The ongoing COVID‐19 pandemic caused by SARS‐CoV‐2 has led to millions of deaths worldwide. Streptococcus pneumoniae (S. pneumoniae) remains a major cause of mortality in underdeveloped countries. A ...vaccine that prevents both SARS‐CoV‐2 and S. pneumoniae infection represents a long‐sought “magic bullet”. Herein, a nanoparticle vaccine, termed SCTV01B, is rationally developed by using the capsular polysaccharide of S. pneumoniae serotype 14 (PPS14) as the backbone to conjugate with the recombinant receptor‐binding domain (RBD) of the SARS‐CoV‐2 spike protein. The final formulation of conjugated nanoparticles in the network structure exhibits high thermal stability. Immunization with SCTV01B induces potent humoral and Type 1/Type 2 T helper cell (Th1/Th2) cellular immune responses in mice, rats, and rhesus macaques. In particular, SCTV01B‐immunized serum not only broadly cross‐neutralizes all SARS‐CoV‐2 variants of concern (VOCs), including the most recent Omicron variant, but also shows high opsonophagocytic activity (OPA) against S. pneumoniae serotype 14. Finally, SCTV01B vaccination confers protection against challenges with the SARS‐CoV‐2 mouse‐adapted strain and the original strain in established murine models. Collectively, these promising preclinical results support further clinical evaluation of SCTV01B, highlighting the potency of polysaccharide‐RBD‐conjugated nanoparticle vaccine platforms for the development of vaccines for COVID‐19 and other infectious diseases.
A bivalent nanoparticle vaccine is rationally developed by conjugating capsular polysaccharide of Streptococcus pneumoniae serotype 14 with the receptor‐binding domain (RBD) of SARS‐CoV‐2 spike protein. Immunization with this vaccine induces potent protective immune responses against both SARS‐CoV‐2 variants and S. pneumoniae. This universal polysaccharide–protein‐conjugated vaccine platform provides a new tool to fight against cocirculating viral and bacterial pathogens.
When taking pictures of electronic screens or objects with high-frequency textures, people often run across colorful rainbow patterns that are known as "moire", seriously affecting the image quality ...and subsequent processing. Current methods for removing moire patterns mostly extract multiscale information by downsampling pooling layers, which may inevitably cause information loss. To address this issue, this paper proposes a demoireing method in the wavelet domain. By employing both discrete wavelet transform (DWT) and inverse discrete wavelet transform (IDWT) instead of traditional downsampling and upsampling, this method can effectively increase the network receptive field without information loss. In addition, to further reconstruct more details of moire patterns, this paper proposes an efficient attention fusion module (EAFM). With a combination of efficient channel attention, spatial attention and local residual learning, this module can self-adaptively learn various weights of feature information at different levels and inspire the network to focus more on effective information such as moire details to improve learning and demoireing performance. Extensive experiments based on public datasets have shown that this suggested method can efficiently remove moire patterns and has a good quantitative and qualitative performance.
Vascular endothelial growth factor receptor 2 (VEGFR2)/KDR plays a critical role in tumor growth, diffusion, and invasion. The amino acid sequence homology of KDR between mouse and human in the VEGF ...ligand‐binding domain was low, thus the WT mice could not be used to evaluate Abs against human KDR, and the lack of a suitable mouse model hindered both basic research and drug developments. Using the CRISPR/Cas9 technique, we successfully inserted different fragments of the human KDR coding sequence into the chromosomal mouse Kdr exon 4 locus to obtain an hKDR humanized mouse that can be used to evaluate the marketed Ab ramucirumab. In addition, the humanized mAb VEGFR‐HK19 was developed, and a series of comparative assays with ramucirumab as the benchmark revealed that VEGFR‐HK19 has higher affinity and superior antiproliferation activity. Moreover, VEGFR‐HK19 selectively inhibited tumor growth in the hKDR mouse model but not in WT mice. The most important binding epitopes of VEGFR2‐HK19 are D257, L313, and T315, located in the VEGF binding region. Therefore, the VEGFR2‐HK19 Ab inhibits tumor growth by blocking VEGF‐induced angiogenesis, inflammation, and promoting apoptosis. To our best knowledge, this novel humanized KDR mouse fills the gaps both in an animal model and the suitable in vivo evaluation method for developing antiangiogenesis therapies in the future, and the newly established humanized Ab is expected to be a drug candidate possibly benefitting tumor patients.
We successfully inserted human KDR CDS into the chromosomal mouse Kdr to obtain an hKDR humanized mouse using CRISPR/Cas9 technique, and V135I, L313R, I266L sites are different ligand‐binding regions of VEGFR2 between humans and mice. Bottom line: DC101, targeting mouse VEGFR2, does not cross‐react with human VEGFR2, is evaluated in WT xenograft tumor mice, showing that the tumor volume is reduced obviously. Ramucirumab, a humanized IgG1 monoclonal antibody ramucirumab (IMC‐1121B, product name: CYRAMZA®), is evaluated in hKDR and WT xenograft tumor mice respectively, showing that the tumor volume is reduced obviously in hKDR mice but not in WT mice, indicating that hKDR mice reproduced the activity of approved Ab in vivo. VEGFR‐HK19, a new humanized mAb, similar with ramucirumab, selectively inhibited tumor growth in the hKDR mouse model but not in WT mice, indicating that VEGFR2‐HK19 showed antitumor activity.
