PharmacologyTier 1Medical Sciences concept

Monoclonal antibody/targeted cancer therapy - target identification (VEGF, EGFR, HER2, CD20)

Core concept

Naming tells you the target and the construct
- -mab monoclonal antibody; -cept receptor-Fc fusion; -nib small-molecule kinase inhibitor
- -o- murine, -xi- chimeric, -zu- humanised, -u- fully human
- Chimeric agents (rituximab, cetuximab, infliximab) carry the highest infusion reaction and anti-drug antibody risk
Antibodies act by blocking ligand or receptor, by ADCC/complement-mediated lysis, or as a delivery vehicle (ADC, radioimmunotherapy)

Target	Agents	Main indications	Signature toxicity
VEGF / VEGFR	bevacizumab, ramucirumab; TKIs sunitinib, sorafenib, lenvatinib	CRC, NSCLC, RCC, ovarian, glioma	Hypertension, proteinuria, bleeding, arterial thrombosis, GI perforation, impaired wound healing
EGFR (HER1)	cetuximab (chimeric), panitumumab (human); TKIs erlotinib, gefitinib, osimertinib	RAS-wild-type CRC, squamous head and neck, EGFR-mutant NSCLC	Acneiform rash (rash intensity correlates with response), hypomagnesaemia, diarrhoea, ILD
HER2 (ERBB2)	trastuzumab, pertuzumab, T-DM1, trastuzumab deruxtecan; lapatinib, tucatinib	HER2+ breast, gastric, CRC	Cardiomyopathy - reversible, not dose-cumulative (contrast anthracyclines); T-DXd ILD
CD20	rituximab, obinutuzumab, ofatumumab	B-cell NHL, CLL, RA, ANCA vasculitis, MS	Infusion reaction, HBV reactivation, hypogammaglobulinaemia, PML
CD38	daratumumab	Myeloma	Interferes with blood group crossmatch
CD19/CD3	blinatumomab (BiTE)	ALL	Cytokine release syndrome, neurotoxicity
SLAMF7	elotuzumab	Myeloma
RANKL	denosumab	Bone metastases, hypercalcaemia	Hypocalcaemia, ONJ
PD-1/PD-L1/CTLA-4	see checkpoint note		irAEs

Cetuximab requires RAS wild-type - a downstream RAS mutation makes EGFR blockade futile
Trastuzumab cardiotoxicity - LVEF fall, reversible on cessation, monitored 3-monthly; risk multiplied by prior anthracycline
Bevacizumab - hold 4-6 weeks around surgery; avoid in squamous NSCLC (haemoptysis) and untreated CNS metastases

The biomarker must be confirmed before the antibody - HER2 by IHC/ISH, RAS/BRAF by sequencing, CD20 by flow or IHC
Screen for hepatitis B (HBsAg and anti-HBc) before rituximab or any B-cell-depleting therapy and give antiviral prophylaxis - reactivation can be fatal
Rash on an anti-EGFR agent is treated, not stopped - doxycycline and topical steroid; it is a marker of efficacy
Hypomagnesaemia on cetuximab or panitumumab is EGFR blockade at the TRPM6 channel in the distal tubule - can be profound and needs IV replacement
Antibodies do not cross the BBB well - CNS relapse on systemic control (the "sanctuary site" problem, classically with trastuzumab)

Predictive biomarkers for targeted cancer therapy
Immunohistochemical markers - HER2, hormone receptors
Antibody-drug conjugate mechanism; CAR-T cell therapy
Immune checkpoint inhibitor mechanism
Biologics in rheumatoid arthritis and asthma - same constructs, different targets

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