Comparison between internalizing anti-HER2 mAbs and non-internalizing anti-CEA mAbs in alpha-radioimmunotherapy of small volume peritoneal carcinomatosis using 212Pb

PLoS One. 2013 Jul 29;8(7):e69613. doi: 10.1371/journal.pone.0069613. Print 2013.

Abstract

Background and purpose: We assessed the contribution of antibody internalization in the efficacy and toxicity of intraperitoneal α-radioimmunotherapy (RIT) of small volume carcinomatosis using (212)Pb-labeled monoclonal antibodies (mAbs) that target HER2 (internalizing) or CEA (non-internalizing) receptors.

Materials and methods: Athymic nude mice bearing 2-3 mm intraperitoneal tumor xenografts were intraperitoneally injected with similar activities (370, 740 and 1480 kBq; 37 MBq/mg) of (212)Pb-labeled 35A7 (anti-CEA), trastuzumab (anti-HER2) or PX (non-specific) mAbs, or with equivalent amounts of unlabeled mAbs, or with NaCl. Tumor volume was monitored by bioluminescence and survival was reported. Hematologic toxicity and body weight were assessed. Biodistribution of (212)Pb-labeled mAbs and absorbed dose-effect relationships using MIRD formalism were established.

Results: Transient hematological toxicity, as revealed by white blood cells and platelets numbering, was reported in mice treated with the highest activities of (212)Pb-labeled mAbs. The median survival (MS) was significantly higher in mice injected with 1.48 MBq of (212)Pb-35A7 (non-internalizing mAbs) (MS = 94 days) than in animals treated with the same activity of (212)Pb-PX mAbs or with NaCl (MS = 18 days). MS was even not reached after 130 days when follow-up was discontinued in mice treated with 1.48 MBq of (212)Pb-trastuzumab. The later efficacy was unexpected since final absorbed dose resulting from injection of 1.48 MBq, was higher for (212)Pb-35A7 (35.5 Gy) than for (212)Pb-trastuzumab (27.6 Gy). These results also highlight the lack of absorbed dose-effect relationship when mean absorbed dose was calculated using MIRD formalism and the requirement to perform small-scale dosimetry.

Conclusions: These data indicate that it might be an advantage of using internalizing anti-HER2 compared with non-internalizing anti-CEA (212)Pb-labeled mAbs in the therapy of small volume xenograft tumors. They support clinical investigations of (212)Pb-mAbs RIT as an adjuvant treatment after cytoreductive surgery in patients with peritoneal carcinomatosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology*
  • Cell Line, Tumor
  • Female
  • Humans
  • Lead Radioisotopes*
  • Mice
  • Mice, Nude
  • Peritoneal Neoplasms / diagnosis*
  • Radioimmunotherapy / methods*
  • Receptor, ErbB-2 / immunology*
  • Receptor, ErbB-2 / metabolism
  • Receptors, Cell Surface / immunology*
  • Receptors, Cell Surface / metabolism

Substances

  • Antibodies, Monoclonal
  • Lead Radioisotopes
  • Receptors, Cell Surface
  • carcinoembryonic antigen binding protein, human
  • ERBB2 protein, human
  • Receptor, ErbB-2

Grants and funding

This work was supported by the Institut National du Cancer, grant R09080FF/RPT09005FFA, by Action N°1.1 of Plan Cancer 2009–2013 (ASC 13038FSA) and by AREVA Med LLC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Julien Torgue and Patrick Maquaire have affiliation to the commercial funders of this research (AREVA Med LLC). This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.