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Biodistribution of Ricin Toxin A Chain-Monoclonal Antibody 791T/36 Immunotoxin and Influence of Hepatic Blocking Agents¹

Cancer Research Campaign Laboratories, University of Nottingham, Nottingham, NG7 2RD, United Kingdom [V. S. B., M. V. P., I. Z. A. P., R. W. B.], and the Xoma Corporation, Berkeley, California 94710 [V. S. B., H. M. L., P. J. S.]

Immunotoxin constructed by conjugating ricin A chain to monoclonal antibody 791T/36 has a markedly altered biodistribution when compared to unconjugated antibody. This is principally manifest as hepatic uptake of immunotoxin which appears to be controlled by the ricin A chain (RTA) moiety. This was established by comparing the blood survival and organ distribution of immunotoxin with that of ricin A chain and free antibody using preparations in which either the RTA or antibody, alone or as components of the immunotoxin, was radiolabeled. Gel filtration chromatography of sera from immunotoxin treated animals demonstrated a preferential blood clearance of immunotoxin with high RTA-antibody ratio. Hepatic uptake is dependent upon Kupffer cell recognition of mannose-containing oligosaccharide structures on the RTA moiety of immunotoxin. Mannose-containing blocking agents given with immunotoxin were shown to prolong circulation time of the immunotoxin in blood including those species with higher RTA-monoclonal antibody ratios and reduce liver uptake. Effective blocking agents include ovalbumin, ovomucoid, and mannosyl-lysine (Man₃Ly₂). These studies demonstrate that agents specifically inhibiting hepatic uptake of immunotoxin significantly alter biodistribution and may improve their therapeutic efficacy.

¹ Supported by grants from XOMA Corporation, Berkeley, CA, and the Cancer Research Campaign, United Kingdom.

² To whom requests for reprints should be addressed, at Cancer Research Campaign Laboratories, University of Nottingham, Nottingham, NG7 2RD, United Kingdom.

Received 3/ 6/87. Revised 7/ 9/87. Accepted 7/13/87.

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