ITC-6102RO, a novel B7-H3 antibody-drug conjugate, exhibits potent therapeutic effects against B7-H3 expressing solid tumors.

BACKGROUND: The B7-H3 protein, encoded by the CD276 gene, is a member of the B7 family of proteins and a transmembrane glycoprotein. It is highly expressed in various solid tumors, such as lung and breast cancer, and has been associated with limited expression in normal tissues and poor clinical outcomes across different malignancies. Additionally, B7-H3 plays a crucial role in anticancer immune responses. Antibody-drug conjugates (ADCs) are a promising therapeutic modality, utilizing antibodies targeting tumor antigens to selectively and effectively deliver potent cytotoxic agents to tumors. METHODS: In this study, we demonstrate the potential of a novel B7-H3-targeting ADC, ITC-6102RO, for B7-H3-targeted therapy. ITC-6102RO was developed and conjugated with dHBD, a soluble derivative of pyrrolobenzodiazepine (PBD), using Ortho Hydroxy-Protected Aryl Sulfate (OHPAS) linkers with high biostability. We assessed the cytotoxicity and internalization of ITC-6102RO in B7-H3 overexpressing cell lines in vitro and evaluated its anticancer efficacy and mode of action in B7-H3 overexpressing cell-derived and patient-derived xenograft models in vivo. RESULTS: ITC-6102RO inhibited cell viability in B7-H3-positive lung and breast cancer cell lines, inducing cell cycle arrest in the S phase, DNA damage, and apoptosis in vitro. The binding activity and selectivity of ITC-6102RO with B7-H3 were comparable to those of the unconjugated anti-B7-H3 antibody. Furthermore, ITC-6102RO proved effective in B7-H3-positive JIMT-1 subcutaneously xenografted mice and exhibited a potent antitumor effect on B7-H3-positive lung cancer patient-derived xenograft (PDX) models. The mode of action, including S phase arrest and DNA damage induced by dHBD, was confirmed in JIMT-1 tumor tissues. CONCLUSIONS: Our preclinical data indicate that ITC-6102RO is a promising therapeutic agent for B7-H3-targeted therapy. Moreover, we anticipate that OHPAS linkers will serve as a valuable platform for developing novel ADCs targeting a wide range of targets.

Effect of ß-resin of binderless coke on mechanical properties of high-density carbon blocks at high molding pressure.

High-density carbon blocks have excellent mechanical, thermal, and electrical properties. In particular, these blocks are applied in various fields while maintaining excellent physical properties even in harsh environments. In this study, binderless coke manufactured under certain conditions was used to form green bodies (GBs) under various pressure conditions of 50 to 250 MPa, and the bodies were carbonized to form a high-density carbon block (CB). Then, the effect of the ß-resin and oxygen functional groups of binderless coke on the mechanical properties of the high-density carbon block according to molding pressure was considered. When molding at a pressure of under 200 MPa, the ratio of O and C (O/C) has a greater effect, and the larger the O/C, the higher the mechanical properties. On the other hand, when molding at a high pressure of 250 MPa, the ß-resin content has a greater effect and steadily increases when the ß-resin content is low and when the mechanical properties are sufficiently reduced. In particular, in the case of CB-N7A3-250, which has the highest ß-resin content of 3.7 wt%, the density was 1.79 g/cm3, the flexural strength was 106 MPa, and the shore hardness was 99 HSD.

Preparation of Isotropic Carbon Fibers from Kerosene-Purified Coal Tar Pitch by Co-Carbonization with Pyrolysis Fuel Oil.

An inexpensive and general-purpose carbon fiber was prepared using coal tar pitch. In contrast to the solvent extraction process employing expensive solvents, a low-cost centrifugal separation method facilitated the reduction of loss due to the pitch purification and an overall yield increase. The coal tar pitch purified by centrifugation and subsequently co-carbonized with pyrolysis fuel oil improved in spinnability. Moreover, the resulting spinnable pitch had a softening point of 250 °C. The obtained carbon fibers were heat-treated at 1000 °C for 5 min, resulting in a tensile strength of approximately 1000 MPa and an average diameter of 9 µm. In this study, we present an effective method for obtaining low-cost general-purpose isotropic carbon fibers.

The Effect of Oxygen Content in Binderless Cokes for High-Density Carbon Blocks from Coal Tar Pitch.

