Ipilimumab

From Wikipedia, the free encyclopedia
Jump to: navigation, search
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
Routes IV
Identifiers
CAS number 477202-00-9 N
ATC code L01XC11
UNII 6T8C155666 YesY
KEGG D04603 YesY
Chemical data
Formula C6742H9972N1732O2004S40 
Mol. mass 148634.914 g/mol
 N (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) for the treatment of melanoma, a type of skin cancer.[2] It is a monoclonal antibody developed by Bristol-Myers Squibb that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system.

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.[3]

In addition to melanoma, ipilimumab is undergoing clinical trials for the treatment of non-small cell lung carcinoma (NSCLC), small cell lung cancer (SCLC),[4] bladder cancer,[5] and metastatic hormone-refractory prostate cancer.[6]

The cost is $120,000 for a course of treatment.[7]

Approvals and indications[edit]

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.[8][9][10] 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."[11] Additionally Ipilimumab was approved in the European Union (EU), for second line treatment of metastatic melanoma, November 2012.[12]

Adverse effects[edit]

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.[10][13]

Interactions[edit]

The combination of ipilimumab and leflunomide may lead to increased hepatotoxicity. Over 90 other drug interactions are known, but none of them severe.[10]

Mechanism of action[edit]

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.[3]

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.[3]

Ipilimumab blocks the CTLA-4 inhibitory signal, and allows the CTLs to destroy the cancer cells.[3]

Ipilimumab is a fully human antibody that binds to CTLA-4.[14][15][16][17][18][19]

Clinical trials[edit]

As of October 2007, there are two fully human anti CTLA-4[20] monoclonal antibodies in advanced clinical trials. Ipilimumab, which is an IgG1 isotype, and tremelimumab (from Pfizer) which is an IgG2 isotype.[21][22]

Melanoma[edit]

On December 10, 2007, Bristol-Myers Squibb and Medarex released the results of three studies on ipilimumab for melanoma.[23] 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.[24] 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.[25][26][27] However, it gained FDA approval in early 2011. In August 2011, it was approved for use in the UK.

Prostate cancer[edit]

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.[28]

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.[29] 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.[30] It was far too early to say whether ipilimumab has made any difference at all.[31]

Lung cancer[edit]

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.[4] It is scheduled to run from February 2008 to December 2011.

Combination trials[edit]

Advanced Melanoma[edit]

In March 2014, an open-label, randomized, two agent, single center trial started combining Ipilimumab with phosphatidylserine-targeting immunotherapy Bavituximab for the treatment of Advanced Melanoma, sponsored by University of Texas Southwestern Medical Center. The number of treated patients in the Arm A (Ipilimumab plus Bavituximab) will be 16, and in the Arm B (Ipilimumab only) will be 8. The trial is expected to complete in March 2016.[32][33] Previously, preclinical studies showed that PS targeting antibodies (such as bavituximab) enhance the anti-tumor activity of anti-CTLA-4 and anti-PD-1 antibodies. Tumor growth inhibition correlates with infiltration of immune cells in tumors and induction of adaptive immunity. The combination of these mechanisms promotes strong, localized, anti-tumor responses without the side-effects of systemic immune activation.[34]

Development[edit]

Anti-CTLA-4 blockade, the invention that subsequently gave rise to Ipilimumab, was conceived by James P. Allison and Matthew F. Krummel as part of Krummel’s PhD thesis work in Allison's lab that uncovered an inhibitory role for CTLA-4 in T cell activation.[35] Allison, then at UCBerkeley, noted similarities between CTLA-4 amino acid structure when compared to a CD28; CD28 at that time was a recently identified "T cell costimulatory" molecule important for T cell activation.[36] Krummel and Allison’s antibodies were first applied to in vitro studies as a means to engage or block CTLA-4 and they were able to demonstrate that CTLA-4 signaling in T cells inhibited T cell responses.[37] Given that antibodies have long half-lives in vivo, they then injected intact antibodies and demonstrated that CTLA-4 blockade enhanced T cell responses in mice responding to vaccines and to super antigens.[38] Using conditions worked out from these studies, Dana Leach, who had just begun as a postdoctoral fellow in Allison’s lab, was tasked by Allison with applying these in tumor models. With remarkable efficacy, antibody-treated but not control-treated mice showed significantly less cancer growth. This work was published in the journal Science.[39]

