Antitumor effects and normal-tissue toxicity of 111In-nuclear localization sequence-trastuzumab in athymic mice bearing HER-positive human breast cancer xenografts.

Abstract

UNLABELLED:

(111)In-nuclear localization sequence-trastuzumab is a radioimmunotherapeutic agent consisting of trastuzumab modified with NLS peptides (CGYGPKKKRKVGG) and labeled with the Auger electron emitter (111)In. Our objectives were to evaluate the tumor growth-inhibitory properties and normal-tissue toxicity of (111)In-NLS-trastuzumab in mice after intraperitoneal administration.

METHODS:

The pharmacokinetics of (111)In-NLS-trastuzumab after intravenous (tail vein) or intraperitoneal injection in BALB/c mice were compared. Normal-tissue toxicity was determined in BALB/c mice at 2 wk after intraperitoneal injection of 3.7-18.5 MBq (4 mg/kg) of (111)In-NLS-trastuzumab by monitoring body weight, histopathologic examination of tissues, and hematology (white blood cell, platelet, red blood cell, and hemoglobin) or clinical biochemistry (alanine transaminase and creatinine) parameters. A no-observable-adverse-effect-level (NOAEL) dose was defined. Athymic mice bearing subcutaneous MDA-MB-361 or MDA-MB-231 human breast cancer xenografts (5.0 x 10(5) or 0.5 x 10(5) HER2/cell, respectively) were treated with a single NOAEL dose or 2 doses administered intraperitoneally and separated by 2 wk. Control groups were administered (111)In-trastuzumab, trastuzumab, nonspecific (111)In-NLS-human IgG (hIgG), or normal saline.

RESULTS:

The bioavailability of (111)In-NLS-trastuzumab after intraperitoneal injection was 0.7. The NOAEL dose was 9.25 MBq (4 mg/kg); doses greater than or equal to 18.5 MBq decreased white blood cell or platelet counts, and doses of 27.7 MBq decreased red blood cell counts. There was no increase in alanine transaminase or creatinine at any doses tested. There were no morphologic changes to the liver, kidneys, heart, or spleen or loss of body weight. A single dose of (111)In-NLS-trastuzumab (9.25 MBq)-compared with mice receiving (111)In-trastuzumab, trastuzumab, (111)In-NLS-hIgG, or normal saline-significantly slowed the rate of growth of MDA-MB-361 tumors over 60 d (0.014 d(-1) vs. 0.033 d(-1), 0.046 d(-1), 0.030 d(-1), and 0.061 d(-1), respectively; P < 0.05). (111)In-NLS-trastuzumab had no effect on the growth of MDA-MB-231 tumors. Two doses of (111)In-NLS-trastuzumab (9.25 MBq; 4 mg/kg) separated by 2 wk increased the survival of mice with MDA-MB-361 tumors, compared with mice treated with trastuzumab or normal saline (>140 d vs. 96 and 84 d, respectively; P < 0.001 or 0.027, respectively).

CONCLUSION:

(111)In-NLS-trastuzumab is a promising radioimmunotherapeutic agent that could be effective for treatment of HER2-overexpressing breast cancer in humans.

• Authors: Danny L Costantini, Kristin McLarty, Helen Lee, Susan J Done, Katherine A Vallis, Raymond M Reilly
• Journal: Journal of nuclear medicine : official publication, Society of Nuclear Medicine (J Nucl Med) Vol. 51 Issue 7 Pg. 1084-91 (Jul 2010) ISSN: 1535-5667 [Electronic] United States
• PMID: 20554744 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Immunoglobulin G
• Indium Radioisotopes
• Nuclear Localization Signals
• Radiopharmaceuticals
• ERBB2 protein, human
• Receptor, ErbB-2
• Trastuzumab

Topics

• Animals
• Antibodies, Monoclonal (pharmacokinetics, pharmacology, toxicity)
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents (pharmacokinetics, pharmacology, toxicity)
• Breast Neoplasms (metabolism, radiotherapy)
• Female
• Humans
• Immunoglobulin G (chemistry)
• Indium Radioisotopes (pharmacokinetics)
• Injections, Intraperitoneal
• Injections, Intravenous
• Isotope Labeling
• Kaplan-Meier Estimate
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Transplantation
• Nuclear Localization Signals (pharmacokinetics, pharmacology, toxicity)
• Radioimmunotherapy
• Radiopharmaceuticals (pharmacokinetics, toxicity)
• Receptor, ErbB-2 (metabolism)
• Survival Analysis
• Trastuzumab