ChEMBL

On June 8th 2012, the US FDA approved pertuzumab (also known as RG-1273 and RhuMAb-2C4, tradename: Perjeta) for the treatment of HER2/ERBB2 positive, late stage metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. Breast cancer is the most common female cancer. About 20% of breast cancers have amplified and over expressed Epidermal Growth Factor Receptor 2 (EGFR2, a.k.a. ERBB2 and HER2). These cancer subtypes are associated with worse prognosis and higher metastatic rates.

Pertuzumab is an anti-ERBB2/HER2 recombinant humanized monoclonal. It has been approved for use as part of a triple combination containing pertuzumab, another anti-ERBB2/HER2 antibody, trastuzumab, and the taxane docetaxel. The added value of combining both anti-ERBB2/HER2 antibodies is that pertuzumab binds to a different part of ERBB2 - the extracellular dimerization domain (Subdomain II) and this way it sterically blocks ligand-dependent heterodimerization with other HER family members. Meanwhile, trastuzumab binds to and inhibits the juxtamembrane portion of the extracellular domain.
Pertuzumab inhibits ligand-initiated intracellular signaling through the MAP kinase pathway, leading to cell growth arrest and the PI3 Kinase pathway, leading to apoptosis.





Superposition of the structures of pertuzumab (red) bound to ERBB2 (pink)- PDBe:1s78, with trastuzumab (blue) with ERBB2 (green) - PDBe:1n8z.


Pertuzumab has been issued a Black Box Warning because it can cause embryo-fetal death and birth defects, and thus cannot be used by women who are pregnant.

The target of pertuzumab is Human Epidermal Growth Factor Receptor 2 (ERBB2, HER2) (Uniprot:P04626; ; chembl:CHEMBL1824; canSAR:ERBB2-P04626).

>sp|P04626|ERBB2_HUMAN Receptor tyrosine-protein kinase erbB-2 OS=Homo sapiens GN=ERBB2 PE=1 SV=1
MELAALCRWGLLLALLPPGAASTQVCTGTDMKLRLPASPETHLDMLRHLYQGCQVVQGNL
ELTYLPTNASLSFLQDIQEVQGYVLIAHNQVRQVPLQRLRIVRGTQLFEDNYALAVLDNG
DPLNNTTPVTGASPGGLRELQLRSLTEILKGGVLIQRNPQLCYQDTILWKDIFHKNNQLA
LTLIDTNRSRACHPCSPMCKGSRCWGESSEDCQSLTRTVCAGGCARCKGPLPTDCCHEQC
AAGCTGPKHSDCLACLHFNHSGICELHCPALVTYNTDTFESMPNPEGRYTFGASCVTACP
YNYLSTDVGSCTLVCPLHNQEVTAEDGTQRCEKCSKPCARVCYGLGMEHLREVRAVTSAN
IQEFAGCKKIFGSLAFLPESFDGDPASNTAPLQPEQLQVFETLEEITGYLYISAWPDSLP
DLSVFQNLQVIRGRILHNGAYSLTLQGLGISWLGLRSLRELGSGLALIHHNTHLCFVHTV
PWDQLFRNPHQALLHTANRPEDECVGEGLACHQLCARGHCWGPGPTQCVNCSQFLRGQEC
VEECRVLQGLPREYVNARHCLPCHPECQPQNGSVTCFGPEADQCVACAHYKDPPFCVARC
PSGVKPDLSYMPIWKFPDEEGACQPCPINCTHSCVDLDDKGCPAEQRASPLTSIISAVVG
ILLVVVLGVVFGILIKRRQQKIRKYTMRRLLQETELVEPLTPSGAMPNQAQMRILKETEL
RKVKVLGSGAFGTVYKGIWIPDGENVKIPVAIKVLRENTSPKANKEILDEAYVMAGVGSP
YVSRLLGICLTSTVQLVTQLMPYGCLLDHVRENRGRLGSQDLLNWCMQIAKGMSYLEDVR
LVHRDLAARNVLVKSPNHVKITDFGLARLLDIDETEYHADGGKVPIKWMALESILRRRFT
HQSDVWSYGVTVWELMTFGAKPYDGIPAREIPDLLEKGERLPQPPICTIDVYMIMVKCWM
IDSECRPRFRELVSEFSRMARDPQRFVVIQNEDLGPASPLDSTFYRSLLEDDDMGDLVDA
EEYLVPQQGFFCPDPAPGAGGMVHHRHRSSSTRSGGGDLTLGLEPSEEEAPRSPLAPSEG
AGSDVFDGDLGMGAAKGLQSLPTHDPSPLQRYSEDPTVPLPSETDGYVAPLTCSPQPEYV
NQPDVRPQPPSPREGPLPAARPAGATLERPKTLSPGKNGVVKDVFAFGGAVENPEYLTPQ
GGAAPQPHPPPAFSPAFDNLYYWDQDPPERGAPPSTFKGTPTAENPEYLGLDVPV

Perjeta is marketed by Genentech Inc, a member of the Roche group

Full prescribing information can be obtained here, and the product website here.