Chimeric bispecific OC/TR monoclonal antibody mediates lysis of tumor cells expressing the folate-binding protein (MOv18) and displays decreased immunogenicity in patients.
The bispecific OC/TR monoclonal antibody (mAb) cross-links the CD3 molecule on T cells with the human folate-binding protein (FBP), which is highly expressed on nonmucinous ovarian carcinomas. Clinical trials of patients with ovarian carcinoma with the OC/TR mAb have shown some complete and partial responses. Most patients developed human anti-murine immunoglobulin antibodies (HAMA), which can inhibit OC/TR mAb-mediated lysis. We generated a chimeric version of the OC/TR mAb to decrease the immunogenicity of the OC/TR mAb and to allow more extended treatment schedules. Sp2/0 myeloma cells were transfected with chimeric heavy- and light-chain genes encoding the anti-CD3 mAb and the MOv18 mAb, respectively, which are reactive with FBP. The resulting cell line produced 80 micrograms/ml of total immunoglobulin G (IgG), of which 11.5% was the functionally active chimeric OC/TR mAb. Chimeric OC/TR F(ab')2 fragments mediated lysis of IGROV-1 ovarian carcinoma cells by human T cells at antibody concentrations of > or = 1 pg/ml. Specific lysis was still detectable at an effector-to-target cell ratio as low as 0.4. Two patients with ovarian carcinoma treated with F(ab')2 fragments of the murine OC/TR developed distinct HAMA titers, which were mainly anti-idiotypic and only partly directed against the murine antibody constant regions. However, of the two patients that were treated with the F(ab')2 fragments of the chimeric OC/TR mAb, only one developed a low transient HAMA response just above background level. In conclusion, the generation of chimeric OC/TR may allow more extended clinical studies of bispecific mAb-mediated immunotherapy of ovarian carcinoma.
Luiten
R M
RM
Department of Pathology, University of Leiden, The Netherlands.
Warnaar
S O
SO
Sanborn
D
D
Lamers
C H
CH
Bolhuis
R L
RL
Litvinov
S V
SV
Zurawski
V R
VR
Coney
L R
LR
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000097:blood; D018033:Antibodies, Bispecific / Q000235:genetics / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology; D002352:Carrier Proteins / Q000032:analysis*; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D015870:Gene Expression; D006801:Humans; D006825:Hybridomas; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D007167:Immunotherapy; D051379:Mice; D010051:Ovarian Neoplasms / Q000276:immunology*; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; D013601:T-Lymphocytes / Q000276:immunology; D014162:Transfection
D000888:Antibodies, Anti-Idiotypic; D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D007140:Immunoglobulin Fab Fragments; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins