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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]

Single‐domain antibody–drug conjugates (sdADCs) have been proven to have deeper solid tumor penetration and intratumor accumulation capabilities due to their smaller size compared with traditional IgG format ADCs. However, one of the key challenges for improving clinical outcomes of sdADCs is their abbreviated in vivo half‐life. In this study, we innovatively fused an antihuman serum albumin (αHSA) nanobody to a sdADCs targeting oncofetal antigen 5T4, conferring serum albumin binding to enhance the pharmacokinetic profiles of sdADCs. The fusion protein was conjugated with monomethyl auristatin E (MMAE) at s224c site mutation. The conjugate exhibited potent cytotoxicity against various tumor cells. Compared with the nonalbumin‐binding counterparts, the conjugate exhibited a 10‐fold extended half‐life in wild‐type mice and fivefold prolonged serum half‐life in BxPC‐3 xenograft tumor models as well as enhanced tumor accumulation and retention in mice. Consequently, n501–αHSA–MMAE showed potent antitumor effects, which were comparable to n501–MMAE in pancreatic cancer BxPC‐3 xenograft tumor models; however, in human ovarian teratoma PA‐1 xenograft tumor models, n501–αHSA–MMAE significantly improved antitumor efficacy. Moreover, the conjugate showed mitigated hepatotoxicity. In summary, our results suggested that fusion to albumin‐binding moiety as a viable strategy can enhance the therapeutic potential of sdADCs through optimized pharmacokinetics. [ABSTRACT FROM AUTHOR]

Vaccines have been the primary remedy in the global fight against coronavirus disease 2019 (COVID-19). The receptor-binding domain (RBD) of the spike protein, a critical viral immunogen, is affected by the heterogeneity of its glycan structures and relatively low immunogenicity. Here, we describe a scalable synthetic platform that enables the precise synthesis of homogeneously glycosylated RBD, facilitating the elucidation of carbohydrate structure–function relationships. Five homogeneously glycosylated RBDs bearing biantennary glycans were prepared, three of which were conjugated to T-helper epitope (Tpep) from tetanus toxoid to improve their weak immune response. Relative to natural HEK293-derived RBD, synthetic RBDs with biantennary N -glycan elicited a higher level of neutralising antibodies against SARS-CoV-2 in mice. Furthermore, RBDs containing Tpep elicited significant immune responses in transgenic mice expressing human angiotensin-converting enzyme 2. Our collective data suggest that trimming the N -glycans and Tpep conjugation of RBD could potentially serve as an effective strategy for developing subunit vaccines providing efficient protection. [ABSTRACT FROM AUTHOR]

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]

The emerging outbreak of monkeypox is closely associated with the viral infection and spreading, threatening global public health. Virus‐induced cell migration facilitates viral transmission. However, the mechanism underlying this type of cell migration remains unclear. Here we investigate the motility of cells infected by vaccinia virus (VACV), a close relative of monkeypox, through combining multi‐omics analyses and high‐resolution live‐cell imaging. We find that, upon VACV infection, the epithelial cells undergo epithelial–mesenchymal transition‐like transformation, during which they lose intercellular junctions and acquire the migratory capacity to promote viral spreading. After transformation, VACV‐hijacked RhoA signaling significantly alters cellular morphology and rearranges the actin cytoskeleton involving the depolymerization of robust actin stress fibers, leading‐edge protrusion formation, and the rear‐edge recontraction, which coordinates VACV‐induced cell migration. Our study reveals how poxviruses alter the epithelial phenotype and regulate RhoA signaling to induce fast migration, providing a unique perspective to understand the pathogenesis of poxviruses. [ABSTRACT FROM AUTHOR]

Enterovirus A71 (EV-A71) infection is a major cause of severe hand, foot and mouth disease (HFMD) in young children. The characteristics of EV-A71 neutralizing antibodies in HFMD patients are not well understood. In this study, we identified and cloned EV-A71-neutralizing antibodies by single cell RNA and B cell receptor sequencing of peripheral blood mononuclear cells. From 145 plasmablasts, we identified two IgG1 monoclonal antibodies (mAbs) and six IgM mAbs that neutralized EV-A71. Four of the IgM mAbs harbor germline variable sequences and neutralize EV-A71 potently. Two genetically similar IgM antibodies from two patients have recurrent heavy chain variable domain gene usage and similar complementarity-determining region 3 sequences. We mapped the residues of EV-A71 critical for neutralization through selection of virus variants resistant to antibody neutralization in the presence of neutralizing mAbs. The residues critical for neutralization are conserved among EV-A71 genotypes. Epitopes for the two genetically similar antibodies overlap with the SCARB2 binding site of EV-A71. We used escape variants to measure the epitope-specific antibody response in acute phase serum samples from EV-A71 infected HFMD patients. We found that these epitopes are immunogenic and contributed to the neutralizing antibody response against the virus. Our findings advance understanding of antibody response to EV-A71 infection in young children and have translational potential: the IgM mAbs could potentially be used for prevention or treatment of EV-A71 infections. Author summary: Hand, foot and mouth disease (HFMD) caused by enterovirus infections affects millions of young children annually. Enterovirus A71 (EV-A71) is a major causative pathogen of severe HFMD. EV-A71-specific antibody response is induced rapidly after illness onset, but the characteristics of primary antibody response to EV-A71 in young children are not well understood. Previous study demonstrated a dominant IgM producing EV-A71-specific antibody-secreting B cell response in children under 3 years old. However, no EV-A71-specific human IgM mAb has been reported. Here, we identified EV-A71 neutralizing mAbs, including two IgG1 and six IgM mAbs, from plasmablasts of EV-A71 infected children. IgM mAbs neutralize EV-A71 potently although possess few somatic mutations. We found sequence similarities between IgM antibodies from two patients. We selected EV-A71 variants in the presence of neutralizing mAbs and demonstrated that residues critical for neutralization are conserved among EV-A71 genotypes. We further explored epitope specific antibody responses in acute phase sera of EV-A71 infected patients and found that these neutralizing epitopes on the virus are immunogenic. Our findings advance understanding of antibody response in EV-A71 infected HFMD patients and can help inform the development of therapies against EV-A71 infections. [ABSTRACT FROM AUTHOR]

