Oncology · Module 3 of 4

Monoclonal Antibodies and Antibody-Drug Conjugates

Targets, mechanisms, toxicities, and clinical rules

Monoclonal antibodies are large-molecule biologics that are not orally bioavailable, do not penetrate the CNS, are not CYP metabolized (no CYP drug interactions), and are catabolized by proteolysis throughout the body. Their long half-life (14–21 days) results from FcRn-mediated recycling in endosomes. The suffix encodes immunogenicity: -omab (murine, highest) → -ximab (chimeric) → -zumab (humanized) → -umab (fully human, lowest). FcRn also mediates placental transfer after the first trimester — an important consideration in pregnancy.
Trastuzumab and pertuzumab target complementary HER2 epitopes: trastuzumab binds domain IV (blocking PI3K/MAPK signaling and mediating ADCC), pertuzumab binds domain II (blocking HER2-HER3 heterodimerization). Both cause reversible LVEF reduction by inhibiting ErbB2-mediated cardiomyocyte repair signaling. The cardinal rule: trastuzumab must never be given concurrently with anthracyclines — the two agents have additive cardiotoxicity. Always sequential. Baseline and serial LVEF monitoring is mandatory.
Bevacizumab binds all VEGF-A isoforms, blocking tumor angiogenesis. VEGF withdrawal reduces nitric oxide → hypertension occurs in most patients. Impaired wound healing (VEGF-A is required for neovascularization) mandates a 28-day hold before and after any elective surgery. It is contraindicated in squamous cell NSCLC due to hemoptysis risk from tumor neovascularization adjacent to major vessels. Daratumumab (anti-CD38) causes pan-reactive indirect Coombs positivity that persists for months — the blood bank must be notified before the first dose to allow pre-treatment type and screen samples.
Antibody-drug conjugates (ADCs) deliver cytotoxic payloads directly to antigen-expressing tumor cells. The payload and linker determine toxicity and bystander killing capacity. T-DXd (trastuzumab deruxtecan) has a membrane-permeable topoisomerase I inhibitor payload that kills adjacent HER2-negative cells (high bystander effect) and has expanded HER2 eligibility to include HER2-low tumors (IHC 1+ or IHC 2+/FISH-negative). Its critical toxicity is interstitial lung disease — any new dyspnea requires immediate evaluation and drug hold pending CT imaging.
Sacituzumab govitecan targets TROP-2 and delivers SN-38 (the active irinotecan metabolite) — patients with UGT1A1*28 homozygosity have impaired SN-38 glucuronidation and are at higher risk of severe toxicity, paralleling the irinotecan pharmacogenomics from Module 4 of the first oncology chapter. Anti-EGFR antibodies (cetuximab, panitumumab) require RAS wild-type status and left-sided primary tumor location in colorectal cancer — RAS mutation confers no benefit and is an absolute contraindication to anti-EGFR therapy.

ADC = antibody-drug conjugate · ADCC = antibody-dependent cellular cytotoxicity · CRC = colorectal cancer · DAR = drug-to-antibody ratio · DLBCL = diffuse large B-cell lymphoma · DM1 = emtansine (maytansinoid microtubule inhibitor) · DXd = deruxtecan (topoisomerase I inhibitor) · FcRn = neonatal Fc receptor · FISH = fluorescence in situ hybridization · HBcAb = hepatitis B core antibody · HBsAg = hepatitis B surface antigen · IHC = immunohistochemistry · ILD = interstitial lung disease · LVEF = left ventricular ejection fraction · mAb = monoclonal antibody · MMAE = monomethyl auristatin E · PML = progressive multifocal leukoencephalopathy · RANKL = receptor activator of NF-κB ligand · TNBC = triple-negative breast cancer · VEGF = vascular endothelial growth factor

Monoclonal Antibody Pharmacokinetics

Large-Molecule ADME

Key PK Differences from Small Molecules

IV or subcutaneous only — no oral bioavailability (degraded in GI tract)
Vd: 3–8 L (plasma + interstitial fluid only; no CNS penetration)
Not CYP metabolized → no CYP drug interactions; catabolized by proteolysis throughout body
Half-life 14–21 days (FcRn recycling); dosing every 1–4 weeks
Target-mediated drug disposition (TMDD): clearance faster at low doses when target is abundant

FcRn Recycling

Half-Life Extension Mechanism

FcRn binds IgG Fc in acidic endosome pH → rescues from lysosomal degradation → releases at physiological pH back to circulation
FcRn also expressed in placenta → mAbs cross placenta after 1st trimester → neonatal immunosuppression risk
Saturable at high doses → nonlinear pharmacokinetics at therapeutic concentrations

Naming Convention

Suffix Encodes Immunogenicity

-omab: murine origin — highest immunogenicity; rarely used in oncology
-ximab: chimeric (human Fc + murine Fab) — e.g., rituximab, cetuximab
-zumab: humanized (>90% human) — e.g., trastuzumab, bevacizumab, pertuzumab
-umab: fully human — e.g., panitumumab, denosumab, ipilimumab; lowest immunogenicity

