Extracellular region of HER2 alone and in complex with the Herceptin Fab

The HER2 breast cancers (~20%) are characterized by amplification of the HER2/neu gene, which is also known as ErbB2. Like EGFR

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trastuzumab, has a higher binding affinity for HER2 (Kd=0.1 nM) than murine MAb 4D5

he ErbB receptor tyrosine kinase 2 (ErbB2 or HER2) belongs to the ErbB (HER) family of receptor tyrosine kinases along with three other members, including epithelial growth factor receptor (EGFR), ErbB3 (HER3), and ErbB4 (HER4) . Generally, these receptors consist of three main domains: (1) the extracellular domain that contains the four subdomains that mediate HER receptor ligand-dependent or -independent dimerization,

Trastuzumab has been shown to bind three distinct regions of domain IV of the HER2 extracellular domain through electrostatic and hydrophobic bindings

HER2 monomer. Mutation Profile via Cancer Genom Atlas

The Cancer Genome Atlas (TCGA) is a comprehensive and coordinated effort to accelerate our understanding of the molecular basis of cancer

The HER2 (also known as ERBB2 or HER2/neu) is a member of the epidermal growth factor receptor (EGFR) family

Trastuzumab binds to the juxtamembrane domain of HER2 and upon receptor binding, the antibody downregulates the expression of HER2

When Herceptin binds to HER2 it is able to flag these cells for destruction.

[Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab]

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Herceptin Fab

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breast tumor development and progression, strategies were developed to therapeutically target HER2 activity. The first successful approach began with the development of a mouse monoclonal antibody (mAb) called 4D5, which targets an extracellular epitope of the HER2 protein . HER2-specific monoclonal antibody 4D5 blocked phosphorylation of HER2 and suppressed growth of HER2-positive breast cancer cell lines and xenografts. In order to translate 4D5 clinically, a derivative that includes the antigen binding loops of 4D5 and the human variable region and immunoglobulin G1 constant domains was constructed [35]. The recombinant humanized anti-HER2 antibody that resulted from this effort is called trastuzumab (Herceptin; Genentech, San Francisco, CA, USA).
Trastuzumab achieved significant regression of human HER2-overexpressing tumor xenografts as monotherapy or in combination with cytotoxic chemotherapeutic agents. The mechanisms underlying the anticancer activity of trastuzumab are not completely known, but several have been proposed . Some studies have suggested that trastuzumab downregulates total levels of HER2 on the cell surface , which may ultimately reduce downstream PI3K and MAPK signaling. Trastuzumab has been shown to block cleavage of the extracellular domain of HER2, thus, preventing formation of the constitutively active membrane-bound 95-kiloDalton HER2 protein called p95 HER2 . Trastuzumab may also selectively inhibit HER2-HER3 heterodimerization , reducing PI3K signaling. Induction of cell cycle arrest by trastuzumab is mediated by p27kip1 and inhibition of cdk2 activity . Furthermore, trastuzumab appears to reduce angiogenesis, which may result in increased permeability of blood vessels, potentially increasing delivery of drugs to the tumor. Finally, HER2-positive cells that become “coated” in trastuzumab will be recognized by specific immune cells, causing antibody-dependent cellular cytotoxicity (ADCC), or lysis of the antibody-bound cells . This last mechanism may be quite important to the overall activity of trastuzumab, as trastuzumab was unable to achieve an antitumor response in mice that lacked Fc gamma receptors present on the ADCC-promoting immune cells, natural killer cells and macrophages, and is discussed in detail below as a mechanism of trastuzumab resistance .

The past decade of research into HER2-overexpressing breast cancer has provided significant insight into the mechanisms by which HER2 signaling drives tumor progression, as well as potential mechanisms by which cancer cells escape the anticancer activity of HER2-targeted therapy. Many of these preclinical findings have been translated into clinical development, resulting in novel combinations of HER2-targeted therapies and combinations of trastuzumab plus inhibitors of resistance pathways

Molecular Mechanisms of Trastuzumab-Based Treatment in HER2-Overexpressing

The interface between antibody and antigen is often depicted as a lock and key, suggesting that an antibody surface can accommodate only one antigen. Here, we describe an antibody with an antigen binding site

Herceptin to HER2 protein in breast cancer

520-CWGPGPTQCV_NCSQFLRGQE_CVEECRVLQGL_PREYVN
ARHCLPCHPECQPQNGSVTCFGPEADQCVACAHYKDPPFCV
ARCPSGVKPDLSYMPIWKFPDEE_GACQPCPINC -630

P04626 · ERBB2_HUMAN

HER2 monomer [520-628]-Fab_blue

HER2 monomer [520-628]-Fab_yell

HER2 monomer [520-628]

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How to read and interpret data?

Let's take two "symmetrical" from the point of analysis quantities lg(cond(W)) and lg[Kd] for which we are looking for a minimum of values. The values ​​of these quantities should tend to a minimum.

We will also take various biological associations, both complete formations and truncated domains, and for each formation we will sign the value of these two quantities.

Next, we analyze similar formations in order to find the minimum values ​​of the calculated quantities.

We draw "flow" arrows for biological formations.

This diagram summarizes the stability (lg(cond(W))) and dissociation constant (lg(Kd)) parameters for different HER2 regions and Fab combinations.
Visual annotations indicate levels of stability: most unstable, unstable, average, and most stable.

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