Search

Increasing the binding affinity of an antibody to its target antigen is a crucial task in antibody therapeutics development. This paper presents a pretrainable geometric graph neural network, GearBind, and explores its potential in in silico affinity maturation. Leveraging multi-relational graph construction, multi-level geometric message passing and contrastive pretraining on mass-scale, unlabeled protein structural data, GearBind outperforms previous state-of-the-art approaches on SKEMPI and an independent test set. A powerful ensemble model based on GearBind is then derived and used to successfully enhance the binding of two antibodies with distinct formats and target antigens. ELISA EC50 values of the designed antibody mutants are decreased by up to 17 fold, and KD values by up to 6.1 fold. These promising results underscore the utility of geometric deep learning and effective pretraining in macromolecule interaction modeling tasks. Increasing the binding affinity of an antibody to its target antigen is key for antibody therapeutics. Here the authors report a pretrainable geometric graph neural network, GearBind, and explore its potential in in silico antibody affinity maturation. [ABSTRACT FROM AUTHOR]

Nipah virus infection, one of the top priority diseases recognized by the World Health Organization, underscores the urgent need to develop effective countermeasures against potential epidemics and pandemics. Here, we identify a fully human single-domain antibody that targets a highly conserved cryptic epitope situated at the dimeric interface of the Nipah virus G protein (receptor binding protein, RBP), as elucidated through structures by high-resolution cryo-electron microscopy (cryo-EM). This unique binding mode disrupts the tetramerization of the G protein, consequently obstructing the activation of the F protein and inhibiting viral membrane fusion. Furthermore, our investigations reveal that this compact antibody displays enhanced permeability across the blood-brain barrier (BBB) and demonstrates superior efficacy in eliminating pseudovirus within the brain in a murine model of Nipah virus infection, particularly compared to the well-characterized antibody m102.4 in an IgG1 format. Consequently, this single-domain antibody holds promise as a therapeutic candidate to prevent Nipah virus infections and has potential implications for vaccine development. The fully human single-domain antibody n425 aginst NiV targets a conserved cryptic epitope on G protein and inhibits membrane fusion by disrupting tetramerization. These insights advance neutralization mechanisms and effective countermeasure design. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T cell therapy shows promise in treating malignant tumors. However, the use of human epidermal growth factor receptor-2 (HER2) CAR-T cells carries the risk of severe toxicity, including cytokine release syndrome, due to their "on-target off-tumor" recognition of HER2. Enhancing the quality and functionality of HER2 CARs could greatly improve the therapeutic potential of CAR-T cells. In this study, we developed a novel anti-HER2 monoclonal antibody, Ab8, which targets domain III of HER2, distinct from the domain IV recognition of trastuzumab. Although two anti-HER2 mAbs induced similar levels of antibody-dependent cellular cytotoxicity, trastuzumab-based CAR-T cells exhibited potent antitumor activity against HER2-positive cancer cells. In conclusion, our findings provide scientific evidence that antibody recognition of the membrane-proximal domain promotes the anti-tumor response of HER2-specific CAR-T cells. [ABSTRACT FROM AUTHOR]

This article, published in the journal Cell Discovery, discusses the structure of a G protein-coupled receptor (GPCR) called UL78, which is encoded by the human cytomegalovirus (HCMV). The authors used cryo-electron microscopy (cryo-EM) to determine the structure of UL78 and found that it forms a homotrimeric architecture, which is different from other known GPCR structures. The study also revealed unique features of UL78 at both the intracellular and extracellular sides, suggesting that it may function through receptor oligomerization. Further research is needed to explore the physiological significance of this discovery. [Extracted from the article]

Tribulus terrestris (T. terrestris) is an herb that has been used in various traditional medicine practices since ancient times. More recently, the pronounced health benefits of this herb have been evaluated within a wide scope, without properly acknowledging its nutraceutical value. Therefore, this article intends to provide an integrated overview on the nutraceutical potential of T. terrestris in the area of human health promotion. This review discusses the potential employability of T. terrestris and its derived products as nutraceuticals in prevention, treatment, and management of prevalent human diseases and associated conditions. The outcomes of several in vitro and in vivo studies elaborate on the ability of T. terrestris supplements and different fractions to act as antioxidant, anti-inflammatory, anticancer, antidiabetic, testosterone boosting, and cardio, renal and liver protective agents. Many studies reveal that T. terrestris would act as an excellent nutraceutical that prevents harmful impacts to the human body. Its bioactivities are driven by various factors, and it has been suggested to be used to replace certain pharmaceuticals and synthetic drugs. In-depth clinical studies on the herbal pharmacodynamics are needed and would broaden the scope of nutraceutical applications of T. terrestris. [ABSTRACT FROM AUTHOR]