A novel approach for targeted elimination of CSPG4-positive triple-negative breast cancer cells using a MAP tau-based fusion protein

作者：Amoury M****; Mladenov Radoslav; Nachreiner Thomas; Anh Tuan Pham; Hristodorov Dmitrij; Di Fiore Stefano; Helfrich Wijnand; Pardo Alessa; Fey Georg; Schwenkert Michael; Thepen Theophilus; Kiessling Fabian; Hussain Ahmad F; Fischer Rainer; Kolberg Katharina; Barth Stefan^*

来源：International Journal of Cancer, 2016, 139(4): 916-927.

DOI：10.1002/ijc.30119

• medical biotechnology
• human cytolytic fusion protein
• immunotherapy
• microtubule-associated protein tau
• triple negative breast cancer

Chondroitin sulfate proteoglycan 4 (CSPG4) has been identified as a highly promising target antigen for immunotherapy of triple-negative breast cancer (TNBC). TNBC represents a highly aggressive heterogeneous group of tumors lacking expression of estrogen, progesterone and human epidermal growth factor receptor 2. TNBC is particularly prevalent among young premenopausal women. No suitable targeted therapies are currently available and therefore, novel agents for the targeted elimination of TNBC are urgently needed. Here, we present a novel cytolytic fusion protein (CFP), designated alpha CSPG4(scFv)-MAP, that consists of a high affinity CSPG4-specific single-chain antibody fragment (scFv) genetically fused to a functionally enhanced form of the human microtubule-associated protein (MAP) tau. Our data indicate that alpha CSPG4(scFv)-MAP efficiently targets CSPG4(+) TNBC-derived cell lines MDA-MB-231 and Hs 578T and potently inhibits their growth with IC50 values of similar to 200 nM. Treatment with alpha CSPG(scFv)-MAP resulted in induction of the mitochondrial stress pathway by activation of caspase-9 as well as endonuclease G translocation to the nucleus, while induction of the caspase-3 apoptosis pathway was not detectable. Importantly, in vivo studies in mice bearing human breast cancer xenografts revealed efficient targeting to and accumulation of alpha CSPG4(scFv)-MAP at tumor sites resulting in prominent tumor regression. Taken together, this preclinical proof of concept study confirms the potential clinical value of alpha CSPG4(scFv)-MAP as a novel targeted approach for the elimination of CSPG4-positive TNBC.

• 出版日期2016-8-15
• 单位RWTH Aachen