Ipilimumab
| Monoclonal antibody | |
|---|---|
| Type | Whole antibody |
| Source | Human |
| Target | CTLA-4 |
| Clinical data | |
| Trade names | Yervoy |
| AHFS/Drugs.com | Consumer Drug Information |
| MedlinePlus | a611023 |
| Licence data | US FDA:link |
| Pregnancy cat. | ? |
| Legal status | ℞-only (US) |
| Routes | IV |
| Identifiers | |
| CAS number | 477202-00-9  |
| ATC code | L01XC11 |
| UNII | 6T8C155666  |
| KEGG | D04603 |
| Chemical data | |
| Formula | C6742H9972N1732O2004S40 |
| Mol. mass | 148634.914 g/mol |
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Ipilimumab (also known as MDX-010 or MDX-101), marketed as Yervoy,[1] is a drug used for the treatment of melanoma, a type of skin cancer. It is a U.S. Food and Drug Administration (FDA) approved human monoclonal antibody developed by Bristol-Myers Squibb, and works by activating the immune system.
Additionally, ipilimumab is undergoing clinical trials for the treatment of non-small cell lung carcinoma (NSCLC), small cell lung cancer (SCLC)[2] and metastatic hormone-refractory prostate cancer.[3]
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[edit] Approvals and indications
Ipilimumab was approved by the FDA in March 2011 to treat patients with late-stage melanoma that has spread or cannot be removed by surgery.[4][5][6]
[edit] Adverse effects
Ipilimumab treatment has been associated with severe and potentially fatal immunological adverse effects due to T cell activation and proliferation. Most of the serious adverse effects are associated with the gastro-intestinal tract; they include stomach pain, bloating, constipation or diarrhea, but also fever, breathing or urinating problems. A "risk evaluation and mitigation strategy" has been set up to inform prescribers of the potential risks.[7][6]
[edit] Interactions
The combination of ipilimumab and leflunomide may lead to increased hepatotoxicity. Over 90 other drug interactions are known, but none of them severe.[6]
[edit] Mechanism of action
Ipilimumab is a fully human antibody that binds to CTLA-4 (cytotoxic T lymphocyte-associated antigen 4), a molecule on cytotoxic T lymphocytes that is believed to play a critical role in regulating natural immune responses.[8] The absence or presence of CTLA-4 can augment or suppress the immune system's T-cell response in fighting disease.[9]
Ipilimumab is designed to block the activity of CTLA-4, thereby sustaining an active immune response in its attack on cancer cells.[10][11][12][13]
[edit] Clinical trials
 |
This section is outdated. Please update this section to reflect recent events or newly available information. Please see the talk page for more information. (March 2011) |
As of October 2007[update], there are two fully human anti CTLA-4[14] monoclonal antibodies in advanced clinical trials. Ipilimumab, which is an IgG1 isotype, and tremelimumab (from Pfizer) which is an IgG2 isotype.[15][16]
[edit] Melanoma
On December 10, 2007, Bristol-Myers Squibb and Medarex released the results of three studies on ipilimumab for melanoma.[17] The three studies tested 487 patients with advanced skin cancer. One of the three studies failed to meet its primary goal of shrinking tumors in at least 10.0% of the study's 155 patients. Side effects included rashes, diarrhea and hepatitis.
In 2010 a study was presented that showed a median survival of 10 months in advanced melanoma patients treated with ipilimumab, compared with 6 months for those treated with gp100, an experimental vaccine (total n=676). Additionally, one year survival was 46% in those treated with only ipilimumab, compared with 25% in those treated with gp100, and 44% for those receiving both.[18] The Phase III clinical studies on the drug were controversial for their unconventional use of a control arm (as opposed to using a placebo or standard treatment). The study tested ipilimumab alone, ipilimumab with gp100, and the vaccine alone. Patients had a higher survival rate with ipilimumab alone, however it is not fully clear whether the vaccine caused toxicity, which would make the drug perform better by comparison.[19][20] [21] However it gained FDA approval in early 2011. In August 2011 it was approved for use in the UK.
[edit] Prostate cancer
As of September 2008[update], Medarex was performing a Phase I/II dose escalation clinical trial of ipilimumab in metastatic hormone-refractory prostate cancer (HRPC). As of 2009[update], some of the patients with advanced prostate cancer had their tumors drastically shrink, promoting further trials.[22]
On June 19, 2009, the Mayo Clinic reported two prostate cancer patients involved in a Phase II study using MDX-010 therapy who had been told initially that their condition was inoperable but had their tumors shrunk by the drug such that operation was possible and are now cancer-free as a result.[23] This press report however was criticized as being somewhat inaccurate and entirely premature. The clinical trials were still at an early stage and were being run alongside other treatments – which could be the real explanation for the tumor shrinkage.[24] It was far too early to say whether ipilimumab has made any difference at all.[25]
[edit] Lung cancer
Medarex is running a Phase II trial of ipilimumab in addition to platinum-based chemotherapy (carboplatin) in patients with small cell and non-small cell lung cancer.[2] It is scheduled to run from February 2008 to December 2011.
[edit] References
- ^ "Yervoy: Medication Guide". http://newdrugreview.com/index.php/amino-acids-peptides-proteins/yervoy. Retrieved 2011-03-25.
- ^ a b ClinicalTrials.gov NCT00527735 Phase II Study for Previously Untreated Subjects With Non Small Cell Lung Cancer (NSCLC) or Small Cell Lung Cancer (SCLC)
- ^ ClinicalTrials.gov NCT00323882 Phase I/II Study of MDX-010 in Patients With Metastatic Hormone-Refractory Prostate Cancer (MDX010-21) (COMPLETED)
- ^ Jefferson E (2011-03-25). "FDA approves new treatment for a type of late-stage skin cancer" (Press release). U.S. Food and Drug Administration (FDA). http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm1193237.htm. Retrieved 2011-03-25.
