Treatment of human lung carcinoma xenografts with a combination of 131I-labelled monoclonal antibody Po66 and doxorubicin.

Po66, a mouse monoclonal antibody, is directed against an intracytoplasmic antigen present in human lung squamous cell carcinoma cells. In previous work it was found that the co-administration of 125I-radiolabelled Po66 and doxorubicin strongly enhanced the uptake of radioactivity by the tumour. The present-work was designed to evaluate, in a tumour-bearing mouse model of lung carcinoma, the ability of 131I-labelled Po66 to retard tumour growth when injected alone, or in combination with doxorubicin (8 mg kg-1 at 1-week intervals). A single dose of 550 microCi 131I-Po66 alone had no effect on tumour growth, whereas three fractionated doses of 250 microCi 131I-Po66 decreased it over two doubling times from 14.5 +/- 1.5 days for untreated control mice to 24.8 +/- 2.7 days. Mice treated with doxorubicin alone had a double tumour doubling time of 22.6 +/- 4.9 days, compared to 35.2 +/- 2.9 days (1.55-fold increase) in mice treated with doxorubicin and a single dose of 550 microCi 131I-Po66. Doxorubicin combined with three fractionated doses of 250 microCi 131I-Po66 provoked a twofold decrease in tumour growth compared to mice treated with doxorubicin alone. The administration of fractionated doses of 131I-Po66 simultaneously with doxorubicin resulted in a highly delayed mortality, which was not observed when 131I-Po66 was administered after doxorubicin. Thus, in a non-small-cell lung tumour model, a 131I-radiolabelled monoclonal antibody, directed against an intracellular antigen, significantly potentiated the effect of chemotherapy. Such a therapeutic approach could be used as an adjuvant therapy and improve the effect of chemotherapy on distant small metastases.

Scintigraphic detection in mice of inflammatory lesions and tumours by an indium-labelled monoclonal antibody directed against Mac-1 antigen.

The monoclonal antibody, 3A33, directed against Mac-1 antigen which is expressed essentially on macrophages and polymorphonuclear cells, was injected i.v. into mice, as part of an attempt to visualize inflammatory lesions and tumours by external scintigraphy. The monoclonal antibody, a rat IgG2a, was conjugated with a bifunctional chelating agent, diethylenetriaminepentaacetic acid at a 1:1 molecular ratio and complexed with 111-indium, a procedure which apparently did not alter its binding to peritoneal macrophages and provided relatively stable cell labelling. An unrelated rat IgG2a of unknown specificity radiolabelled in the same manner as 3A33 served as a control. The uptake of i.v. injected 3A33 by peritoneal macrophages was up to 50 times that of unrelated IgG2a. After i.v. inoculation, the antibody accumulated in the liver, spleen, lung, in foot-pad inflammatory reactions induced by injection of Freund's adjuvant and in experimentally grafted tumours. The 3A33: non-specific IgG2a uptake ratio in inflammatory lesions and tumours, however, was much lower than for peritoneal macrophages and was generally close to 2. This was sufficient to obtain scintigraphic images of inflammations and tumours. The images obtained after injection of 3A33 were clearly of better quality than those given by the non-specific immunoglobulin. They could be improved by subtraction of the vascular images obtained after injection of 99m-technetium serum albumin. The labelling of Mac-1-positive blood mononuclear cells by in vitro incubation with radioactive 3A33 was not intense enough to allow scintigraphic imaging after in vivo re-infusion but seemed more selective than the injection of whole antibody in detecting inflammatory reactions. These results seem interesting in view of the potential human application to the detection inflammatory lesions and the appreciation of tumour inflammatory components. Possible improvements in the technique are discussed.