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Development of New Multivalent-bispecific Agents for Pretargeting Tumor Localization and Therapy¹

IBC Pharmaceuticals, Inc., Morris Plains, New Jersey 07950 [E. A. R., L. Z., D. M. G., C-H. C.]; Immunomedics, Inc., Morris Plains, New Jersey 07950 [W. M., H. J. H., D. M. G., C-H. C.]; and Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, New Jersey 07109 [R. M. S., H. K., D. M. G.]

Purpose: Two bispecific diabodies (BS1.5 and BS1.5H) and two bispecific trivalent proteins (BS6 and BS8) were produced and tested as potential agents for pretargeted delivery of radiolabeled bivalent haptens to tumors expressing carcinoembryonic antigen.

Experimental Design: Each of the four proteins was expressed in Escherichia coli and purified from the soluble fraction. BS1.5 and BS1.5H (a humanized version of BS1.5) were evaluated in the GW-39 human colonic tumor-nude mouse model using a di-HSG-1,4,7,10-tetra-azacyclododecane-N,N',N'' N'''-tetraacetic acid peptide (IMP-241) radiolabeled with ¹¹¹In. The biodistribution and T/NT ratios were compared with those of hMN-14 x m679 (Fab' x Fab') prepared chemically.

Results: In animals, both BS1.5 and BS1.5H cleared more rapidly than hMN-14 x m679 and showed tumor to nontumor ratios far superior to those of hMN-14 x m679. For example, with BS1.5 injected 8 h before ¹¹¹In-IMP-241, the tumor uptake of ¹¹¹In was 10.3 ± 2.7 and 6.3 ± 2.2% ID/g at 3 and 24 h, respectively, with the tumor to blood ratios being 167 ± 35 at 3 h and 631 ± 231 at 24 h. In comparison, the tumor to blood ratios of ¹¹¹In observed for hMN-14 x m679 given 24 h earlier were 8 ± 2 at 3 h and 16 ± 3 at 24 h.

Conclusions: These results indicate that BS1.5 and BS1.5H are promising candidates for use in a variety of pretargeting applications, including tumor therapy with radionuclides and drugs. BS6 and BS8 may be even more attractive because of their potential to achieve higher levels of tumor uptake because of divalent carcinoembryonic antigen binding.

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