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Monoclonal antibodies

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Monoclonal antibodies

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Monoclonal antibodies

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Imatinib is associated with the side effect of fluid (excretion/retention) .

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A 54-year-old woman comes to the office because of a breast lump for 6 months. She states that while lump has been growing, it is not painful, nor is it associated with any nipple discharge. Breast examination shows a hard lump in the right breast. Core biopsy of the lump shows invasive ductal carcinoma. The carcinoma is estrogen receptor negative, progesterone receptor negative, and Her2 receptor positive. The patient is scheduled for wide local excision and radiation therapy. Which of the following may also be appropriate for this patient?

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With monoclonal antibodies, antibodies means that they target a specific antigen on the cell surface with an antibody-antigen binding; and monoclonal means that each antibody is produced from a specific B cell line consisting of identical B cells.

Okay, now monoclonal antibodies are used for the treatment of cancer and various autoimmune diseases like multiple sclerosis and rheumatoid arthritis.

In this video, we are focusing on the monoclonal antibodies that are used for cancer.

Normally, all of our cells grow and divide through a tightly regulated cell cycle once they receive growth factor signals.

During the cell cycle, if a cell appears abnormal in any way to the immune cells that do constant surveillance, the cell has to fix the problem or undergo apoptosis, or programmed cell death - a bit like cellular suicide, rather than proceed to the next phase of the cell cycle.

But cells can become mutated due to environmental or genetic factors.

A mutated cell becomes cancerous when it starts to divide uncontrollably.

As cancer cells start piling up on each other, they form a small tumor mass and they need to induce blood vessel growth, called angiogenesis, to supply themselves with enough energy.

Some tumors produce vascular endothelial growth factor, or VEGF, which binds to VEGF receptors found on vascular endothelial cells and stimulates angiogenesis.

Also, many tumors overexpress growth factor receptors like the epidermal growth factor receptor, or EGFR, and the human epidermal receptor 2, or HER2, that stimulate cell proliferation and tumor growth.

Malignant tumors are ones that are able to break through the basement membrane.

Some of these malignant tumors go a step further and detach from their basement membrane at the primary tumor site, enter nearby blood vessels or the lymphatic system, and establish secondary sites of tumor growth throughout the body—a process called metastasis.

Now, the monoclonal antibodies that are used for the treatment of cancer target specific antigens that are usually overexpressed on the surface of cancer cells.

Once these antibodies bind to the surface of cancer cells, they can trigger apoptosis, promote the formation of MAC complexes which trigger complement-mediated cell lysis, or attract other immune cells to attack the cancer cells.

Furthermore, a lot of these antigens are actually the cell receptors that promote growth and proliferation.

So when the monoclonal antibodies bind, they prevent these receptors from functioning.

These medications are all administered intravenously because they’re all proteins, which means they’ll be destroyed in the GI tract if taken perorally.

Alright, now let’s go over some basic nomenclature.

First, all monoclonal antibodies have the characteristic suffix “-mab”, like trastuzumab and cetuximab.

If a monoclonal antibody is produced by a human cell and therefore, it has only human components, it is referred to as a human monoclonal antibody and it has the characteristic suffix “-umab” with a “u” before “mab”.

An example is denosumab.

Human antibodies are less likely to be recognized by the immune system as foreign and thus, they’re less likely to lead to hypersensitivity reactions.

Now, there are also chimeric monoclonal antibodies which means that they have both human and non-human components, such as mouse components.

These antibodies have the suffix “-ximab”, with a “xi” before the “mab”, like rituximab and cetuximab.

They’re more likely to be recognized as foreign, leading to hypersensitivity reactions like skin rashes, pruritus, headache, fever, and hypotension.

Finally, there are humanized monoclonal antibodies which are produced by non-human species, such as mice, but they have been humanized, or modified to look similar to those produced by humans.

Humanized antibodies have the suffix “-zumab”, with a “zu” before the “mab”, like bevacizumab, and they’re less likely to cause hypersensitivity reactions than the chimeric antibodies.

