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): Joining a highly toxic payload to an antibody safely and at scale. Few contractors can do it, which shapes 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 a guided missile: an antibody homes to the tumour cell, is swallowed, and releases a chemotherapy so potent it could never be given on its own.
• 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.
• 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.
• Immune-stimulating antibody conjugate (ISAC): An immune-stimulating antibody conjugate (ISAC) is an ADC whose payload wakes up the immune system inside the tumour rather than poisoning the cell.

• POLARIX (phase 3, n=879): Progression-free survival at 2 years: 76.7% vs 70.2%, HR 0.73
• ALFA-0701 (phase 3, n=271): Event-free survival (median): 17.3 months vs 9.5 months, HR 0.56
• ECHELON-1 (phase 3, n=1,334): Modified PFS at 2 years: 82.1% vs 77.2%, HR 0.77
• innovaTV 301 / ENGOT-cx12 / GOG-3057 (phase 3, n=502): Overall survival: 11.5 months vs 9.5 months, HR 0.7
• INO-VATE ALL (phase 3, n=326): Complete remission / CRi: 80.7% vs 29.4%
• MIRASOL / GOG-3045 (phase 3, n=453): Progression-free survival: 5.62 months vs 3.98 months, HR 0.65

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.