Our Research & Initiatives

At Gentech, we are driven by the desire to make a positive impact on the world through scientific breakthroughs. Our team of dedicated researchers constantly explore new avenues of discovery, working tirelessly to bring about the next generation of medicine. We are committed to providing affordable access to our breakthroughs to serve our patients and community.

HER2 Subtype

A normal cell and a HER2 overexpressing cell. Image created with Biorender

Human epidermal growth factor receptor-2 (HER2) belongs to the epidermal growth factor receptor family (EGFR/ErbB). Extracellular ligands such as epidermal growth factor (EGF) binds to the EGFR receptors resulting in homo or hetero dimerization of the receptors. This phosphorylates the cytoplasmic domains and triggering the signaling pathway which controls cell proliferation, differentiation and survival. Intriguingly, to date there has been no HER2 ligands identified and HER2 has been shown to form both homo and hetero dimers easily without ligands.

20 to 30% of human breast cancers have an overexpression of HER2 receptors. Breast cancer cells with overexpressing HER2 receptors are known a the HER2 positive subtype and is associated with poor prognosis. Overexpression of about a 100 fold HER2 or 2 million receptors have been shown these breast tumor cells resulting in uncontrolled proliferation of these tumor cells.

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Herceptini Targets HER2

Herceptini binds to extracellular domain IV of HER2 receptor through electrostatic and hydrophobic bindings and interferes with both the homo and the hetero dimerization. The half life of Herceptini is 5.8 days in therapeutic doses in breast cancers.

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Herceptini in red and pink binding to a HER2 receptor in blue

(Figure adapted from RCSB: PDB-101, 2022)

Mechanism of Action

The 3 main mechanisms of action of Herceptini. Image created with Biorender

As Herceptini binds to the HER2 receptors in HER2 positive breast cancer it activates its anti-tumour effect in these three main mechanisms of action.

1. Activates Antibody-dependent cellular cytotoxicity (ADCC)

The fc region of Herceptini binds to Fcγ receptors on immune effector cells and activates the ADCC process. This initiates the secretion of perforin and granzymes from immune effector cells, destroying the HER2 overexpressing breast cancer cells.

2. Suppresses intracellular HER2 signaling pathways

Dimerized HER receptors signals cell proliferation through the PI3K/AKT signaling pathway.

Herceptini inhibits the HER2-HER3 heterodimer‘s PI3K/AKT signaling pathway which has the most oncogenic outcome of the dimer pairs, by inhibiting phosphorylation. Studies also show that Herceptini activates PTEN a tumor suppressor which inhibits the PI3K/AKT pathway thereby stopping the excessive proliferation.

3. Stops HER2 shedding

Cleaved HER2 fragment known as p95HER2, is detected in patients with high HER2 expressing breast cancers. These p95HER2 are active and can activate the PI3K/AKT pathway. Herceptini is shown to reduces MMP-mediated HER2 shredding and lowers the PI3K/AKT signaling.

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Herceptini Side Effects

Common side effects include headache, diarrhea, nausea, chills, fever, infection, congestive heart failure, insomnia, cough, and rash.

The less common side effects includes cardiomyopathy, infusion reactions, bronchospasm, anaphylaxis, angioedema, hypoxia, and severe hypotension, embryo-fetal toxicity, pulmonary toxicity, exacerbation of chemotherapy-induced neutropenia.

Please seek medical attention if you experience any of these side effects.

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Image credit: <a href="https://www.freepik.com/free-photo/asian-woman-sitting-sad-by-her bed_17431301.htm#query=side%20effect&position=1&from_view=search&track=ais">Image by rawpixel.com</a> on Freepik

Quality Assessment

Image credit: <a href="https://www.freepik.com/free-photo/women-working-together-chemical-project_11383358.htm#&position=2&from_view=collections">Freepik</a>

At Gentech, every batch of Herceptini produced, goes through these stringent quality assessments.

