Find me a -mAb drug assignment: Trastuzumab
annotated-Trastuzumab.docxMonoclonal antibodies are immune system proteins produced in a laboratory environment. They can be utilized as targeted cancer therapies or as immunotherapies marking cancer cells for the immune system to recognize and destroy(1). Trastuzumab, brand name Herceptin, is a monoclonal antibody utilized in the treatment of both breast and stomach cancer. Trastuzumab is an IgG1 antibody that has undergone the process of humanization, targeting the human epidermal growth factor receptor 2 (HER2) (2). Human epidermal growth factor receptor 2 (HER2) is a transmembrane glycoprotein receptor in the epidermal growth factor family(EGRF). Changes in the signaling of HER2, particularly overexpression and amplification, are connected to the growth and proliferation of stomach and breast cancers. Activating mutations to HER2 are connected with the alliteration of tumorigenesis and metastasis(3). The suggested rate of breast cancer patients who have HER2 mutations is 1.6% (4). Another suggested rate for HER2 overexpression in cases of breast cancer is 20-30%(5) (6). primarily binds with itself or other EGFR family proteins, these pairings activate growth signals that drive the processes of cellular division, survival, and migration. Since the HER2 pathways discovery multiple therapies have been developed including Trastuzumab (Herceptin), Pertuzumab (Perjeta), Ado-trastuzumab emtansine (Kadcyla), Trastuzumab deruxtecan (T-DXd), Neratinib that block HER2 signaling(3). Trastuzumab particularly binds the extracellular domain of the HER2 protein, inhibiting homodimerization, thus blocking HER2 signaling(3)(7). Antibody-dependent cell-mediated cytotoxicity (ADCC), an immune host surveillance mechanism targeting tumors, is thought to be an additional way that Trastuzumab works against HER2 positive cancers(8). First described by Schechter et al. in 1984 the neu gene discovered in rat neuro/glioblastomas its product protein HER2 was first described by Coussens et al in 1985(9)(10). Trastuzumab, the first drug targeting HER2, was developed by Genentech and approved for sale in the US in 1998(11) (12). Trastuzumab is typically administered in the form of an intravenous infusion with an initial loading dose of 8 mg/kg and a maintenance dose of 2-6 mg/kg every 3 weeks(7). Trastuzumab is known to induce cardiomyopathy, leading to the increase in reactive oxygen species in Cardiomyocytes, as a side effect(13).
References:
- Monoclonal antibodies. National Cancer Institute, https://www.cancer.gov/about-
cancer/treatment/types/immunotherapy/monoclonal-antibodies - Karagiannis, P. et al (2009). Characterisation of an engineered trastuzumab IGE antibody and
effector cell mechanisms targeting HER2/neu-positive tumour cells. U.S. National Library of
Medicine, 58(6), 915-930. https://pmc.ncbi.nlm.nih.gov/articles/PMC3017872/ - Cheng, X. (2024). A comprehensive review of HER2 in cancer biology and therapeutics. U.S.
National Library of Medicine. https://pmc.ncbi.nlm.nih.gov/articles/PMC11275319/ - Bose, R. et al (2013). Activating HER2 Mutations in HER2 Gene Amplification Negative
Breast Cancer. American Association for Cancer Research.
https://aacrjournals.org/cancerdiscovery/article/3/2/224/3639/Activating-HER2-Mutations-in-
HER2-Gene - McKeage, K.; Perry, CM. (2012). Trastuzumab – Drugs. Springer International Publishing.
https://link.springer.com/article/10.2165/00003495-200262010-00008 - Dennis, S. J. et al (1987). Human Breast Cancer: Correlation of Relapse and Survival with
Amplification of the HER-2/neu Oncogene. Science, 245(4785), 177-182.
https://www.science.org/doi/10.1126/science.3798106 - Karl, G.; Karam, K. (2024). Trastuzumab. StatPearls.
https://www.ncbi.nlm.nih.gov/books/NBK532246/ - Namboodiri, A. M.; Pandey, J. P. (2011). Differential inhibition of trastuzumab- and
cetuximab-induced cytotoxicity of cancer cells by immunoglobulin G1 expressing different GM
allotypes. Clinical & Experimental Immunology, 166(3), 361-365.
https://pmc.ncbi.nlm.nih.gov/articles/PMC3232384/ - Alan, S. L. et al (1984). The neu oncogene: an erb-B-related gene encoding a 185,000-Mr
tumour antigen. Nature, 312, 513–516.
https://www.nature.com/articles/312513a0 - Lisa, C. et al (1985). Tyrosine Kinase Receptor with Extensive Homology to EGF Receptor
Shares Chromosomal Location with neu Oncogene. Science, 230(4730), 1132-1139.
https://www.science.org/doi/10.1126/science.2999974 - Sujata, G. (2017). Trials and tribulations. Nature, 548, 28-31.