Okay, let’s start with cetuximab.

Cetuximab binds EGFR, or epidermal growth factor receptors, that has tyrosine kinase activity.

Once activated, this receptor phosphorylates various target proteins in signaling pathways.

One of these is a protein called K-ras, which activates cell proliferation, migration, and angiogenesis.

Now, many cancer cells overexpress EGFRs or have mutated EGFRs that are more active than normal, so cetuximab can block these receptors and prevent the cancer cells from proliferating and metastasizing.

However, in certain cases there could be a mutation in the K-ras gene, causing the protein that’s produced to always be turned on.

In these cases, they’re not regulated by EGFR, so cetuximab will have no effect.

Common uses for cetuximab include the treatment of the metastatic stage of colorectal cancer and for the treatment of head and neck cancers.

Alright, let’s move on to side effects.

Cetuximab is a chimeric antibody and thus, it can lead to various hypersensitivity reactions.

Other side effects include gastrointestinal symptoms like diarrhea, elevation of liver enzymes, and skin toxicity like acneiform skin rashes, dryness, and pruritus.

Okay, next up is trastuzumab, also known as herceptin.

Trastuzumab targets human epidermal growth factor receptor 2, or HER2, which also has tyrosine kinase activity.

Since HER2 activation stimulates signaling pathways that lead to cellular proliferation, a mutation or overexpression of this receptor can lead to cancer.

Now trastuzumab is most commonly used to treat breast cancer that’s HER2 positive, meaning the cancer cells overexpress the HER2 protein.

It’s also used in gastric, ovarian, and lung cancers that are caused by HER2 mutations, but they are more rare than breast cancer.

Now the main side effect of trastuzumab is cardiotoxicity, since cardiomyocytes also have a lot of HER2, and trastuzumab can damage these cells, leading to heart failure.

Other side effects include gastrointestinal symptoms like nausea, diarrhea, fever, chills, and headache.

Next up is bevacizumab, which binds to VEGF, or vascular endothelial growth factors.

Cancer cells have these growth factors on their surface which causes nearby blood vessels to grow offshoots towards the tumor to supply it.

When VEGF is blocked, it causes the cancer to become deprived of its blood supply and dies off. Bevacizumab is used for the treatment of solid tumors like colorectal cancer, renal cell carcinoma, breast cancer, and non-small cell lung cancer, especially in metastatic stages.

Another use for bevacizumab is for the treatment of age related macular degeneration, which is caused by the growth of abnormal, leaky blood vessels that cause damage to the retina.

Moving on to side effects, bevacizumab can cause inhibition of angiogenesis in normal tissues and leads to impaired wound healing.

It can also cause hemorrhages, which can present as epistaxis or nosebleed; hemoptysis, or coughing up of blood; gastrointestinal bleeding; and intracerebral hemorrhage.

Other side effects include perforation of the GI tract and increased thrombosis, leading to strokes and myocardial infarctions.

Sources
  1. "Katzung & Trevor's Pharmacology Examination and Board Review,12th Edition" McGraw-Hill Education / Medical (2018)
  2. "Rang and Dale's Pharmacology" Elsevier (2019)
  3. "Goodman and Gilman's The Pharmacological Basis of Therapeutics, 13th Edition" McGraw-Hill Education / Medical (2017)
  4. "Overview of hemostasis" J.C. Aster, H. Bunn (Eds.), Pathophysiology of Blood Disorders, 2e. McGraw-Hill. (2016)
  5. "Clinical development of targeted and immune based anti-cancer therapies" Journal of Experimental & Clinical Cancer Research (2019)
  6. "Exploring the Immunological Mechanisms Underlying the Anti-vascular Endothelial Growth Factor Activity in Tumors" Frontiers in Immunology (2019)
  7. "Clinical development of targeted and immune based anti-cancer therapies" Journal of Experimental & Clinical Cancer Research (2019)