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CLEC 14A antibody
Cancer Research Horizons
Antibody Conjugated
Oncology
Hit To Lead or Lead Optimization
Abstract
Tumour endothelial markers (TEMs) that are highly expressed in human tumour vasculature compared with vasculature in normal tissue hold clear therapeutic potential. C-type lectin CLEC14A is a novel TEM, a transmembrane protein that is specifically expressed on the surface of tumour endothelial cells and is absent or expressed at a low level on healthy tissues and on non-tumour diseased tissues that often co-occur with cancer. Extensive immunohistochemical data demonstrates that CLEC14A is strongly and specifically overexpressed on the tumour vasculature in a wide range of tumours tested, in contrast to vessels of the corresponding normal tissues.
CLEC14A-targeted treatments are expected to be more efficacious than other vasculature targeting agents (e.g. Avastin), as they act as vasculature disrupting agents on existing and newly formed blood vessels, eradicating tumour vasculature that expresses the protein. The distinction from angiogenesis targeting agents such as Avastin is that CLEC14A-targeting agents block neo-angiogenesis by inhibiting VEGF-A, but they do not eradicate established tumour vasculature. Researchers at the University of Birmingham have now developed antibody-drug conjugates that cause endothelial cell cytotoxicity in vitro, disrupting established tumour vasculature and decreasing tumour burden in mice with Lewis lung carcinoma. These antibody-drug conjugates targeting CLEC14A represent promising potential therapies for solid tumours.
CLEC14A ADCs
• CLEC14A is a C-type lectin transmembrane protein expressed on the surface of tumour endothelial cells but not on normal cells.
• Five antibodies selectively targeting CLEC14A have been generated. Two of them (CRT3 (C3) and CRT4 (C4)) were developed as antibody drug conjugates (ADCs) linked to SG3249, a pyrrolobenzodiazepine dimer-based DNA crosslinking agent.
• Whilst angiogenesis-targeting agents block tumour neo-angiogenesis, ADCs against CLEC14A disrupt already established tumour vasculature.
• CLEC14A ADCs show in vitro cytotoxicity in endothelial cells, and a reduced tumour vascularisation in a murine model of Lewis lung carcinoma, correlating with reduced tumour burden.
• This work was developed in the lab of Professor Roy Bicknell at the Institute of Cardiovascular Sciences, University of Birmingham, and is protected by three granted or pending patents.
• A commercial partner for collaboration and/or licensing, to enable further clinical validation and commercialisation of the CLEC14A ADC programs.
Roy Bicknell, Peter Noy, Kabir Ali Khan
• US 9255148 B2 (2016.02.09)
Patent Family: US, EP, JP, CA, AU, HU
• US 10808031 B2 (2020.10.20)
Patent Family: US, EP, JP, CA, AU
• US 11566075 B2 (2023.01.31)
Patent Family: US, EP, JP, CN, CA, AU
• "CAR T cells targeting tumor endothelial marker CLEC14A inhibit tumor growth". Zhuang, X. et al. JCI Insight. 2020;5(19). https://doi.org/10.1172/jci.insight.138808
• "An evaluation of the tumour endothelial marker CLEC14A as a therapeutic target in solid tumours". Robinson, J. A. et al. The Journal of Pathology. 2020;6(4), 308–319. https://doi.org/10.1002/cjp2.176
• "Identification and angiogenic role of the novel tumor endothelial marker CLEC14A". Mura, M. et al. Oncogene. 2011;31(3), 293–305. https://doi.org/10.1038/onc.2011.233
