ADC payload & linker registry
An ADC is three parts. The antibody gets most of the attention, but payload and linker decide bystander killing, cross-resistance, and the side-effect profile. This registry cross-references both to the products in the map.
Payloads
| Payload | Class | Mechanism | Bystander | Efflux substrate | Typical DAR | Characteristic toxicities | Products |
|---|---|---|---|---|---|---|---|
| SN-38 7-ethyl-10-hydroxycamptothecin | Topoisomerase-I inhibitor | Active metabolite of irinotecan; stabilises TOP1–DNA cleavage complexes, causing replication-associated double-strand breaks. Moderate potency (nM) compensated by very high DAR and a linker that releases payload in the tumour microenvironment. | Yes | yes | ~7.6 | Neutropenia, diarrhoea (UGT1A1*28 homozygotes at higher risk), alopecia. | |
| DXd MAAA-1181a, exatecan derivative | Topoisomerase-I inhibitor | Exatecan-derived TOP1 inhibitor ~10× more potent than SN-38; short systemic half-life once released. | Yes | partial | 8 (T-DXd), 4 (Dato-DXd) | Interstitial lung disease/pneumonitis, nausea, neutropenia, fatigue; stomatitis and ocular surface events with Dato-DXd. | |
| Exatecan (and derivatives) DX-8951; Ed-04 in iza-bren; ZD06519 | Topoisomerase-I inhibitor | Highly potent camptothecin analogue; the parent scaffold for many next-generation payloads (iza-bren's Ed-04, Zymeworks' ZD06519, MediLink's C24). Hydrophilic linkers are what make DAR 8 exatecan ADCs manufacturable. | Yes | partial | 8 | Myelosuppression (notably with iza-bren), nausea, ILD class signal. | |
| T030 (belotecan derivative) KL610023 | Topoisomerase-I inhibitor | Belotecan-derived TOP1 inhibitor used in sacituzumab tirumotecan; reported to be a weaker efflux-pump substrate than SN-38. | Yes | low | ~7.4 | Stomatitis, neutropenia, anaemia, nausea. | |
| MMAE monomethyl auristatin E, vedotin | Tubulin inhibitor | Synthetic dolastatin-10 analogue; blocks tubulin polymerisation, arresting mitosis. Sub-nanomolar potency. | Yes | yes | ~4 | Peripheral neuropathy, neutropenia, rash and skin reactions (Nectin-4), hyperglycaemia (enfortumab), ocular events (tisotumab). | |
| MMAF monomethyl auristatin F, mafodotin | Tubulin inhibitor | Charged C-terminal phenylalanine variant of MMAE; poorly membrane-permeable, so little bystander killing. | No | low | ~4 | Corneal keratopathy (belantamab), thrombocytopenia. | |
| DM1 mertansine, emtansine | Tubulin inhibitor | Maytansinoid binding tubulin at the vinca site; released as Lys-MCC-DM1 from non-cleavable linker (impermeable). | No | yes | ~3.5 | Thrombocytopenia, hepatotoxicity (transaminases), peripheral neuropathy. | |
| DM4 ravtansine, soravtansine | Tubulin inhibitor | Maytansinoid released via disulfide cleavage; S-methylated metabolite is permeable, giving bystander effect. | Yes | yes | ~3.5 | Ocular (blurred vision, keratopathy), peripheral neuropathy, nausea. | |
| PBD dimer (SG3199 / tesirine) pyrrolobenzodiazepine dimer | DNA crosslinker (PBD dimer) | Sequence-selective interstrand DNA crosslinks in the minor groove; picomolar potency, cell-cycle independent. | Yes | low | ~2 | Oedema/effusions, photosensitivity, skin reactions, thrombocytopenia; narrow window has limited solid-tumour use. | |
| Calicheamicin ozogamicin (N-acetyl-γ-calicheamicin) | DNA cleaver | Enediyne antibiotic that binds the DNA minor groove and generates diradicals causing double-strand breaks. | Yes | yes | 2–3 (heterogeneous) | Hepatotoxicity including veno-occlusive disease, myelosuppression; first-generation linker instability. | |
| Duocarmycin (seco-DUBA) duocarmazine | DNA alkylator | Alkylates adenine N3 in the DNA minor groove; active in non-dividing cells. Trastuzumab duocarmazine (SYD985) showed PFS benefit in TULIP but was not approved in the US; included as a class reference. | Yes | unknown | ~2.8 | Ocular toxicity and ILD (trastuzumab duocarmazine, whose BLA was withdrawn). |
Linkers
| Linker | Type | Trigger | Releases | Products |
|---|---|---|---|---|
| CL2A | cleavable | pH-sensitive carbonate hydrolysis (and lysosomal) | Free SN-38 in tumour microenvironment and inside cells Deliberately moderate stability: ~50% payload released over ~1 day in serum, giving extracellular bystander delivery. | |
| Tetrapeptide GGFG (maleimide-GGFG-aminomethyl) | cleavable | Lysosomal cathepsins (B, L) | Free DXd (membrane-permeable) Very stable in plasma; the design that enabled DAR 8 with low aggregation. | |
| mc-Val-Cit-PABC | cleavable | Cathepsin B cleavage of Val-Cit dipeptide; self-immolative PABC spacer | Free MMAE The workhorse linker of second-generation ADCs; susceptible to neutrophil elastase and carboxylesterase Ces1c in mice, less so in humans. | |
| SMCC (thioether, non-cleavable) | non-cleavable | Complete antibody degradation in the lysosome | Lys-MCC-DM1, charged and impermeable (no bystander) Explains T-DM1's inactivity in HER2-low disease and its inferiority to T-DXd. | |
| Sulfo-SPDB (disulfide) | cleavable | Glutathione/disulfide reduction inside the cell | DM4 → S-methyl-DM4 (permeable) | |
| Acid-labile hydrazone (AcBut) | cleavable | Low pH in endosomes/lysosomes; also slowly in plasma | Calicheamicin Plasma instability contributed to Mylotarg's first-generation toxicity. | |
| Val-Ala dipeptide | cleavable | Cathepsin cleavage | PBD dimer SG3199 Less hydrophobic than Val-Cit; used with PEG8 spacer in tesirine. | |
| Maleimidocaproyl (mc), non-cleavable | non-cleavable | Antibody degradation | Cys-mc-MMAF (impermeable) | |
| Hydrophilic next-generation linkers (TMALIN, Dolaflexin, sulfonyl-pyrimidine, PEG-containing) | cleavable | Protease and/or pH; TMALIN is cleaved in the tumour microenvironment and lysosome | TOP1 payloads at DAR 8 without aggregation Hydrophilicity, not payload chemistry, is what allows DAR 8 exatecan-class ADCs. MediLink's TMALIN is licensed to Zai Lab, BioNTech, and Roche. |
Bystander effect requires both a cleavable linker and a membrane-permeable payload. Efflux susceptibility is summarised from published transporter studies and sponsor claims; treat “low” as a claim until confirmed clinically.