Tremelimumab

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 g/mol
 NYesY (what is this?)  (verify)

Tremelimumab (formerly ticilimumab, CP-675,206) is a fully human monoclonal antibody against CTLA-4. It is an immune checkpoint blocker. Previously in development by Pfizer,[1] it is now in investigation by MedImmune, a wholly owned subsidiary of AstraZeneca.[2] It has been undergoing human trials for the treatment of various cancers but has not attained approval for any.

Mechanism of action

Tremelimumab aims to stimulate an immune system attack on 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.[3] This is immune checkpoint blockade.

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.

Unlike Ipilimumab (another fully human anti-CTLA-4 monoclonal antibody), which is an IgG1 isotype, tremelimumab is an IgG2 isotype.[4][5]

Clinical trials

Melanoma

Phase 1 and 2 clinical studies in metastatic melanoma showed some responses.[6] However, based on early interim analysis of phase III data, Pfizer designated tremelimumab as a failure and terminated the trial in April 2008.[1][7]

However, within a year, the survival curves showed separation of the treatment and control groups.[8] The conventional Response Evaluation Criteria in Solid Tumors (RECIST) may underrepresent the merits of immunotherapies. Subsequent immunotherapy trials (e.g. ipilimumab) have used the Immune-Related Response Criteria (irRC) instead.

Mesothelioma

Although it was designated in April 2015 as orphan drug status in mesothelioma,[9] tremelimumab failed to improve lifespan in the phase IIb DETERMINE trial, which assessed the drug as a second or third-line treatment for unresectable malignant mesothelioma.[10][11]

References

  1. 1 2 "Pfizer Announces Discontinuation of Phase III Clinical Trial for Patients with Advanced Melanoma". Pfizer.com. 1 April 2008. Retrieved 5 December 2015.
  2. ↑ Mechanism of Pathway: CTLA-4 Inhibition
  3. ↑ 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. ↑ Tomillero A, Moral MA (October 2008). "Gateways to clinical trials". Methods Find Exp Clin Pharmacol 30 (8): 643–72. PMID 19088949.
  5. ↑ Poust J (December 2008). "Targeting metastatic melanoma". Am J Health Syst Pharm 65 (24 Suppl 9): S9–S15. doi:10.2146/ajhp080461. PMID 19052265.
  6. ↑ 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.
  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. ↑ FDA Grants AstraZeneca's Tremelimumab Orphan Drug Status for Mesothelioma
  10. ↑ Tremelimumab Fails Mesothelioma Drug Trial
  11. ↑ AZ' tremelimumab fails in mesothelioma trial.


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