Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ASCO Annual Meeting 2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

2024 ASCO Annual Meeting

Keep up to date with all the top stories and latest evidence with our hub page, including official congress videos and expert takeaways.
ADVANCED SEARCH
Log in
Top
Targeted Oncology
Published in: Targeted Oncology 3/2014

01-09-2014 | Original Research

A bispecific EpCAM/CD133-targeted toxin is effective against carcinoma

Authors: Nate N. Waldron, Sanford H. Barsky, Phillip R. Dougherty, Daniel A. Vallera

Published in: Targeted Oncology | Issue 3/2014

Login to get access

Abstract

The discovery of chemoresistant cancer stem cells (CSCs) in carcinomas has created the need for therapies that specifically target these subpopulations of cells. Here, we characterized a bispecific targeted toxin that is composed of two antibody fragments and a catalytic protein toxin allowing it to bind two CSC markers on the same cell killing this resistant subpopulation. CD133 is a well-known CSC marker and has been successfully targeted and caused regression of head and neck squamous cell carcinoma (HNSCC) in vivo. To enable it to bind a broader range of CSCs, an anti-epithelial cell adhesion molecule (EpCAM) scFv was added to create dEpCAMCD133KDEL, a deimmunized bispecific targeted toxin on a single amino acid chain. This bispecific potently inhibited protein translation and proliferation in vitro in three different types of carcinoma. Furthermore, in a CSC spheroid model dEpCAMCD133KDEL eliminated Mary-X spheroids, an inflammatory breast carcinoma. Finally, this bispecific also caused tumor regression in an in vivo model of HNSCC. This represents the first bispecific CSC-targeted toxin and warrants further development as a possible therapy for carcinoma.
Literature
1.
Trzpis M, McLaughlin PM, de Leij LM, Harmsen MC (2007) Epithelial cell adhesion molecule: More than a carcinoma marker and adhesion molecule. Am J Pathol 171:386–395PubMedCentralPubMedCrossRef
2.
Munz M, Baeuerle PA, Gires O (2009) The emerging role of EpCAM in stem cell signaling. Cancer Res 69:5627
3.
Takahashi-Yanaga F, Kahn M (2010) Targeting Wnt signaling: can we safely eradicate cancer stem cells? Clin Cancer Res 16:3153–3162PubMedCrossRef
4.
Moncharmont C, Levy A, Gilormini M, Bertrand G, Chargari C, Alphonse G, Ardail D, Rodriguez-Lafrasse C, Magne N (2012) Targeting a cornerstone of radiation resistance: cancer stem cell. Cancer Lett 322:139–147PubMedCrossRef
5.
Van der Gun BT, Melchers LJ, Ruiters MH, de Leij LF, McLaughlin PM, Rots MG (2010) EpCAM in carcinogenesis: the good, the bad or the ugly. Carcinogenesis 31:1913–1921PubMedCrossRef
6.
Visvader JE, Lindeman GJ (2008) Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer 8:755–768PubMedCrossRef
7.
Yin AH, Miraglia S, Zanjani ED, Almeida-Porada G, Ogawa M, Leary AG, Olweus J, Kearney J, Buck DW (1997) AC133, A novel marker for human hematopoietic stem and progenitor cells. Blood 90:5002–5012PubMed
8.
9.
Ferrandina G, Petrillo M, Bonanno G, Scambia G (2009) Targeting CD133 antigen in cancer. Expert Opin Ther Targets 13:823–837PubMedCrossRef
10.
Rappa G, Fodstad O, Lorico A (2008) The stem cell-associated antigen CD133 (Prominin-1) is a molecular therapeutic target for metastatic melanoma. Stem Cells 26:3008–3017PubMedCentralPubMedCrossRef
11.
Mak AB, Nixon AM, Kittanakom S, Stewart JM, Chen GI, Curak J, Gingras AC, Mazitschek R, Neel BG, Stagljar I, Moffat J (2012) Regulation of CD133 by HDAC6 promotes β-catenin signaling to suppress cancer cell differentiation. Cell Rep 2:951–963PubMedCentralPubMedCrossRef
12.
Takenobu H, Shimozato O, Nakamura T, Ochiai H, Yamaguchi Y, Ohira M, Nakagawara A, Kamijo T (2011) CD133 suppresses neuroblastoma cell differentiation via signal pathway modification. Oncogene 30:97–105PubMedCrossRef
13.
