Myeloma cells used in hybridoma technology are selected to be:
Trastuzumab humanized IgG1 kappa mAb 148 kDa targets HER2 proto-oncogene extracellular domain IV juxtamembrane receptor overexpressed due ERBB2 amplification 17q12 20 percent breast gastric cancers poor prognosis. HER2 no known ligand but dimerizes HER1 HER2 HER3 after EGF binding autophosphorylating intracellular tyrosines Tyr1221 Tyr1222 recruiting Grb2 Shc activating PI3K Akt survival phosphorylating Bad Forkhead preventing apoptosis plus RAS RAF MEK ERK proliferation cyclin D1. Trastuzumab binds KD 5 nM sterically hindering dimerization preventing proteolytic cleavage shedding ECD generating constitutively active p95 truncated lacking ectodomain and inducing internalization clathrin-mediated requiring c-Cbl E3 ubiquitin ligase ubiquitination lysosomal degradation reducing surface density. Fc human IgG1 engages Fc gamma RIIIa CD16a NK cells triggering perforin granzyme ADCC and macrophage ADCP phagocytosis. Combination taxane docetaxel increased response 32 to 50 percent overall survival prolongation establishing HER2 testing companion diagnostic immunohistochemistry score 3+ FISH ratio >2.0 guiding patient selection achieving paradigm targeted immunotherapy solid tumors effective safe with cardiac monitoring due occasional LV dysfunction.
Ref: NEJM Trastuzumab HER2 Mechanism Slamon 2001 Clinical; FDA Herceptin Package Insert MOA Description; Janeway ADCC Trastuzumab Immune Mechanism NK Chapter 14.