Trastuzumab: Difference between revisions
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< | <StructureSection load='3be1' size='450' side='right' caption='Tastuzumab, better known as Herceptin, ([[3be1]])' scene='Trastuzumab/Trastuzumab/1'> | ||
__TOC__ | |||
===Better Known as: Herceptin=== | ===Better Known as: Herceptin=== | ||
* Marketed By: Genentech<br /> | * Marketed By: Genentech<br /> | ||
| Line 7: | Line 8: | ||
* 2008 Sales: $4.75 Billion | * 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. | * 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=== | ===Mechanism of Action=== | ||
[[Epidermal Growth Factor Receptor|Human Epidermal Growth Factor Receptor 2]] (HER2) is overexpressed in approximately 30% of breast [[Cancer|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]] <scene name='Trastuzumab/Trastuzumab_h/1'>that binds to the domain IV</scene> 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.<ref>PMID:14528282</ref> <scene name='Trastuzumab/Vouns/5'>The extremely precise binding interaction</scene> 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. | |||
<scene name='81/816443/Cv/24'>The overview of the distinct epitopes of HuA21, Trastuzumab and Pertuzumab</scene>. 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.<ref>doi 10.1107/S2059798319006995</ref> | |||
===Pharmacokinetics=== | ===Pharmacokinetics=== | ||
{| class="wikitable" border="1" width=" | {| class="wikitable" border="1" width="40%" style="text-align:center" | ||
|- | |- | ||
! colspan="12" align="center"| EGFR Inhibitor [[ | ! colspan="12" align="center"| EGFR Inhibitor [[Pharmacokinetics]]<ref>DOI: 10.1200/JCO.2003.12.109</ref><ref> B. Leyland-Jones, et al. Pharmacologic insights into the future of trastuzumab. Annals of Oncology 12 (Suppl. I): S43-S47, 2001.</ref> | ||
|- | |- | ||
! Parameter | ! Parameter | ||
! [[Trastuzumab]] | ! [[Trastuzumab]] | ||
|- | |- | ||
! [[ | ! [[Pharmacokinetics#Tmax|T<sub>max</sub>]] (hr) | ||
! 1.7 | ! 1.7 | ||
|- | |- | ||
! [[ | ! [[Pharmacokinetics#Cmax|C<sub>max</sub>]] (ng/ml) | ||
! 203000 | ! 203000 | ||
|- | |- | ||
! [[ | ! [[Pharmacokinetics#Bioavailability_.28F.29|Bioavailability]] (%) | ||
! 54 | ! 54 | ||
|- | |- | ||
! [[ | ! [[Pharmacokinetics#Half_Life_.28T1.2F2.29|T<sub>1/2</sub>]] (days) | ||
! 27 | ! 27 | ||
|- | |- | ||
! [[ | ! [[Pharmacokinetics#Area_Under_the_Curve_.28AUC.29|AUC]] (ug/ml/hr) | ||
! 45036 | ! 45036 | ||
|- | |- | ||
! [[ | ! [[Pharmacokinetics#Clearance_.28Cl.29|Clearance]] (L/h) | ||
! .009 | ! .009 | ||
|- | |- | ||
| Line 43: | Line 46: | ||
! Unknown | ! Unknown | ||
|} | |} | ||
</StructureSection> | |||
===References=== | ===References=== | ||
<references/> | <references/> | ||
__NOEDITSECTION__ | __NOEDITSECTION__ | ||
Latest revision as of 16:30, 15 June 2022
Better Known as: Herceptin
Mechanism of ActionHuman 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 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] 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. . 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
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References
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ B. Leyland-Jones, et al. Pharmacologic insights into the future of trastuzumab. Annals of Oncology 12 (Suppl. I): S43-S47, 2001.