- ^ Pollack, Andrew (2011-03-25). "Approval for Drug That Treats Melanoma". The New York Times. http://www.nytimes.com/2011/03/26/business/26drug.html. Retrieved 2011-03-27.
- ^ a b c Drugs.com: Yervoy
- ^ "FDA Rubber-Stamps Bristol-Myers Squibb’s Melanoma mAb". Genetic Engineering & Biotechnology News. 2011-03-28. http://www.genengnews.com/gen-news-highlights/fda-rubber-stamps-bristol-myers-squibb-s-melanoma-mab/81244882/. Retrieved 2011-03-28.
- ^ Tarhini AA, Iqbal F (2010). "CTLA-4 blockade: therapeutic potential in cancer treatments". Onco Targets Ther 3: 15–25. PMC 2895779. PMID 20616954. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2895779.
- ^ Robert C, Ghiringhelli F (August 2009). "What is the role of cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma?". Oncologist 14 (8): 848–61. doi:10.1634/theoncologist.2009-0028. PMID 19648604.
- ^ Gail M. Wilkes; Margaret Barton-Burke (11 December 2009). 2010 oncology nursing drug handbook. Jones & Bartlett Learning. pp. 1–. ISBN 9780763781248. http://books.google.com/books?id=3_zMtsAA39MC&pg=RA1-PA588. Retrieved 30 March 2011.
- ^ L. Harivardhan Reddy; Patrick Couvreur (1 June 2009). Macromolecular Anticancer Therapeutics. Springer. pp. 522–. ISBN 9781441905062. http://books.google.com/books?id=fYPRZ7cJQE4C&pg=PA522. Retrieved 30 March 2011.
- ^ Zhiqiang An (8 September 2009). Therapeutic Monoclonal Antibodies: From Bench to Clinic. John Wiley and Sons. pp. 134–. ISBN 9780470117910. http://books.google.com/books?id=agdx2rtK7E0C&pg=PA134. Retrieved 30 March 2011.
- ^ Ralph Blum; Mark Scholz (24 August 2010). Invasion of the Prostate Snatchers: No More Unnecessary Biopsies, Radical Treatment Or Loss of Sexual Potency. Other Press, LLC. pp. 227–. ISBN 9781590513422. http://books.google.com/books?id=kCJSQS5GezYC&pg=PA227. Retrieved 30 March 2011.
- ^ "CTLA-4 strategies: Abatacept / Belatacept". healthvalue.net. http://www.healthvalue.net/ctlaigenglish.html. Retrieved 2009-06-24.
- ^ Tomillero A, Moral MA (October 2008). "Gateways to clinical trials". Methods Find Exp Clin Pharmacol 30 (8): 643–72. PMID 19088949.
- ^ Poust J (December 2008). "Targeting metastatic melanoma". Am J Health Syst Pharm 65 (24 Suppl 9): S9–S15. doi:10.2146/ajhp080461. PMID 19052265.
- ^ "Top-Line Data Available from Three Ipilimumab Pivotal Trials in Patients with Advanced Metastatic Melanoma". Medarex, Inc.. 2007-12-10. http://www.medarex.com/cgi-local/item.pl/20071210-1085876. Retrieved 2009-06-24.[dead link]
- ^ "Bristol drug cuts death risk in advanced melanoma". Reuters. 2010-06-05. http://www.reuters.com/article/idUSN0218461520100605.
- ^ Langreth R (2010-06-06). "The Risk For Bristol". Forbes. http://blogs.forbes.com/sciencebiz/2010/06/the-risk-for-bristol/. Retrieved 2011-03-25.
- ^ "Phase 3 clinical study: Ipilimumab boosts, sustains immune system responses against melanoma tumors". News-Medical.Net. 2010-06-09. http://www.news-medical.net/news/20100609/Phase-3-clinical-study-Ipilimumab-boosts-sustains-immune-system-responses-against-melanoma-tumors.aspx. Retrieved 2011-03-25.
- ^ Silverman E (2010-06-07). "Bristol-Myers’ Melanoma Med And Wall Street Wags // Pharmalot". Pharma Blog PHARMALOT. http://www.pharmalot.com/2010/06/bristol-myers-melanoma-med-and-wall-street-wags/. Retrieved 2011-03-25.
- ^ "'Surprise' prostate result probed". BBC News. 2009-06-19. http://news.bbc.co.uk/2/hi/health/8110103.stm. Retrieved 2009-06-24.
- ^ "Mayo Researchers: Dramatic Outcomes in Prostate Cancer Study". Mayo Clinic. 2009-06-01. http://www.mayoclinic.org/news2009-rst/5318.html. Retrieved 2009-06-24.
- ^ Boyles S (2009-06-19). "New Therapy May Fight Prostate Cancer". WebMD. http://www.webmd.com/prostate-cancer/news/20090619/new-therapy-may-fight-prostate-cancer. Retrieved 2009-06-24.
- ^ Lowe D (2009-06-23). "Medarex, Ipilimumab, Prostate Cancer, And Reality. :". Corante. http://pipeline.corante.com/archives/2009/06/23/medarex_ipilimumab_prostate_cancer_and_reality.php. Retrieved 2009-06-24.
[edit] External links
- U.S. National Library of Medicine: Drug Information Portal - Ipilimumab
- U.S. FDA-approved Prescribing Information - ipilimumab
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