Selection of monoclonal antibody E48 IgG or U36 IgG for adjuvant radioimmunotherapy in head and neck cancer patients

Abstract

Summary Preliminary data from recent clinical radioimmunoscintigraphy studies indicate that 99mTc-labelled murine monoclonal antibodies (MAbs) E48 and U36 have a similar ability to target squamous cell carcinoma of the head and neck (HNSCC) selectively. In the present study we describe additional aspects of murine and chimeric MAb (mMAb and cMAb) E48 and U36, which might influence the selection of one MAb for adjuvant radioimmunotherapy. To make direct comparison possible, ten patients received 11.2 ± 0.3 and 11.1 ± 0.2 mg (n = 5) or 51.1 ± 0.1 and 51.0 ± 0.4 mg (n= 5) of both mE48 IgG and mU36 IgG labelled with 1311 and 1251 simultaneously and underwent surgery 7-8 days after injection. The mean uptake of iodine-labelled mE48 IgG and mU36 was highest in tumour tissue, 8.9 ± 8.9 and 8.2 ± 4.4 %ID kg-' respectively. Tumour to non-tumour ratios for oral mucosa, skin, muscle, blood and bone marrow aspirate were 2.5, 5.5, 25.2, 4.7 and 4.0 respectively in the case of mE48 IgG and 2.3, 4.1, 21.0, 5.8 and 5.8 respectively in the case of mU36 IgG. The distribution of mMAbs E48 and U36 throughout tumours that had been collected in previous studies was heterogeneous when administered at a dose of 1 or 12 mg, and homogeneous when administered at a dose of 52 mg. Administration of mE48 IgG (1-52 mg) resulted in a human anti-mouse antibody response in 12 out of 28 patients, while for mU36 IgG (1-52 mg), this figure was three out of 18 patients. cMAb E48 was shown to be highly effective in mediating antibody-dependent cellular cytotoxicity in vitro, while cMAb U36 and mMAbs E48 and U36 were not effective at all. Rationales are provided that give priority to the start of adjuvant radioimmunotherapy trials with 1'6Re-labelled cMAb U36 IgG in head and neck cancer patients who are at high risk for the development of locoregional recurrences and distant metastases.Keywords: monoclonal antibodies; head and neck cancer; squamous cell carcinoma; biodistribution; human anti-mouse antibody response; antibody-dependent cellular cytotoxicityDuring 1996 approximately 41 090 Americans will develop head and neck cancer and 12 510 will die from it. Worldwide more than 500 000 new cases are projected annually, and the incidence is rising. In head and neck cancer, squamous cell carcinoma accounts for approximately 90% of all tumours (Parker et al, 1996). About one-third of these patients present with early-stage (I and II) head and neck squamous cell carcinoma (HNSCC), while two-thirds present with advanced disease (stage III and IV) (Vernham and Crowther, 1994). Although early-stage HNSCC can, in the great majority of cases, be cured with surgery or radiotherapy alone, the local failure rate after surgery and/or radiotherapy in advanced stages is more than 50%. Moreover, about 25% of these patients develop distant metastases (Stupp et al, 1994).Despite an increase in the locoregional control of HNSCC, owing to improved surgery and radiotherapy, current therapy regimens have failed to increase the 5-year survival rate in HNSCC patients (Pa...

Performance of Immuno–Positron Emission Tomography with Zirconium-89-Labeled Chimeric Monoclonal Antibody U36 in the Detection of Lymph Node Metastases in Head and Neck Cancer Patients

“…False-negative observations in the present study were mostly due to the presence of small metastatic lymph nodes with minimal tumor involvement (Table 5), whether or not such small tumors are efficiently targeted by mAb U36, as previously shown in a biodistribution study with mmAb U36 (19).…”

“…In clinical radioimmunoscintigraphy and radioimmunotherapy studies done at our institute, the potential of the CD44v6-specific murine mAb (mmAb) U36 for these purposes has been shown. Radioimmunoscintigraphy with technetium99m ( 99m Tc)-labeled mmAb U36 IgG was found to be as reliable as the radiological imaging techniques computed tomography (CT) and magnetic resonance imaging (MRI) for the detection of lymph node metastases in patients with head and neck squamous cell carcinoma (HNSCC), but the detection of tumor deposits smaller than 1 cm seemed to be a problem despite the proven accumulation of the mAb in these tumors (3). Subsequently, chimeric mAb (cmAb) U36 was tested in clinical phase I dose escalation radioimmunotherapy trials (4,5).…”

A Phase I Dose Escalation Study with Anti-CD44v6 Bivatuzumab Mertansine in Patients with Incurable Squamous Cell Carcinoma of the Head and Neck or Esophagus

“…For this purpose, the chimeric mAb U36 (cmAb U36) and the humanized mAb BIWA 4 (bivatuzumab), both directed against CD44v6, have been evaluated (9,10). Although not a primary objective, phase I dose escalation radioimmunotherapy studies with 186 Re-labeled cmAb U36 and 186 Re-labeled bivatuzumab showed promising antitumor effects with consistent stable disease at higher radioactivity dose levels (11 -13).…”

The GPI-linked Ly-6 Antigen E48 Regulates Expression Levels of the FX Enzyme and of E-selectin Ligands on Head and Neck Squamous Carcinoma Cells

“…Rolling adhesions were persistent at 1 dyn/cm 2 but weaker than those of neutrophils because 10-fold elevation of the shear stress enhanced the detachment of these cells but not of PMN from the E-selectin coated substrate (data not shown). Nevertheless, the majority of E48 cDNA-transfected 14C-CMV16 cells that accumulated on E-selectin at low flow remained adherent and continued to roll on the selectin at medium shear stress range of 5 dyn/cm 2 (Fig. 9A).…”

“…The mAb E48 recognizes an outer membrane antigen that was expressed by the majority of HNSCC. The biodistribution of the E48 mAb in HNSCC patients as well as preclinical anti-E48-based therapy experiments showed that radioimmunotherapy using this antibody as a targeting vehicle was a feasible approach for the eradication of small tumor deposits (2,3). In view of its potential importance, the mAb E48 defined antigen was characterized by cDNA cloning (4).…”