High-density carbon blocks are much lighter than metals and have excellent mechanical properties and are one of the materials garnering attention to replace existing metal parts. In this study, a binderless coke was produced by changing the flow rates of nitrogen and air as a carrier gas during heat treatment of coal tar pitch and using this, a green body was formed at 150 MPa and carbonized to produce a high-density carbon block. We express the binderless coke produced in this way by N10A0, N7A3, N5A5, N3A7, N0A10 according to the ratio of nitrogen and air, and in the case of carbon block, we have added CB in front of it. We then considered the effect of oxygen content in the binderless cokes on the optical, chemical, and mechanical properties. It was observed that the produced binderless cokes develop into a dense mosaic structure with a small particle size as the air flow rate increased. To survey the change in oxygen content of the produced binderless coke, O1s and C1s regions were measured using X-ray photoelectric spectroscopy (XPS), and O1s/C1s was calculated. The O1s/C1s ratio steadily increased as the air flow rate increased, and in the case of N0A10, it increased about twice as much as that of N10A0 to 11.20%. ß-resin has a very large effect on the mechanical strength of the carbon block in addition to air in the pitch. And in the case of CB-N0A10, it shows the best mechanical strength with a density of 1.72 g/cm3, bending strength of 87 MPa, and shore hardness of 93 HSD.

A CMOS Multi-Modal Electrochemical and Impedance Cellular Sensing Array for Massively Paralleled Exoelectrogen Screening.

The paper presents a 256-pixel CMOS sensor array with in-pixel dual electrochemical and impedance detection modalities for rapid, multi-dimensional characterization of exoelectrogens. The CMOS IC has 16 parallel readout channels, allowing it to perform multiple measurements with a high throughput and enable the chip to handle different samples simultaneously. The chip contains a total of 2 × 256 working electrodes of size 44 µm × 52 µm, along with 16 reference electrodes of dimensions 56 µm × 399 µm and 32 counter electrodes of dimensions 399 µm × 106 µm, which together facilitate the high resolution screening of the test samples. The chip was fabricated in a standard 130nm BiCMOS process. The on-chip electrodes are subjected to additional fabrication processes, including a critical Al-etch step that ensures the excellent biocompatibility and long-term reliability of the CMOS sensor array in bio-environment. The electrochemical sensing modality is verified by detecting the electroactive analyte NaFeEDTA and the exoelectrogenic Shewanella oneidensis MR-1 bacteria, illustrating the chip's ability to quantify the generated electrochemical current and distinguish between different analyte concentrations. The impedance measurements with the HEK-293 cancer cells cultured on-chip successfully capture the cell-to-surface adhesion information between the electrodes and the cancer cells. The reported CMOS sensor array outperforms the conventional discrete setups for exoelectrogen characterization in terms of spatial resolution and speed, which demonstrates the chip's potential to radically accelerate synthetic biology engineering.

Aryl Sulfate is a Useful Motif for Conjugating and Releasing Phenolic Molecules: Sulfur Fluorine Exchange Click Chemistry Enables Discovery of Ortho-Hydroxy-Protected Aryl Sulfate Linker.

A new self-immolative linker motif, Ortho Hydroxy-Protected Aryl Sulfate (OHPAS), was devised, and OHPAS-containing antibody drug conjugates (ADC) were tested in vitro and in vivo. Conveniently synthesized using Sulfur Fluorine Exchange (SuFEx) chemistry, it is based structurally on diaryl sulfate, with one aryl acting as a payload and the other as a self-immolative sulfate unit having a latent phenol function at the ortho position. The chemically stable OHPAS linker was stable in plasma samples from 5 different species, yet it can release the payload molecule smoothly upon chemical or biological triggering. The payload release proceeds via intramolecular cyclization, producing a cyclic sulfate coproduct that eventually hydrolyzes to a catechol monosulfate. A set of OHPAS-containing ADCs based on Trastuzumab were prepared with a drug to antibody ratio of ∼2, and were shown to be cytotoxic in 5 different cancer cell lines in vitro and dose-dependently inhibited tumor growth in a NCI-N87 mouse xenograft model. We conclude that OHPAS conjugates will be of considerable use for delivering phenol-containing payloads to tissues targeted for medical intervention.

Manufacture of high density carbon blocks by self-sintering coke produced via a two-stage heat treatment of coal tar.

High-strength and high-density carbonized carbon blocks from self-sintering coke were manufactured using coal tar and two-stage heat treatments (1st and 2nd stage treatments). First, the molecular weight distribution of the refined coal tar was controlled through a pressured heat treatment (1st stage treatment). Second, the 1st stage heat-treated coal tar (1S-CT) was treated using a delayed coking system (2nd stage treatment) to become the self-sintering coke. Finally, carbon blocks were molded from 2nd stage heat-treated coke (2S-C) and carbonized at 1200 °C for 1 h. Through rapid decomposition of the high molecular weight components in the coal tar at 360 °C in the 1st stage treatment, the molecular weight distribution of coal tar was confirmed to be controllable by the 1st stage treatment. Swelling during carbonization was observed in carbon blocks manufactured from 2S-C containing more than 15 wt% of volatile matter from 150-450 °C. The optimum conditions of the two-stage heat treatments were confirmed to be 300 °C for 3 h and 500 °C for 1 h. The highest density and flexural strength of the carbonized carbon blocks manufactured from 2S-C were 1.46 g/cm3 and 69.2 MPa, respectively.