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  • #41901
    Joe
    Participant

    Our immune system  produce antibodies when a pathogen invades into our body.   Antibodies are protein mediated immunes.  Once our immune system produces antibodies against certain pathogen, the antibodies will circulate in our body three blood vessels.  Once the known pathogen invades into our body, the antibodies which were primed specifically against the pathogen will bind to various proteins on the surface of the pathogen and make the pathogen dysfunctional.   For example, the vaccines for COVID-19 virus  such as mRNA based Pfizer-Biontech, Modern, and adenovirus based Astrazenaca- Oxfiord vaccines utilize our immune system to produce antibodies to bind to spike proteins of the virus.  Spike proteins on the virus interact with angiotensin enzyme receptor (ACE2) of epithelial cells of lung and enable rna of the virus to get into cytoplasm of the lung cells, and the virus to replicate.  The antibodies which are produced by our immune system when the vaccine is jabbed to our arm, which are circulating in our body will bind the spike protein on the virus and prevent it from interacting with ACE2, hence prevent the infection.   Our immune system produces wide range of antibodies against a given antigen, which is protein part of a pathogen.   Several drugs have been developed to treat bladder cancer using engineeringly created antibodies.  So far, those drugs are targeting a unique antigen (protein), so the antibody which  is designed to bind to a unique antigen is called Monocolonal antibody.   Those drugs have generic name which ends with MAB(Monocolonal AntiBody).  Well known drug names which end with mab are immunotherapy drugs, such as Pembrolizumab (Keytruda), Atezolizumab (Trecentic), Avelumab (Bavencio).  Those drugs will bind to either PD-1 protein on T-cells or PD-L1 protein on cancer cells prevent the interaction of PD-1 protein of T-cells and PD-L1 protein of cancer cells.  One of hallmarks of cancer is its ability to evade our immune responses.  So, even T-cells called in to kill bladder cancer cells, the cancer cells prevent T-cells to attack by presenting PD-L1 protein on the surface of the cancer cells.   Then PD-1 proteins of T-cells interreact with PD-L1 proteins on the cancer cells, and recognize it as a single that they are healthy cells and go away instead of attacking.    The mechanism of action of immunotherapy drug is to bind to either PD-1 protein or PD-L1 protein and disable their interaction and enable T-cells kill the cancer cells.   In recent years, a new type of antibody bladder cancer treatment have been developed and some have been approved by FDA.  These are called Antibody Drug Conjugate (ADC).  These drugs are monoclonal antibody and their names also end with “MAB.   Two approved drugs are for advanced bladder cancers and they are Enfortumab vedotin-ejfv (PADCEV) from Seattle Genetics and the other recently approved drug is Sacituzumab govitecan-hziy (Trodelvy) from Gilead Sciences.  The difference between moncolonal antibody drugs such as immunotherapy drugs and antibody drug conjugate drugs is that ADC carries cytotoxic drug as its payload.  Once ADC binds to a certain protein of a cancer cell, it unload cytotoxic drug in to the cancer cell and kills cancer  the cancer cell.   PADCEV will bind to the protein called NECTIN-4.   Nectin-4 is a cellular adhesion protein that is overexpressed (many) in bladder cancer.  The cytotoxic drug (payload) which is attached to ADC is monomethyl auristatin E, or MMAE, a type of chemotherapy drug called a microtubule inhibitor.  When our cell diving into two daughter cells, the cell goes different stages (cell cycle).  Once DNA is duplicated,  chromosomes are duplicated, organells in cystoplasm are duplicated and everything else to make up two cells are duplicated, the cell goes into the stage to divide.  Then the microtubules attach to the chromosomes.  The spindle tubules then shorten and move toward the poles of the cell. As they move, they pull the one copy of each chromosome with them to opposite poles of the cell.  MMAE, the cytotoxic drug which ADC insert to the cell which the ADC binds to NECTIN-4 protein of the cancer cell then release MMAE, which disrupt the microtube network within the cancer cell.  This makes the cancer cell to divide and the cell cycle stops and lead to cell death.    Trodelvy binds to Trop-2 protein.  Trop-2 protein is highly expressed ( found many) on the surface of mediatized cancer cells, including bladder cancer cells.  Once Trodelvy binds to Trop-2 protein on the bladder cancer cell, it release cytotoxic drug called SN-38 into the cell.    SN-38 interacts with Topoisomerase which is enzyme in winding and unwinding of DNA. Each DNA is a very long chain of four different nucleic acids (Adenine , Guanine, Thymine, Cytosine).  A human cell’s DNA totals about 3 meters in length.  Urothelial cell is about 20 micrometer in diameter, which is 0.000,020 meter.  To fit 3m long DNA into 0.000,020 m cell, DNA has to wind tightly to be compact.  When a cell needs to divide, DNA must be duplicated.  For a DNA to be duplicated,  the tightly wound compacted DNA must unwind.  The enzyme Topolisomerase helps the DNA to unwide.  Because SN-38 drug was released by Trodelvy, the DNA cannot unwind which leads to cell death.    Enfortumab vedotin-ejfv (PADCEV)  was approved fully by FDA in July 9, 2021 and Sacituzumab govitecan-hziy (Trodelvy) was approved by FDA on April 7, 2021.   I have noticed that PADCEV has been used by bladder cancer patients for a few years.   PADCEV or Trodelvy have not been approved by Health Canada yet.   It is noted that PADCEV and Trodelvy have been approved for advanced bladder cancer patients who did not respond to chemotherapy and immunotherapy.  So, we have chemotherapy as the first line, immunotherapy as the second line, and andibody drug conjugate (ADC) as the third line treatment for advanced bladder cancer patients.   There are not many ADC drugs which have been approved by FDA.  Many ADC drugs have been withdrawn from its clinical trial as it could not provide the sufficient benefit (improvement on cancer) vs the side effects.  The side effects happen because ADC drugs binds to healthy cells though the drugs are targeted on the cells with a particular protein on its surface, namely PADCEV targeting NECTIN-4 protein and TRODELVY targeting on Trop-2 protein.    Another reason which causes the side effects is the leaking of cytotoxin drugs – MMAE of PADCEV and SN-38 of TRODELVY to outside of the cells.   I call ADC drugs – targeted or precision chemotherapy.   General chemotherapy drugs such as cisplatin will not differentiate normal cells or cancer cells.  But, ADC drugs only attack to cells with a certain protein on its surface.   I hope ADC improves and more ADC drugs targeting different proteins which are found on the surface of bladder cancer.   There is another ADC drug has been developed for the treatment of non muscle invasive bladder cancer. The drug name is oprtuzumab monatox-qqrs (Vicineum) from Sesen Bio.    Vicineum is instilled into bladder just like intravesical BCG.   Vicineum target epithelial cellular adhesion molecule (EpCAM ) protein.  This gene encodes a carcinoma-associated antigen. This protein is found in epithelial cells such as urothelial cells of bladder and epithelial cells of colon.    Like other ADC drugs, Vicineum binds to EpCAM protein of bladder cancer cells, then delivers a variant peudomonas exotoxin.  Peudomonas exotoxin is a bacteral exotoxin.  Exotoxin is a toxin released by bacterial cell.  The exotoxin first mediates tumor cell death by blocking protein synthesis then dying tumor cells display an immunogenic cell death with a response to a neo-antigen known to promote an adaptive T-cell mediated anti-tumor response. So Sesen Bio describes the mechanism of  action of Vicineum.   Vicineum is for BCG unresponsive non-muscle bladder cancer.  The efficacy is about the same as  Keytruda for BCG unresponsive non-muscle invasive bladder cancer.  The advantage is that Vicineum is administered intravesical like BCG though Keytruda is administered intravenously.   The one criticism that this therapy has received is the onerous administration schedule – lots of visits in short time.   Vincineum was expected to receive the approval from FDA this fall, but this August, The FDA has determined that it cannot approve its Biologics License Application for Vicineum in its present form and has provided recommendations specific to additional clinical/statistical data and analyses in addition to Chemistry, Manufacturing and Controls (CMC) issues pertaining to a recent pre-approval inspection and product quality.  So, we have to wait.  Incidentally Vicineum was initially developed by a Canadian company Viventia Bio Inc., then acquired SeSen Bio in 2016.      There may be a few errors in what I have written, but I think mostly correct. I hope someone find it relevant.

