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Improved Pharmacokinetics and Tumor Localization of Immunotoxins Constructed with the M_r 30,000 Form of Ricin A Chain

XOMA Corporation, Berkeley, California 94710

The two naturally occurring forms of ricin A chain, M_r 33,000 and M_r 30,000 (RTA₃₃ and RTA₃₀) have been purified, and their chemical compositions, toxicities, and tissue distributions have been determined. As reported previously, the in vitro and in vivo toxicities of RTA₃₀ and RTA₃₃ are similar. However, RTA₃₀, which contains less carbohydrate with a lower mannose content than RTA₃₃, accumulated less in the liver than did RTA₃₃. Monoconjugate immunotoxins (i.e., containing one RTA per monoclonal antibody molecule) were constructed between RTA₃₀ or RTA₃₃ and the antitumor monoclonal antibody 791T/36, which recognizes a M_r 72,000 antigen on osteosarcoma and colon carcinoma cells. The two immunotoxins had similar cytoxicities in vitro but differed substantially in their pharmacokinetics and tissue distributions in vivo in nude mice bearing C170 human colorectal carcinoma xenografts. The immunotoxin derived from RTA₃₀ (IT₃₀) accumulated less in the liver than the immunotoxin derived from RTA₃₃ (IT₃₃) and cleared more slowly from the blood; the and ß half-lives for IT₃₀ and IT₃₃ were 0.50 and 20.5 versus 0.17 and 14.6 h, respectively. As a probable consequence, IT₃₀ accumulated to approximately 3-fold higher levels in the C170 xenografts than IT₃₃. The reduced clearance of IT₃₀ by the reticuloendothelial system thus resulted in prolonged survival in the blood and enhanced tumor localization relative to IT₃₃.

¹ To whom requests for reprints should be addressed, at XOMA Corporation, 2910 Seventh Street, Berkeley, CA 94710.

² Present address: Genetics Institute, 87 Cambridge Park Drive, Cambridge, MA 02140.

Received 2/25/91. Accepted 6/10/91.

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