Skip to content
Login Register

#Herceptin

3 public questions tagged with this topic.

Immunological Applications

Trastuzumab (Herceptin) is used in treatment of:

HER2 proto-oncogene ERBB2 located chromosome 17q12 encoding 185 kDa receptor tyrosine kinase member EGFR family characterized by extracellular cysteine-rich domains, single transmembrane helix, and intracellular kinase domain. Amplification in 15 to 20 percent invasive breast carcinomas leads to overexpression up to two million receptors per cell versus normal 20,000, facilitating ligand independent homodimerization and heterodimerization with HER3 bound to neuregulin, triggering transphosphorylation of tyrosine residues creating docking sites for Shc, Grb2, p85 subunit of PI3K. Downstream PI3K-AKT-mTOR pathway inhibits BAD promoting survival plus cyclin D1 driving proliferation, MAPK cascade induces transcription of EGR1. Trastuzumab humanized IgG1 generated by grafting murine CDRs onto human framework binds domain IV juxtamembrane region near transmembrane spanning, sterically hindering metalloprotease ADAM10 cleavage that would release active extracellular domain and preventing dimerization interface exposure. Additional actions include antibody-dependent endocytosis reducing surface density, suppression of shed ECD, blockade of downstream signaling, and recruitment of NK cells for ADCC. Combined with paclitaxel or docetaxel improves disease-free survival by approximately 50 percent. Companion diagnostic immunohistochemistry scores 3+ or fluorescence in situ hybridization ratio above 2.0 identifies HER2-positive breast cancer candidates before therapy.

Ref: Slamon et al NEJM 2001 344:783 HER2 trastuzumab domain IV; Harari & Yarden Oncogene 2000 HER2 dimer PI3K signaling.

View Details
Immunological Applications

Trastuzumab (Herceptin) is used in treatment of:

Alemtuzumab humanized IgG1 mAb 150 kDa directed CD52 glycopeptide 21-28 kDa GPI-anchored highly expressed 500k copies normal malignant B T lymphocytes monocytes macrophages eosinophils dendritic cells but absent HSC permitting immune reconstitution after depletion absent neutrophils limiting neutropenia. CD52 function incompletely understood proposed T-costimulation binding Siglec-10 inhibitory modulating migration L-selectin. Binding clusters GPI protein lipid rafts inducing proximity Fc enabling C1q multivalent binding activating classical complement C4 C2 cleavage forming C3 convertase C4b2a opsonizing C3b membrane attack complex C5b-9 osmotic lysis. Simultaneously Fc gamma RI CD64 macrophages Fc gamma RIIIa CD16a NK engage triggering ADCC perforin granzyme B caspase-3 phagocytosis clearing circulating lymphocytes within hours profound lymphopenia year. Repopulation B cells returning 6 months CD8 12 months CD4 longer regulatory T dominance inducing tolerance. Indications B-CLL previously and relapsing multiple sclerosis as induction immune reset therapy requiring monitoring thyroid autoimmunity due reconstitution aberration and anti-GBM disease risk managed REMS program.

Ref: Hale 1983 Transplantation Alemtuzumab CD52 Expression; FDA Campath Lemtrada Label CD52 Depletion; Janeway CD52 Depletion Reconstitution Chapter 14.

View Details
Cell Signaling ELR Pathways - I

Trastuzumab (Herceptin) targets

HER2, is consistent with established principles of cell signaling, receptor pharmacology and cellular regulation. Experimental measurements of binding parameters, genetic loss-of-function studies and pharmacological interventions all converge on the same interpretation. Related options address neighboring concepts but do not satisfy the precise criterion stated in the question.

Ref: NCERT Biology Class 11–12 Alberts et al Molecular Biology of the Cell Lodish et al, Molecular Cell Biology Cooper & Hausman, The Cell Abbas et al., Cellular and Molecular Immunology (for immunology sections)

View Details