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    #41941
    Joe
    Participant

     

    Below is the link to American Cancer Society which explains monocolonal antibodies and its side effects, though they are not for bladder cancer specific.

     

    Conjugated monoclonal antibodies
    Conjugated mAbs are combined with a chemotherapy drug or a radioactive particle. These mAbs are used as a homing device to take one of these substances directly to the cancer cells. The mAb circulates throughout the body until it can find and hook onto the target antigen. It then delivers the toxic substance where it is needed most. This lessens the damage to normal cells in other parts of the body. Conjugated mAbs are also sometimes referred to as tagged, labeled, or loaded antibodies.

    Radiolabeled antibodies: Radiolabeled antibodies have small radioactive particles attached to them. Ibritumomab tiuxetan (Zevalin) is an example of a radiolabeled mAb. This is an antibody against the CD20 antigen, which is found on lymphocytes called B cells. The antibody delivers radioactivity directly to cancer cells. It is made of both an mAb drug (rituximab) and a radioactive substance (Yttrium-90). Treatment with this type of antibody is sometimes known as radioimmunotherapy (RIT). The drug and radiation are delivered directly to the target cells because the mAb looks for the target, then the radiation affects the target and nearby cells to a certain extent.
    Chemolabeled antibodies: These mAbs have powerful chemotherapy (or other) drugs attached to them. Examples include:Brentuximab vedotin (Adcetris), an antibody that targets the CD30 antigen (found on lymphocytes), attached to a chemo drug called MMAE.
    Ado-trastuzumab emtansine (Kadcyla, also called TDM-1), an antibody that targets the HER2 protein, attached to a chemo drug called DM1.

    https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/immunotherapy/monoclonal-antibodies.html

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