N-Glycan analysis

Therapeutic efficacies could drop by just slightest modification through glycan additions, which may occasionally occur during production. The Glycan profiles are montitored through our state-of-the-art Acquity™ ultra-performance liquid chromatography system to meet strict consistency.

Anti-proliferation assay

Herceptini is incubated with BT-474 a breast cancer tumor cell line, and the anti-proliferation activity is monitored with CellTiter-Blue® cell viability assay kit.

Antibody-dependent cellular cytotoxicity (ADCC assay)

ADCC is the primary mechanism of action by Herceptini. Fc-related activity of Herceptini is assessed with SKBR3 a breast cancer cell line and a natural killer cell line NK92-CD16. The ADCC activity will be inferred by the the CytoTox-Glo® kit, which analyses luminescence signals from dead cell signals.

Non-reducing capillary electrophoresis-sodium dodecyl sulfate (CE-SDS)

The intact monoclonal antibody in our final product is measured to ensure high degree of consistency and purity.

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Research & Development

Gentech pushes the boundaries of science, innovating and developing the next generation of therapeutics that could transform patients lives with improved outcomes and better quality life.

One of the recent technology developments is with Ado-trastuzumab emtansine (T-DM1), an antibody-drug conjugate (ADC) that has just moved into the clinical trial. T-DM1 selectively delivers cytotoxic drugs to only to HER2 expressing breast cancer cells. This technology combines the specificity of Herceptini with the high toxicity of cytotoxic drugs and maximises the anti-tumor efficacy.

7 References

1. Maadi, H., Soheilifar, M.H., Choi, W.-S., Moshtaghian, A. and Wang, Z. (2021). Trastuzumab Mechanism of Action; 20 Years of Research to Unravel a Dilemma. Cancers, 13(14), p.3540. doi:https://doi.org/10.3390/cancers13143540.

2. Gutierrez, C. and Schiff, R. (2011). HER2: biology, detection, and Clinical Implications. Archives of Pathology & Laboratory Medicine, [online] 135(1), pp.55–62. doi:https://doi.org/10.1043/2010-0454-RAR.1.

3. Yu, X., Wang, L., Shen, Y., Wang, C., Zhang, Y., Meng, Y., Yang, Y., Liang, B., Zhou, B., Wang, H., Wei, H., Lei, C., Hu, S. and Li, B. (2017). Targeting EGFR/HER2 heterodimerization with a novel anti-HER2 domain II/III antibody. Molecular Immunology, 87, pp.300–307. doi:https://doi.org/10.1016/j.molimm.2017.05.010.

4. Goldenberg, M.M. (1999). Trastuzumab, a recombinant DNA-derived humanized monoclonal antibody, a novel agent for the treatment of metastatic breast cancer. Clinical Therapeutics, 21(2), pp.309–318. doi:https://doi.org/10.1016/s0149-2918(00)88288-0.

5. HIGHLIGHTS OF PRESCRIBING INFORMATION. (n.d.). Available at: https://www.gene.com/download/pdf/herceptin_prescribing.pdf.

6. Kim, S., Song, J., Park, S., Ham, S., Paek, K., Kang, M., Chae, Y., Seo, H., Kim, H.-C. and Flores, M. (2017). Drifts in ADCC-related quality attributes of Herceptin®: Impact on development of a trastuzumab biosimilar. mAbs, 9(4), pp.704–714. doi:https://doi.org/10.1080/19420862.2017.1305530.

7. Ferraro, E., Drago, J.Z. and Modi, S. (2021). Implementing antibody-drug conjugates (ADCs) in HER2-positive breast cancer: state of the art and future directions. Breast Cancer Research, 23(1). doi:https://doi.org/10.1186/s13058-021-01459-y.

8. RCSB: PDB-101. (2022). PDB101: Molecule of the Month: HER2/neu and Trastuzumab. [online] Available at: https://pdb101.rcsb.org/motm/268