Swaminathan SK, Niu L, Waldron NN, Kalscheuer S, Zellmer D, Olin MR, Ohlfest JR, Vallera DA, Panyam J (2013) Identification and characterization of a novel scFv recognizing human and mouse CD133. Drug Deliv Transl Res. doi:10.​1007/​s13346-012-0099-6
14.
Waldron NN, Kaufman DS, Oh S, Inde Z, Hexum MK, Ohlfest JR, Vallera DA (2011) Targeting tumor-initiating cancer cells with dCD133KDEL shows impressive tumor reductions in a xenotransplant model of human head and neck cancer. Mol Cancer Ther 10:1829–1838PubMedCentralPubMedCrossRef
15.
Ohlfest JR, Zellmer D, Panyam J, Swaminathan SK, Oh S, Waldron NN, Toma S, Vallera DA (2012) Immunotoxin targeting CD133+ breast carcinoma cells. Drug Deliv Transl Res. doi:10.​1007/​s13346-012-0066-2
16.
Skubitz APN, Taras EP, Boylan KLM, Waldron NN, Oh, S, Panoskaltsis-Mortari A, Vallera DA (2013) Targeting CD133 in an in vivo ovarian cancer model reduces ovarian cancer progression. Gynecol Oncol. doi:10.​1016/​j.​ygyno.​2013.​05.​027
17.
Stish BJ, Oh S, Chen H, Dudek AZ, Kratzke RA, Vallera DA (2009) Design and modification of EGF4KDEL 7mut, a novel bispecific ligand-directed toxin, with decreased immunogenicity and potent anti-mesothelioma activity. Br J Cancer 101:1114–1123PubMedCentralPubMedCrossRef
18.
Tsai AK, Oh S, Chen H, Shu Y, Ohlfest JR, Vallera DA (2011) A novel bispecific ligand-directed toxin designed to simultaneously target EGFR on human glioblastoma cells and uPAR on tumor neovasculature. J Neurooncol 103:255–266PubMedCentralPubMedCrossRef
19.
Vallera DA, Oh S, Chen H, Shu Y, Frankel AE (2010) Bioengineering a unique deimmunized bispecific targeted toxin that simultaneously recognizes human CD22 and CD19 receptors in a mouse model of B-cell metastases. Mol Cancer Ther 9:1872–1883PubMedCentralPubMedCrossRef
20.
Stish BJ, Chen H, Shu Y, Panoskaltsis-Mortari A, Vallera DA (2007) Increasing anticarcinoma activity of an anti-erbB2 recombinant immunotoxin by the addition of an anti-EpCAM sFv. Clin Cancer Res 13:3058–3067PubMedCrossRef
21.
MacDonald GC, Rasamoelisolo M, Entwistle J, Cizeau J, Bosc D, Cuthbert W, Kowalski M, Spearman M, Glover N (2009) A phase I clinical study of VB4-845: Weekly intratumoral administration of an anti-EpCAM recombinant fusion protein in patients with squamous cell carcinoma of the head and neck. Drug Des Devel Ther 2:105–114PubMedCentralPubMed
22.
Kowalski M, Entwistle J, Cizeau J, Niforos D, Loewen S, Chapman W, MacDonald GC (2010) A phase I study of an intravesically administered immunotoxin targeting EpCAM for the treatment of nonmuscle-invasive bladder cancer in BCG-refractory and BCG-intolerant patients. Drug Des Devel Ther 4:313–320PubMedCentralPubMed
23.
Kowalski M, Guindon J, Brazas L, Moore C, Entwistle J, Cizeau J, Jewett MA, MacDonald GC (2012) A phase II study of oportuzumab monatox: an immunotoxin therapy for patients with noninvasive urothelial carcinoma in situ previously treated with Bacillus Calmette–Guérin. J Urol 188:1712–1718PubMedCrossRef
24.
Fitzgerald D, Pastan I (1989) Targeted toxin therapy for the treatment of cancer. J Natl Cancer Inst 81:1455–1463PubMedCrossRef
25.
Kreitman RJ, Pastan I (1995) Importance of the glutamate residue of KDEL in increasing the cytotoxicity of Pseudomonas exotoxin derivatives and for increased binding to the KDEL receptor. Biochem J 307(697):29–37PubMedCentralPubMed
26.
Vallera DA, Chen H, Sicheneder AR, Panoskaltsis-Mortari A, Taras EP (2009) Genetic alteration of a bispecific ligand directed toxin targeting human CD19 and CD22 receptors resulting in improved efficacy against systemic. Leuk Res 33:1233–1242PubMedCentralPubMedCrossRef
27.
Worsham MJ, Chen KM, Meduri V, Nygren AO, Errami A, Schouten JP, Benninger MS (2006) Epigenetic events of disease progression in head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 132:668–677PubMedCrossRef
28.
