Trastuzumab

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Contents

Better Known as: Herceptin

  • Marketed By: Genentech
  • Major Indication: Breast Cancer
  • Drug Class: Human Epidermal Growth Factor Receptor 2 (HER2) Inhibitor
  • Date of FDA Approval (Discontinued): 1998 (2015)
  • 2008 Sales: $4.75 Billion
  • Importance: It is a very effective treatment against HER2-positive metastatic breast cancer compared to other cancer therapies. Controversial due to its cost of nearly $100,000 per year. Is often pointed to as an example of the benefits of personalized medicine in which a patent's genetic profile is used to optimize their medication regimen.
  • See Pharmaceutical Drugs for more information about other drugs and disorders

Mechanism of Action

Human Epidermal Growth Factor Receptor 2 (HER2) is overexpressed in approximately 30% of breast cancers. Upon receiving a mitogenic signal, HER2, located in the cell membrane, dimerizes and transfers signals to receptors within the cell. This activates different pathways including the PI3K pathway and MAPK pathway, promoting cellular survival and replication. Trastuzumab is a humanized monoclonal antibody that binds to the domain IV of the extracellular segment of the HER2 receptor. It has been suggested that Trastuzumab binding disrupts receptor dimerization, preventing the errant signal from being transfered. This ultimately causes cells to arrest druing the G1 phase of the cell cycle, halting cellular proliferation.[1] The extremely precise binding interaction between the Trastuzumab antibody Fab and HER2 involves residues Arg 58, Arg 50, Tyr 33, Tyr 100, & Gly 99 on the heavy chain Fab, Thr 94, His 91, Tyr 92, Tyr 32, & Tyr 53 on the light chain Fab, and Glu 558, Gln 561, Asp 560, Phe 573, Lys 569, Pro 572, Pro 571, Lys 593, Cys 601, Cys 604 & Gln 602 on the HER2 polypeptide.

The overview of the distinct epitopes of HuA21, Trastuzumab and Pertuzumab. HuA21, Trastuzumab and Pertuzumab are labelled and colored slate, magenta and cyan, respectively. The HER2 subdomains I, II, III and IV are colored red, green, blue and yellow, respectively.[2]

Pharmacokinetics

EGFR Inhibitor Pharmacokinetics[3][4]
Parameter Trastuzumab
Tmax (hr) 1.7
Cmax (ng/ml) 203000
Bioavailability (%) 54
T1/2 (days) 27
AUC (ug/ml/hr) 45036
Clearance (L/h) .009
Dosage (mg) 250
Metabolism Unknown

Tastuzumab, better known as Herceptin, (3be1)

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References

  1. ↑ Menard S, Pupa SM, Campiglio M, Tagliabue E. Biologic and therapeutic role of HER2 in cancer. Oncogene. 2003 Sep 29;22(42):6570-8. PMID:14528282 doi:10.1038/sj.onc.1206779
  2. ↑ Wang Z, Cheng L, Guo G, Cheng B, Hu S, Zhang H, Zhu Z, Niu L. Structural insight into a matured humanized monoclonal antibody HuA21 against HER2-overexpressing cancer cells. Acta Crystallogr D Struct Biol. 2019 Jun 1;75(Pt 6):554-563. doi:, 10.1107/S2059798319006995. Epub 2019 May 31. PMID:31205018 doi:http://dx.doi.org/10.1107/S2059798319006995
  3. ↑ Leyland-Jones B, Gelmon K, Ayoub JP, Arnold A, Verma S, Dias R, Ghahramani P. Pharmacokinetics, safety, and efficacy of trastuzumab administered every three weeks in combination with paclitaxel. J Clin Oncol. 2003 Nov 1;21(21):3965-71. Epub 2003 Sep 24. PMID:14507946 doi:10.1200/JCO.2003.12.109
  4. ↑ B. Leyland-Jones, et al. Pharmacologic insights into the future of trastuzumab. Annals of Oncology 12 (Suppl. I): S43-S47, 2001.

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David Canner, Alexander Berchansky, Joel L. Sussman

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