The worldwide spread of COVID-19 continues to impact our lives and has led to unprecedented damage to global health and the economy. This highlights the need for an efficient approach to rapidly develop therapeutics and prophylactics against SARS-CoV-2. We modified a single-domain antibody, SARS-CoV-2 VHH, to the surface of the liposomes. These immunoliposomes demonstrated a good neutralizing ability, but could also carry therapeutic compounds. Furthermore, we used the 2019-nCoV RBD-SD1 protein as an antigen with Lip/cGAMP as the adjuvant to immunize mice. Lip/cGAMP enhanced the immunity well. It was demonstrated that the combination of RBD-SD1 and Lip/cGAMP was an effective preventive vaccine. This work presented potent therapeutic anti-SARS-CoV-2 drugs and an effective vaccine to prevent the spread of COVID-19. [ABSTRACT FROM AUTHOR]

Over the years, infectious diseases with high morbidity and mortality disrupted human healthcare systems and devastated economies globally. Respiratory viruses, especially emerging or re-emerging RNA viruses, including influenza and human coronavirus, are the main pathogens of acute respiratory diseases that cause epidemics or even global pandemics. Importantly, due to the rapid mutation of viruses, there are few effective drugs and vaccines for the treatment and prevention of these RNA virus infections. Of note, a class of antibodies derived from camelid and shark, named nanobody or single-domain antibody (sdAb), was characterized by smaller size, lower production costs, more accessible binding epitopes, and inhalable properties, which have advantages in the treatment of respiratory diseases compared to conventional antibodies. Currently, a number of sdAbs have been developed against various respiratory RNA viruses and demonstrated potent therapeutic efficacy in mouse models. Here, we review the current status of the development of antiviral sdAb and discuss their potential as therapeutics for respiratory RNA viral diseases. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic caused by the novel SARS-CoV-2 virus has caused havoc across the entire world. Even though several COVID-19 vaccines are currently in distribution worldwide, with others in the pipeline, treatment modalities lag behind. Accordingly, researchers have been working hard to understand the nature of the virus, its mutant strains, and the pathogenesis of the disease in order to uncover possible drug targets and effective therapeutic agents. As the research continues, we now know the genome structure, epidemiological and clinical features, and pathogenic mechanism of SARS-CoV-2. Here, we summarized the potential therapeutic targets involved in the life cycle of the virus. On the basis of these targets, small-molecule prophylactic and therapeutic agents have been or are being developed for prevention and treatment of SARS-CoV-2 infection. SARS-CoV-2 enters the cell by recognizing the host cell receptor through the S protein and uses the cell's system for genome and protein synthesis and viral particle assembly, each of these steps can serve as a target for identification of inhibitors against SARS-CoV-2 infection. [Display omitted] [ABSTRACT FROM AUTHOR]

As a result, neutralization of RBM antibodies was affected the most by current circulating mutations, followed by that of the outer surface antibodies, and barely in antibody recognizing the inner face, suggesting that the inner face is more resilient to viral escape. Interestingly, the levels of non-RBM antibodies in vaccine recipients were positively associated with their neutralizing activity against Omicron, while the correlation was not observed in RBM- or whole RBD-binding antibodies. In contrast, the proportion of non-RBM antibodies in all the RBD-specific antibodies in plasma may be a useful parameter to indicate the antibody breadth and Omicron neutralizing activity. [Extracted from the article]

Background: Colorectal cancer is a commonly diagnosed cancer with high mortality worldwide. Postoperative recidivation and metastasis still are the main challenges in clinical treatments. Thus, it is urgent to develop new therapies against colorectal cancer. Epithelial Cell Adhesion Molecule (EpCAM) is overexpressed in colorectal cancer cells and strongly associated with cancer development. Bispecific antibody (BsAb) is a kind of promising immunotherapy, which could recognize T cells and cancer cells simultaneously to achieve the anti-tumor effects. Methods: A bispecific antibody targeting EpCAM and CD3 with IgG format was genereated by split intein based on the Bispecific Antibody by Protein Splicing" platform. In vitro , the affinity of CD3×EpCAM BsAb was determined by Biolayer interferometry, its cytotoxicity was detected by LDH release assay, T cell recruitment and activation was detected by Flow Cytometry. In vivo , its pharmacokinetic parameters were detected, and anti-tumor effects were evaluated on the tumor cell xenograft mouse model. Results: The results showed that the CD3×EpCAM BsAb could activate and recruit T cells via binding colorectal cells and T cells, which could lead to more potent cytotoxicity to various colorectal cell lines than its parent EpCAM monoclonal antibody (mAb) in vitro. The CD3×EpCAM BsAb had similar pharmacokinetic parameters with EpCAM mAb and inhibits tumor growth on the SW480 tumor cell xenograft mouse model. Conclusion: The CD3×EpCAM BsAb could be a promising candidate for colorectal cancer treatment. [ABSTRACT FROM AUTHOR]