Improved targeting of an anti-epidermal growth factor receptor variant III monoclonal antibody in tumor xenografts after labeling using N-succinimidyl 5-iodo-3-pyridinecarboxylate

Cancer Res. 1997 Apr 15;57(8):1510-5.

Abstract

Monoclonal antibody (mAb) L8A4, specific for the tumor-associated mutant epidermal growth factor receptor variant III (EGFRvII), 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 lodogen (24.4 +/- 2.2% injected dose/g). The specificity of mAb uptake in HC2 20 d2 and U87MG(delta)EGFR 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells / metabolism
  • Affinity Labels*
  • Animals
  • Antibodies, Monoclonal / metabolism
  • Antibodies, Monoclonal / pharmacokinetics
  • Antibodies, Monoclonal / therapeutic use*
  • Antibody Specificity
  • ErbB Receptors / immunology*
  • ErbB Receptors / metabolism
  • Mice
  • Mice, Nude
  • Nicotinic Acids / pharmacokinetics*
  • Succinimides / pharmacokinetics*
  • Tissue Distribution
  • Transplantation, Heterologous
  • Tyramine / pharmacokinetics

Substances

  • Affinity Labels
  • Antibodies, Monoclonal
  • Nicotinic Acids
  • Succinimides
  • N-succinimidyl-5-iodo-3-pyridinecarboxylic acid
  • ErbB Receptors
  • Tyramine