A bispecific antibody AP203 targeting PD-L1 and CD137 exerts potent antitumor activity without toxicity.

BACKGROUND: Bispecific antibody has garnered considerable attention in the recent years due to its impressive preliminary efficacy in hematological malignancies. For solid tumors, however, the main hindrance is the suppressive tumor microenvironment, which effectively impedes the activation of infiltrating T cells. Herein, we designed a bispecific antibody AP203 with high binding affinity to PD-L1 and CD137 and assessed its safety and anti-tumor efficacy, as well as explored the mechanism of action. METHODS: The optimal antibody binders against PD-L1 and CD137 were screened from the OmniMab phagemid library. The binding affinity of the constructed AP203 were evaluated using enzyme-linked immunosorbent assay (ELISA) and biolayer interferometry (BLI). T-cell stimulatory capacity was assessed using the allogeneic mixed lymphocyte reaction (MLR), antigen-specific recall response, and coculture with PD-L1-expressing cells. In vivo antitumor efficacy was evaluated using two models of tumor-xenografted humanized mice with profiling of tumor infiltrating lymphocytes (TILs). The possible toxicity of AP203 was examined using in vitro cytokine release assay by human PBMCs. RESULTS: AP203, which simultaneously targeted PD-L1 and costimulatory CD137, elicit superior agonistic effects over parental antibodies alone or in combination in terms of T cell activation, enhanced memory recall responses, and overcoming Treg-mediated immunosuppression (P < 0.05). The agonistic activity of AP203 was further demonstrated PD-L1-dependent by coculturing T cells with PD-L1-expressing cells. In vivo animal studies using immunodeficient or immunocompetent mice both showed a dose-related antitumor efficacy superior to parental antibodies in combination (P < 0.05). Correspondingly, AP203 significantly increased tumor infiltrating CD8 + T cells, while decreased CD4 + T cells, as well as Treg cells (P < 0.05), resulting in a dose-dependent increase in the CD8 + /CD4 + ratio. Moreover, either soluble or immobilized AP203 did not induce the production of inflammatory cytokines by human PBMCs. CONCLUSIONS: AP203 exerts potent antitumor activity not only by blocking PD-1/PD-L1 inhibitory signaling, but also by activating CD137 costimulatory signaling in effector T cells that consequently counteracts Treg-mediated immunosuppression. Based on promising preclinical results, AP203 should be a suitable candidate for clinical treatment of solid tumors.

Stepwise manipulation of cardiac computed tomography multi-planar reconstruction to mimic transesophageal echocardiography.

Cardiac computed tomography (CT) is increasingly used to plan transcatheter structural heart interventions. However, intraoperative guidance relies on transesophageal echocardiography (TEE) and fluoroscopy. This study sought to develop a stepwise CT multi-planar reconstruction manipulation method to mimic TEE, bridging the gap between preoperative planning and intraoperative guidance tools. This CT manipulation reproduced similar configurations as TEE views in the mid-esophageal left ventricle (LV) views, transgastric LV 2-chamber views for mitral apparatus, and other miscellaneous views. Stepwise cardiac CT manipulation to mimic TEE is the final piece of the puzzle in the mental co-registration of these three crucial imaging modalities. Now, we can predict the TEE images and fluoroscopy projections in a preoperative rehearsal, thus improving the intraoperative accuracy of interventions.

Release of lead, copper, zinc from the initial corrosion of brass water meter in drinking water: Influences of solution composition and electrochemical characterization.

