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 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Current Oncology Reports
Published in: Current Oncology Reports 8/2015

01-08-2015 | Evolving Therapies (R Bukowski, Section Editor)

Adnectin-Targeted Inhibitors: Rationale and Results

Authors: Esha Sachdev, Jun Gong, Bobbie Rimel, Monica Mita

Published in: Current Oncology Reports | Issue 8/2015

Login to get access

Abstract

Adnectins are a family of binding proteins derived from the 10th type III domain of human fibronectin (10Fn3), which is part of the immunoglobulin superfamily and normally binds integrin. The 10Fn3 has the potential for broad therapeutic applications given its structural stability, ability to be manipulated, and its abundance in the human body. The most commonly studied adnectin is CT-322, which is an inhibitor of vascular endothelial growth factor receptor-2. A bispecific adnectin, El-Tandem, has also been developed and binds to epidermal growth factor receptor and insulin-like growth factor-1 receptor simultaneously. Pre-clinical studies have shown promising results in relation to reducing tumor growth, decreasing microvessel density, and promoting normalization of tumor architecture. The phase I trial with CT-322 demonstrates relatively low toxicities. However, the phase II study done with CT-322 in recurrent glioblastoma does not reveal as promising results.
Literature
1.
Lipovsek D. Adnectins: engineered target-binding protein therapeutics. Protein Eng Des Sel PEDS. 2011;24:3–9.PubMedCrossRef
2.
Ramamurthy V, Krystek Jr SR, Bush A, Wei A, Emanuel SL, Das Gupta R, et al. Structures of adnectin/protein complexes reveal an expanded binding footprint. Structure. 2012;20:259–69.PubMedCrossRef
3.•
Mamluk R, Carvajal IM, Morse BA, Wong H, Abramowitz J, Aslanian S, et al. Anti-tumor effect of CT-322 as an adnectin inhibitor of vascular endothelial growth factor receptor-2. mAbs. 2010;2:199–208. This is one of the earlier papers summarizing the development of CT-322 and its function as a VEGFR-2 inhibitor. Also shows promising results of CT-322 for tumor reduction in orthotopic breast carcinoma in athymic mice and a COLO-205 xenograft model.PubMedCentralPubMedCrossRef
4.
Iacob RE, Chen G, Ahn J, Houel S, Wei H, Mo J, et al. The influence of adnectin binding on the extracellular domain of epidermal growth factor receptor. J Am Soc Mass Spectrom. 2014;25:2093–102.PubMedCrossRef
5.•
Waters JD, Sanchez C, Sahin A, Futalan D, Gonda DD, Scheer JK, et al. CT322, a VEGFR-2 antagonist, demonstrates anti-glioma efficacy in orthotopic brain tumor model as a single agent or in combination with temozolomide and radiation therapy. J Neuro-Oncol. 2012;110:37–48. This was a preclinical model to observe the efficacy of CT-322 in glioblastoma as single agent or with standard therapy. This study demonstrated promising results, especially when used in combination with temozolomide and radiation therapy. Demonstrated decreased CD31 staining when treated with CT-322, which indicates angiogenesis inhibition.CrossRef
6.•
Emanuel SL, Engle LJ, Chao G, Zhu RR, Cao C, Lin Z, et al. A fibronectin scaffold approach to bispecific inhibitors of epidermal growth factor receptor and insulin-like growth factor-I receptor. mAbs. 2011;3:38–48. This paper summarized the development and efficacy of El-Tandem Adnectin, which is a bispecific adnectin that binds to EGFR and IGF-1R simultaneously. El Tandem binds with greater affinity to both receptors than other adnectins that bind to either alone.PubMedCentralPubMedCrossRef
7.
Dineen SP, Sullivan LA, Beck AW, Miller AF, Carbon JG, Mamluk R, et al. The adnectin CT-322 is a novel VEGF receptor 2 inhibitor that decreases tumor burden in an orthotopic mouse model of pancreatic cancer. BMC Cancer. 2008;8:352.PubMedCentralPubMedCrossRef