Jeff Bluestone’s lab, then at University of Chicago, and Peter Linsley’s group at Oncogen and then Bristol-Meyer Squib in Seattle also noted the similarities between CD28 and CTLA-4 and studied them extensively. Bluestone’s lab published studies, one of which was published together with Krummel and Allison, for in vitro studies of CTLA-4 function.[40][41] In collaboration with Mark Jenkin’s lab at the University of Minnesota, they were also able to see effects of their own anti-CTLA-4 antibodies in vivo in an immunization setting[42] but did not effectively carry this into tumor biology. Linsley and colleagues had also made monoclonal antibodies against CTLA-4 three years prior to those of Krummel/Allison or Walunas/Bluestone. They concluded that the molecule functioned similarly to CD28 and was a "postive costimulator".[43] They also did not apparently pursue targeting of CTLA-4 in tumors, although BMS ultimately came to license the Allison/Leach/Krummel patent though their acquisition of Medarex and the fully humanized antibody MDX010 (which later became Ipilimumab, trade-name Yervoy).

References[edit]

  1. ^ USAN. "STATEMENT ON A NONPROPRIETARY NAME ADOPTED BY THE USAN COUNCIL - ipilimumab" (Press release). American Medical Association (AMA). Retrieved 2013-01-12. 
  2. ^ Lacroix, Marc (2014). Targeted Therapies in Cancer. Hauppauge , NY: Nova Sciences Publishers. ISBN 978-1-63321-687-7. 
  3. ^ a b c d Antoni Ribas (28 June 2012). "Tumor immunotherapy directed at PD-1". New England Journal of Medicine 366 (26): 2517–9. doi:10.1056/nejme1205943. 
  4. ^ 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)
  5. ^ ClinicalTrials.gov NCT01524991
  6. ^ ClinicalTrials.gov NCT00323882 Phase I/II Study of MDX-010 in Patients With Metastatic Hormone-Refractory Prostate Cancer (MDX010-21) (COMPLETED)
  7. ^ 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
  8. ^ 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. 
  9. ^ Pollack, Andrew (2011-03-25). "Approval for Drug That Treats Melanoma". The New York Times. Retrieved 2011-03-27. 
  10. ^ a b c Drugs.com: Yervoy
  11. ^ Notice of Decision for YERVOY
  12. ^ "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. 
  13. ^ "FDA Rubber-Stamps Bristol-Myers Squibb’s Melanoma mAb". Genetic Engineering & Biotechnology News. 2011-03-28. Retrieved 2011-03-28. 
  14. ^ Tarhini AA, Iqbal F (2010). "CTLA-4 blockade: therapeutic potential in cancer treatments". Onco Targets Ther 3: 15–25. doi:10.2147/ott.s4833. PMC 2895779. PMID 20616954. 
  15. ^ 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. 
  16. ^ 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. 
  17. ^ L. Harivardhan Reddy; Patrick Couvreur (1 June 2009). Macromolecular Anticancer Therapeutics. Springer. pp. 522–. ISBN 978-1-4419-0506-2. Retrieved 30 March 2011. 
  18. ^ 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. 
  19. ^ 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. 
  20. ^ "CTLA-4 strategies: Abatacept / Belatacept". healthvalue.net. Retrieved 2009-06-24. 
  21. ^ Tomillero A, Moral MA (October 2008). "Gateways to clinical trials". Methods Find Exp Clin Pharmacol 30 (8): 643–72. PMID 19088949. 
  22. ^ Poust J (December 2008). "Targeting metastatic melanoma". Am J Health Syst Pharm 65 (24 Suppl 9): S9–S15. doi:10.2146/ajhp080461. PMID 19052265. 
  23. ^ "Top-Line Data Available from Three Ipilimumab Pivotal Trials in Patients with Advanced Metastatic Melanoma". Medarex, Inc. 2007-12-10. Retrieved 2009-06-24. [dead link]
