Immunoscintigraphy of small-cell lung cancer xenografts with anti neural cell adhesion molecule monoclonal antibody, 123C3: improvement of tumour uptake by internalisation

Abstract

Summary The efficacy of three murine monoclonal antibodies (MAbs) for immunoscintigraphy of small-cell lung cancer (SCLC) xenografts was studied in a Balb/c nu/nu mouse model. These MAbs, 123C3, 123A8 and MOCl91, belong to cluster 1 of anti-SCLC MAbs and bind to the neural cell adhesion molecule (NCAM) with similar affinity. After intraperitoneal injection of these MAbs, labelled with 1251, the highest uptake in tumour tissue was obtained with MAb 123C3. Seven days after administration of this MAb 13.9% of the injected dose per gram of tumour tissue was retained in the tumour. The corresponding tumour to tissue ratios ranged from 3.97 for blood to 31.03 for colon. The imaging results and the tumour uptake were less favourable for the two other MAbs, 123A8 and MOCl91 (fractions of injected dose respectively 6.7% and 9.2%), although affinity, biological activity after labelling and uptake in non-tumour tissues were very similar for all three MAbs. These results may be explained by the differences in the interaction between the MAbs and the tumour cells. MAb 123C3 is internalised into tumour cells, whereas both other anti-NCAM MAbs are not. Internalisation into NCI H69 cells was demonstrated in vitro by a radioimmunoassay, confocal laser scanning microscopy and electron microscopy. The internalised fraction of MAb 123C3 was 22.3% after 24 h, whereas this fraction was only 7.5% for MAb 123A8. Although the internalised radiolabelled MAbs are usually degraded and dehalogenated intracellularly, the retained radioactivity is high. Apparently, intracellular degradation of radiolabelled MAb 123C3 and subsequent secretion of radioactive iodine did not prevent the accumulation of intracellular radioactivity. In conclusion, accumulation and retention of radioactivity in the tumour tissue, due to internalisation of radiolabelled MAbs, may improve the results of immunoscintigraphy.

A Human Immunoglobulin G1 Antibody Originating from an in Vitro-Selected Fab Phage Antibody Binds Avidly to Tumor-Associated MUC1 and Is Efficiently Internalized

“…After internalization of the radioactively labeled antibody there is a retention of the radiolabel inside the cells, even after degradation of the antibody, which makes the tumor targeting more efficient in radioimmunoscintigraphy as well as in radioimmunotherapy. 22,41,42 Alternatively, provided the antibody PH1 does not bind to serum MUC1 (studies ongoing), the MUC1-binding site may be combined with immunomodulatory molecules (immunocytokines) or made into a bispecific antibody for retargeting T cells. As before, internalization of the antibody-antigen complex may aid in the efficacy of the recombinant drug.…”

Biodistribution of a radiolabelled monoclonal antibody NY3D11 recognizing the neural cell adhesion molecule in tumour xenografts and patients with small-cell lung cancer

“…A previous study in patients with SCLC using the NCAM monoclonal MAb 123C also found no localization to primary tumours, although a single liver metastasis was detected (Michalides et al, 1994). This negative result occurred despite immunoscintigraphy studies in mice that suggest that MAb 123C3 has superior localization compared with other cluster-1 antibodies because of its internalization (Kwa et al, 1996). However, it is clear that other anti-NCAM antibodies that do not internalize can also localize well in mouse studies (Boerman et al, 1991;Waibel et al, 1993;Hosono et al, 1994) and the present study further highlights that successful localization of antibodies in mice is not necessarily reproduced in human studies.…”

Radioimmunoimaging with Mixed Monoclonal Antibodies of Nude Mice Bearing Human Lung Adenocarcinoma Xenografts

“…Extensive animal experiments and clinical research for RII have been performed in non-small-cell lung cancer (NSCLC) in recent years (Kwa et al, 1996;Machac et al, 2002;Egri and Takáts, 2005;Goldenberg et al, 2006;Goldenberg et al, 2007). The United States has approved the clinical use of 99m Tc-NR-LU-10 for the diagnosis of lung cancer using the RII kit (Rusch et al, 1993).…”