Antitumor Effects and Normal-Tissue Toxicity of ¹¹¹In-Nuclear Localization Sequence-Trastuzumab in Athymic Mice Bearing HER-Positive Human Breast Cancer Xenografts

Abstract

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 · 10 5 or 0.5 · 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.

Correlation between energy deposition and molecular damage from Auger electrons: A case study of ultra-low energy (5-18 eV) electron interactions with DNA

“…[6][7][8][9] Despite this limitation that requires a sophisticated carrier system, AE radionuclides have been suggested as a promising therapeutic approach for treating numerous cancers, particularly for the treatment of single-cell metastatic cancers, leukemia and disseminated diseases. [10][11][12][13] AE radionuclides mainly decay via internal conversion and/or electron capture, which result in the emission of a cascade of electrons, including Auger, Coster-Kronig, and super Costerkronig electrons (generally termed Auger electrons), and characteristic x rays with energies between a few eV and 1 keV. 14 Owing to the very short range of these electrons, they deposit a substantial fraction of their energy in a nanoscopic volume.…”

Imaging Diagnostic and Therapeutic Targets: Human Epidermal Growth Factor Receptor 2

“…Several anti-HER2 Affibody molecules have also been labeled with 68 Ga, 18 F, 64 Cu, and 11 C for PET and with 99m Tc and 111 In for SPECT (18)(19)(20)(21). Affibody ABY-002 radiolabeled with 111 In for SPECT as well as with 68 Ga for PET was shown to specifically target HER2-expressing xenografts in vivo with both isotopes, but the pharmacokinetic profile for 68 Ga-radiolabeled ABY-002 was favored (20).…”

“…A modified RNA aptamer with HER2-specific targeting was labeled with 99m Tc and allowed SPECT imaging of HER2 expression (26,27). Another group used 64 Cu-WT4340 for PET imaging of HER2 messenger RNA and also demonstrated its successful use for evaluating the therapeutic efficacy of doxorubicin therapy in immunocompromised mice carrying human HER2-positive BC xenografts (28). These new types of radiotracers have so far been investigated only in preclinical models.…”

“…The study also highlighted the importance of the mass of administered protein, concluding that in trastuzumab-naive patients, a higher mass of (nonradiolabeled) trastuzumab (50 mg) enabled better distribution of the tracer into the metastatic lesions. In addition, trastuzumab was also labeled with 64 Cu in studies of both early and advanced HER2-positive BC (34,35). In both studies, the best time for imaging was 48 h after tracer injection.…”

“…In contrast, its bioengineered derived fragments [Fab fragments, F(ab9) 2 ] and variants (scFv, diabodies, and minibodies) and nontraditional protein scaffolds (Affibody molecules, Nanobodies, and anticalins) result in faster pharmacokinetics with similar affinity and specificity (9). These low-molecular-weight probes can be radiolabeled with isotopes-such as 68 Ga, 18 F, 64 Cu, and 76 Br for PET imaging-that have a short halflife, allowing imaging on the day of injection with a low radiation burden. In contrast, when mAbs are radiolabeled with isotopes that have a longer half-life-such as 89 Zr, 124 I, and 86 Y for PET imaging and 111 In for SPECT imaging-images can be retrieved up to several days after tracer injection, allowing optimal uptake in tumor tissue.…”