Eradication of tumors from a human colon cancer cell line and from ovarian cancer metastases in immunodeficient mice by a single-chain Ep-CAM-/CD3-bispecific antibody construct.
Bispecific T-cell engager (BiTE) are a class of bispecific single-chain antibodies that can very effectively redirect cytotoxic T cells for killing of tumor target cells. Here, we have assessed the in vivo efficacy of one representative, called bscEp-CAMxCD3, with specificity for tumors overexpressing epithelial cell adhesion molecule (Ep-CAM) in human xenograft models. Cells of the human colon carcinoma line SW480 were mixed at a 1:1 ratio with unstimulated human peripheral mononuclear cells, s.c. injected in nonobese diabetes/severe combined immunodeficiency (NOD/SCID) mice, and animals were treated with bscEp-CAMxCD3. Five daily i.v. injections of as little as 100 ng per mouse of bscEp-CAMxCD3 completely prevented tumor outgrowth when treatment was started at the day of tumor cell inoculation. BscEp-CAMxCD3 was also efficacious when administered up to 8 days after xenograft injection. Established tumors could be eradicated in all animals by five 10 microg doses given between days 8 and 12 after tumor cell inoculation. To test the efficacy of bscEp-CAMxCD3 in a more physiologic model, pieces of primary metastatic tumor tissue from ovarian cancer patients were implanted in NOD/SCID mice. Partial tumor engraftment and growth was observed with four of six patient samples. Treatment of established tumors with daily 5 microg doses led to a significant reduction and, in some cases, eradication of human tumor tissue. These effects obviously relied on the tumor-resident T cells reactivated by bscEp-CAMxCD3. Our data show that the class of single-chain bispecific antibodies has very high antitumor efficacy in vivo and can use previously unstimulated T cells at low effector-to-target ratios.
Schlereth
Bernd
B
Micromet AG, Munich, Germany.
Fichtner
Iduna
I
Lorenczewski
Grit
G
Kleindienst
Petra
P
Brischwein
Klaus
K
da Silva
Antonio
A
Kufer
Peter
P
Lutterbuese
Ralf
R
Junghahn
Ilse
I
Kasimir-Bauer
Sabine
S
Wimberger
Pauline
P
Kimmig
Rainer
R
Baeuerle
Patrick A
PA
D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology*; D000918:Antibody Specificity; D000951:Antigens, Neoplasm / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000276:immunology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000276:immunology / Q000628:therapy*; D000071858:Epithelial Cell Adhesion Molecule; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010051:Ovarian Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D010534:Peritoneal Neoplasms / Q000276:immunology / Q000556:secondary* / Q000628:therapy*; D023041:Xenograft Model Antitumor Assays
D018033:Antibodies, Bispecific; D000951:Antigens, Neoplasm; D017252:CD3 Complex; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule