trophoblast glycoprotein | Tumour-associated antigens | IUPHAR/BPS Guide to PHARMACOLOGY

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trophoblast glycoprotein

target has curated data in GtoImmuPdb

Target id: 3009

Nomenclature: trophoblast glycoprotein

Family: Tumour-associated antigens

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 420 6q14.1 TPBG trophoblast glycoprotein 13
Mouse 1 426 9 E3.1; Chromosome 9, 46.40 cM Tpbg trophoblast glycoprotein
Rat 1 426 8q31 Tpbg trophoblast glycoprotein
Previous and Unofficial Names
5T4 | 5T4-Ag | 5T4 oncofetal antigen | Wnt-activated inhibitory factor 1 | WAIF1
Database Links
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia

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Antibodies
Key to terms and symbols Click column headers to sort
Antibody Sp. Action Value Parameter Reference
naptumomab estafenatox Hs Binding ~9.0 pKd 5
pKd ~9.0 (Kd ~1x10-9 M) [5]
anatumomab mafenatox Hs Binding 8.9 pKd 4
pKd 8.9 (Kd 1.2x10-9 M) [4]
Description: Binding affinity for 5T4 expressed on human Calu-1 lung cancer cells.
Antibody Comments
Alligator Bioscience and Aptevo Therapeutics have a bispecific mAb called ALG.APV-527 in preclinical development. ALG.APV-527 simultaneously targets trophoblast glycoprotein 5T4 and the co-stimulatory receptor 4-1BB (CD137) to promote potent, tumour-directed immune T-cell activation. This construct enables the immune-activating effect of ALG.APV-527 to be directed specifically to tumour cells and not against normal tissue.
Immunopharmacology Comments
Trophoblast glycoprotein (commonly referred to as 5T4) is included in GtoImmuPdb as it is a target of several anti-tumour immunotherapy strategies [2,10,20]. Anti-5T4 monoclonal antibodies [7], antibody drug conjugates (ADCs, as fusion proteins with T cell-activating superantigens) [3,11-12,15,17,19,21], a CAR-T cell therapy [14], and anti-5T4 vaccines [1,6,8] have been reported in the literature [16]. To date the only agents to be tested in human patients are the TROVAX® vaccine (ISRCTN54669986) [1] and three ADCs- PF-06263507 (NCT01891669) [17], ABR-217620 (naptumomab estafenatox, NCT00420888) [3], and ABR-214936 (anatumomab mafenatox, [18]). Preliminary beneficial effects of TROVAX® (in combination with low-dose cyclophosphamide) have been reported in patients with metastatic colorectal cancer [16]. First-in-human trial results for PF-06263507 were reported by Shapiro et al. (2017) [17], but further development of PF-06263507 has been terminated due to company portfolio re-prioritisation, and not because of any satety concerns. Naptumomab estafenatox and anatumomab mafenatox have completed Phase 2 clinical evaluation in patients with metastatic/advanced renal cell carcinoma [3,9,18], and further evalaution is planned in targeted patient groups.
Clinically-Relevant Mutations and Pathophysiology
Disease:  Renal cell carcinoma
Disease Ontology: DOID:4450
Role: 
References:  3,9,18,20
Gene Expression and Pathophysiology Comments
Trophoblast glycoprotein 5T4 is expressed by a large number of solid tumour types, as a mechanism to evade immune surveillance [2,20].
General Comments
Trophoblast glycoprotein (a.k.a. 5T4 oncofetal antigen) is a 72-kDa oncofetal protein whose expression on trophoblast cells mediates survival of the foetus as a semi-allograft in the mother. Whilst expression by normal adult tissues is limited, 5T4 is highly expressed on many carcinomas (where it allows the tumour to evade immune surveillance by the host), is a marker associated with poor clinical outcome, and is the target of several tumour immunotherapy strategies.

References

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1. Amato RJ, Stepankiw M. (2012) Evaluation of MVA-5T4 as a novel immunotherapeutic vaccine in colorectal, renal and prostate cancer. Future Oncol, 8 (3): 231-7. [PMID:22409460]

2. Cappuccini F, Pollock E, Stribbling S, Hill AVS, Redchenko I. (2017) 5T4 oncofoetal glycoprotein: an old target for a novel prostate cancer immunotherapy. Oncotarget, 8 (29): 47474-47489. [PMID:28537896]

3. Eisen T, Hedlund G, Forsberg G, Hawkins R. (2014) Naptumomab estafenatox: targeted immunotherapy with a novel immunotoxin. Curr Oncol Rep, 16 (2): 370. [PMID:24445502]

4. Forsberg G, Ohlsson L, Brodin T, Björk P, Lando PA, Shaw D, Stern PL, Dohlsten M. (2001) Therapy of human non-small-cell lung carcinoma using antibody targeting of a modified superantigen. Br. J. Cancer, 85 (1): 129-36. [PMID:11437414]

5. Forsberg G, Skartved NJ, Wallén-Ohman M, Nyhlén HC, Behm K, Hedlund G, Nederman T. (2010) Naptumomab estafenatox, an engineered antibody-superantigen fusion protein with low toxicity and reduced antigenicity. J. Immunother., 33 (5): 492-9. [PMID:20463598]

6. Hanwell DG, McNeil B, Visan L, Rodrigues L, Dunn P, Shewen PE, Macallum GE, Turner PV, Vogel TU. (2013) Murine responses to recombinant MVA versus ALVAC vaccines against tumor-associated antigens, gp100 and 5T4. J. Immunother., 36 (4): 238-47. [PMID:23603858]