https://www.nature.com/articles/548S28a - Hamid , G. et al (2021). Trastuzumab Mechanism of Action; 20 Years of Research to
Unravel a Dilemma. Cancers, 13(14), 3540.
https://pmc.ncbi.nlm.nih.gov/articles/PMC8303665/#B5-cancers-13-03540 - Nishant, M. et al (2016). Trastuzumab, but Not Pertuzumab, Dysregulates HER2 Signaling to
Mediate Inhibition of Autophagy and Increase in Reactive Oxygen Species Production in Human
Cardiomyocytes. Molecular Cancer Therapy, 15(6), 1321-1331
https://pubmed.ncbi.nlm.nih.gov/27197303/
COVID vax paper summary: Why T Cells Are Key to Durable Protection Against SARS-CoV-2
The article “T cell immunity to COVID-19 vaccines” examines the current state of
SARS-CoV-2 vaccine design strategies and how a focus on generating high neutralizing
antibody (NAb) titers limits variant resistance and long-term protection. The authors argue that
because of these limitations of the current vaccine design strategies, the focus of future designs
should be on inducing T cell immunity of CD8⁺ T cells. Neutralizing antibodies block SARS-
CoV-2 through targeting the spike receptor-binding domain (RBD) and preventing engagement
with the ACE2 receptor on host cells. But as the NAb titers decline or as variants mutate,
especially on their spike proteins, the authors argue that infection will continue without the
involvement of CD8⁺ T cells. T cell immunity can overcome the limitations of an NAb focused
approach, as infected cells can present viral peptides, made from highly conserved viral proteins,
on MHC 1, and CD8⁺ T cells can recognize these presented peptides and kill the infected cell.
Exemplifying this, the authors note that even against the SARS-CoV-2 variants, greater than
80% of T cell epitopes were conserved. T cells cannot, however, prevent the initial infection like
neutralizing antibodies and can only respond once an infection occurs.
The authors utilize a series of immunological and clinical case studies to substantiate
their hypothesis that long-lasting protection against SARS-CoV-2 will need to utilize T-cell
immunity rather than neutralizing antibodies alone. The authors found that NAb titers decline
within 4-6 months after mRNA vaccination and that the Omicron variant escapes demonstrate
NAb immune escape. Demonstrating the effects of decreased NAb titers, the efficacy of mRNA
vaccination protecting against SARS-CoV-2 infection appeared to be transient, even after
booster vaccination. The authors found that robust protection against hospitalization can happen
in the absence of high-titer NAbs, demonstrating that the more durable T cell and B cell
immunity was likely responsible for preventing hospitalization. To demonstrate the efficacy of
specifically T cell immunity, the authors find that in cancer patients with B cell deficiencies, a
CD8⁺ T cell response was correlated with milder disease outcomes. This is also supported by the
finding that in Omicron vaccination failures, a lack of CD8⁺ T cells was demonstrated.
The figure in the article summarizes the key findings of the article into three scenarios:
when NAb titers are high, when there are low titers of NAbs with a High amount of memory T
cells, and both low titers of NAb and a low amount of memory T cells. The first scenario
demonstrates that high NAb titers can block the initial infection of the upper respiratory tract.
But once those NAb titers decrease, the second scenario demonstrates T cells becoming essential
to halting viral spread towards the lower respiratory tract. Through this visual, the figure
reinforces the central argument that CD8⁺ T cell immunity is essential for long-term protection
against SARS-CoV-2 infection.
The article discussed how CD8⁺ T cell cytotoxic mechanisms limited the spread of
infection towards the lower respiratory tract. This matches what was learned in class about how
Cytotoxic T Lymphocytes utilize Granzyme B to initiate a cascade to activate the apoptotic
pathway in an infected cell. The authors make a compelling case for reframing how we can
evaluate the performance of SARS-CoV-2 towards prevention against not just infection and
transmission but severe disease and Long Covid. There is potential in utilizing viral vectored
vaccines, which have been demonstrated an effective method for inducing strong and broad T
cell responses (Gilbert, 2011). Overall, the articles give an evidence-based argument for focusing
scientific attention on the induction of T cell immunity in future SARS-CoV-2 vaccine designs.
References:
Wherry, E. J., & Barouch, D. H. (2022). T cell immunity to COVID-19 vaccines. Science,
377(6608), 821–822. https://doi.org/10.1126/science.add2897
Gilbert, S. C. (2011). T‐cell‐inducing vaccines – what’s the future. Immunology, 135(1), 19–26.
https://doi.org/10.1111/j.1365-2567.2011.03517.x
End-of-term reflection:
One thing I have learned this semester is about the process of binding specificity of antibodies and antigens. This directly applies to my research as I utilize Immunofluorescence in my ovarian research project. This class has also made it easier to understand the related topics in my current and previous courses. For example, the immunology protocol Enzyme-Linked Immunosorbent Assay (ELISA) has come up as an important topic in my microbiology coursework. The lessons learned in this class will, in all likelihood, apply throughout my whole career as I hope to practice medicine and continue biomedical research.