Teaching pack: Antibody-Drug Conjugates

ADCs combine a targeting antibody, a linker, and a cytotoxic payload. Third-generation ADCs (T-DXd, sacituzumab govitecan, datopotamab deruxtecan) with topoisomerase-I payloads and bystander killing have reshaped breast, lung, and urothelial cancer. Next generation: bispecific ADCs, dual payloads, degrader and immune-stimulating payloads, masked ADCs, and radio-conjugates.

• ADC bioconjugation manufacturing (CDMOs): ADC bioconjugation manufacturing joins a payload so toxic it needs the top containment class (OEB 5) to an antibody, then checks drug-to-antibody ratio and free payload. Capacity sits with a handful of contractors such as Lonza, WuXi XDC and Samsung Biologics, so long queues and China-based exposure shape who can develop ADCs.
• ADC payload neutralisers: An ADC payload neutraliser is an antibody given alongside an ADC that mops up the poison once it leaks into the bloodstream, so the ADC can hit the tumour with fewer side effects.
• Antibody manufacturing (CHO bioprocessing): Antibody manufacturing means growing antibody drugs like pembrolizumab or trastuzumab in vats of engineered hamster cells, then purifying them. It is the industrial base for most modern cancer drugs.
• Antibody-drug conjugate (ADC): An antibody-drug conjugate is an antibody that homes to a protein on the tumour cell, is swallowed, and releases a chemotherapy payload inside it. That widens chemotherapy's safe dose window about a hundredfold, which is why payloads too toxic to give alone can be used, though lung inflammation, neutropenia and eye toxicity from the payload still occur.
• Antibody-oligonucleotide conjugates: An ADC that carries a gene-silencing strand instead of a chemotherapy, so it can switch a protein off rather than poison the cell.
• Bispecific ADC: A bispecific ADC is an ADC whose antibody grabs two different proteins on the cancer cell, so it sticks better to tumour and less to healthy tissue.
• Degrader-antibody conjugate (DAC): An ADC that delivers a protein-destroying molecule instead of chemotherapy, hitting targets inside the cell that were previously unreachable.
• Downstream purification (Protein A capture, viral clearance, polishing): After hamster cells have grown an antibody drug, the antibody has to be fished out of a soup of cells, DNA and viruses and made pure enough to inject. Purification is where much of the cost and many of the bottlenecks of biologics sit.
• Dual-payload ADC: A dual-payload ADC is an ADC carrying two different poisons at once, so the tumour cannot escape by becoming resistant to one.
• HER2 PET: HER2 PET is a PET scan using radiolabelled trastuzumab or smaller HER2 binders to map HER2 across all metastases at once.

• ADC roadmap: from Mylotarg to bispecific and dual-payload ADCs · Concept and first attempt (historic)
• ADC roadmap: from Mylotarg to bispecific and dual-payload ADCs · Second generation proves the class (historic)
• ADC roadmap: from Mylotarg to bispecific and dual-payload ADCs · Third generation: TOP1 payloads and bystander killing (current)
• ADC roadmap: from Mylotarg to bispecific and dual-payload ADCs · Third generation matures: earlier lines, more targets, combinations (current)
• ADC roadmap: from Mylotarg to bispecific and dual-payload ADCs · Fourth generation, wave 1: bispecific ADCs (emerging)
• ADC roadmap: from Mylotarg to bispecific and dual-payload ADCs · Fourth generation, wave 2: new payload logic (emerging)
• Lymphoma roadmap: from a jaw tumour in Uganda and the first human cancer virus to gene-expression subtypes, PET-adapted chemotherapy, CAR-T cells, bispecific antibodies and the genetics-directed trials now recruiting · Two viruses, found because lymphoma is the cancer you can get hold of (historic)
• Lymphoma roadmap: from a jaw tumour in Uganda and the first human cancer virus to gene-expression subtypes, PET-adapted chemotherapy, CAR-T cells, bispecific antibodies and the genetics-directed trials now recruiting · How little is enough: the Hodgkin de-escalation programme begins (historic)
• Lymphoma roadmap: from a jaw tumour in Uganda and the first human cancer virus to gene-expression subtypes, PET-adapted chemotherapy, CAR-T cells, bispecific antibodies and the genetics-directed trials now recruiting · Reading the genes, and the twenty years it took to make that useful (historic)
• Lymphoma roadmap: from a jaw tumour in Uganda and the first human cancer virus to gene-expression subtypes, PET-adapted chemotherapy, CAR-T cells, bispecific antibodies and the genetics-directed trials now recruiting · Everything that failed to beat R-CHOP, and the one thing that did (current)
• Lymphoma roadmap: from a jaw tumour in Uganda and the first human cancer virus to gene-expression subtypes, PET-adapted chemotherapy, CAR-T cells, bispecific antibodies and the genetics-directed trials now recruiting · The scan after two cycles, and what it is good for (current)
• Lymphoma roadmap: from a jaw tumour in Uganda and the first human cancer virus to gene-expression subtypes, PET-adapted chemotherapy, CAR-T cells, bispecific antibodies and the genetics-directed trials now recruiting · Indolent lymphoma: how long to treat, and the two-year mark that splits the disease (current)
• TNBC roadmap: from 'nothing to target' to ADC + immunotherapy first line · Chemotherapy only (historic)
• TNBC roadmap: from 'nothing to target' to ADC + immunotherapy first line · Immunotherapy and PARP arrive (historic)
• TNBC roadmap: from 'nothing to target' to ADC + immunotherapy first line · Curative setting transformed (historic)
• TNBC roadmap: from 'nothing to target' to ADC + immunotherapy first line · ADCs move to first line; bispecific ADC succeeds (current)
• TNBC roadmap: from 'nothing to target' to ADC + immunotherapy first line · Next: residual disease, de-escalation, selection (emerging)
• TNBC roadmap: from 'nothing to target' to ADC + immunotherapy first line · Speculative: cure for most, control for the rest (speculative)
• Triple-negative breast cancer roadmap: from a remainder defined by three negative tests to immunotherapy, antibody-drug conjugates and the residual disease problem · Defined by three negative tests (historic)
• Triple-negative breast cancer roadmap: from a remainder defined by three negative tests to immunotherapy, antibody-drug conjugates and the residual disease problem · The basal-like subtype and its link to BRCA1 (historic)
• Triple-negative breast cancer roadmap: from a remainder defined by three negative tests to immunotherapy, antibody-drug conjugates and the residual disease problem · Founder mutations: hereditary disease has a geography (historic)
• Triple-negative breast cancer roadmap: from a remainder defined by three negative tests to immunotherapy, antibody-drug conjugates and the residual disease problem · A name, a natural history and a disparity (historic)
• Triple-negative breast cancer roadmap: from a remainder defined by three negative tests to immunotherapy, antibody-drug conjugates and the residual disease problem · Anthracycline and taxane chemotherapy, and the residual disease paradox (historic)
• Triple-negative breast cancer roadmap: from a remainder defined by three negative tests to immunotherapy, antibody-drug conjugates and the residual disease problem · Several diseases: molecular subtypes (historic)
• TROP2 ADC roadmap: sacituzumab govitecan → Dato-DXd → sac-TMT → bispecifics and PET · Target discovery and antibody development (historic)
• TROP2 ADC roadmap: sacituzumab govitecan → Dato-DXd → sac-TMT → bispecifics and PET · Sacituzumab govitecan proves the target (historic)
• TROP2 ADC roadmap: sacituzumab govitecan → Dato-DXd → sac-TMT → bispecifics and PET · Second entrant: datopotamab deruxtecan (current)
• TROP2 ADC roadmap: sacituzumab govitecan → Dato-DXd → sac-TMT → bispecifics and PET · First line: three positive phase 3 trials (current)
• TROP2 ADC roadmap: sacituzumab govitecan → Dato-DXd → sac-TMT → bispecifics and PET · Third entrant: sacituzumab tirumotecan and the Merck programme (emerging)
• TROP2 ADC roadmap: sacituzumab govitecan → Dato-DXd → sac-TMT → bispecifics and PET · Unsolved: selection, sequencing, resistance (emerging)

