Which of the following is an example of therapeutic monoclonal antibody?
Cetuximab chimeric IgG1 mAb 152 kDa murine variable regions grafted human constant domains preserving antigen binding specificity reducing HAMA response versus purely murine. Target EGFR HER1 encoded EGFR 7p11.2 overexpressed colorectal lung HNSCC via amplification autocrine loop. Physiologic ligands EGF TGF-alpha amphiregulin bind ECD III inducing conformational change exposing dimerization arm domain II allowing homo hetero-dimerization HER2 HER3 autophosphorylation tyrosines Tyr1068 Tyr1086 Tyr1173 recruiting adaptors Grb2 Shc activating KRAS GTP exchange GDP GTP triggering BRAF MEK ERK proliferation Elk1 PI3K p110alpha generating PIP3 Akt mTOR survival. Cetuximab competitively occupies ligand-binding site affinity 0.1 nM exceeding EGF 1 nM blocks ligand access inhibits dimer formation promotes internalization degradation clathrin pits reducing nuclear translocation where EGFR acts transcription cofactor cyclin D1 iNOS. Fab also mediates ADCC via NK Fc gamma RIIIa. Efficacy confined RAS wild-type because constitutive KRAS G12D G13D NRAS mutations bypass receptor requirement rendering blockade ineffective necessitating companion diagnostic KRAS testing before use explaining infusion reaction due preexisting IgE alpha-gal epitope murine Fab glycosylation mammalian expression system.
Ref: FDA Erbitux Cetuximab EGFR MOA Label; NEJM Cetuximab Colorectal KRAS Wild-type 2008 Van Cutsem; Janeway EGFR Antibody Therapy ADCC Mechanism.