Targeting Breast Cancer Using 177 Lu-Labeled Trastuzumab and Trastuzumab Fragment : First-in-Human Clinical Experience.

PURPOSE: A monoclonal antibody, trastuzumab, is used for immunotherapy for HER2-expressing breast cancers. Large-sized antibodies demonstrate hepatobiliary clearance and slower pharmacokinetics. A trastuzumab fragment (Fab; 45 kDa) has been generated for theranostic use. PATIENTS AND METHODS: Fab was generated by papain digestion. Trastuzumab and Fab have been radiolabelled with 177 Lu after being conjugated with a bifunctional chelating. The affinity and target specificity were studied in vitro. The first-in-human study was performed. RESULTS: The bifunctional chelating agent conjugation of 1-2 molecules with trastuzumab and Fab was detected at the molar ratio 1:10 in bicarbonate buffer (0.5 M, pH 8) at 37°-40°C. However, 2-3 molecules of bifunctional chelating agent were conjugated when DMSO in PBS (0.1 M, pH 7) was used as a conjugation buffer at a molar ratio of 1:10. The radiolabelling yield of DOTA-conjugated Fab and trastuzumab at pH 5, 45°C to 50°C, with incubation time 2.5-3 hours was 80% and 41.67%, respectively. However, with DOTAGA-conjugated trastuzumab and Fab, the maximum radiolabelling yield at pH 5.5, 37°C, and at 2.5-3 hours was 80.83% and 83%, respectively. The calculated K d of DOTAGA Fab and trastuzumab with HER2-positive SKBR3 cells was 6.85 ± 0.24 × 10 -8 M and 1.71 ± 0.10 × 10 -8 M, respectively. DOTAGA-Fab and trastuzumab showed better radiolabelling yield at mild reaction conditions.177 Lu-DOTAGA-Fab demonstrated higher lesion uptake and lower liver retention as compared with 177 Lu-DOTAGA-trastuzumab. However, 177 Lu-DOTAGA-Fab as compared with 177 Lu-DOTAGA-trastuzumab showed a relatively early washout (5 days) from the lesion. CONCLUSIONS: 177 Lu-DOTAGA-Fab and trastuzumab are suitable for targeting the HER2 receptors.

Nuclear medicine in the management of superficial skin abnormalities and institutional experience.

Keloid, hypertrophic scars and basal cell carcinoma (BCC) falls under the category of non-melanoma skin cancer. Intralesional steroids, external beam radiation therapy, 5-Fluorouracil, cryotherapy, laser, etc are the available treatment options. However, recurrence has been reported with each type of treatment mode. In the present article, various treatment modes have been discussed and institutional experience of Rhenium-188 skin patches for the treatment of keloids and BCC has been discussed.

Development 68Ga trastuzumab Fab and bioevaluation by PET imaging in HER2/neu expressing breast cancer patients.

INTRODUCTION: Receptors on breast cancer cells play a crucial role in the management of patients. Trastuzumab is a widely used drug for the treatment of HER2/neu expressing tumors. ImmunoPET with trastuzumab is not feasible due to slow pharmacokinetics. Fragment of antigen-binding (Fab) radiolabeled with positron emitters can be used for immunoPET. METHODS: Fab has been generated by papain digestion and conjugated with the bifunctional chelating agent NOTA. The SDS-PAGE and MALDI-TOF were used to see the integrity of Fab and conjugated Fab. In-vitro stability and target specificity for HER2/neu receptors were performed in plasma and receptor binding with bio-layer interferometry (BLI) techniques. Radiolabeling was standardized with 68GaCl3 and PET imaging was performed in seven patients showing 18F fluorodeoxyglucose (18F-FDG) uptake and correlated with HER2/neu expression by immunohistochemistry. RESULTS: Fab production was optimized at molar ratio 23:1 of trastuzumab and papain at 37 °C with a constant stirrer at 850 rpm for 22-24 h, at pH 8. Conjugation with NOTA was standardized at molar ratio 1:25 of trastuzumab Fab and NOTA. Molecular mass of trastuzumab Fab-NOTA was found approximately 46.3 kDa (~1/3 of intact antibody). Trastuzumab Fab-NOTA showed radiolabelling efficiency of 48-70% with incubation time 15 min at 37-40 °C and pH 4.5-5.0. BLI demonstrated the affinity of trastuzumab, trastuzumab Fab and trastuzumab Fab-NOTA towards HER2/neu receptor with KD of <1pM, ~0.5nM and ~20nM, respectively. All immunohistochemistry proven patients showed uptake in primary breast lesion and lymph nodes. CONCLUSION: Trastuzumab Fab-NOTA is suitable for radiolabelling with 68Ga and ImmunoPET imaging of HER2/neu receptor.

Radiation Exposure to the Personnel Performing Robotic Arm-Assisted Positron Emission Tomography/Computed Tomography-Guided Biopsies.

PURPOSE: The aim of the study was to estimate the radiation burden to personnel performing robotic arm-assisted positron emission tomography/computed tomography (PET/CT)-guided metabolic biopsies and to staff assisting the procedure in a PET/CT facility. MATERIALS AND METHODS: We estimated the whole-body exposures to physicians and staff based on the dose rate measurement with an ionization chamber-based calibrated survey monitor and pocket dosimeters during the robotic arm-assisted 2-[F-18]-fluoro-2-deoxy-D-glucose PET/CT-guided biopsies from September 2016 to February 2017. In addition, we also noted the time to biopsy after injection and total biopsy time during which the staff was exposed to the radiation. RESULTS: In this prospective study, PET/CT-guided biopsy was performed in 50 patients (males - 36, females - 14) with a mean age of 54 ± 15 years (range17-78 years). Of the 50 biopsy procedures, 18 were lung biopsies, 10 were bone biopsies, and 22 biopsies were from abdomen/pelvic lesions. The mean time taken for the procedure was 26 ± 11 min. The mean time elapsed between injection and procedure was 182 ± 85 min and mean injected activity of 138.38 ± 74 MBq. The mean whole-body exposure per procedure to an interventionist and an assistant was 1.88 ± 0.82 µSv and 1.04 ± 0.75 µSv, respectively. The mean exposure rates at 0-m and 1-m distance from the patient were 30.77 ± 14.61 µSv/h and 2.59 ± 1.49 µSv/h, respectively. CONCLUSION: We conclude that the interventionist received the highest mean effective dose as compared to the helping staffs. The occupational radiation exposure was found to be within the limits as specified by the regulatory authorities (International Commission on Radiological Protection-103), and PET/CT-guided biopsies were safe from radiation protection point of view.