No abstract

Immunotherapy with checkpoint inhibitor programmed cell death 1 (PD-1)/programmed death ligand-1 (PD-L1) antibodies demonstrates improvements in treatment of advanced non-small cell lung cancer. Treatment stratification depends on immunohistochemical PD-L1 measurement of biopsy material, an invasive method that does not account for spatiotemporal heterogeneity. Using a single-domain antibody, NM-01, against PD-L1, radiolabeled site-specifically with 99m Tc for SPECT imaging, we aimed to assess the safety, radiation dosimetry, and imaging characteristics of this radiopharmaceutical and correlate tumor uptake with PD-L1 immunohistochemistry results. Methods: Sixteen patients (mean age, 61.7 y; 11 men) with non-small cell lung cancer were recruited. Primary tumor PD-L1 expression was measured by immunohistochemistry. NM-01 was radiolabeled with [ 99m Tc(OH 2) 3 (CO) 3 ] 1 complex binding to its C-terminal hexahistidine tag. Administered activity was 3.8-10.4 MBq/kg, corresponding to 100 μg or 400 μg of NM-01. Whole-body planar and thoracic SPECT/CT scans were obtained at 1 and 2 h after injection in all patients, and 5 patients underwent additional imaging at 10 min, 3 h, and 24 h for radiation dosimetry calculations. All patients were monitored for adverse events. Results: No drug-related adverse events occurred in this study. The mean effective dose was 8.84 • 10 −3 ± 9.33 • 10 −4 mSv/MBq (3.59 ± 0.74 mSv per patient). Tracer uptake was observed in the kidneys, spleen, liver, and bone marrow. SPECT primary tumor-to-blood-pool ratios (T:BP) varied from 1.24 to 2.3 (mean, 1.79) at 1 h and 1.24 to 3.53 (mean, 2.22) at 2 h (P 5 0.005). Two-hour primary T:BP ratios correlated with PD-L1 immunohistochemistry results (r 5 0.68, P 5 0.014). Two-hour T:BP was lower in tumors with #1% PD-L1 expression (1.89 vs. 2.49, P 5 0.048). Nodal and bone metastases showed tracer uptake. Heterogeneity (.20%) between primary tumor and nodal T:BP was present in 4 of 13 patients. Conclusion: This first-inhuman study demonstrates that 99m Tc-labeled anti-PD-L1-single-domain antibody SPECT/CT imaging is safe and associated with acceptable dosimetry. Tumor uptake is readily visible against background tissues, particularly at 2 h when the T:BP ratio correlates with PD-L1 immunohistochemistry results.

Purpose The aim of the present paper is to review the role of HER2 antibodies, affibodies and nanobodies as vehicles for imaging and therapy approaches in breast cancer, including a detailed look at recent clinical data from antibody drug conjugates and nanobodies as well as affibodies that are currently under development. Results Clinical and preclinical studies have shown that the use of monoclonal antibodies in molecular imaging is impaired by slow blood clearance, associated with slow and low tumor uptake and with limited tumor penetration potential. Antibody fragments, such as nanobodies, on the other hand, can be radiolabelled with short-lived radioisotopes and provide high-contrast images within a few hours after injection, allowing early diagnosis and reduced radiation exposure of patients. Even in therapy, the small radioactively labeled nanobodies prove to be superior to radioactively labeled monoclonal antibodies due to their higher specificity and their ability to penetrate the tumor. Conclusion While monoclonal antibodies are well established drug delivery vehicles, the current literature on molecular imaging supports the notion that antibody fragments, such as affibodies or nanobodies, might be superior in this approach.

Ovarian epithelial carcinomas (OECs) frequently exhibit amplifications at the 20q13 locus which is the site of several oncogenes, including the eukaryotic elongation factor EEF1A2 and the transcription factor ZNF217. We reported previously that overexpressed ZNF217 induces neoplastic characteristics in precursor cells of OEC. Unexpectedly, ZNF217, which is a transcriptional repressor, enhanced expression of eEF1A2. In our study, array comparative genomic hybridization, single nucleotide polymorphism and Affymetrix analysis of ZNF217-overexpressing cell lines confirmed consistently increased expression of eEF1A2 but not of other oncogenes, and revealed early changes in EEF1A2 gene copy numbers and increased expression at crisis during immortalization. We defined the influence of eEF1A2 overexpression on immortalized ovarian surface epithelial cells, and investigated interrelationships between effects of ZNF217 and eEF1A2 on cellular phenotypes. Lentivirally induced eEF1A2 overexpression caused delayed crisis, apoptosis resistance and increases in serum-independence, saturation densities and anchorage independence. siRNA to eEF1A2 reversed apoptosis resistance and reduced anchorage independence in eEF1A2-overexpressing lines. Remarkably, siRNA to eEF1A2 was equally efficient in inhibiting both anchorage independence and resistance to apoptosis conferred by ZNF217 overexpression. Our data define neoplastic properties that are caused by eEF1A2 in nontumorigenic ovarian cancer precursor cells, and suggest that eEF1A2 plays a role in mediating ZNF217-induced neoplastic progression. Published 2008 Wiley-Liss, Inc. This article is a U.S. Government work, and, as such, is in the public domain in the United States of America.Key words: ovarian cancer; ZNF217; EEF1A2; oncogene; ovarian epithelial cells; neoplastic progressionThe transcription factor ZNF217 and the eukaryotic translation elongation factor EEF1A2 are both located on chromosome 20q13, a locus which is frequently amplified in ovarian epithelial carcinomas. There is both clinical and experimental evidence that these 2 proteins act as oncogenes in ovarian carcinogenesis as well as in other forms of cancer. However, because of the coexistence of multiple putative oncogenes on chromosome 20q, it has been difficult to define their individual specific influence on malignant progression.20q13 amplification and overexpression of ZNF217 have been described in many types of human cancers, including ovarian carcinomas. 1,2 Recent evidence indicates that ZNF217 is a transcriptional repressor 3,4 and that it may contribute to neoplastic progression by attenuating apoptotic signals. 5,6 In experimental systems, overexpression of ZNF217 has been shown to immortalize cell lines with limited life spans, such as human mammary epithelial cell lines and SV40 Tag/tag transduced ovarian surface epithelial cells (IOSE cells). In both of these cell types, ZNF217 increased telomerase activity and stabilized telomere lengths. 7,8 ZNF217-transduced IOSE cells also acquired anchorage ind...