Superior localisation and imaging of radiolabelled monoclonal antibody E48 F(ab')2 fragment in xenografts of human squamous cell carcinoma of the head and neck and of the vulva as compared to monoclonal antibody E48 IgG

Abstract

Monoclonal antibody (MAb) E48 and its F(ab')2 fragment, radiolabelled with 131I, were tested for tumour localisation and imaging in nude mice bearing a squamous cell carcinoma xenograft line derived from a head and neck carcinoma (HNX-HN) or from a vulva carcinoma (VX-A431). MAb IgG or F(ab')2 fragments were injected in parallel and at day 1, 2, 3 and 6 or 7, mice were either scanned with a gamma camera or dissected for determination of isotope biodistribution. In HNX-HN bearing mice, E48 IgG as well as F(ab')2 showed highly specific localisation in tumour tissue. The mean tumour uptake (n = 4) expressed as the percentage of the injected dose per gram of tumour tissue (percentage ID/g) of IgG was 11.9% at day 1 and increased to 14.6% at day 6 whereas percentage ID/g of F(ab')2 was 7.2% at day 1 and decreased during subsequent days. Tumour to blood ratios (T/B) at day 1 were 1.2 for IgG and 13.6 for F(ab')2 and reached a maximum at day 6 with values of 6.4 and 54.2 respectively. In VX-A431 bearing mice, only E48 F(ab')2 showed preferential localisation in tumour tissue. At day 1, Percentage ID/g of IgG was 3.7 and T/B was 0.3, while percentage ID/g of F(ab')2 was 2.4 and T/B was 3.2. Percentage ID/g decreased after day 1 while T/B increased. In these experiments no preferential localisation of either isotype matched 125I-labelled control IgG or F(ab')2 was observed. In F(ab')2 injected HNX-HN bearing mice as well as VX-A431 bearing mice, tumours could be visualised at day 1 and 2 without any appreciable background activity. With MAb IgG this was also possible in HNX-HN bearing mice (but not in VX-A431 bearing mice) but only at day 3 and 6. These findings suggest that the superior tumour to non-tumour ratios render the E48 F(ab')2 fragment more qualified for specific targeting of radioisotopes to tumour xenografts in this experimental setting. Images Figure 1 Figure 2 Figure 6 Figure 7 Figure 8

Comparison of the pharmacokinetics, biodistribution and dosimetry of monoclonal antibodies OC125, OV-TL 3, and 139H2 as IgG and F(ab')2 fragments in experimental ovarian cancer

“…In our study, we observed higher tumour to non-tumour ratios after administration of radiolabelled F(ab')2 fragments compared with IgG. Other investigators demonstrated improved immunoscintigraphic detection of experimental tumours using radiolabelled fragments (Buchegger et al, 1983;Hansson et al, 1988;Gerretsen et al, 1991). Thus far, clinical data from radioimmunodetection of cancer confirmed an increase in sensitivity for F(ab')2 fragments compared with intact IgG (Lamki et al, 1990).…”

Potential for targeting head and neck squamous cell carcinoma with monoclonal antibody K984

“…This mAb E48 is also reactive with normal squamous epithelia and squamous cell carcinomas and has a similar tumour selectivity in xenografted nude mice to that seen for mAb K984 in this study [11,12,27]. Preliminary results of this clinical study look very promising and demonstrate that the 99mTc-labelled E48 F(ab')2 conjugate is capable of detecting lymph node metastases (manuscript in preparation).…”

“…For diagnosis and therapy of SCC of the head and neck, monoclonal antibodies (mAbs) directed to tumour-associated cell-surface antigens are potentially powerful tools [7,16]. Among the potential applications of such tumour-preferential mAbs is their use as targeting agents for the selective delivery of radionuclides [2,8,11,12,17,20,22,27] or anti-tumour agents [2,9,10,15,25,37] to primary tumours and particularly to lymph node and distant metastases. Other approaches make use of unconjugated mAbs that eliminate tumour cells by activating immunological effector mechanisms, or mAbs that block mmour-associated processes, like proliferation and metastases, by binding to cell-surface receptors directly involved in these processes [13,33,36,37,39].…”

Lysyl oxidase like‐4 monoclonal antibody demonstrates therapeutic effect against head and neck squamous cell carcinoma cells and xenografts

“…We also developed an affinity purified polyclonal antibody raised against the 85 kD LOXL4 antigen to demonstrate its expression in HNSCC tissues of different grading and staging, and studied its involvement in the structural organisation of squamous epithelia . So far, most of the described antibodies against HNSCC showed considerable cross reactivity with normal tissue or showed only reactivity with SCC of distinct sites of origin . The first successful radioimmunotherapy results for HNSCC were shown with the E48 mAb in the early 1990 sec .…”