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


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.
Institut National de la Santé et de la Recherche Médicale U896, Université Montpellier, Montpellier, France.
Vincent
V
Boudousq
Laure
L
Bobyk
Muriel
M
Busson
Véronique
V
Garambois
Marta
M
Jarlier
Paraskevi
P
Charalambatou
André
A
Pèlegrin
Salomé
S
Paillas
Nicolas
N
Chouin
François
F
Quenet
Patrick
P
Maquaire
Julien
J
Torgue
Isabelle
I
Navarro-Teulon
Jean-Pierre
JP
Pouget
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007856:Lead Radioisotopes; D051379:Mice; D008819:Mice, Nude; D010534:Peritoneal Neoplasms / Q000175:diagnosis*; D016499:Radioimmunotherapy / Q000379:methods*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000276:immunology* / Q000378:metabolism
D000911:Antibodies, Monoclonal; D007856:Lead Radioisotopes; D018719:Erb-b2 Receptor Tyrosine Kinases; D011956:Receptors, Cell Surface; C065686:carcinoembryonic antigen binding protein, human; C508053:ERBB2 protein, human