title: Targeting of tumours with murine and reshaped human monoclonal antibodies against placental alkaline phosphatase: immunolocalisation, pharmacokinetics and immune response.
abstract: Anti-tumour monoclonal murine and humanised (reshaped human) antibodies (H17E2 and Hu2PLAP, respectively) against placental alkaline phosphatase (PLAP), radioactively labelled with indium-111 (111In) and iodine-123 (123I), 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 [111In]- or [123I]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 [111In]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 [111In]DOTA labelled. One of these was imaged twice, with H17E2- and Hu2PLAP-DOTA-111In, 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 [123I]- and [111In]H17E2, respectively. None of these patients developed human anti-mouse antibody responses (HAMA). Successful imaging with the reshaped human antibody, Hu2PLAP-DOTA-111In, was seen in 3 patients with PLAP-positive tumours (2 ovarian and 1 gastric cancer). The 3 negative patients were 1 in complete remission, 1 with PLAP-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-111In scan. One patient with PLAP-negative breast carcinoma had a false-positive scan with Hu2PLAP, showing localisation to the pleural effusion. Antibody pharmacokinetics showed a mean t1/2 beta = 73.1 +/- 30.2 h (n = 5) for Hu2PLAP versus t1/2 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.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Department of Clinical Oncology, Royal Postgraduate Medical School, Hammersmith Hospital, London, U.K.
authors.forename: H P
authors.initials: HP
authors.lastname: Kalofonos
authors.forename: C
authors.initials: C
authors.lastname: Kosmas
authors.forename: V
authors.initials: V
authors.lastname: Hird
authors.forename: D E
authors.initials: DE
authors.lastname: Snook
authors.forename: A A
authors.initials: AA
authors.lastname: Epenetos
mesh_terms: D000328:Adult; D000368:Aged; D000469:Alkaline Phosphatase / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000917:Antibody Formation; D005260:Female; D058851:GPI-Linked Proteins; D006801:Humans; D007124:Immunoenzyme Techniques; D007205:Indium Radioisotopes; D007457:Iodine Radioisotopes; D007527:Isoenzymes / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009373:Neoplasms, Germ Cell and Embryonal / Q000000981:diagnostic imaging* / Q000201:enzymology; D016719:Radioimmunodetection / Q000379:methods*; D013045:Species Specificity
chemical_list: D000911:Antibodies, Monoclonal; D058851:GPI-Linked Proteins; C106201:H17E2 monoclonal antibody; D007205:Indium Radioisotopes; D007457:Iodine Radioisotopes; D007527:Isoenzymes; D000469:Alkaline Phosphatase; C019839:alkaline phosphatase, placental