Effect of the extent of chelate substitution on the immunoreactivity and biodistribution of 2IT-BAT-Lym-1 immunoconjugates.

Abstract

Trial therapy for lymphoma with the radiolabeled chelate-antibody conjugate 67Cu-2IT-BAT-Lym-1 has been promising. It is desirable to deliver therapeutic doses of radiometal using a minimum amount of 2IT-BAT-Lym-1 to minimize the risks of adverse patient reaction and antigenic response to antibody. This is readily accomplished by increasing the number of metal-binding sites (i.e., chelating agents) conjugated per antibody, but the ability of the antibody to bind antigen and target tumor cells in vivo must not be impaired by the conjugation reaction. To determine the maximum chelator:antibody ratio (c/a) of 2IT-BAT-Lym-1 at which functional integrity is preserved, immunoconjugates with a c/a of 1.3-23 were prepared and examined by radioimmunoassay and competitive antigen binding versus lightly iodinated Lym-1. The biodistribution in tumored mice of conjugates with c/a of 2.1, 4.3, 8.4, and 11.4 also was examined. Conjugates with c/a up to 5 exhibited no loss of immunoreactivity, and conjugates with c/a up to 11 retained 75% or greater immunoreactivity relative to unmodified Lym-1. All conjugates examined competed less effectively than did unmodified Lym-1 for antigen binding, but the effect at c/a 5 was slight. Tumor uptake declined with increasing c/a, but the effect was insignificant at c/a 2.1 and 4.3. Conjugates of c/a 4-5 were found to be optimal for the preparation of radioimmunoconjugate of high specific activity with minimal, if any, loss of functional integrity.

• Authors: D L Kukis, G L DeNardo, S J DeNardo, G R Mirick, L A Miers, D P Greiner, C F Meares
• Journal: Cancer research (Cancer Res) Vol. 55 Issue 4 Pg. 878-84 (Feb 15 1995) ISSN: 0008-5472 [Print] United States
• PMID: 7850803 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies, Monoclonal
• Chelating Agents
• Copper Radioisotopes
• Cross-Linking Reagents
• Heterocyclic Compounds
• Imidoesters
• Immunotoxins
• 6-(4-bromoacetamidobenzyl)-1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid
• methyl 4-mercaptobutyrimidate

Topics

• Animals
• Antibodies, Monoclonal (immunology, pharmacokinetics)
• Binding, Competitive
• Chelating Agents (pharmacokinetics, pharmacology)
• Copper Radioisotopes
• Cross-Linking Reagents (pharmacokinetics, pharmacology)
• Female
• Heterocyclic Compounds (pharmacokinetics, pharmacology)
• Imidoesters (pharmacokinetics, pharmacology)
• Immunotoxins (immunology, pharmacokinetics)
• Isoelectric Focusing
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Neoplasms, Experimental (immunology, radiotherapy)
• Radioimmunotherapy
• Tissue Distribution
• Transplantation, Heterologous