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Efficient targeting of CD13 on cancer cells by the immunotoxin scFv13-ETA ' and the bispecific scFv [13xds16]

: Grieger, E.; Gresch, G.; Niesen, J.; Woitok, M.; Barth, S.; Fischer, R.; Fendel, R.; Stein, C.


Journal of cancer research and clinical oncology 143 (2017), Nr.11, S.2159-2170
ISSN: 0171-5216 (Print)
ISSN: 0084-5353
ISSN: 0943-9382
ISSN: 1432-1335 (Online)
Fraunhofer IME ()

Treatment of cancer using standard chemotherapy still offers a poor prognosis combined with severe side effects. Novel antibody-based therapies have been shown to overcome low efficiency and lack of selectivity by targeting cancer-associated antigens, such as aminopeptidase CD13. We isolated a high-affinity CD13-specific single-chain fragment variable (scFv13) from a phage display library of V-genes from mice immunized with soluble antigen. An immunotoxin comprising the scFv13 and a truncated version of the exotoxin A of Pseudomonas aeruginosa (ETA', scFv13-ETA') and a bispecific scFv targeting CD13 and CD16 simultaneously (bsscFv[13xds16]) was generated and investigated for their therapeutic potential. Both fusion proteins bound specifically to target cells with high affinity. Furthermore, scFv13-ETA' inhibited the proliferation of human cancer cell lines efficiently at low concentrations (IC50 values of 408 pM-7 nM) and induced apoptosis (40-85% of target cells). The bsscFv triggered dose-dependent antibody-dependent cell-mediated cytotoxicity, resulting in the lysis of up to 23.9% A2058 cells, 18.0% MDA-MB-468 cells and 19.1% HL-60 cells. The provided data demonstrate potent therapeutic activity of the scFv13-ETA' and the bsscFv[13xds16]. The CD13-specific scFv is therefore suitable for the direct and specific delivery of both cytotoxic agents and effector cells to cancer-derived cells, making it ideal for further therapeutic evaluation.