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PD-(L)1 inhibitor has revolutionized cancer treatment, but there are unmet clinical needs for PD-(L)1 inhibitor-resistant/refractory patients. Activation of T cells in tumor microenvironment by 4-1BB agonist antibodies is one of the promising approaches to complement the current limitation of PD-(L)1 inhibitors. Although 4-1BB is a promising target for immunotherapy, clinical studies using 4-1BB agonist antibodies showed systemic immune cell activation resulting in dose-limiting hepatotoxicity. We generated ABL503 (TJ-L14B), a bispecific antibody that combines PD-(L)1 blockade and PD-L1-dependent 4-1BB agonistic activity by binding both PD-L1 and 4-1BB to limit unwanted toxicities while exerting a potent anti-tumor efficacy. Here, we reported the pre-clinical properties of ABL503 (TJ-L14B) in various studies.
Methods
The activity of ABL503 (TJ-L14B) was characterized and evaluated in 1) PD-1 and 4-1BB signaling reporter cells cocultured with various tumor cells and PBMCs, 2) hPD-L1/h4-1BB knock-in mice implanted with MC38 tumor expressing different level of hPD-L1, 3) patient-derived lung cancer organoids cocultured with autologous PBMCs, and 4) PBMCs from healthy donors to measure cytokine release.
Results
Functional evaluation of ABL503 (TJ-L14B) indicates the activation of 4-1BB signaling was solely dependent on engagement of hPD-L1 expressed on immune cells as well as on tumor cells, pointing to pivotal roles of PD-L1 on both immune cells and tumor cells for the activity of ABL503 (TJ-L14B). In vivo anti-tumor activity of ABL503 (TJ-L14B) across different hPD-L1 levels showed prominent anti-tumor effect with significantly increased number of CD8+ cells and 4-1BB+ cells in the tumor. This anti-tumor activity was correlated with the proliferation (Ki-67+) of CD8+ T cells in the tumor microenvironment. Ex vivo assays utilizing patient-derived lung cancer organoids revealed that ABL503 (TJ-L14B) exhibits superior tumor-killing activity than that by benchmark PD-L1 antibody, Atezolizumab. In addition, cytokine release assay demonstrated that ABL503 (TJ-L14B) did not induce non-specific pro-inflammatory cytokine release by human PBMCs.
Conclusions
Our data indicate that PD-L1 and 4-1BB dual targeting bispecific antibody, ABL503 (TJ-L14B), shows potent 4-1BB agonistic activity and anti-tumor effect in a PD-L1-dependent fashion concomitant with 4-1BB+/CD8+ T cell activation and proliferation to overcome limitations of PD-(L)1-targeted therapy while minimizing the risk of peripheral toxicity. The phase 1 clinical trial in the U.S. is currently ongoing in patients with locally advanced or metastatic solid tumors (NCT04762641).
The Membrane Electrode Assembly (MEA) stands as the pivotal element in electrochemical devices such as fuel cells and electrochemical hydrogen pumps (EHP). Notably, ion-pair High-Temperature Proton Exchange Membrane Fuel Cells (HT-PEMFCs) with reduced phosphoric acid concentrations within the MEA have been innovatively designed, allowing for the integration of diverse ion-conducting binders, known as ionomers, into both the cathode and anode electrodes [1] . This study delineates initial distinctions in MEA configurations among different device types (HT-Fuel cell and EHP), conducting a comprehensive analysis of performance disparities between traditional polybenzimidazole-based systems and various ion-pair proton exchange membranes [2] . Subsequently, a detailed exploration unfolds, focusing on the utilization of ion-pair membranes and different ionomer types for the three aforementioned devices. This comprehensive examination offers a unified comparative analysis encompassing ionomer type, membrane thickness, catalyst:ionomer ratio, and phosphoric acid doping levels, particularly in the context of performance at intermediate temperatures (160℃). Conclusions are drawn based on results derived from both half-cell and single-cell evaluations. Finally, overarching guidelines are presented to inform the formulation of high-performance MEA configurations tailored for ion-pair HT-PEMFCs and EHPs. References: [1] Lim, K. H.; Lee, A. S.; Atanasov, V.; Kerres, J.; Park, E. J.; Adhikari, S.; Maurya, S.; Manriquez, L. D.; Jung, J.; Fujimoto, C.; Matanovic, I.; Jankovic, J.; Hu, Z.; Jia, H.; Kim, Y. S. Protonated phosphonic acid electrodes for high power heavy-duty vehicle fuel cells, Nature Energy , 7, 248 (2022). [2] Lim, K, H; Matanovic, I; Maurya, S; Kim Y; De Castro E. S; Jang, J-H; Park, H; Kim, Y.S. High Temperature Polymer Electrolyte Membrane Fuel Cells with High Phosphoric Acid Retention. ACS Energy Lett. , 8, 1, 529–536 (2023).
