Antibody Drug Conjugates

Antibody drug conjugates link a monoclonal antibody, which binds a tumour surface antigen, to a potent cytotoxic payload by a chemical linker. After binding and internalisation the payload is released inside the tumour cell, with limited release into healthy tissue. A bystander effect from membrane-permeable payloads also kills neighbouring cells with low antigen expression. Toxicity is set mainly by the payload.

Classification. By payload: microtubule inhibitors (monomethyl auristatin E and F, maytansinoid DM1), topoisomerase I inhibitors (deruxtecan, SN-38), and DNA-damaging agents (calicheamicin, pyrrolobenzodiazepine).

Pharmacokinetics. Antibody half life of 3 to 7 days for conjugates (shorter than naked antibodies because of payload release); payloads are metabolised by CYP3A4 and cleared by the liver.

• Trastuzumab emtansine 3.6 mg/kg every 3 weeks (HER2-positive breast cancer).
• Trastuzumab deruxtecan 5.4 mg/kg every 3 weeks (breast cancer); 6.4 mg/kg for gastric cancer.
• Enfortumab vedotin 1.25 mg/kg on days 1, 8 and 15 of a 28-day cycle (urothelial cancer).
• Sacituzumab govitecan 10 mg/kg on days 1 and 8 of a 21-day cycle (triple-negative breast cancer).
• Brentuximab vedotin 1.8 mg/kg every 3 weeks (maximum 180 mg) in CD30-positive lymphoma.
• Polatuzumab vedotin 1.8 mg/kg every 3 weeks with chemotherapy in diffuse large B-cell lymphoma.
• Inotuzumab ozogamicin and gemtuzumab ozogamicin in CD22- or CD33-positive leukaemia, with weight- or surface-area-based, fractionated dosing set by specialists.
• Mirvetuximab soravtansine (folate receptor alpha-positive ovarian cancer): 6 mg/kg adjusted ideal body weight every 3 weeks.

Differences. Auristatin conjugates cause peripheral neuropathy and neutropenia; maytansinoid conjugates cause thrombocytopenia and hepatotoxicity; deruxtecan causes interstitial lung disease; SN-38 conjugates cause neutropenia and diarrhoea; calicheamicin conjugates cause sinusoidal obstruction syndrome; mirvetuximab and brentuximab affect the eye and nerves.

• Match the antigen: HER2 (trastuzumab emtansine, trastuzumab deruxtecan), CD30 (brentuximab vedotin), CD79b (polatuzumab vedotin), Nectin-4 (enfortumab vedotin), TROP2 (sacituzumab govitecan), CD22 and CD33 (inotuzumab, gemtuzumab).
• Premedication: antihistamine, paracetamol and corticosteroid for infusion reactions; antiemetics by emetic risk; for sacituzumab govitecan add primary G-CSF prophylaxis when risk of febrile neutropenia is high.
• Brentuximab vedotin: contraindicated with bleomycin (fatal pulmonary toxicity); screen for John Cunningham virus and progressive multifocal leukoencephalopathy symptoms.
• Sacituzumab govitecan: test for UGT1A1*28 where possible; start loperamide at the first loose stool and give atropine for early diarrhoea; hold for grade 3 neutropenia or diarrhoea.
• Enfortumab vedotin: check glucose before each dose; stop for Stevens-Johnson syndrome or toxic epidermal necrolysis; monitor for neuropathy.
• Trastuzumab deruxtecan: assess for cough, dyspnoea and fever at each visit; hold and give corticosteroid for suspected interstitial lung disease (prednisolone 1 mg/kg daily for grade 2 or more).

Selection. Use in cancers that express the target antigen after confirmatory testing; funding and access are very limited in East Africa.

Contraindications. Pregnancy; hypersensitivity; severe hepatic impairment (several); uncontrolled interstitial lung disease (trastuzumab deruxtecan); concurrent bleomycin (brentuximab vedotin).

Adverse effects. Infusion reactions, myelosuppression, nausea and vomiting, diarrhoea, fatigue, alopecia, peripheral neuropathy, ocular toxicity (dry eye, keratopathy, blurred vision), interstitial lung disease, hepatotoxicity, thrombocytopenia and bleeding, hyperglycaemia, severe skin reactions, and extravasation injury.

Interactions. Strong CYP3A4 inhibitors (ritonavir-boosted regimens, azoles, clarithromycin) raise payload exposure; inducers lower efficacy; UGT1A1 inhibitors (atazanavir) raise SN-38 exposure; warfarin and antiplatelet drugs with thrombocytopenic conjugates.

Special groups.

• Pregnancy: avoid; contraception during treatment and for 7 months afterwards for most.
• Breastfeeding: avoid.
• Children: brentuximab and inotuzumab are used in specialist regimens.
• Older adults: more neutropenia and neuropathy.
• Kidney impairment: no adjustment for most; caution in severe impairment.
• Liver impairment: avoid in moderate to severe impairment for brentuximab and others.

Monitoring. Full blood count before each dose, liver function and glucose, neuropathy assessment, eye examination (slit lamp for mirvetuximab, ophthalmic review for others), chest symptoms and imaging, and left ventricular ejection fraction with HER2 conjugates.

Referral and escalation. New cough or dyspnoea (possible interstitial lung disease), severe diarrhoea, febrile neutropenia, blistering rash, visual loss, jaundice with weight gain and tender hepatomegaly, and neurological symptoms need urgent care.