Abu-Ali S, Fotovati A, Shirasuna K (2008) Tyrosine-kinase inhibition results in EGFR clustering at focal adhesions and consequent exocytosis in uPAR down-regulated cells of head and neck cancers. Mol Cancer 7:47PubMedCentralPubMedCrossRef
29.
Eyler CE, Rich JN (2008) Survival of the fittest: cancer stem cells in therapeutic resistance and angiogenesis. J Clin Onc 26:2839–2845CrossRef
30.
31.
Dylla SJ, Beviglia L, Park IK, Chartier C, Raval J, Ngan L, Pickell K, Aguilar J, Lazetic S, Smith-Berdan S, Clarke MF, Hoey T, Lewicki J, Gurney AL (2008) Colorectal cancer stem cells are enriched in xenogeneic tumors following chemotherapy. PLoS One 3:e2428PubMedCentralPubMedCrossRef
32.
Dallas NA, Xia L, Fan F, Gray MJ, Gaur P, van Buren G 2nd, Samuel S, Kim MP, Lim SJ, Ellis LM (2009) Chemoresistant colorectal cancer cells, the cancer stem cell phenotype, and increased sensitivity to insulin-like growth factor-I receptor inhibition. Cancer Res 69:1951–1957PubMedCentralPubMedCrossRef
33.
Alpaugh ML, Tomlinson JS, Shao ZM, Barsky SH (1999) A novel human xenograft model of inflammatory breast cancer. Cancer Res 59:5079–5084PubMed
34.
Hirschhaeuser F, Menne H, Dittfeld C, West J, Mueller-Klieser W, Kunz-Schughart LA (2010) Multicellular tumor spheroids: an underestimated tool is catching up again. J Biotechnol 148:3–15PubMedCrossRef
35.
36.
Yamashita T, Ji J, Budhu A, Forgues M, Yang W, Wang HY, Jia H, Ye Q, Qin L, Wauthier E, Reid LM, Minato H, Honda M, Kaneko S, Tang ZY, Wang XW (2009) EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology 136:1012–1024PubMedCentralPubMedCrossRef
37.
Rutella S, Bonanno G, Marone M, De Ritis D, Mariotti A, Voso MT, Scambia G, Mancuso S, Leone G, Pierelli L (2003) Identification of a novel subpopulation of human cord blood CD34–CD133− CD7–CD45þ lineage-cells capable of lymphoid/NK cell differentiation after in vitro exposure to IL-15. J Immunol 171:2977–2988
38.
Floor S, van Staveren WC, Larsimont D, Dumont JE, Maenhaut C (2011) Cancer cells in epithelial-to-mesenchymal transition and tumor-propagating-cancer stem cells: distinct, overlapping or same populations. Oncogene 30:4609–4621PubMedCrossRef
39.
Suuronen EJ, Wong S, Kapila V, Waghray G, Whitman SC, Mesana TG, Ruel M (2006) Generation of CD133+ cells from CD133− peripheral blood mononuclear cells and their properties. Cardiovasc Res 70:126–135PubMedCrossRef
40.
Onda M, Beers R, Xiang L, Nagata S, Wang QC, Pastan I (2008) An immunotoxin with greatly reduced immunogenicity by identification and removal of B-cell epitopes. Proc Natl Acad Sci U S A 105(701):11311–11316PubMedCentralPubMedCrossRef
41.
Hassan R, Broaddus VC, Wilson S, Liewehr DJ, Zhang J (2007) Anti-mesothelin immunotoxin SS1P in combination with Gemcitabine results in increased activity against mesothelin-expressing tumor xenografts. Clin Cancer Res 13:7166–7171PubMedCrossRef
42.
Pearson JW, Sivam G, Manger R, Wiltrout RH, Morgan AC Jr, Longo DL (1989) Enhanced therapeutic efficacy of an immunotoxin in combination with chemotherapy against an intraperitoneal human tumor xenograft in athymic mice. Cancer Res 49:4990–4995PubMed
43.
Fujiwara S, Wada H, Miyata H, Kawada J, Kawabata R, Nishikawa H, Gnjatic S, Sedrak C, Sato E, Nakamura Y, Sakakibara M, Kanto T, Shimosegawa E, Hatazawa J, Takahashi T, Kurokawa Y, Yamasaki M, Nakajima K, Takiguchi S, Nakayama E, Mori M, Doki Y (2012) Clinical trial of the intratumoral administration of labeled DC combined with systemic chemotherapy for esophageal cancer. J Immunother 35(6):513–521PubMedCrossRef
Metadata
Title
A bispecific EpCAM/CD133-targeted toxin is effective against carcinoma
Authors
Nate N. Waldron
Sanford H. Barsky
Phillip R. Dougherty
Daniel A. Vallera
Publication date
01-09-2014
Publisher
Springer International Publishing
Published in
Targeted Oncology / Issue 3/2014
Print ISSN: 1776-2596
Electronic ISSN: 1776-260X
DOI
https://doi.org/10.1007/s11523-013-0290-9