  24. ^ "Bristol drug cuts death risk in advanced melanoma". Reuters. 2010-06-05. 
  25. ^ Langreth R (2010-06-06). "The Risk For Bristol". Forbes. Archived from the original on 2011-07-22. Retrieved 2011-03-25. 
  26. ^ "Phase 3 clinical study: Ipilimumab boosts, sustains immune system responses against melanoma tumors". News-Medical.Net. 2010-06-09. Retrieved 2011-03-25. 
  27. ^ Silverman E (2010-06-07). "Bristol-Myers’ Melanoma Med And Wall Street Wags // Pharmalot". Pharma Blog PHARMALOT. Retrieved 2011-03-25. 
  28. ^ "'Surprise' prostate result probed". BBC News. 2009-06-19. Retrieved 2009-06-24. 
  29. ^ "Mayo Researchers: Dramatic Outcomes in Prostate Cancer Study". Mayo Clinic. 2009-06-01. Retrieved 2009-06-24. 
  30. ^ Boyles S (2009-06-19). "New Therapy May Fight Prostate Cancer". WebMD. Retrieved 2009-06-24. 
  31. ^ Lowe D (2009-06-23). "Medarex, Ipilimumab, Prostate Cancer, And Reality. :". Corante. Retrieved 2009-06-24. 
  32. ^ "A Two-arm, Single Center Phase 1b Trial of Bavituximab Plus Ipilimumab in Advanced Melanoma Patients". ClinicalTrials.gov. 
  33. ^ "Peregrine Pharmaceuticals Announces Initiation of an Investigator-Sponsored Trial Combining Its Immunotherapy Bavituximab and Ipilimumab (Yervoy®) in Advanced Melanoma". Peregrine Pharmaceuticals, Inc. 
  34. ^ "Data Presented at AACR Support Potential of Peregrine's PS-Targeting Immunotherapy Bavituximab to Enhance Anti-Tumor and Immune-Stimulating Effects of Anti-CTLA-4 and Anti-PD-1 Treatments in Models of Melanoma and Colon Cancer". Reuters. 2014-04-09. Retrieved 2014-04-09. 
  35. ^ Krummel, M.F. (1995). Identification and Characterization of a CTLA-4 Dependent Regulatory Mechanism for T Cell Activation (University of California, Berkeley).
  36. ^ Harding, F., McArthur, J.G., Gross, J.A., Raulet, D.H., and Allison, J.P. (1992). CD28 mediated signalling costimulates murine T cells and prevents the induction of anergy in T cell clones. Nature 356, 607–609.
  37. ^ Krummel, M.F., and Allison, J.P. (1995). CD28 and CTLA-4 deliver opposing signals which regulate the response of T cells to stimulation. Journal of Experimental Medicine 182, 459-465.
  38. ^ Krummel, M.F., Sullivan, T.J., and Allison, J.P. (1995). Superantigen responses and costimulation: CD28 and CTLA-4 have opposing effects on T cell expansion In Vitro and In Vivo. International Immunol 8, 101-105.
  39. ^ Leach, D.R., Krummel, M.F., and Allison, J.P. (1996). Enhancement of antitumor immunity by CTLA-4 blockade. Science 271, 1734-1736.
  40. ^ Walunas, T.L., Bakker, C.Y., and Bluestone, J.A. (1996). CTLA-4 ligation blocks CD28-dependent T cell activation. Journal of Experimental Medicine 183, 2541-2550.
  41. ^ Walunas, T.L., Lenschow, D.J., Bakker, C.Y., Linsley, P.S., Freeman, G.J., Green, J.M., Thompson, C.B., and Bluestone, J.A. (1994) CTLA-4 can function as a negative regulator of T cell activation. Immunity 1, 405-413.
  42. ^ Kearney, E.R., Walunas, T.L., Karr, R.W., Morton, P.A., Loh, D.Y., Bluestone, J.A., and Jenkins, M.K. (1995). Antigen-dependent clonal expansion of a trace population of antigen-specific CD4+ T cells in vivo is dependent on CD28 costimulation and inhibited by CTLA-4. JImmunol 155, 1032-1036.
  43. ^ Linsley, P.S., Greene, J.L., Tan, P., Bradshaw, J., Ledbetter, J.A., Anasetti, C., and Damle, N.K. (1992). Coexpression and functional cooperativity of CTLA-4 and CD28 on activated T lymphocytes. Journal of Experimental Medicine 176, 1595-1604.

External links[edit]