• CLARITY-Gastric 01 (phase 3, n=594): Overall survival, third-line or later (dual primary): Met with a statistically significant, clinically meaningful improvement per the sponsor (27 July 2026); OS in the whole second-line-or-later population (key secondary) also significant. Medians and hazard ratios pending presentation.
• NAPOLI 3 (phase 3, n=770): Overall survival: 11.1 months vs 9.2 months, HR 0.83
• DESTINY-Gastric04 (phase 3, n=494): Overall survival: 14.7 months vs 11.4 months, HR 0.7
• POLARGO (phase 3, n=255): Overall survival (median): 19.5 months vs 12.5 months, HR 0.6
• DESTINY-Breast05 (phase 3, n=1,635): 3-year invasive disease-free survival: 92.4% vs 83.7%, HR 0.47
• KATHERINE (phase 3, n=1,486): 3-year invasive disease-free survival: 88.3% vs 77%, HR 0.5

1. What is the first bispecific ADC to succeed in a phase 3 trial, and in which cancer?
   Answer

   Izalontamab brengitecan (iza-bren, BL-B01D1), an EGFR×HER3 bispecific ADC from SystImmune/BMS, met PFS and OS in previously treated TNBC (BL-B01D1-307, February 2026) and also in oesophageal squamous cell carcinoma.
2. Does the TROP2 level measured on a biopsy tell you whether Trodelvy will work?
   Answer

   Not reliably. ASCENT showed benefit regardless of TROP2 IHC, so no companion diagnostic is required; expression is heterogeneous and archival tissue may not reflect current status. TROP2 PET tracers are being developed to map expression across the body and over time.
3. How could a TROP2 PET scan change how ADCs are used?
   Answer

   It would map antigen expression across all lesions and over time, potentially selecting patients, choosing between TROP2 ADCs, and detecting antigen loss at progression to guide a switch to a different target, as PSMA PET does for Pluvicto. First-in-human tracers exist; no outcome data yet.
4. What are the three parts of an antibody-drug conjugate and what does each do?
   Answer

   An antibody that finds the tumour cell, a linker that holds the payload in the blood and releases it inside the cell, and a payload, a very potent chemotherapy such as a topoisomerase-I inhibitor.
5. What is drug-to-antibody ratio and why does it matter?
   Answer

   The number of payload molecules per antibody, typically 2-8. Higher DAR delivers more drug per binding event (T-DXd about 8) but increases hydrophobicity and clearance unless hydrophilic linkers are used.
6. What is a bispecific ADC and why might it beat a normal one?
   Answer

   Its antibody binds two different tumour antigens (for example EGFR and HER3), improving avidity, internalisation, and tumour selectivity and hitting cells that express either antigen, addressing heterogeneity; iza-bren is the first with positive phase 3 data.

• NCI: Dictionary of Cancer Terms: antibody-drug conjugate: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/antibody-drug-conjugate