Monoclonal antibodies

Definitions & Key takeaways

Monoclonal antibodies (mAbs) are laboratory-produced proteins that are designed to recognize and bind to specific molecules or cells in the body. They are produced by cloning a single type of immune cell and using the cells to produce large amounts of a specific antibody. Monoclonal antibodies have a variety of medical uses including treatment of cancers, autoimmune, and infectious diseases.

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Introduction0:00–0:32

With monoclonal antibodies, antibodies means that they target a specific antigen with an antibody-antigen binding; and monoclonal means that each antibody is produced from a specific B cell line.
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.

Pathophysiology0:32–1:59

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 in cancer cells.

Mechanism of Action1:59–4:07

Once these antibodies bind to the 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.
Common monoclonal antibodies include bevacizumab, cetuximab, rituximab, trastuzumab, and alemtuzumab; they all have the suffix “-mab,” which is characteristic of 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, which means that it has both human and non-human components and thus the immune system recognizes it as foreign, leading to various hypersensitivity reactions like skin rashes, pruritus, headache, fever, and mild hypotension.

Cetuximab4:07–5:27

Now, 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.

Trastuzumab5:27–6:25

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.

Bevacizumab6:25–7:35

Okay, let’s move on to rituximab. Rituximab binds to CD20, an antigen found on B cell membranes and leads to cell death through multiple mechanisms.
First it activates the complement system initiating the formation of the membrane attack complex that creates holes on the cell membrane, ultimately leading to cell lysis.
Also, rituximab induces apoptosis, or programmed cell death. In addition, rituximab activates antibody-dependent cell-mediated cytotoxicity, where the bound antigen-antibody complex gets recognized by immune cells called natural killer cells, which form pores in the cell that allow the entry of enzymes that work like silent assassins to cause cell death.
Moving on to indications. The CD20 antigen is found on both normal and malignant B cells, so rituximab is used primarily for the treatment of non-Hodgkin B cell lymphomas.
It’s also indicated for chronic lymphocytic leukemia, or CLL, where there is abnormal proliferation of B cells and T cells.
Aside from cancer, it’s also useful for treating autoimmune diseases where there is abnormal activation of the immune cells like in rheumatoid arthritis.

Rituximab7:35–9:21

Rituximab is also used for the treatment of idiopathic thrombocytopenic purpura, or ITP, where B cells produce antibodies that destroy platelets.
The bad news is that rituximab can cause hypersensitivity reactions because it’s a chimeric antibody like cetuximab. Other side effects include suppression of the immune system and reactivation of viruses such as JC virus, or John Cunningham virus.
This particular virus causes a demyelinating disease of the central nervous system called progressive multifocal leukoencephalopathy, or PML and is potentially life threatening.
Finally, alemtuzumab is a humanised monoclonal antibody that’s similar to rituximab since it also binds targets immune cells.
However, instead of binding to CD20, it binds to CD52, which is found on the membrane of all lymphocytes including B cells, T cells, and natural killer cells, as well as monocytes and dendritic cells.
Alemtuzumab binds to both the normal and malignant versions of these cells and designate them for destruction by natural killer cells, complement-mediated lysis, or just apoptosis.
It’s main indications include chronic lymphoid leukemia, or CLL, and immune-mediated disorders like multiple sclerosis. Since we are killing the lymphocytes and monocytes, the main adverse effects are immunosuppression and an increased risk of infections.
Now, let’s make a simple and fun mnemonic that’ll help you efficiently memorize these pharmacology facts about monoclonal antibodies.
So for monoclonal antibodies, let’s use a colony of ants. For cetuximab, let’s have an ant wearing a tuxedo covered in cement.
He’s bringing a plate of Fried Eggs back to the colony, which represents its target antigen, EGFR. For indications, let’s use crabs to represent cancer, since in the zodiac, cancer is a giant crab.

Alemtuzumab9:21–10:11

For cetuximab, there’s a crab pinching the ant’s neck for head and neck cancers, and there’s one pinching his butt for colorectal cancer.
For side effects, unfortunately the ant was allergic to eggs so he developed a hypersensitivity reaction and is covered in rashes.
Next up is rituximab, so here we have an ant wearing a ripped tuxedo. He’s selling his music CDs for 20 cents each, which represents CD20.
For indications, we’ve used a hedgehog for hodgkin's lymphoma, but since rituximab is used for non-hodgkin’s lymphoma, we’ll have a hedgehog without spines.
Now, he’s trying to buy the CDs but these CDs are clearly pirated, so let’s put the poor guy in a prison CeLL for CLL, and there’s a little Teepee inside for ITP.

Memory Palace10:11–13:15

In terms of side effects, this ant also have a rash to represent a hypersensitivity reaction. He’s wearing a dead white blood cell like a hat to help you remember immune suppression, and there are large white spots on his head for progressive multifocal leukoencephalopathy.
The next ant is eating a giant almond for alemtuzumab. He’s also selling his pirated CDs but they are 52 cents each which represents CD52.
Three scarecrows representing multiple sclerosis are trying to buy the CDs and they are also arrested and put into a Cell for CLL.
For side effects, let’s put a dead white blood cell on the ant’s head for immune suppression, but he doesn’t have any rashes because the alemtuzumab is a humanized antibody, so it’s less likely to cause a hypersensitivity reaction.
Okay, the next drug is bevacizumab, which will be represented by an ant wearing a beaver mask and a fake tail. This ant is carrying a basket full of vegetables for VEGF, and he’s sitting on a large stone crab statue to help you remember it’s used for tumors that are solid, rock solid!
For noncancerous indications, we’ll give the ant an old fashioned monocle, to help you remember it’s also used to treat age-related macular degeneration.
For side effects, let’s cover his vegetables in blood clots to help you remember it increases the risk of thrombosis. He was wounded while foraging for food and there’s a big hole in his abdomen through which you can see the intestines.
This will help you remember bevacizumab-impaired wound healing and GI perforation. Lastly, there’s a pool of blood under him to represent hemorrhaging.
Okay, for the final drug, let’s have a lady ant carrying a trash can since she represents trastuzumab. She brought along HER 2 daughters since this drug targets HER2.
The 2 of them are holding a giant bra with a crab hanging off of it to help you remember it’s mainly used to treat HER2 positive breast cancer.
For side effects, there’s a large shattered heart in the trash can, to represent heart failure. All right, as a quick recap… Monoclonal antibodies that are used for the treatment of cancer, include bevacizumab, cetuximab, rituximab, trastuzumab, and alemtuzumab.
Bevacizumab targets VEGF and is used for the treatment of solid tumors. Cetuximab targets EGFR and is used primarily for colorectal cancer or cancers of the head and neck.
Rituximab binds to CD20 found on B cell membranes and is used primarily for the treatment of non-Hodgkin’s lymphomas, but also for CLL, rheumatoid arthritis, and ITP.
Trastuzumab, also known as herceptin, binds to HER2 and is used primarily in breast cancers that overexpress HER2. Alemtuzumab binds to CD52 found on lymphocytes and monocytes and is used for CLL and multiple sclerosis.
But wait, there’s more: Here’s a mind map with all of the mnemonics. Go ahead and pause the video so you can test yourself to see what you remember.
Stay tuned for the answers after the credits.

Review13:15–14:06

Mind Map14:06–13:09