CANCER 2024 ANTIBODY --2. DRUG CONJUGATES

 

    The blood flowing through our bodies contains protein rich fluid and cells.  Red cells bring oxygen to every corner of our body and white cells protect us from invading bacteria and viruses.  One group of white cell, B lymphocytes, make millions of antibodies, and like snowflakes, no two antibodies are exactly the same.  The antibodies are Y-shaped and are composed of two identical light chains and two identical heavy chains. Each arm of the Y is a binding site that can tag a specific antigen--foreign intruder like bacteria and viruses.  In nature both tips of the "Y" attach to the same antigen and when they bind they activate part of the immune system.

Antibody drug conjugates (ADCs) “embody a simple but elegant vision for cancer therapy.”  one of the Y arms is a monoclonal antibody that is specific for a protein in a cancer cell.  The other arm is attached to a cytotoxic chemical.   When they work the antibody enters a cancer cell, one arm attaches to a protein inside the cell, and the other arm releases a potent agent.  They thus, hopefully,  maximally destroy cancer cells and limit the damage done to normal cells. 

The first of these medications was FDA approved in 2000 and a number have since been developed and used. 

One of them is an experimental drug for ovarian cancer.  It uses  a humanized monoclonal antibody called Raludotatug--an antibody that targets and binds to CDH6-expressing tumor cells; the antibody is also bound to a cytotoxic drug.   

(The CDH6 gene (human cadherin-6) normally directs ribosomes to make cadherin proteins-- membrane proteins that have something to do with cell to cell binding.  The proteins play a role in the maintenance of orderly structures such as epithelium.) 

The CDH6 gene is over-expressed in several cancers and an estimated 65% to 85% of patients with ovarian cancer express CDH6.

Raludotatug deruxtecan is the potential first-in-class CDH6-directed antibody drug conjugate.  The monoclonal antibody (Raludotatug) targets cadherin-6 (CDH6), and it is conjugated to deruxtecan, (DXd), a derivative of exatecan--a cytotoxic DNA topoisomerase I inhibitor. 

the complex is infused into the person's body and it somehow knows which cells to attack  The drug and antibody enter the cancer cell and is degraded by lysosomes.  (lysosomes are “membrane-enclosed organelles that contain an array of enzymes capable of breaking down all types of biological polymers”).  Then the deruxtecan—(DXd) targets, binds, and the cytotoxic drug inhibits DNA topoisomerase I.

Topoisomerases are enzymes found in the nucleus of mammalian cells and are required for normal DNA replication and cellular division.  “They work by creating, then repairing nicks in DNA.  These incisions allow super-coiled double stranded DNA to untangle and relax, and that allows replication to proceed. Once the DNA torsional strain has been relieved, the topoisomerase re-seals the relaxed double helix. Topoisomerase activity is increased in rapidly dividing and in cancer cells.”

We currently have four drugs that block topoisomerases, prevent the resealing of DNA breaks, and thus inhibit DNA replication and promote cell death.

Two of them are topoisomerase I inhibitors irinotecan and topotecan.  They are derivatives of camptothecins, chemicals that were initially isolated from the bark of the Chinese tree, Camptotheca acuminata.  

The other two are topoisomerase II inhibitors etoposide and teniposide. They are semisynthetic derivatives of extracts of the American mandrake plant or Mayapple (Podophyllum peltatum).

When given parenterally these drugs often injure the bone marrow and gi track.

https://www.ncbi.nlm.nih.gov/books/NBK548372/

Raludotatug deruxtecan was developed by Daiichi Sankyo and Merck & Co., Inc.,

Approximately 70% to 80% of patients diagnosed with ovarian cancer will have a recurrence of disease following standard treatment with platinum-based chemotherapy regimens.  An estimated 65% to 85% of patients with ovarian cancer have expression of CDH6, which is associated with poor prognosis.

A confirmed objective response rate (ORR) of 46% by investigator assessment was observed in the subgroup of 50 patients with measurable ovarian cancer receiving raludotatug deruxtecan in the phase 1 trial. One complete response, 22 partial responses, and four unconfirmed responses were seen. A disease control rate of 98% was observed. Median duration of response was 11.2 months and median progression-free survival was 7.9 months.

https://www.ncbi.nlm.nih.gov/books/NBK548372/

https://in.marketscreener.com/quote/stock/MERCK-CO-INC-13611/news/Merck-1st-patient-in-raludotatug-study-46349901/

Rise of antibody drug conjugates: https://ascopubs.org/doi/10.1200/EDBK_390094#:~:text=Inception%20of%20the%20hybridoma%20technology,trials%20underway%20in%20the%201980s.&text=The%20first%20approved%20ADC%20was,to%20an%20antitumor%20antibiotic%2C%20calicheamicin.

https://www.daiichisankyo.com/files/news/pressrelease/pdf/202310/20231022_E2.pdf

 

 

 

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