7. Harper J, Lloyd C, Dimasi N, Toader D, Marwood R, Lewis L, Bannister D, Jovanovic J, Fleming R, D'Hooge F et al.. (2017) Preclinical Evaluation of MEDI0641, a Pyrrolobenzodiazepine-Conjugated Antibody-Drug Conjugate Targeting 5T4. Mol. Cancer Ther., 16 (8): 1576-1587. [PMID:28522587]

8. Harrop R, Chu F, Gabrail N, Srinivas S, Blount D, Ferrari A. (2013) Vaccination of castration-resistant prostate cancer patients with TroVax (MVA-5T4) in combination with docetaxel: a randomized phase II trial. Cancer Immunol. Immunother., 62 (9): 1511-20. [PMID:23877659]

9. Hawkins RE, Gore M, Shparyk Y, Bondar V, Gladkov O, Ganev T, Harza M, Polenkov S, Bondarenko I, Karlov P et al.. (2016) A Randomized Phase II/III Study of Naptumomab Estafenatox + IFNα versus IFNα in Renal Cell Carcinoma: Final Analysis with Baseline Biomarker Subgroup and Trend Analysis. Clin. Cancer Res., 22 (13): 3172-81. [PMID:26851187]

10. Kerk SA, Finkel KA, Pearson AT, Warner KA, Zhang Z, Nör F, Wagner VP, Vargas PA, Wicha MS, Hurt EM et al.. (2017) 5T4-Targeted Therapy Ablates Cancer Stem Cells and Prevents Recurrence of Head and Neck Squamous Cell Carcinoma. Clin. Cancer Res., 23 (10): 2516-2527. [PMID:27780858]

11. Leal M, Wentland J, Han X, Zhang Y, Rago B, Duriga N, Spriggs F, Kadar E, Song W, McNally J et al.. (2015) Preclinical Development of an anti-5T4 Antibody-Drug Conjugate: Pharmacokinetics in Mice, Rats, and NHP and Tumor/Tissue Distribution in Mice. Bioconjug. Chem., 26 (11): 2223-32. [PMID:26180901]

12. McGinn OJ, Krishnan S, Bourquin JP, Sapra P, Dempsey C, Saha V, Stern PL. (2017) Targeting the 5T4 oncofetal glycoprotein with an antibody drug conjugate (A1mcMMAF) improves survival in patient-derived xenograft models of acute lymphoblastic leukemia. Haematologica, 102 (6): 1075-1084. [PMID:28341731]

13. Myers KA, Rahi-Saund V, Davison MD, Young JA, Cheater AJ, Stern PL. (1994) Isolation of a cDNA encoding 5T4 oncofetal trophoblast glycoprotein. An antigen associated with metastasis contains leucine-rich repeats. J. Biol. Chem., 269 (12): 9319-24. [PMID:8132670]

14. Owens GL, Sheard VE, Kalaitsidou M, Blount D, Lad Y, Cheadle EJ, Edmondson RJ, Kooner G, Gilham DE, Harrop R. (2018) Preclinical Assessment of CAR T-Cell Therapy Targeting the Tumor Antigen 5T4 in Ovarian Cancer. J. Immunother., 41 (3): 130-140. [PMID:29239915]

15. Patterson KG, Dixon Pittaro JL, Bastedo PS, Hess DA, Haeryfar SM, McCormick JK. (2014) Control of established colon cancer xenografts using a novel humanized single chain antibody-streptococcal superantigen fusion protein targeting the 5T4 oncofetal antigen. PLoS ONE, 9 (4): e95200. [PMID:24736661]

16. Scurr M, Pembroke T, Bloom A, Roberts D, Thomson A, Smart K, Bridgeman H, Adams R, Brewster A, Jones R et al.. (2017) Effect of Modified Vaccinia Ankara-5T4 and Low-Dose Cyclophosphamide on Antitumor Immunity in Metastatic Colorectal Cancer: A Randomized Clinical Trial. JAMA Oncol, 3 (10): e172579. [PMID:28880972]

17. Shapiro GI, Vaishampayan UN, LoRusso P, Barton J, Hua S, Reich SD, Shazer R, Taylor CT, Xuan D, Borghaei H. (2017) First-in-human trial of an anti-5T4 antibody-monomethylauristatin conjugate, PF-06263507, in patients with advanced solid tumors. Invest New Drugs, 35 (3): 315-323. [PMID:28070718]

18. Shaw DM, Connolly NB, Patel PM, Kilany S, Hedlund G, Nordle O, Forsberg G, Zweit J, Stern PL, Hawkins RE. (2007) A phase II study of a 5T4 oncofoetal antigen tumour-targeted superantigen (ABR-214936) therapy in patients with advanced renal cell carcinoma. Br. J. Cancer, 96 (4): 567-74. [PMID:17285137]

19. Shor B, Kahler J, Dougher M, Xu J, Mack M, Rosfjord E, Wang F, Melamud E, Sapra P. (2016) Enhanced Antitumor Activity of an Anti-5T4 Antibody-Drug Conjugate in Combination with PI3K/mTOR inhibitors or Taxanes. Clin. Cancer Res., 22 (2): 383-94. [PMID:26319086]

20. Stern PL, Harrop R. (2017) 5T4 oncofoetal antigen: an attractive target for immune intervention in cancer. Cancer Immunol. Immunother., 66 (4): 415-426. [PMID:27757559]

21. Wang R, Lai Q, Tang L, Tao Y, Yao Y, Liu Y, Lu Y, Shen C, Lu R, Fan C et al.. (2018) A novel 5T4-targeting antibody-drug conjugate H6-DM4 exhibits potent therapeutic efficacy in gastrointestinal tumor xenograft models. Am J Cancer Res, 8 (4): 610-623. [PMID:29736307]

How to cite this page

Tumour-associated antigens: trophoblast glycoprotein. Last modified on 10/05/2018. Accessed on 22/07/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=3009.