Corrosion of brass plumbing materials may lead to metal release and deteriorate the drinking water quality. In this study, the initial corrosion of brass coupon cut from commercially available water meter was investigated. High rates of Pb, Cu and Zn release from the brass coupon were found during the early stage of corrosion (0-5 d) due to general corrosion and galvanic corrosion. The corrosion current density (Icorr) increased and resistance (RF) decreased during this period indicating that severe corrosion had occurred. In a later stage (5-30 d), a decreased Icorr and an increased RF were observed due to the development of a denser layer of Pb and Cu corrosion products which regulated the release of soluble Pb and Cu. The release of Zn continued and no significant Zn precipitation was found. Overall, particulate Pb, particulate Cu and soluble Zn dominated in the metal release during the initial corrosion of brass. The release of Pb, Cu and Zn was enhanced by a lower pH. Free chlorine was found to slightly reduce the release of Pb but promote the release of Cu and Zn. The presence of Pb on the brass surfaces was found to alleviate the dezincification process. A conceptual model based on metal release profile and electrochemical characterization was proposed to describe the initial corrosion of brass in typical drinking water.

Fully human chitinase-3 like-1 monoclonal antibody inhibits tumor growth, fibrosis, angiogenesis, and immune cell remodeling in lung, pancreatic, and colorectal cancers.

Considering the limited efficacy of current therapies in lung, colorectal, and pancreatic cancers, innovative combination treatments with diverse mechanisms of action are needed to improve patients' outcomes. Chitinase-3 like-1 protein (CHI3L1) emerges as a versatile factor with significant implications in various diseases, particularly cancers, fostering an immunosuppressive tumor microenvironment for cancer progression. Therefore, pre-clinical validation is imperative to fully realize its potential in cancer treatment. We developed phage display-derived fully human monoclonal CHI3L1 neutralizing antibodies (nAbs) and verified the nAbs-antigen binding affinity and specificity in lung, pancreatic and colorectal cancer cell lines. Tumor growth signals, proliferation and migration ability were all reduced by CHI3L1 nAbs in vitro. Orthotopic or subcutaneous tumor mice model and humanized mouse model were established for characterizing the anti-tumor properties of two CHI3L1 nAb leads. Importantly, CHI3L1 nAbs not only inhibited tumor growth but also mitigated fibrosis, angiogenesis, and restored immunostimulatory functions of immune cells in pancreatic, lung, and colorectal tumor mice models. Mechanistically, CHI3L1 nAbs directly suppressed the activation of pancreatic stellate cells and the transformation of macrophages into myofibroblasts, thereby attenuating fibrosis. These findings strongly support the therapeutic potential of CHI3L1 nAbs in overcoming clinical challenges, including the failure of gemcitabine in pancreatic cancer.

Removal of nano-sized polystyrene plastic from aqueous solutions using untreated coffee grounds.

Nanoplastic (NP) pollution is an emerging global concern due to its adverse impact on aquatic ecosystems. Nevertheless, the removal of aqueous NPs from aquatic environments remains a significant challenge. This study aims to investigate whether polystyrene NP in aqueous solutions can be removed using coffee grounds. Due to the difficulty associated with directly measuring NP levels and monitoring the biosorption process, we used fluorescent-orange amine-modified polystyrene beads (fluo-NP, 100 nm) to evaluate the efficacy of the biosorption process. The factors including pH, coffee grounds concentration, initial fluo-NP concentration, and contact time were optimized on batch experiments. In addition, the isotherm and kinetic models were employed to clarify the adsorption behaviors and mechanisms. It was found that aqueous fluo-NP particles were effectively adsorbed onto the coffee grounds over a wide pH range (pH 2-12), with a coffee ground concentration of 25 g/L leading to the maximum adsorption efficiency (74%). The equilibrium adsorption capacity of the coffee grounds was 4 mg/g for a reaction time of 40 min. Coffee grounds demonstrated the highest removal efficiency when the initial fluo-NP concentration was 100-125 mg/L. The Dubinin-Radushkevich model and pseudo-second-order model described the adsorption isotherm and kinetics well, respectively, and the adsorption at high fluo-NP concentration range was favorable. Moreover, the results suggest that the mechanism lies in the electrostatic interactions and hydrogen bonding between surface functional groups of the coffee grounds and the fluo-NP particles. Given that there is an urgent need to remove NPs from aqueous systems, this study illustrates that it is possible to use coffee ground biowaste for this purpose.