Purpose
To date, there is no effective therapy for triple-negative breast cancer (TNBC), which has dismal clinical outcome. Upregulation of tissue factor (TF) expression leads to increased patient morbidity and mortality in many solid tumor types, including TNBC. Our goal is to employ the Fab fragment of ALT-836, a chimeric anti-human TF mAb, for PET imaging of TNBC, which can be used to guide future TNBC therapy.
Methods
ALT-836-Fab was generated by enzymatic papain digestion. SDS-PAGE and FACS studies were performed to evaluate the integrity and TF binding affinity of ALT-836-Fab before NOTA conjugation and 64Cu-labeling. Serial PET imaging and biodistribution studies were carried out to evaluate the tumor targeting efficacy and pharmacokinetics in MDA-MB-231 TNBC model, which expresses high level of TF on the tumor cells. Blocking studies, histological assessment, as well as RT-PCR was performed to confirm TF specificity of 64Cu-NOTA-ALT-836-Fab.
Results
ALT-836-Fab was produced with high purity, which exhibited superb TF binding affinity and specificity. Serial PET imaging revealed rapid and persistent tumor uptake of 64Cu-NOTA-ALT-836-Fab (5.1 ± 0.5 %ID/g at 24 h post-injection; n = 4) and high tumor/muscle ratio (7.0 ± 1.2 at 24 h post-injection; n = 4), several-fold higher than that of the blocking group and tumor models that do not express significant level of TF, which was confirmed by biodistribution studies. TF specificity of the tracer was also validated by histology and RT-PCR.
Conclusions
64Cu-NOTA-ALT-836-Fab exhibited prominent tissue factor targeting efficiency in MDA-MB-231 TNBC model. The use of a Fab fragment led to fast tumor uptake and good tissue/muscle ratio, which may be translated into same-day immunoPET imaging in the clinical setting to improve TNBC patient management.
Enteric drainage in pancreas transplantation is complicated by an enteric leak in 5%–8%, frequently necessitating pancreatectomy. Pancreatic salvage outcomes are not well studied. Risk factors for enteric leak were examined and outcomes of attempted graft salvage were compared to immediate pancreatectomy. Pancreas transplants performed between 1995 and 2018 were reviewed. Donor, recipient, and organ variables including demographics, donor type, ischemic time, kidney donor profile index, and pancreas donor risk index were analyzed. Among 1153 patients, 33 experienced enteric leaks (2.9%). Donors of allografts that developed leak were older (37.9y vs. 29.0y, p = .001), had higher KDPI (37% vs. 24%, p < .001), higher pancreas donor risk index (1.83 vs. 1.32, p < .001), and longer cold ischemic time (16.5 vs. 14.8 h, p = .03). Intra‐abdominal abscess and higher blood loss decreased the chance of successful salvage. Enteric leak increased 6‐month graft loss risk (HR 13.9[CI 8.5–22.9], p < .001). However, 50% (n = 12) of allografts undergoing attempted salvage survived long‐term. After 6 months of pancreas graft survival, salvage and non‐leak groups had similar 5‐year graft survival (82.5% vs. 81.5%) and mortality (90.9% vs. 93.5%). Enteric leaks remain a challenging complication. Pancreatic allograft salvage can be attempted in suitable patients and accomplished in 50% of cases without significantly increased graft failure or mortality risk.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.