleimidocaproyl monomethyl auristatin F (mcMMAF); binds BCMA on myeloma cells → cell-cycle arrest.
• Indications: Relapsed/refractory multiple myeloma after ≥2 prior lines including a proteasome inhibitor and an immunomodulatory agent, in combination with bortezomib + dexamethasone (DREAMM-7; FDA Oct 2025). Original 2020 monotherapy approval was withdrawn (GSK request Nov 2022; FDA revocation effective Feb 6, 2023).
• Toxicities: Keratopathy, blurred vision (can progress to blindness), myelosuppression.

Other Notable ADCs

Polatuzumab vedotin (Polivy)

• Target: CD79b (B-cell antigen); payload = MMAE.
• Indications: Diffuse large B-cell lymphoma (DLBCL).
• Toxicities: Peripheral neuropathy.

Sacituzumab govitecan (Trodelvy)

• Target: TROP-2 (tumor-associated calcium signal transducer 2); payload = SN-38 (topoisomerase I inhibitor, irinotecan active metabolite).
• Indications: Metastatic TNBC (1L as monotherapy if not a PD-1/PD-L1 candidate, or with pembrolizumab if PD-L1 CPS ≥10; 2L+ per ASCENT) and HR+/HER2-negative MBC after endocrine therapy and ≥2 additional systemic therapies in the metastatic setting (TROPiCS-02). Urothelial indication withdrawn (2024).

Moxetumomab pasudotox (Lumoxiti)

• Target/payload: anti-CD22 fused to PE38 (38 kDa Pseudomonas exotoxin A fragment) → blocks protein synthesis.
• Indications: Relapsed/refractory hairy cell leukemia (withdrawn from the US market in 2023 for low uptake, not safety).
• Toxicities: Hemolytic uremic syndrome (HUS), capillary leak syndrome.

Loncastuximab tesirine (Zynlonta)

• Target/payload: anti-CD19 linked to a PBD dimer (DNA crosslinker).
• Indications: Relapsed/refractory DLBCL.
• Toxicities: ↑ GGT, neutropenia.

2026 update: expanded ADC landscape

Trastuzumab deruxtecan (T-DXd, Enhertu): new indications

• DESTINY-Breast04 (Modi NEJM 2022; mature 2024): HER2-low (IHC 1+ or 2+/ISH-negative) HR+ or TNBC MBC post 1 to 2L chemo; mPFS 9.9 vs 5.1 mo; mOS 23.4 vs 16.8 mo. Established HER2-low as a distinct actionable subset.
• DESTINY-Breast06 (Bardia NEJM 2024): T-DXd vs chemo in HR+ MBC HER2-low or HER2-ultralow (IHC 0 with membrane staining) post-endocrine, chemo-naive. mPFS 13.2 vs 8.1 mo. FDA Jan 2025 supplemental approval extended T-DXd to HER2-ultralow (first ADC to move into the IHC 0 subgroup).
• HER2+ breast expansion: T-DXd now FDA-approved 1L with pertuzumab for HER2+ MBC (DESTINY-Breast09), neoadjuvant followed by THP for stage II to III disease (DESTINY-Breast11), and adjuvant for residual invasive disease after neoadjuvant therapy (DESTINY-Breast05).
• DESTINY-PanTumor02 (Meric-Bernstam JCO 2024): tumor-agnostic HER2 IHC 3+ solid tumors (cervical, endometrial, ovarian, biliary, bladder, other). ORR 37.1% overall (published); IHC 3+ 61.3% (FDA efficacy population 51.4%); endometrial IHC 3+ 84.6%. FDA Apr 2024 tumor-agnostic accelerated approval for HER2 IHC 3+ solid tumors post-prior therapy.
• DESTINY-Gastric04: T-DXd vs paclitaxel + ramucirumab in 2L HER2+ gastric/GEJ; OS benefit (primary endpoint; Shitara NEJM 2025). Confirms the existing US 2L gastric approval (Jan 2021, DESTINY-Gastric01).
• DESTINY-Lung02: T-DXd in HER2-mutant (kinase-domain, mostly ex20) NSCLC; FDA Aug 2022 accelerated approval (still accelerated; confirmatory DESTINY-Lung04).

Datopotamab deruxtecan (Dato-DXd, Datroway): TROP2-ADC

• TROPION-Breast01 (Bardia JCO 2024): Dato-DXd vs chemo in HR+/HER2-negative MBC post-endocrine + 1 to 2L chemo; mPFS 6.9 vs 4.9 mo. FDA Jan 17, 2025 approval for HR+/HER2-negative MBC.
• TROPION-Lung05 / TROPION-Lung01: Dato-DXd in EGFR-mutant NSCLC after prior TKI + platinum. FDA Jun 23, 2025 accelerated. ILD signal similar to T-DXd.