8.
Ackermann M, Carvajal IM, Morse BA, Moreta M, O'Neil S, Kossodo S, et al. Adnectin CT-322 inhibits tumor growth and affects microvascular architecture and function in COLO205 tumor xenografts. Int J Oncol. 2011;38:71–80.PubMed
9.
Ackermann M, Morse BA, Delventhal V, Carvajal IM, Konerding MA. Anti-VEGFR2 and anti-IGF-1R-adnectins inhibit Ewing’s sarcoma A673-xenograft growth and normalize tumor vascular architecture. Angiogenesis. 2012;15:685–95.PubMedCrossRef
10.••
Tolcher AW, Sweeney CJ, Papadopoulos K, Patnaik A, Chiorean EG, Mita AC, et al. Phase I and pharmacokinetic study of CT-322 (BMS-844203), a targeted adnectin inhibitor of VEGFR-2 based on a domain of human fibronectin. Clin Cancer Res Off J Am Assoc Cancer Res. 2011;17:363–71. This is the only phase I trial involving adnectins that has been published. It demonstrates what the maximum tolerated dose is as well as the more common adverse effects of CT-322. The results from this trial demonstrate that CT-322 is well tolerated and secondarily demonstrate promising results regarding tumor regression.CrossRef
11.••
Schiff D, Kesari S, de Groot J, Mikkelsen T, Drappatz J, Coyle T, et al. Phase 2 study of CT-322, a targeted biologic inhibitor of VEGFR-2 based on a domain of human fibronectin, in recurrent glioblastoma. Investig New Drugs. 2015;33:247–53. This is the only phase II trial published involving adnectins, specifically CT-322. This study was also just published win 2015. From this study, the null hypothesis could not be rejected since adequate enrollment was not achieved and so CT-322 was said to be ineffective for the treatment of recurrent glioblastoma.CrossRef
12.
Ranpura V, Pulipati B, Chu D, Zhu X, Wu S. Increased risk of high-grade hypertension with bevacizumab in cancer patients: a meta-analysis. Am J Hypertens. 2010;23:460–8.PubMedCrossRef
13.
14.
15.
Wu S, Kim C, Baer L, Zhu X. Bevacizumab increases risk for severe proteinuria in cancer patients. J Am Soc Nephrol JASN. 2010;21:1381–9.PubMedCrossRef
16.
Chinot OL, de La Motte RT, Moore N, Zeaiter A, Das A, Phillips H, et al. AVAglio: phase 3 trial of bevacizumab plus temozolomide and radiotherapy in newly diagnosed glioblastoma multiforme. Adv Ther. 2011;28:334–40.PubMedCrossRef
17.
Eskens FA, Verweij J. The clinical toxicity profile of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors; a review. Eur J Cancer. 2006;42:3127–39.PubMedCrossRef
18.
Higa GM, Abraham J. Biological mechanisms of bevacizumab-associated adverse events. Expert Rev Anticancer Ther. 2009;9:999–1007.PubMedCrossRef
19.
Liu JF, Barry WT, Birrer M, Lee JM, Buckanovich RJ, Fleming GF, et al. Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study. Lancet Oncol. 2014;15:1207–14.PubMedCrossRef
Metadata
Title
Adnectin-Targeted Inhibitors: Rationale and Results
Authors
Esha Sachdev
Jun Gong
Bobbie Rimel
Monica Mita
Publication date
01-08-2015
Publisher
Springer US
Published in
Current Oncology Reports / Issue 8/2015
Print ISSN: 1523-3790
Electronic ISSN: 1534-6269
DOI
https://doi.org/10.1007/s11912-015-0459-8

Other articles of this Issue 8/2015

Current Oncology Reports 8/2015 Go to the issue

Sarcomas (SR Patel, Section Editor)

Cytoreductive Surgery Followed by Hyperthermic Intraperitoneal Chemotherapy in DSRCT: Progress and Pitfalls

Lung Cancer (T Mekhail, Section Editor)

The Role of Radiotherapy in Small Cell Lung Cancer: a Revisit

Lymphomas (PA Hamlin, Section Editor)

Novel Agents in Mantle Cell Lymphoma

Sarcomas (SR Patel, Section Editor)

Contemporary Management of Retroperitoneal Soft Tissue Sarcomas

Gynecologic Cancers (NS Reed, Section Editor)

When Is It Safe to Omit Surgery in Primary Peritoneal Cancer With Small Volume Disease?
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