Antibody Therapies for the Treatment of Acute Myeloid Leukemia: Exploring Current and Emerging Therapeutic Targets

INTRODUCTION: Acute myeloid leukemia (AML) is the most common and deadly type of leukemia affecting adults. It is typically managed with rounds of non-targeted chemotherapy followed by hematopoietic stem cell transplants, but this is only possible in patients who can tolerate these harsh treatments and many are elderly and frail. With the identification of novel tumor-specific cell surface receptors, there is great conviction that targeted antibody therapies will soon become available for these patients. AREAS COVERED: In this review, we describe the current landscape of known target receptors for monospecific and bispecific antibody-based therapeutics for AML. Here, we characterize each of the receptors and targeted antibody-based therapeutics in development, illustrating the rational design behind each therapeutic compound. We then discuss the bispecific antibodies in development and how they improve immune surveillance of AML. For each therapeutic, we also summarize the available pre-clinical and clinical data, including data from discontinued trials. EXPERT OPINION: One antibody-based therapeutic has already been approved for AML treatment, the CD33-targeting antibody-drug conjugate, gemtuzumab ozogamicin. Many more are currently in pre-clinical and clinical studies. These antibody-based therapeutics can perform tumor-specific, elaborate cytotoxic functions and there is growing confidence they will soon lead to personalized, safe AML treatment options that induce durable remissions

Towards Layer-Selective Quantum Spin Hall Channels in Weak Topological Insulator Bi4Br2I2

Weak topological insulators, constructed by stacking quantum spin Hall insulators with weak interlayer coupling, offer promising quantum electronic applications through topologically nontrivial edge channels. However, the currently available weak topological insulators are stacks of the same quantum spin Hall layer with translational symmetry in the out-of-plane direction, leading to the absence of the channel degree of freedom for edge states. Here, we study a candidate weak topological insulator, Bi4Br2I2, which is alternately stacked by three different quantum spin Hall insulators, each with tunable topologically non-trivial edge states. Our angle-resolved photoemission spectroscopy and first-principles calculations show that an energy gap opens at the crossing points of different Dirac cones correlated with different layers due to the interlayer interaction. This is essential to achieve the tunability of topological edge states as controlled by varying the chemical potential. Our work offers a perspective for the construction of tunable quantized conductance devices for future spintronic applications

LILRB3 Supports Immunosuppressive Activity of Myeloid Cells and Tumor Development

The existing T cell-centered immune checkpoint blockade therapies have been successful in treating some but not all patients with cancer. Immunosuppressive myeloid cells, including myeloid-derived suppressor cells (MDSC), that inhibit antitumor immunity and support multiple steps of tumor development are recognized as one of the major obstacles in cancer treatment. Leukocyte Ig-like receptor subfamily B3 (LILRB3), an immune inhibitory receptor containing tyrosine-based inhibitory motifs (ITIM), is expressed solely on myeloid cells. However, it is unknown whether LILRB3 is a critical checkpoint receptor in regulating the activity of immunosuppressive myeloid cells, and whether LILRB3 signaling can be blocked to activate the immune system to treat solid tumors. Here, we report that galectin-4 and galectin-7 induce activation of LILRB3 and that LILRB3 is functionally expressed on immunosuppressive myeloid cells. In some samples from patients with solid cancers, blockade of LILRB3 signaling by an antagonistic antibody inhibited the activity of immunosuppressive myeloid cells. Anti-LILRB3 also impeded tumor development in myeloid-specific LILRB3 transgenic mice through a T cell-dependent manner. LILRB3 blockade may prove to be a novel approach for immunotherapy of solid cancers

Ligand-assisted cation-exchange engineering for high-efficiency colloidal Cs1−xFAxPbI3 quantum dot solar cells with reduced phase segregation

The mixed caesium and formamidinium lead triiodide perovskite system (Cs1−xFAxPbI3) in the form of quantum dots (QDs) offers a pathway towards stable perovskite-based photovoltaics and optoelectronics. However, it remains challenging to synthesize such multinary QDs with desirable properties for high-performance QD solar cells (QDSCs). Here we report an effective oleic acid (OA) ligand-assisted cation-exchange strategy that allows controllable synthesis of Cs1−xFAxPbI3 QDs across the whole composition range (x = 0–1), which is inaccessible in large-grain polycrystalline thin films. In an OA-rich environment, the cross-exchange of cations is facilitated, enabling rapid formation of Cs1−xFAxPbI3 QDs with reduced defect density. The hero Cs0.5FA0.5PbI3 QDSC achieves a certified record power conversion efficiency (PCE) of 16.6% with negligible hysteresis. We further demonstrate that the QD devices exhibit substantially enhanced photostability compared with their thin-film counterparts because of suppressed phase segregation, and they retain 94% of the original PCE under continuous 1-sun illumination for 600 h

Cohesin Promotes the Myelination Transcriptional Program in Oligodendrocytes

The general metadata -- e.g., title, author, abstract, subject headings, etc. -- is publicly available, but access to the submitted files is restricted to UT Southwestern campus access and/or authorized UT Southwestern users.The cohesin complex is crucial for sister-chromatid cohesion and chromatin spatial organization in the interphase nucleus. Cohesin-extruded DNA loops have regulatory functions in gene expression. Mutations of cohesin subunits and regulators cause human developmental diseases termed cohesinopathies. The vertebrate cohesin consists of SMC1, SMC3, RAD21, and either STAG1 or STAG2. STAG1-cohesin and STAG2-cohesin are redundant in sister-chromatid cohesion, but appear to exert specific functions in gene regulation. How they achieve their functions in gene expression is poorly understood. I characterized the outcomes of Stag2 loss in the mouse nervous system. Conditional knockout (CKO) of Stag2 in the nervous system causes severe growth retardation, neurological defects, and premature death, in part due to insufficient myelination of nerve fibers. Expression profiling reveals that myelination-related genes are downregulated in oligodendrocytes of Stag2 CKO mice. Chromatin conformational capture experiments (Hi-C) reveal that Stag2-deficient oligodendrocytes contain fewer DNA loops than wild-type cells do. In particular, promoter-anchored DNA loops at downregulated genes are significantly reduced by Stag2 loss. Interestingly, downregulated genes exhibit promoter-anchored "stripes", indicative of strong loop extrusion. We propose that STAG2-cohesin generated promoter-anchored loops at myelination-promoting genes are critical for the proper gene expression during oligodendrocyte differentiation and brain development. Our study implicates defective myelination as a contributing factor to cohesinopathy and establishes oligodendrocytes as a relevant cell type to explore the mechanism by which cohesin regulates transcription