Other articles of this Issue 3/2014

Targeted Oncology 3/2014 Go to the issue

Original Research

Anti-Sp17 monoclonal antibody–doxorubicin conjugates as molecularly targeted chemotherapy for ovarian carcinoma

Original Research

Pulmonary complications with the use of mTOR inhibitors in targeted cancer therapy: a systematic review and meta-analysis

Original Research

EGFR ligands as pharmacodynamic biomarkers in metastatic colorectal cancer patients treated with cetuximab and irinotecan

Original Research

In vitro induction of potent tumor-specific cytotoxic T lymphocytes using TLR agonist-activated AML-DC

Review

New agents in renal cell carcinoma

Original Research

Recombinant TIMP-1-GPI inhibits growth of fibrosarcoma and enhances tumor sensitivity to doxorubicin

2024 ASCO Annual Meeting Coverage

Highlights of the Day: Breast cancer – metastatic

Breast Cancer Video

In this session, Dr. Wolff provides his key takeaways from the data presented in the metastatic breast cancer oral abstract session at ASCO 2024.

Watch now

Highlights of the Day: Gynecologic cancer

Gynecologic Cancer Video

Highlights of the Day: Breast Cancer – local/regional/adjuvant

Breast Cancer Video

Neoadjuvant dual immunotherapy improves melanoma outcomes

04-06-2024 Melanoma News

» View more highlights on the ASCO 2024 congress hub page

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits