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Improved Targeting of an Anti-Epidermal Growth Factor Receptor Variant III Monoclonal Antibody in Tumor Xenografts after Labeling Using N-Succinimidyl 5-Iodo-3-Pyridinecarboxylate¹

Departments of Pathology [C. J. R., G. E. A., C. J. W., D. D. B., M. R. Z.] and Radiology [M. R. Z.], Duke University Medical Center, Durham, North Carolina 27710

Monoclonal antibody (mAb) L8A4, specific for the tumor-associated mutant epidermal growth factor receptor variant III (EGFRvIII), is internalized and degraded after cell binding. Four paired-label experiments were performed in athymic mice bearing EGFRvIII-positive xenografts to determine the suitability of N-succinimidyl 3-iodo-5-pyridinecarboxylate (SIPC) for labeling this internalizing mAb. In mice with HC2 20 d2 xenografts, tumor uptake reached a maximum of 32.7 ± 2.0% injected dose/g when labeled using SIPC, a value significantly higher (P < 0.05, paired t test) than that observed when L8A4 was labeled using Iodogen (24.4 ± 2.2% injected dose/g). The specificity of mAb uptake in HC2 20 d2 and U87MGEGFR xenografts was measured in separate experiments by coadministration of L8A4 and nonspecific, isotype-matched P3X63Ag8 mAb, both radioiodinated using SIPC. Tumor localization indices were approximately 10 or more by 72 h, a degree of specificity 3–4 times higher than that reported previously when labeling was performed using the tyramine cellobiose (TCB) method. In a final study directly comparing L8A4 labeled using SIPC and TCB, similar tumor levels were obtained (SIPC, 33.7 ± 6.1% injected dose/g at 24 h; TCB, 37.8 ± 6.7% injected dose/g at 24 h); however, tumor-to-tissue ratios for the liver, spleen, and kidneys were 3 times higher with SIPC at later time points. These results suggest that SIPC is a promising method for labeling this anti-EGFRvIII mAb and possibly other mAbs that internalize after binding.

¹ This work was supported in part by Grants CA42324, NS20023, and CA11898 from the NIH and Grant DE-FG02-96ER62148 from the Department of Energy.

² To whom requests for reprints should be addressed, at Duke University Medical Center, Department of Radiology, Box 3808, Durham, NC 27710. Phone: (919) 684-7708; Fax: (919) 684-7121.

Received 9/23/96. Accepted 2/17/97.

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