Tremelimumab

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Tremelimumab
Monoclonal antibody
Type Whole antibody
Source Human
Target CTLA-4
Identifiers
CAS Number 745013-59-6 N
ATC code None
IUPHAR/BPS 8462
ChemSpider none
UNII QEN1X95CIX YesY
Chemical data
Formula C6500H9974N1726O2026S52
Molar mass 146380.472 Da
 NYesY (what is this?)  (verify)

Tremelimumab (formerly ticilimumab, CP-675,206) is a fully human IgG2 monoclonal antibody produced by Pfizer, undergoing human trials for the treatment of cancer. Tremelimumab stimulates patients’ immune systems to attack their tumors.

Cytotoxic T lymphocytes (CTLs) can recognize and destroy cancer cells. However, there is also an inhibitory mechanism (immune checkpoint) that interrupts this destruction. Tremelimumab turns off this inhibitory mechanism and allows CTLs to continue to destroy the cancer cells.[1] This is immune checkpoint blockade.

Mechanism of action[edit]

Tremelimumab binds to the protein CTLA-4, which is expressed on the surface of activated T lymphocytes and inhibits the killing of cancer cells. Tremelimumab blocks the binding of the antigen-presenting cell ligands B7.1 and B7.2 to CTLA-4, resulting in inhibition of B7-CTLA-4-mediated downregulation of T-cell activation; subsequently, B7.1 or B7.2 may interact with another T-cell surface receptor protein, CD28, resulting in a B7-CD28-mediated T-cell activation unopposed by B7-CTLA-4-mediated inhibition.

Clinical trials[edit]

It has induced durable tumor responses in patients with metastatic melanoma in Phase 1 and Phase 2 clinical studies.[2]

On April 2, 2008, Pfizer announced that it has discontinued a Phase III clinical trial for patients with advanced melanoma after the review of interim data showed that the trial would not demonstrate superiority to standard chemotherapy.[3] Studies for other tumors are planned as of October 2009, namely for prostate cancer[4] and bladder cancer.[5]

On October 4, 2011, MedImmune LLC gained worldwide rights on Tremelimumab to develop and commercialize the drug for treatment of cancer, while Pfizer retains all rights for combination therapies.

Unfortunate design of clinical trial[edit]

The Phase III clinical failure of Pfizer's tremelimumab anti-CTLA-4 monoclonal antibody, which competed with ipilimumab, showed the problems with the conventional Response Evaluation Criteria in Solid Tumors (RECIST) for immunotherapies. An early interim analysis found no survival advantage for the treated patients, leading to the termination of the trial in April 2008[6] .[7] However within a year of this development, Pfizer's investigators were beginning to notice a separation of survival curves between treatment and control groups.[8] Some subsequent immunotherapy trials (eg ipilimumab) used the Immune-Related Response Criteria (irRC) instead.

Similar drugs[edit]

As of October 2009, there are two fully human anti CTLA-4 monoclonal antibodies in advanced clinical trials, tremelimumab and ipilimumab (from Medarex and Bristol-Myers Squibb).[9]

References[edit]

  1. ^ Antoni Ribas (28 June 2012). "Tumor immunotherapy directed at PD-1". New England Journal of Medicine 366 (26): 2517–9. doi:10.1056/nejme1205943. 
  2. ^ Reuben, JM; et al. (1 Jun 2006). "Biologic and immunomodulatory events after CTLA-4 blockade with tremelimumab in patients with advanced malignant melanoma". Cancer 106 (11): 2437–44. doi:10.1002/cncr.21854. PMID 16615096. 
  3. ^ Pfizer Inc. press release – Pfizer Announces Discontinuation of Phase III Clinical Trial for Patients with Advanced Melanoma
  4. ^ Clinical trial number NCT00702923 for "CP-675,206 in Combination With Short Term Androgen Deprivation in Patients With Stage D0 Prostate Cancer" at ClinicalTrials.gov
  5. ^ Clinical trial number NCT00880854 for "Study of CP-675,206 in Bacillus Calmette-Guerin (BCG)-Resistant Bladder Cancer" at ClinicalTrials.gov
  6. ^ "Pfizer Announces Discontinuation of Phase III Clinical Trial for Patients with Advanced Melanoma". Pfizer.com. 1 April 2008. Retrieved 5 December 2015. 
  7. ^ A. Ribas, A. Hauschild, R. Kefford, C. J. Punt, J. B. Haanen, M. Marmol, C. Garbe, J. Gomez-Navarro, D. Pavlov and M. Marsha (May 20, 2008). "Phase III, open-label, randomized, comparative study of tremelimumab (CP-675,206) and chemotherapy (temozolomide [TMZ] or dacarbazine [DTIC]) in patients with advanced melanoma". Journal of Clinical Oncology, 26 (15S). 
  8. ^ M.A. Marshall, A. Ribas, B. Huang; (May 2010). "Evaluation of baseline serum C-reactive protein (CRP) and benefit from tremelimumab compared to chemotherapy in first-line melanoma". Journal of Clinical Oncology, 28 (15S). 
  9. ^ Healthvalue.net: CTLA-4 Strategies