Herceptin, generic trastuzumab, is a monoclonal antibody [2].

Herceptin is an effective treatment for

breast cancer for the reason that it binds to the extracellular domain of HER2 and by multiple mechanisms of
action can prevent cell proliferation as well as target these HER2+ cells for destruction by the immune
system [2]. Herceptin acts by four different mechanisms of action [3]:
activation of antibody-dependent cellular cytotoxicity
prevention of formation of p95HER2
inhibition of cell proliferation
inhibition of angiogenesis
When Herceptin binds to HER2 it is able to flag these cells for destruction [3]. This works by
attracting lymphocytes to these HER2+ cells. Lymphocytes are then stimulated to release substances that
cause cellular apoptosis.
An added significant mechanism of action of Herceptin is the prevention of the formation of
p95HER2 [3]. By binding to the juxtamembrane region Herceptin sterically hinders any cleavage of the site
ultimately preventing the formation of the highly active p95HER2.
The next two mechanisms of action for Herceptin involve intracellular inhibition [3]. By the binding
of Herceptin to the extracellular region of HER2 Herceptin is able to prevent downstream activation of cell
signals that induce cell proliferation and angiogenesis. By repression of the proangiogenic factors Herceptin
is also able to induce antiangiogenic factors. Inhibiting these intracellular processes Herceptin prevents any
further blood vessels from developing towards the tumor and prevents the tumor from growing any larger.
Herceptin binds to the juxtamembrane region of
HER2 on the C-terminal portion of subdomain IV.
The interaction formed by Herceptin and HER2 is
mediated by three regions on HER2 that form three
loops: residues 557-561 (loop 1), 570-573 (loop 2),
and 593-603 (loop 3). Loops 1 and 3 are formed
primarily by electrostatic interactions and loop 2 is
formed by hydrophobic contacts. Herceptin's key
amino acids include: Asn 30 and Thr 94 on the light
chain and Tyr 33, Arg 50, Trp 99, Gly 103, and Tyr
105 on the heavy chain [1]. Key amino acids
involved in HER2 are as follows: loop 1 which includes Glu 558 and Asp 560, loop 2 which includes Asp
570 and Phe 573, and loop 3 which includes Gln 602.
Reference
1. Satyanarayanajois, S., Stephanie, V., Liu, J., Go, M.L., 2009, Design, Synthesis, and Docking Studies of
Peptidomimetics based on HER2-Herceptin Binding Site with Potential Antiproliferative Activity
Against Breast Cancer Cell lines, Chem Biol Drug Des. 2009 September ; 74(3): 246257.
doi:10.1111/j.1747-0285.2009.00855.x.NIH-P
2. Jiang, B., Wenbiu, L., Hong, Q., Lin, M., Shumei, S., Tao, O., Chengchao, S., 2005, A Novel Peptide
Isolated from a Phage, Display Peptide Library with Trastuzumab Can Mimic Antigen Epitope of HER2, J. Biol. Chem. 2005, 280:4656-4662. doi: 10.1074/jbc.M411047200.
3. Gajria, Devika, Sarat, Chandarlapaty, 2011, HER2-amplified breast cancer: mechanisms of trastuzumab
resistance and novel targeted therapies, Expert Rev Anticancer Ther. 2011 February ; 11(2): 263275.
doi:10.1586/era.10.226.