PredictionProbe (United States)

Abstract T cell engager (TCE) antibodies have been proven to be effective for a variety of hematological malignancies, with at least 10 marketed drugs to date; however, their efficacy in many solid tumors is still very limited due to a number of challenges. One of the leading challenges is the lack of tumor-specific targets, leading to an increased risk of on-target, off-tumor toxicity. An approach to address this challenge is to build a “prodrug” TCE that is conditionally activated in the tumor microenvironment (TME), taking advantages of various masking technology platforms that block the release of active TCE drug outside of the TME. To develop such a novel TCE molecule with improved tumor selectivity, potency, and safety profile, we first discovered a masking peptide specific to a CD3 VHH antibody that we previously developed, and demonstrated that the masked CD3 VHH can effectively reduce T cell activation several hundred-fold. Next, we fused this masking peptide to the CD3 VHH arm via a proteolytically-labile linker containing sequence motifs sensitive to proteases enriched in the TME, and showed that upon cleavage by proteases, the T cell-activating potency of such a masked CD3 VHH can be effectively recovered. Finally, with such a CD3 VHH armed with cleavable linker and masking peptide, we built a series of prodrug TCE molecules targeting ENPP3 (ectonucleotide pyrophosphatase/phosphodiesterase family member 3), a tumor associated antigen with good tumor selectivity for renal cell carcinoma. Our in vitro validation studies demonstrated that the potency of these TCE prodrugs in killing ENPP3+ tumor cells can be restored to a similar level as the unmasked, active TCE molecule upon proteolytic cleavage. Our in vivo studies using an ENPP3+ CDX model with transplanted human PBMCs demonstrated two important points: (i) the prodrug/masked ENPP3-targeted TCE can potently inhibit tumor growth to a comparable level as the unmasked version and clinical benchmarks, and (ii) the prodrug TCE can be dosed at least 100-fold higher than the active drugs without any observed toxicity, suggesting a greatly improved safety profile. Further preclinical development of these ENPP3-targeted prodrug TCE molecules, including pharmacokinetics and toxicity studies in non-human primates, is ongoing. Citation Format: Yu Liang, Li Chen, Lindi Wang, Yingyu Li, Xin Wang, Yang Xin, Mingzhu Shao, Jiangtao Ning, Ziyu Chen, Cheng Luo, Jingjing Nie, Yue Wu, Tingting Yang, Hai Huang, Miaomiao Song. The discovery and development of a bispecific t cell engager prodrug targeting ENPP3 for renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Kidney Cancer Research: From Molecular Insights to Therapeutic Breakthroughs; 2026 Mar 13-16; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_2):Abstract nr A010.

The physical and dynamic properties of marine mud are a function of the interaction of clay fabric, organic matter (OM), and seawater physico-chemistry, and, when present, free gas. OM is the focus of this presentation and is a determinant of several properties in mud deposits including (1) free water available versus total water content in clay fabric pore space as a result of (2) OM seawater hydration, (3) reduction of permeability by volumetric contribution of hydrated OM in pore space, (4) OM density reduction by seawater hydration versus dry OM density, (5) dynamic behavior by physico-chemical attachment of OM to clay particles in potential energy fields created by the clay fabric signatures (edge-to-face, edge-to-edge, and offset face-to-face) in seawater, (6) high percentages of OM (TOC >2%) result in a high degree of compressibility at considerably lower stress compared to mud deposits with <2%TOC. Measurement and characterization of OM, previously often neglected, is expected to provide new significant insights and understanding of marine mud physical and dynamic properties and contribute to more reliable research data for scientists and engineers. Handling and storage methods used for mud samples containing OM are critical for accurate results.

Abstract This article discusses the practice of FIB-based in situ lift-out, a sample preparation method that has proven particularly useful for failure analysis. It explains how samples are now being made for a wide range of TEM techniques, including holography, tomography, high-angle annular dark-field scanning, and electron energy-loss spectroscopy. In most cases, achieving optimal quality requires the use of alternate FIB milling angles, as in plan-view, sideways, and backside milling, all of which are discussed.

Extended abstract of a paper presented at Microscopy and Microanalysis 2010 in Portland, Oregon, USA, August 1 – August 5, 2010.

Abstract The availability of the focused ion beam (FIB) microscope with its excellent imaging resolution, depth of focus and ion milling capability has made it an appealing platform for materials characterization at the sub-micron, or "nano" level. This article focuses on nanomechanical characterization in the FIB, which is an extension of the FIB capabilities into the realm of nano-technology. It presents examples that demonstrate the power and flexibility of nanomechanical testing in the FIB or scanning electron microscope with a probe shaft that includes a built-in strain gauge. Loads that range from grams to micrograms are achievable. Calibration is limited only by the availability of calibrated load cells in the smallest load ranges. Deflections in the range of a few nanometers range can be accurately applied. Simultaneous electrical, mechanical, and visual data can be combined to provide a revealing study of physical behavior of complex and dynamic nanostructures.