Monoclonal Antibodies and Antibody-Drug Conjugates

Targets, mechanisms, toxicities, and clinical rules

mAb = monoclonal antibody  ·  ADC = antibody-drug conjugate  ·  ADCC = antibody-dependent cellular cytotoxicity  ·  FcRn = neonatal Fc receptor  ·  TMDD = target-mediated drug disposition  ·  DAR = drug-to-antibody ratio  ·  IHC = immunohistochemistry  ·  FISH = fluorescence in situ hybridization  ·  LVEF = left ventricular ejection fraction  ·  PML = progressive multifocal leukoencephalopathy  ·  ILD = interstitial lung disease  ·  MMAE = monomethyl auristatin E

Monoclonal Antibody Pharmacokinetics

Large-Molecule ADME
  • IV or SC administration (no oral bioavailability)
  • Vd: 3–8 L (plasma + interstitial only; no CNS penetration)
  • Not CYP metabolized → no CYP drug interactions
  • Catabolized by proteolysis throughout body
  • Half-life 14–21 days (FcRn recycling)
FcRn Recycling
  • FcRn binds IgG in acidic endosome → rescues from degradation
  • Releases IgG at physiological pH → back to circulation
  • FcRn in placenta → mAbs cross placenta after 1st trimester
  • Saturable at high doses → nonlinear pharmacokinetics
Naming Convention
  • -omab: murine (highest immunogenicity)
  • -ximab: chimeric (e.g., rituximab, cetuximab)
  • -zumab: humanized (e.g., trastuzumab, bevacizumab)
  • -umab: fully human (e.g., panitumumab, denosumab)

Anti-HER2 and Anti-VEGF Antibodies

Trastuzumab / Pertuzumab (HER2)
  • Trastuzumab: binds HER2 domain IV; ADCC + PI3K/MAPK inhibition
  • Pertuzumab: binds HER2 domain II; blocks HER2-HER3 dimerization
  • Cardiotoxicity: reversible LVEF reduction (inhibits ErbB2 cardiac repair)
  • RULE: Anthracycline → THEN trastuzumab (never concurrent)
  • Baseline LVEF assessment mandatory; monitor during therapy
Bevacizumab (VEGF-A)
  • Binds all VEGF-A isoforms → inhibits tumor angiogenesis
  • Hypertension: VEGF withdrawal → reduced nitric oxide → vasoconstriction
  • Impairs wound healing (VEGF-A required for neovascularization)
  • RULE: Hold 28 days before and after elective surgery
  • Contraindicated: squamous cell NSCLC (hemoptysis risk)
  • Bowel perforation and PRES: rare but serious

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

Agent Target Companion Dx Key Toxicity Clinical Rule
Cetuximab / Panitumumab EGFR RAS wild-type; left-sided CRC Acneiform rash; hypomagnesemia; alpha-gal reactions (cetuximab) RAS mutation = no benefit; excluded from anti-EGFR
Rituximab / Obinutuzumab CD20 (B cells) CD20 expression HBV reactivation; PML (JC virus) Screen HBsAg and HBcAb; live vaccines contraindicated
Daratumumab CD38 (myeloma) CD38 expression Blood bank interference (pan-reactive indirect Coombs) Notify blood bank before first dose; DTT crossmatch required
Denosumab RANKL (osteoclasts) None Hypocalcemia; osteonecrosis of jaw Calcium + vitamin D supplementation mandatory; dental evaluation first

Antibody-Drug Conjugates — Payload and Toxicity

ADC Target Payload Bystander Killing Key Toxicity Special Rule
T-DM1 (trastuzumab emtansine) HER2 DM1 (microtubule) Minimal Thrombocytopenia; hepatotoxicity Not interchangeable with trastuzumab
T-DXd (trastuzumab deruxtecan) HER2 / HER2-low DXd (topo I) High (membrane-permeable) ILD/pneumonitis HER2-low now eligible; any dyspnea → evaluate ILD
Brentuximab vedotin CD30 (Hodgkin) MMAE (microtubule) Yes Peripheral neuropathy MMAE: CYP3A4 substrate
Polatuzumab vedotin CD79b (DLBCL) MMAE (microtubule) Yes Peripheral neuropathy Same MMAE interactions as brentuximab
Sacituzumab govitecan TROP-2 (TNBC) SN-38 (topo I) Yes Neutropenia; diarrhea UGT1A1*28 genotype → increased SN-38 toxicity

Non-Negotiable Clinical Rules

Trastuzumab + anthracycline: sequential only — never concurrent. Bevacizumab: hold 28 days before and after surgery. Daratumumab: notify blood bank before first dose — pan-reactive indirect Coombs persists for months. Rituximab: screen for HBV (HBsAg and HBcAb) before every course. T-DXd ILD: any new dyspnea requires immediate evaluation — hold drug pending assessment. Anti-EGFR in colorectal cancer: RAS wild-type and left-sided tumor are both required.