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Molecular Immunology 43 (8): 1129-1143 (2006-03)

Brischwein K.; Schlereth B.; Guller B.; Steiger C.; Wolf A.; Lutterbuese R.; Offner S.; Locher M.; Urbig T.; Raum T.; Kleindienst P.; Wimberger P.; Kimmig R.; Fichtner I.; Kufer P.; Hofmeister R.; da Silva A.J.; Baeuerle P.A.

MT110: A novel bispecific single-chain antibody construct with high efficacy in eradicating established tumors

Description:
We have developed a novel single-chain Ep-CAM-/CD3-bispecific single-chain antibody construct designated MT110. MT110 redirected unstimulated human peripheral T cells to induce the specific lysis of every Ep-CAM-expressing tumor cell line tested. MT110 induced a costimulation independent polyclonal activation of CD4- and CD8-positive T cells as seen by de novo expression of CD69 and CD25, and secretion of interferon gamma, tumor necrosis factor alpha, and interleukins 2, 4 and 10. CD8-positive T cells made the major contribution to redirected tumor cell lysis by MT110. With a delay, CD4-positive cells could also contribute presumably as consequence of a dramatic upregulation of granzyme B expression. MT110 was highly efficacious in a NOD/SCID mouse model with subcutaneously growing SW480 human colon cancer cells. Five daily doses of 1 μg MT110 on days 0–4 completely prevented tumor outgrowth in all mice treated. The bispecific antibody construct also led to a durable eradication of established tumors in all mice treated with 1 μg doses of MT110 on days 8–12 after tumor inoculation. Finally, MT110 could eradicate patient-derived metastatic ovarian cancer tissue growing under the skin of NOD/SCID mice. MT110 appears as an attractive bispecific antibody candidate for treatment of human Ep-CAM-overexpressing carcinomas.

Keywords: Ep-CAM, CD3, BiTE, Single-chain antibody, Xenograft model, Tumor, Animals, Mice

Type: Article

PubMed: 16139892
Official URL: https://doi.org/10.1016/j.molimm.2005.07.034
MDC Repository: https://edoc.mdc-berlin.de/8017/