Anti-HER2 and Anti-VEGF Antibodies

Anti-HER2

Trastuzumab & Pertuzumab

Trastuzumab: binds HER2 extracellular domain IV → blocks PI3K/MAPK signaling + mediates ADCC; requires HER2 IHC 3+ or FISH-amplified
Pertuzumab: binds domain II → blocks HER2-HER3 heterodimerization (complementary to trastuzumab); combines with trastuzumab for synergy
Cardiotoxicity: reversible LVEF reduction — inhibition of ErbB2 repair signaling in cardiomyocytes; baseline LVEF required; monitor every 3 months
Concurrent anthracyclines + trastuzumab: prohibited — additive cardiotoxicity; always sequential (anthracycline first, then trastuzumab)

Anti-VEGF

Bevacizumab

Binds all VEGF-A isoforms → neutralizes tumor angiogenic signal; used in colorectal, lung, ovarian, renal, and glioblastoma
Hypertension: VEGF withdrawal reduces nitric oxide → vasoconstriction; occurs in majority; manage with antihypertensives
Impaired wound healing: VEGF-A required for neovascularization → hold 28 days before and after elective surgery
Contraindicated: squamous cell NSCLC (hemoptysis from tumor neovascularization adjacent to major vessels)
Serious risks: bowel perforation, arterial thromboembolism, posterior reversible encephalopathy syndrome

Anti-EGFR, Anti-CD20, Anti-CD38, and Anti-RANKL

Agent	Target	Companion Dx	Key Toxicity	Clinical Rule
Cetuximab / Panitumumab	EGFR (anti-proliferative + ADCC)	RAS wild-type (KRAS + NRAS exons 2, 3, 4); left-sided CRC	Acneiform rash; hypomagnesemia (EGFR in renal tubules); cetuximab: alpha-gal hypersensitivity (US south-east)	RAS mutation = no benefit — absolute contraindication to anti-EGFR; left-sided tumor required in CRC
Rituximab / Obinutuzumab	CD20 (B-cell surface antigen)	CD20 expression confirmed	HBV reactivation (fulminant hepatitis); PML from JC virus reactivation (rare)	Screen HBsAg and HBcAb before every course; antiviral prophylaxis if HBcAb-positive; live vaccines contraindicated
Daratumumab	CD38 (plasma cells and myeloma cells)	CD38 expression	Pan-reactive indirect Coombs positivity (daratumumab binds CD38 on reagent red cells); persists months	Notify blood bank before first dose; pre-treatment type and screen sample required; DTT-treated crossmatch needed
Denosumab	RANKL (blocks osteoclast activation)	None required	Hypocalcemia (suppress osteoclast bone calcium release); osteonecrosis of the jaw	Calcium + vitamin D supplementation mandatory throughout; dental evaluation and treatment before starting

Antibody-Drug Conjugates — Payload, Bystander Effect, and Toxicity

ADC	Target	Payload Class	Bystander Killing	Key Toxicity	Special Rule
T-DM1 (trastuzumab emtansine)	HER2 (IHC 3+ or FISH+)	DM1: maytansinoid microtubule inhibitor	Minimal (charged linker, non-permeable)	Thrombocytopenia; hepatotoxicity (transaminase elevation)	Not interchangeable with trastuzumab — different agents with different dosing and toxicity
T-DXd (trastuzumab deruxtecan)	HER2-positive and HER2-low (IHC 1+ or IHC 2+/FISH−)	DXd: topoisomerase I inhibitor	High (membrane-permeable payload kills adjacent HER2-negative cells)	Interstitial lung disease / pneumonitis (rate ~10–15%)	Any new dyspnea → hold drug and evaluate with CT; do not re-challenge after grade 2+ ILD
Brentuximab vedotin	CD30 (Hodgkin lymphoma, ALCL)	MMAE: auristatin microtubule inhibitor	Yes (MMAE membrane-permeable)	Peripheral neuropathy (cumulative, dose-limiting)	MMAE is a CYP3A4 substrate — avoid strong CYP3A4 inhibitors
Polatuzumab vedotin	CD79b (DLBCL)	MMAE: auristatin microtubule inhibitor	Yes	Peripheral neuropathy; neutropenia	Same MMAE CYP3A4 drug interaction profile as brentuximab vedotin
Sacituzumab govitecan	TROP-2 (TNBC, urothelial)	SN-38: active topoisomerase I metabolite of irinotecan	Yes (hydrolyzable linker)	Neutropenia; diarrhea (SN-38 mucosal toxicity)	UGT1A1*28 homozygotes: impaired SN-38 glucuronidation → higher exposure → increased severe toxicity risk

Non-Negotiable Clinical Rules

Six Safety Rules for This Module

Trastuzumab and anthracyclines: sequential only — never concurrent; the combination carries additive cardiotoxicity that has caused treatment-related heart failure. Bevacizumab: hold 28 days before and after any elective surgery; wound healing failure and anastomotic dehiscence have occurred with inadequate washout. Daratumumab: notify the blood bank before the first dose — pan-reactive indirect Coombs positivity persists for months and will invalidate standard crossmatching. Rituximab: screen HBsAg and HBcAb before every course; HBV reactivation can cause fulminant hepatitis and is preventable with antiviral prophylaxis.

T-DXd ILD: any new dyspnea, cough, or oxygen desaturation requires immediate drug hold and CT chest evaluation — re-challenge is contraindicated after grade 2 or higher ILD. Anti-EGFR antibodies in colorectal cancer: RAS wild-type status and left-sided primary tumor are both required for meaningful benefit; RAS mutation is an absolute contraindication.

References

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