Intratumour therapy of solid tumours with ricin-antibody conjugates.
Immunotoxin conjugates of whole ricin with monoclonal antibody were prepared with the galactose binding site on the ricin B chain blocked. These whole ricin-antibody conjugates were then injected directly into tumours (IT) in mice with established solid tumours. The conjugates were found to be effective, in vivo, in (C57BL/6XBALB/c)F1 mice carrying thymoma grafts and in nude mice bearing human tumour xenografts. Thymomas (Ly-1.1-, 2.1+) completely regressed following IT injection of either ricin-anti-Ly-2.1 or 'modified' (periodate treated to remove carbohydrate) ricin-anti-Ly-2.1 but did not regress when treated with the non-reactive ricin-anti-Ly-1.1. Similarly, established CEM (transferrin receptor+) or HT-29 (17.1/2+) tumours in nude mice completely regressed following IT injection of ricin-anti-transferrin receptor antibody or ricin-17.1/2 antibody conjugates. The tumours disappeared within 48 h, and in 80-100% of these there was no recurrence. Intact ricin-antibody conjugates did not require the presence of lactose to block the binding of native ricin and selective activity was entirely dependent on the reactivity of the monoclonal antibodies (MoAb). Further, the killing of target cells was specific because non-reactive ricin-antibody conjugates did not cause regression of tumours and MoAb alone did not inhibit tumour growth. In addition, there was no systemic toxicity evident in mice treated with reactive conjugates. By contrast, in mice treated with only ricin or with non-reactive ricin-antibody conjugates there was toxicity to liver and spleen due to diffusion from the tumour; thus the MoAb moiety of the immunotoxin serves to target the ricin to the tumour, to hold ricin in the tumour, and little escapes. It was found that ricin-antibody conjugate treatment (IT) with 1-2 micrograms of ricin-antibody conjugate was not harmful to mice, in contrast to ricin alone, which killed all treated tumour bearing mice at a dose of 0.5 micrograms. Thus whole ricin-antibody conjugates can be used successfully in vivo for local therapy, leading to the eradication of solid tumours by direct injection of the tumour.
Kanellos
J
J
Department of Pathology, University of Melbourne, Parkville, Vic. Australia.
McKenzie
I F
IF
Pietersz
G A
GA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000950:Antigens, Ly; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use*; D007518:Isoantibodies / Q000008:administration & dosage; D051379:Mice; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000628:therapy*; D012276:Ricin / Q000627:therapeutic use*; D013945:Thymoma / Q000628:therapy; D013953:Thymus Neoplasms / Q000628:therapy; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D000950:Antigens, Ly; D000922:Immunotoxins; D007518:Isoantibodies; D012276:Ricin