Tremelimumab

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.

Tremelimumab
Fab fragment of tremelimumab (blue) binding CTLA-4 (green). From PDB entry 5GGV.
Monoclonal antibody
TypeWhole antibody
SourceHuman
TargetCTLA-4
Clinical data
ATC code
  • none
Identifiers
CAS Number
IUPHAR/BPS
ChemSpider
  • none
UNII
Chemical and physical data
FormulaC6500H9974N1726O2026S52
Molar mass146382.47 g·mol−1
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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]

Non-small cell lung cancer

In a phase III trial, AstraZeneca paired tremelimumab with a PD-L1 inhibitor, durvalumab, for the first-line treatment of non-small cell lung cancer.[12] The trial was conducted across 17 countries, and in July 2017, AstraZeneca announced that it had failed to meet its primary endpoint of progression-free survival.[13]

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References
  1. "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. PMID 22658126.
  4. Tomillero A, Moral MA (October 2008). "Gateways to clinical trials". Methods Find Exp Clin Pharmacol. 30 (8): 643–72. doi:10.1358/mf.2008.30.5.1236622. 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): LBA9011. doi:10.1200/jco.2008.26.15_suppl.lba9011.CS1 maint: multiple names: authors list (link)
  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): 2609. doi:10.1200/jco.2010.28.15_suppl.2609.CS1 maint: multiple names: authors list (link)
  9. FDA Grants AstraZeneca's Tremelimumab Orphan Drug Status for Mesothelioma
  10. "Tremelimumab Fails Mesothelioma Drug Trial". Archived from the original on 2016-03-06. Retrieved 2016-03-06.
  11. AZ' tremelimumab fails in mesothelioma trial
  12. "AstraZeneca's immuno-oncology combo fails crucial Mystic trial in lung cancer | FierceBiotech".
  13. "AstraZeneca reports initial results from the ongoing MYSTIC trial in Stage IV lung cancer".
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