Trastuzumab

Brand Name: Herceptin, Ogivri, Herzuma, Ontruzant, Trazimera, Kanjinti, Hercessi

Trastuzumab is used to treat HER2-overexpressing breast cancer and HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma. It is used either as a monotherapy or alongside other chemotherapy drugs such as paclitaxel.1

How Does Trastuzumab Work?

Tyrosine kinase using ATP to attach a phosphate tag on other proteins, which results in the transmission of growth signals.

Cellular growth signals are often transmitted through a process called phosphorylation, in which an enzyme called tyrosine kinase attaches a phosphate tag to another protein. This phosphate tag is derived from a molecule called ATP.2

HER2 protein on the surface of the cell.

HER2 is a protein in the receptor tyrosine kinase family. This protein consists of a receptor domain outside the cell connected to a tyrosine kinase domain inside the cell.3

Inactive monomeric HER2 tyrosine kinase domain and active dimeric HER2 tyrosine kinase domains.

The kinase domain of HER2 is inactive by itself, but when two kinase domains come together to form a dimer, the kinase is activated, allowing phosphorylation to transmit growth signals.3

HER2 and EGFR or HER3 dimer producing controlled growth signals.

HER2 is activated during specific stages of development by dimerizing with other similar proteins, such as EGFR or HER3. It is responsible for the development of various organs, such as the heart and the mammary gland.4,5 Of note, the expression level of HER2 is tightly controlled so that growth signals are generated only when necessary.

HER2 and EGFR or HER3 dimer as well as HER2 and HER2 dimer producing uncontrolled growth signals.

However, in some types of cancer, HER2 is overexpressed. Due to enhanced pairing of HER2 with other similar proteins and also itself, uncontrolled growth signals are produced that drive cancer proliferation.3

Trastuzumab binding to receptor domain of HER2.

Trastuzumab is an antibody drug that can recognize and bind to HER2.6

Antibody receptor on natural killer cells recognizing trastuzumab and releasing toxins to kills cancer cells.

(1) Natural killer (NK) cells, a type of immune cells, express antibody receptors on their surface that can recognize antibodies. When these receptors bind to antibodies like trastuzumab, NK cells are activated. (2) Active NK cells release toxins that (3) punctures and kills nearby cells.7 Since trastuzumab specifically recognizes HER2, cells expressing the highest amounts of HER2, i.e. the cancer cells, are targeted for killing by natural killer cells, while most other cells are spared.

Side Effects of Trastuzumab

Side effects profile is adapted from a study8 of single-agent trastuzumab as a treatment for HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy.

References

1. HERCEPTIN - Label. U.S. Food and Drug Administration (2024).

2. Hubbard, S. R. & Till, J. H. Protein Tyrosine Kinase Structure and Function. Annual Review of Biochemistry 69, 373-398 (2000).

3. Tebbutt, N., Pedersen, M. W. & Johns, T. G. Targeting the ERBB family in cancer: couples therapy. Nature Reviews Cancer 13, 663-673 (2013).

4. Lee, KF. et al. Requirement for neuregulin receptor erbB2 in neural and cardiac development. Nature 378, 394-398 (1995).

5. Stern, D. F. ErbBs in mammary development. Experimental Cell Research 284, 89-98 (2003).

6. Cho, HS. et al. Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature 421, 756-760 (2003).

7. Wang, W., Erbe, A. K., Hank, J. A., Morris, Z. S. & Sondel, P. M. NK cell-mediated antibody-dependent cellular cytotoxicity in cancer immunotherapy. Frontiers in Immunology 6, 368 (2015).

8. Cobleigh, M. A. et al. Multinational Study of the Efficacy and Safety of Humanized Anti-HER2 Monoclonal Antibody in Women Who Have HER2-Overexpressing Metastatic Breast Cancer That Has Progressed After Chemotherapy for Metastatic Disease. Journal of Clinical Oncology 17, 2639-2648 (1999).

9. PERJETA - Label. U.S. Food and Drug Administration (2020).