Neutralizing antibodies have been proven to be highly effective in treating mild and moderate COVID-19 patients, but continuous emergence of SARS-CoV-2 variants poses significant challenges. Antibody ...cocktail treatments reduce the risk of escape mutants and resistance. In this study, a new cocktail composed of two highly potent neutralizing antibodies (HB27 and H89Y) was developed, whose binding epitope is different from those cocktails that received emergency use authorization. This cocktail showed more potent and balanced neutralizing activities (IC
0.9-11.3 ng mL
) against a broad spectrum of SARS-CoV-2 variants over individual HB27 or H89Y antibodies. Furthermore, the cocktail conferred more effective protection against the SARS-CoV-2 Beta variant in an aged murine model than monotherapy. It was shown to prevent SARS-CoV-2 mutational escape in vitro and effectively neutralize 61 types of pseudoviruses harbouring single amino acid mutation originated from variants and escape strains of Bamlanivimab, Casirivimab and Imdevimab with IC
of 0.6-65 ng mL
. Despite its breadth of variant neutralization, the HB27+H89Y combo and EUA cocktails lost their potencies against Omicron variant. Our results provide important insights that new antibody cocktails covering different epitopes are valuable tools to counter virus mutation and escape, highlighting the need to search for more conserved epitopes to combat Omicron.
Enterovirus 71 (EV71) and coxsackievirus A16 (CVA16) are members of the Picornaviridae family and are considered the main causative agents of hand, foot and mouth disease (HFMD). In recent decades ...large HFMD outbreaks caused by EV71 and CVA16 have become significant public health concerns in the Asia-Pacific region. Vaccines and antiviral drugs are unavailable to prevent EV71 and CVA16 infection. In the current study, a chimeric antibody targeting a highly conserved peptide in the EV71 VP4 protein was isolated by using a phage display technique. The antibody showed cross-neutralizing capability against EV71 and CVA16 in vitro. The results suggest that this phage display-derived antibody will have great potential as a broad neutralizing antibody against EV71 and CVA16 after affinity maturation and humanization.
With the emergence and rapid spread of new pandemic variants, especially variants of concern (VOCs), the development of next-generation vaccines with broad-spectrum neutralizing activities is of ...great importance. In this study, SCTV01C, a clinical stage bivalent vaccine based on trimeric spike extracellular domain (S-ECD) of SARS-CoV-2 variants Alpha (B.1.1.7) and Beta (B.1.351) with a squalene-based oil-in-water adjuvant was evaluated in comparison to its two corresponding (Alpha and Beta) monovalent vaccines in mouse immunogenicity studies. The two monovalent vaccines induced potent neutralizing antibody responses against the antigen-matched variants, but drastic reductions in neutralizing antibody titers against antigen-mismatched variants were observed. In comparison, the bivalent vaccine SCTV01C induced relatively higher and broad-spectrum cross-neutralizing activities against various SARS-CoV-2 variants, including the D614G variant, VOCs (B.1.1.7, B.1.351, P.1, B.1.617.2, B.1.1.529), variants of interest (VOIs) (C.37, B.1.621), variants under monitoring (VUMs) (B.1.526, B.1.617.1, B.1.429, C.36.3) and other variants (B.1.618, 20I/484Q). All three vaccines elicited potent Th1-biased T-cell immune responses. These results provide direct evidence that variant-based multivalent vaccines could play important roles in addressing the critical issue of reduced protective efficacy against the existing and emerging SARS-CoV-2 variants.
We previously developed a polysaccharide--RBD-conjugated nanoparticle vaccine which induced protective efficacy against SARS-CoV-2 in a mouse model. Here, we newly developed a vaccine, SCTV01A, by ...chemically conjugating recombinant SARS-CoV-2 RBD-Fc and PPS14 (
serotype type 14 capsular polysaccharide). The immunogenicity and toxicity of SCTV01A were evaluated in animal models. The PPS14 conjugation enhanced the immunogenicity of RBD-Fc in C57BL/6 mice whether formulated with SCT-VA02B or Alum adjuvant. SCTV01A also induced high opsonophagocytic activity (OPA) against
serotype 14. In addition, SCTV01A stimulated potent neutralizing titers in rhesus macaques and effectively reduced lung inflammation after SARS-CoV-2 infection with neither antibody-dependent enhancement (ADE) nor vaccine-enhanced diseases (VED) phenomenon. Importantly, the long-term toxicity study of SCTV01A in rhesus macaques did not cause any abnormal toxicity and was tolerated at the highest tested dose (120 μg). The existing immunogenicity and toxicological evaluation results have demonstrated the safety and efficacy of SCTV01A, which will be a promising and feasible vaccine to protect against SARS-CoV-2 infection.
Purpose
Bispecific antibodies (BsAbs), capable of targeting two antigens simultaneously, represent a significant advancement by employing dual mechanisms of action for tumor suppression. However, how ...to pair targets to develop effective and safe bispecific drugs is a major challenge for pharmaceutical companies.
Methods
Using machine learning models, we refined the biological characteristics of currently approved or in clinical development BsAbs and analyzed hundreds of membrane proteins as bispecific targets to predict the likelihood of successful drug development for various target combinations. Moreover, to enhance the interpretability of prediction results in bispecific target combination, we combined machine learning models with Large Language Models (LLMs). Through a Retrieval-Augmented Generation (RAG) approach, we supplement each pair of bispecific targets’ machine learning prediction with important features and rationales, generating interpretable analytical reports.
Results
In this study, the XGBoost model with pairwise learning was employed to predict the druggability of BsAbs. By analyzing extensive data on BsAbs and designing features from perspectives such as target activity, safety, cell type specificity, pathway mechanism, and gene embedding representation, our model is able to predict target combinations of BsAbs with high market potential. Specifically, we integrated XGBoost with the GPT model to discuss the efficacy of each bispecific target pair, thereby aiding the decision-making for drug developers.
Conclusion
The novelty of this study lies in the integration of machine learning and GPT techniques to provide a novel framework for the design of BsAbs drugs. This holistic approach not only improves prediction accuracy, but also enhances the interpretability and innovativeness of drug design.
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