Sacituzumab govitecan (Trodelvy): mature

• ASCENT (Bardia NEJM 2021; mature 2024): 2L+ mTNBC vs chemo. Class TROP2-ADC with SN-38 payload. Also TROPiCS-02 (Rugo Lancet 2023): HR+/HER2-negative MBC post-endocrine + 2 to 4 chemo lines; mPFS 5.5 vs 4.0 mo.
• Sacituzumab tirumotecan (sac-TMT, MK-2870): TROP2-ADC with a belotecan-derived payload (Kelun/Merck). OptiTROP-Breast01 (Xu ESMO 2024): positive in mTNBC. FDA action pending.

Enfortumab vedotin (Padcev): Nectin-4 / MMAE

• EV-302 / KEYNOTE-A39 (Powles NEJM 2024): EV + pembro vs gemcitabine + cisplatin or carboplatin in 1L platinum-eligible metastatic urothelial. mPFS 12.5 vs 6.3 mo; mOS 31.5 vs 16.1 mo. FDA Dec 15, 2023 1L approval, first chemo-free 1L combination irrespective of cisplatin eligibility (earlier 2017 ICI monotherapy approvals were limited to select cisplatin-ineligible pts), new SOC.
• Class toxicity: hyperglycemia (severe DKA reported), skin (SJS/TEN), peripheral neuropathy, ocular disorders.

Mirvetuximab soravtansine (Elahere): FRα / DM4

• MIRASOL (Moore NEJM 2023): FRα-high platinum-resistant ovarian post 1 to 3 prior lines vs chemo; mPFS 5.6 vs 4.0 mo; mOS 16.5 vs 12.7 mo. FDA Mar 22, 2024 full approval (converted from 2022 accelerated).
• Ocular toxicity distinctive: keratopathy / corneal microcysts; ophtho baseline + q2 cycles; steroid + lubricating drops prophylaxis.

Tisotumab vedotin (Tivdak): Tissue Factor / MMAE

• innovaTV 301 (Vergote NEJM 2024): recurrent/metastatic cervical cancer post 1 to 2 lines. mOS 11.5 vs 9.5 mo. FDA Apr 29, 2024 full approval (converted from 2021 accelerated).
• Ocular toxicity similar to mirvetuximab; mandate ophtho monitoring.

Telisotuzumab vedotin (Emrelis): c-Met / MMAE

• LUMINOSITY (Camidge JCO 2024): c-Met-overexpressing (IHC 3+ ≥50% cells) EGFR-wt non-squamous NSCLC post-platinum. ORR ~35% in high-expressors. FDA May 14, 2025 accelerated approval, first c-Met-directed ADC for NSCLC.

Zanidatamab (Ziihera): biparatopic anti-HER2

• HERIZON-BTC-01 (Harding Lancet Oncol 2023, mature 2024): HER2 IHC 2+/3+ in HERIZON-BTC-01; FDA indication restricted to HER2-positive (IHC 3+) unresectable/metastatic BTC post-gem/cis. ORR 41%. FDA Nov 20, 2024 accelerated approval, first HER2-directed therapy for BTC.
• HERIZON-GEA-01 (Tabernero ESMO 2024): zanidatamab + chemo ± tislelizumab vs trastuzumab + chemo 1L HER2+ gastric/GEJ; PFS positive; now FDA-approved 1L with chemo ± tislelizumab. Note: zanidatamab is a bispecific antibody, not an ADC.

Belantamab mafodotin (Blenrep): return of the BCMA-ADC

• Withdrawn from the US market Nov 2022 after DREAMM-3 failed. DREAMM-7 (Hungria NEJM 2024): belamaf + Vd vs DVd in 2L+ R/R MM; mPFS 36.6 vs 13.4 mo, OS benefit. DREAMM-8 (Dimopoulos NEJM 2024): belamaf + Pd (BPd) vs PVd; 12-mo PFS 71% vs 51% (HR 0.52). FDA re-approved Oct 23, 2025 as BVd for R/R MM after ≥2 prior lines incl a PI and an IMiD (BPd not FDA-approved).

Class pearls (2024 to 2026)

• Topoisomerase I payloads dominate (deruxtecan: T-DXd, Dato-DXd; sac-TMT/MK-2870; patritumab deruxtecan HER3-DXd): bystander effect via a membrane-permeable payload → activity in heterogeneous / low-antigen tumors.
• ILD/pneumonitis is a deruxtecan class-effect: baseline chest imaging, hold for any G≥1 pneumonitis; permanent discontinuation for G2+.
• Ocular toxicity: belamaf keratopathy; mirvetuximab and tisotumab keratitis → mandatory ophtho monitoring.
• Hyperglycemia + skin (SJS/TEN): enfortumab vedotin class-effect.