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. | C (US) |
| 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 |
| (what is this?) (verify) | |
Ipilimumab (i pi lim′ ue mab; also known as MDX-010[1] and MDX-101), marketed as Yervoy, is a drug used for the treatment of cancer. It is approved by the U.S. Food and Drug Administration (FDA) approved human for treatment of melanoma, a type of skin cancer. It is a monoclonal antibody developed by Bristol-Myers Squibb, and works by activating the immune system by targeting CTLA-4.
Cytotoxic T lymphocytes (CTLs) can recognize and destroy cancer cells. However, there is also an inhibitory mechanism that interrupts this destruction. Ipilimumab turns off this inhibitory mechanism and allows CTLs to continue to destroy cancer cells.[2]
In addition to melanoma, ipilimumab is undergoing clinical trials for the treatment of non-small cell lung carcinoma (NSCLC), small cell lung cancer (SCLC)[3] and metastatic hormone-refractory prostate cancer.[4]
The cost is $120,000 for a course of treatment. [5]
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.[6][7][8] On February 1, 2012, Health Canada approved ipilimumab for "treatment of unresectable or metastatic melanoma in patients who have failed or do not tolerate other systemic therapy for advanced disease."[9] Additionally Ipilimumab was approved in the European Union (EU), for second line treatment of metastatic melanoma, November 2012.[10]
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.[8][11]
Interactions
The combination of ipilimumab and leflunomide may lead to increased hepatotoxicity. Over 90 other drug interactions are known, but none of them severe.[8]
Mechanism of action
Cytotoxic T lymphocytes (CTLs) can recognize and destroy cancer cells. However, there is also an inhibitory mechanism that interrupts this destruction. Ipilimumab turns off this inhibitory mechanism and allows CTLs to continue to destroy the cancer cells.[2]
Cancer cells produce antigens, which the immune system can use to identify and destroy them. These antigens are recognized by dendritic cells, which present the antigens to CTLs in the lymph nodes. The CTLs can then recognize the cancer cells by those antigens and destroy them. However, dendritic cells also present the antigens to CTLs along with an inhibitory signal, which binds to a receptor, CTLA-4 (cytotoxic T lymphocyte-associated antigen 4), on the CTL and turns off the cytotoxic reaction. This allows the cancer cells to survive.[2]
Ipilimumab blocks the CTLA-4 inhibitory signal, and allows the CTLs to destroy the cancer cells.[2]
Ipilimumab is a fully human antibody that binds to CTLA-4.[12][13][14][15][16][17]
Clinical trials
As of October 2007, there are two fully human anti CTLA-4[18] monoclonal antibodies in advanced clinical trials. Ipilimumab, which is an IgG1 isotype, and tremelimumab (from Pfizer) which is an IgG2 isotype.[19][20]
Melanoma
On December 10, 2007, Bristol-Myers Squibb and Medarex released the results of three studies on ipilimumab for melanoma.[21] 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.[22] 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.[23][24][25] However, it gained FDA approval in early 2011. In August 2011, it was approved for use in the UK.
Prostate cancer
As of September 2008, Medarex was performing a Phase I/II dose escalation clinical trial of ipilimumab in metastatic hormone-refractory prostate cancer (HRPC). As of 2009, some of the patients with advanced prostate cancer had their tumors drastically shrink, promoting further trials.[26]
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.[27] 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.[28] It was far too early to say whether ipilimumab has made any difference at all.[29]
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.[3] It is scheduled to run from February 2008 to December 2011.
Development
References
- ↑ USAN. "STATEMENT ON A NONPROPRIETARY NAME ADOPTED BY THE USAN COUNCIL - ipilimumab" (Press release). American_Medical_Association (AMA). Retrieved 2013-01-12.
- ↑ 2.0 2.1 2.2 2.3 Antoni Ribas (28 June 2012). "Tumor immunotherapy directed at PD-1". New England Journal of Medicine 366 (26): 2517–9.
- ↑ 3.0 3.1 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)
- ↑ Breakthrough of the Year: Cancer Immunotherapy, Science 20 December 2013, Vol. 342 no. 6165 pp. 1432-1433, DOI: 10.1126/science.342.6165.1432, Jennifer Couzin-Frankel
- ↑ 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). Retrieved 2011-03-25.
- ↑ Pollack, Andrew (2011-03-25). "Approval for Drug That Treats Melanoma". The New York Times. Retrieved 2011-03-27.
- ↑ 8.0 8.1 8.2 Drugs.com: Yervoy
- ↑ Notice of Decision for YERVOY
- ↑ "Bristol-Myers Squibb Receives Positive Decision from National Institute of Health and Clinical Excellence (NICE) for YERVOY® (ipilimumab)" (Press release). November 1, 2012. Retrieved December 17, 2012.
- ↑ "FDA Rubber-Stamps Bristol-Myers Squibb’s Melanoma mAb". Genetic Engineering & Biotechnology News. 2011-03-28. 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.
- ↑ 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 978-0-7637-8124-8. Retrieved 30 March 2011.
- ↑ L. Harivardhan Reddy; Patrick Couvreur (1 June 2009). Macromolecular Anticancer Therapeutics. Springer. pp. 522–. ISBN 978-1-4419-0506-2. Retrieved 30 March 2011.
- ↑ Zhiqiang An (8 September 2009). Therapeutic Monoclonal Antibodies: From Bench to Clinic. John Wiley and Sons. pp. 134–. ISBN 978-0-470-11791-0. 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 978-1-59051-342-2. Retrieved 30 March 2011.
- ↑ "CTLA-4 strategies: Abatacept / Belatacept". healthvalue.net. 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. Retrieved 2009-06-24.
- ↑ "Bristol drug cuts death risk in advanced melanoma". Reuters. 2010-06-05.
- ↑ Langreth R (2010-06-06). "The Risk For Bristol". Forbes. Archived from the original on 2011-07-22. Retrieved 2011-03-25.
- ↑ "Phase 3 clinical study: Ipilimumab boosts, sustains immune system responses against melanoma tumors". News-Medical.Net. 2010-06-09. Retrieved 2011-03-25.
- ↑ Silverman E (2010-06-07). "Bristol-Myers’ Melanoma Med And Wall Street Wags // Pharmalot". Pharma Blog PHARMALOT. Retrieved 2011-03-25.
- ↑ "'Surprise' prostate result probed". BBC News. 2009-06-19. Retrieved 2009-06-24.
- ↑ "Mayo Researchers: Dramatic Outcomes in Prostate Cancer Study". Mayo Clinic. 2009-06-01. Retrieved 2009-06-24.
- ↑ Boyles S (2009-06-19). "New Therapy May Fight Prostate Cancer". WebMD. Retrieved 2009-06-24.
- ↑ Lowe D (2009-06-23). "Medarex, Ipilimumab, Prostate Cancer, And Reality. :". Corante. Retrieved 2009-06-24.
External links
- U.S. National Library of Medicine: Drug Information Portal - Ipilimumab
- U.S. FDA-approved Prescribing Information - ipilimumab
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