Noninternalizing Monoclonal Antibodies Are Suitable Candidates for ¹²⁵I Radioimmunotherapy of Small-Volume Peritoneal Carcinomatosis

Abstract

We have previously shown that, in vitro, monoclonal antibodies (mAbs) labeled with the Auger electron emitter 125 I are more cytotoxic if they remain at the cell surface and do not internalize in the cytoplasm. Here, we assessed the in vivo biologic efficiency of internalizing and noninternalizing 125 I-labeled mAbs for the treatment of small solid tumors. Methods: Swiss nude mice bearing intraperitoneal tumor cell xenografts were injected with 37 MBq (370 MBq/mg) of internalizing (anti-HER1) 125 I-m225 or noninternalizing (anti-CEA) 125 I-35A7 mAbs at days 4 and 7 after tumor cell grafting. Nonspecific toxicity was assessed using the irrelevant 125 I-PX mAb, and untreated controls were injected with NaCl. Tumor growth was followed by bioluminescence imaging. Mice were sacrificed when the bioluminescence signal reached 4.5 · 10 7 photons/s. Biodistribution analysis was performed to determine the activity contained in healthy organs and tumor nodules, and total cumulative decays were calculated. These values were used to calculate the irradiation dose by the MIRD formalism. Results: Median survival (MS) was 19 d in the NaCltreated group. Similar values were obtained in mice treated with unlabeled PX (MS, 24 d) and 35A7 (MS, 24 d) or with 125 I-PX mAbs (MS, 17 d). Conversely, mice treated with unlabeled or labeled internalizing m225 mAb (MS, 76 and 77 d, respectively) and mice injected with 125 I-35A7 mAb (MS, 59 d) showed a significant increase in survival. Irradiation doses were comparable in all healthy organs, independently from the mAb used, whereas in tumors the irradiation dose was 7.4-fold higher with 125 I-labeled noninternalizing than with internalizing mAbs. This discrepancy might be due to iodotyrosine moiety release occurring during the catabolism of internalizing mAbs associated with high turnover rate. Conclusion: This study indicates that 125 I-labeled noninternalizing mAbs could be suitable for radioimmunotherapy of small solid tumors and that the use of internalizing mAbs should not be considered as a requirement for the success of treatments with 125 I Auger electrons.

Experimental Radionuclide Therapy of HER2-Expressing Xenografts Using Two-Step Targeting Nuclisome Particles

“…Already at 0.1 MBq per mouse the survival was prolonged. This is a remarkably low dose, especially in comparison with 125 I-labeled targeting proteins (18). Survival increased with increasing dose, and at 2 MBq per mouse most of the mice survived the study.…”

Emerging Trends for Radioimmunotherapy in Solid Tumors

“…33 Subsequently, the therapeutic superiority of noninternalizing 125 I-labeled antibodies in treating peritoneal carcinomatosis was demonstrated in vivo using the vulvar squamous carcinoma xenograft model. 20 After intravenous administration, the maximal tumor accretion of 125 I-labeled noninternalizing anti-CEA MAb 35A7 was significantly higher than radioiodinated internalizing anti-EGFR MAb m225. Further, 125 I-35A7 resulted in a higher dose deposition in the tumor than 125 I-m225, produced greater reduction in tumor size and significantly prolonged the median survival.…”

“…Several studies have been undertaken to identify the most suitable radionuclides (b-, a-or auger-emitters), antibody formats [F(ab¢) 2 IgG, IgM] and types (internalizing vs. noninternalizing), and evaluating the toxicity of radionuclides on the peritoneal membrane. [18][19][20][21][22][23][24] In the context of intraperitoneal RIT involving a-particle emitters, recent studies have also explored their utility in several ways: multiple administrations 25 and the impact of using variable specific activities 26 ; compared the efficacy of intraperitoneal RIT with pretargeted intraperitoneal RIT 27 ; and investigated the impact of antibody glycosylation on efficacy. 28 …”

“…On the other hand, the dose deposition in the normal organs was comparable. 20 Although the enhanced tumor accumulation can be attributed to the resistance of noninternalized antibody to dehalogenation, differences in antigen density and pharmacokinetic properties of the antibodies should also be carefully examined before drawing definitive conclusions. Recently, a ''brief intraperitoneal RIT'' approach involving high dose administration of noninternalizing 125 I-35A7 was described.…”

Radio-immunothérapie alpha

“…Le ciblage final de l'émetteur doit, par conséquent, se réaliser dans un compartiment sensible de la cellule (comme le noyau dont la taille varie de 10 à 20 µm) car les électrons Auger sont hautement cytotoxiques lorsqu'ils se situent à proximité des molécules d'ADN. La RIT Auger reste à un stade de développement préclinique, essentiellement dans des modèles de xénogreffes chez des souris nude (dépourvues de système immunitaire) [17]. Cette revue sera consacrée uniquement à la RITα ainsi qu'aux diffé-rentes caractéristiques de cette modalité thérapeutique.…”