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Progranulin (PGRN, encoded by the GRN gene) plays a key role in the development, survival, function, and maintenance of neurons and microglia in the mammalian brain. It regulates lysosomal biogenesis, inflammation, repair, stress response, and aging. GRN loss-of-function mutations cause neuronal ceroid lipofuscinosis or frontotemporal dementia-GRN (FTD-GRN) in a gene dosage-dependent manner. Mutations that reduce PGRN levels increase the risk for developing Alzheimer's disease, Parkinson's disease, and limbic-predominant age-related transactivation response DNA-binding protein 43 encephalopathy, as well as exacerbate the progression of amyotrophic lateral sclerosis (ALS) and FTD caused by the hexanucleotide repeat expansion in the C9orf72 gene. Elevating and/or restoring PGRN levels is an attractive therapeutic strategy and is being investigated for neurodegenerative diseases through multiple mechanisms of action.

Background - Inhibitory sialic acid-binding immunoglobulin-type lectins (Siglecs) are a subset of the Siglec family of cell surface receptors that potentiate immune tolerance. A multitude of inhibitory Siglecs on myeloid cells become engaged in sialic acid-rich tumor microenvironments, suggesting that disrupting Siglec-sialic acid signaling could confer therapeutic benefit in cancer. To accomplish this, we designed AL009, an engineered Siglec-9 extracellular domain-Fc fusion molecule that acts as a sialic acid trap and a multi-Siglec inhibitor, repolarizing suppressive myeloid cells and activating an anti-cancer response. Methods - Cooperative binding of AL009 was analyzed by flow cytometry using cultured human tumor cell lines and myeloid-derived suppressor cells (MDSCs) differentiated from primary human monocytes. Monocytes, MDSCs, and macrophages differentiated from primary human monocytes were assessed for AL009 binding by flow cytometry. AL009m (AL009 with a mouse Fc) was fluorophore-labeled and intravenously injected into B6 mice to analyze biodistribution via ex vivo tissue imaging over time. Initial toxicology screening was conducted in cynomolgus monkeys in a non-terminal study. Results - AL009 displays cooperative binding with sialic acid and Fc gamma receptors on myeloid cells. When comparing binding among myeloid cell subsets, AL009 preferentially binds MDSCs. Analysis of the biodistribution of labeled AL009m in mice showed the greatest accumulation in the spleen, consistent with immune cell targeting in vivo. Further, Fc engineering of AL009 improved the pharmacodynamic profile compared to a non-engineered Fc. In cynomolgus monkeys, single doses of 80 mg/kg appeared safe and without clinically significant findings. Conclusions - The engineered structure of AL009 leads to preferential binding to an immunosuppressive subset of myeloid cells. This targeting leads to repolarization of myeloid cells and activates an innate and adaptive anti-cancer response. Pharmacologically relevant doses of AL009 appear well-tolerated in initial studies in non-human primates, supporting further development for entry into clinical studies. Citation Format: Sam Nalle, Helen Lam, Cheryl Barner, Hua Long, Spencer Liang, Arnon Rosenthal, Daniel Maslyar. AL009 is a multi-Siglec inhibitor engineered to bind myeloid cells that enhances innate and adaptive immunity to cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 613.

Wang et al. demonstrate that a mAb specific for the human microglial receptor TREM2 induces microglia proliferation, ameliorates Aβ-induced pathology in a mouse model of Alzheimer’s disease, and can be given safely in a first-in-human phase I clinical trial., TREM2 is a receptor for lipids expressed in microglia. The R47H variant of human TREM2 impairs ligand binding and increases Alzheimer’s disease (AD) risk. In mouse models of amyloid β (Aβ) accumulation, defective TREM2 function affects microglial response to Aβ plaques, exacerbating tissue damage, whereas TREM2 overexpression attenuates pathology. Thus, AD may benefit from TREM2 activation. Here, we examined the impact of an anti-human TREM2 agonistic mAb, AL002c, in a mouse AD model expressing either the common variant (CV) or the R47H variant of TREM2. Single-cell RNA-seq of microglia after acute systemic administration of AL002c showed induction of proliferation in both CV- and R47H-transgenic mice. Prolonged administration of AL002c reduced filamentous plaques and neurite dystrophy, impacted behavior, and tempered microglial inflammatory response. We further showed that a variant of AL002c is safe and well tolerated in a first-in-human phase I clinical trial and engages TREM2 based on cerebrospinal fluid biomarkers. We conclude that AL002 is a promising candidate for AD therapy., Graphical Abstract

Data standards are a powerful, real-world tool for enterprise interoperability, yet there exists no well-grounded methodology for selecting among alternative standards approaches. We focus on a specific sub-problem within a community's data sharing challenge and identify four major standards-based approaches to that task. We present characteristics of a data sharing community that one should consider in selecting a standards approach--such as relative power, motivation level, and technical sophistication of different participants--and illustrate with real-world examples. These characteristics and other factors are then analyzed to develop decision rules for selecting among the four approaches. Independent of the data exchange problem, we suggest two general practices in choosing a standards approach: (1) vertical decomposition of interoperability issues, in order to define a narrow, formal, tractable problem, and (2) option-exclusion rules, as they are much simpler than stating optimal-choice rules.