Abstract More active electrocatalysts for H 2 and O 2 evolution reactions, efficient membranes, and robust porous transport layers (PTL) are required for designing advanced proton exchange membrane water electrolysis (PEMWE) systems. An N‐doped carbon matrix is introduced in this study to surpass the existing Ti PTLs. One‐step pyrolysis results in the carbonization of polyaniline films to the N‐doped carbon matrix, simultaneous formation of desiccation cracks and Ir x Ru y nanoparticles, and partial impregnation of the synthesized particles into the carbon matrix. The embedded Ir x Ru y nanoparticles are firmly bound to the surface of the carbon matrix, inhibiting the dissolution and detachment of the nanoparticles during the O 2 evolution reaction (OER). The cracks in the carbon matrix allow the steady transport of the produced O 2 , comparable to conventional PTLs. After optimizing the Ir and Ru contents of the nanoparticles based on the electrocatalytic performance, Ir 88 Ru 12 embedded in the N‐doped carbon matrix is found to be the most suitable catalyst for enhancing the OER performance of the PEMWE system with negligible degradation. These findings can potentially contribute to the industrial application of PEMWE. Relevant electrochemical systems with membrane electrode assemblies, such as fuel cells and CO 2 reduction systems, can be modified using the suggested structure.
Fe–N active site-exposed carbon nanofibers were synthesized via electrospinning and Fe-ZIF in situ growth. The Fe–S bonds enhanced polysulfide adsorption and redox kinetics, exhibiting excellent cycling stability in lithium–sulfur batteries.
We studied the interaction of SO2 with ice films at temperatures above 80 K, with emphasis on the examination of the precursor states of SO2 hydrolysis, or SO2 surface complexes. Cs+ reactive ion scattering (RIS) and low energy sputtering (LES) techniques were used to examine the surface reaction products, in conjunction with temperature-programmed desorption (TPD) to monitor the desorbing species. The study indicated that the reaction of SO2 with the ice surface occurred through several distinct intermediate states, including a solvated SO2 species, a DSO2 species, and a strongly ionic molecular species, and these intermediates could be isolated on the ice surface due to kinetic trapping.
The rheology of petroleum coke (petcoke) water slurries was investigated with a variety of nonionic and anionic dispersants including poly(ethylene oxide) (PEO)-b-poly(propylene oxide) (PPO)-b-PEO triblock copolymers (trade name: Pluronic, BASF), poly(vinyl alcohol) (PVA), polyvinylpyrrolidone (PVP), poly(ethylene oxide) (PEO), poly(carboxylate acid) (PCA), sodium lignosulfonate (SLS), and poly(acrylic acid) (PAA). Each effective dispersant system shared very similar rheological behavior to the others when examined at the same volume fraction from its maximum petcoke loading. Triblock copolymer, Pluronic F127 (F127), was found to be the best dispersant by comparing the maximum petcoke loading for each dispersant. The yield stress was measured as a function of petcoke loading and dispersant concentration for F127, and a minimum dispersant concentration was observed. An adsorption isotherm and atomic force microscopy (AFM) images reveal that this effective dispersion of petcoke particles by F127 is due to the formation of a uniform monolayer of brushes where hydrophobic PPO domains of F127 adhere to the petcoke surface, while hydrophilic PEO tails fill the gap between petcoke particles. F127 was then compared to other Pluronics with various PEO and PPO chain lengths, and the effects of surface and dispersant hydrophilicity were examined. Finally, xanthan gum (XG) was tested as a stabilizer in combination with F127 for potential industrial application, and F127 appears to break the XG aggregates into smaller aggregates through competitive adsorption, leading to an excellent degree of dispersion but the reduced stability of petcoke slurries.
Methanol crossover is one of the largest problems in direct methanol fuel cells (DMFCs). Methanol passing from the anode to the cathode through the membrane is oxidized at the cathode, degrading the DMFC performance, and the intermediates of the methanol oxidation reaction (MOR) cause cathode catalyst poisoning. Therefore, it is essential to develop a cathode catalyst capable of inhibiting MOR while promoting the oxygen reduction reaction (ORR), which is a typical cathode reaction in DMFCs. In this study, a carbon-encapsulated Pt cathode catalyst was synthesized for this purpose. The catalyst was simply synthesized by heat treatment of Pt-aniline complex-coated carbon nanofibers. The carbon shell of the catalyst was effective in inhibiting methanol from accessing the Pt core, and this effect became more prominent as the graphitization degree of the carbon shell increased. Meanwhile, the carbon shell allowed O2 to permeate regardless of the graphitization degree, enabling the Pt core to participate in ORR. The synthesized catalyst showed higher performance and stability in single-cell tests under various conditions compared to commercial Pt/C.
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