For Manuscript Submission, Check or Review Login please go to Submission Websites List.
For the academic login, please select your country in the dropdown list. You will be redirected to verify your credentials.
Targeting of Human Breast Cancer by a Bispecific Antibody Directed against Two Tumour-Associated Antigens: ErbB-2 and Carcinoembryonic AntigenDorvillius M.a · Garambois V.a · Pourquier D.b · Gutowski M.c · Rouanet P.c · Mani J.-C.d · Pugnière M.d · Hynes N.E.e · Pèlegrin A.a
aEMI 0227 INSERM and GDR CNRS 2352, Université Montpellier I, Cancer Research Centre, Departments of bPathology, Cancer Institute Val d’Aurelle-Paul Lamarque, cOncologic and Reconstructive Surgery, and dCentre National de la Recherche Scientifique, Unité Mixte de Recherche 5094, Faculty of Pharmacy, Montpellier, France; eFriedrich Miescher Institute, Basel, Switzerland
Carcinoembryonic antigen (CEA) and ErbB-2 are expressed in about 50 and 30% of breast cancers, respectively. We hypothesised that targeting of these two antigens by a bispecific antibody (BAb) might provide efficient tumour uptake and prolonged tumour residence time. In the present study, we first studied the expression of CEA and ErbB-2 on primary breast tumours screened by immunohistochemistry. Of 106 primary breast cancers, 69 (65%) were positive for CEA, 20 (19%) were positive for ErbB-2, and 13 (12%) expressed both antigens. We then prepared and evaluated a BAb directed against CEA and ErbB-2. Using BIACORE technology, we showed that the BAb recognised both CEA and ErbB-2 with affinities of 0.9 × 10 and 0.8 × 10 M–1, respectively. In vivo, BAb tumour localisation was compared with that of its parental homodimeric F(ab′)2-ortho-phenylene- dimaleimide (PDM) fragments. Uptake of 125I-BAb was lower than that of 131I-35A7F(ab′)2-PDM in LS174T tumours, used as a model of CEA expressing tumours, and was similar to that of 131I-FWP51 F(ab′)2-PDM in SKOv3 tumours, used as a model of ErbB-2 expressing tumours. In a double-positive model, the SKOv3-CEA-1B9 tumour, BAb showed a similar uptake to that of 35A7 F(ab′)2-PDM and we demonstrated that, although BAb had double specificity, it internalised as a homodimeric anti-ErbB-2 antibody. BAb showed a greater uptake than that of FWP51 F(ab′)2-PDM and this difference was even more important 72 h after injection with an uptake of 7.3 ± 2.1 vs. 1.4 ± 0.5% of the injected dose per gram of tissue. The results obtained with the BAb in the double-positive tumour-bearing nude mice suggest that targeting two distinct tumour-associated antigens on the same cell could improve tumour localisation.
© 2002 S. Karger AG, Basel