TARGETING OF TUMORS WITH MURINE AND RESHAPED HUMAN MONOCLONAL-ANTIBODIES AGAINST PLACENTAL ALKALINE-PHOSPHATASE - IMMUNOLOCALIZATION, PHARMACOKINETICS AND IMMUNE-RESPONSE

Anti-tumour monoclonal murine and humanised (reshaped human) antibodies (H17E2 and Hu2PLAP, respectively) against placental alkaline phosphatase (FLAP), radioactively labelled with indium-lll (In-111) and iodine-123 (I-123), were evaluated for their ability to localise mainly testicular and ovarian tumours in sequential pilot studies of the Hammersmith Oncology Group. 33 patients with active primary and/or metastatic testicular cancer were studied with the [In-111]- or [I-123]H17E2 antibody. 8 patients with testicular cancer were studied with the same antibody after being rendered free of disease after induction chemotherapy and surgical resection of residual tumour. 3 additional patients, 2 with ovarian cancer and 1 with testicular seminoma, were studied with [In-111]H17E2 via a macrocyclic chelating agent (DOTA). 7 patients; 5 with ovarian cancer, 1 with breast cancer, and 1 with gastric cancer, received the reshaped human Hu2PLAP antibody [In-111]DOTA labelled. One of these was imaged twice, with H17E2- and Hu2PLAP-DOTA-In-111, respectively. In the initial 33 patients with active primary and/or metastatic testicular cancer, the presence of tumour was confirmed and correlated well with conventional radiological diagnostic methods, and in addition, the antibody scan revealed the presence of active disease in 2 patients with negative conventional imaging, but elevated serum tumour markers. In the 8 patients with complete remission (CR), imaging studies with the radiolabelled antibody did not show any localisation. The best images were obtained at 24 and 48 h after the [I-123]- and [In-111]H17E2, respectively. None of these patients developed human anti-mouse antibody responses (HAMA). Successful imaging with the reshaped human antibody, Hu2PLAP-DOTA-In-111, was seen in 3 patients with FLAP-positive tumours (2 ovarian and 1 gastric cancer). The 3 negative patients were 1 in complete remission, 1 with FLAP-negative tumour and 1 who cleared the Hu2PLAP antibody immediately after infusion due to the presence of anti-chelating agent (anti-DOTA) antibodies from a previous H17E2-DOTA-In-111 scan. One patient with FLAP-negative breast carcinoma had a false-positive scan with Hu2PLAP, showing localisation to the pleural effusion. Antibody pharmacokinetics showed a mean t(1/2)beta = 73.1 +/- 30.2 h (n = 5) for Hu2PLAP versus t(1/2)beta = 27.2 +/- 5.9 h (n = 3) for H17E2 (P < 0.05). 2 patients receiving Hu2PLAP were excluded due to the rapid clearance of the radiolabel as a result of the presence of high HAMA and anti-chelate antibody levels, respectively. At 96 h, the mean cumulative urine excretion of In-111 was 11 +/- 8% for Hu2PLAP versus 14 +/- 5% for H17E2. HAMA developed in 1 patient undergoing sequential imaging with both antibodies, and in another who already had HAMA after intraperitoneal monoclonal antibody therapy for ovarian cancer. Antibodies to the chelating agent developed in 3 patients. In conclusion, immunolocalisation of FLAP-positive tumours is feasible with both murine and reshaped human monoclonal antibodies. The sensitivity and specificity of the method appear to be very high in this pilot study, and, in view of the absence of toxicity, the diagnostic contribution of this approach should be evaluated prospectively.