Unlocking the potential of bispecific ADCs for targeted cancer therapy

Antibody–drug conjugates(ADCs)are biologically targeted drugs composed of antibodies and cytotoxic drugs connected by linkers.These innovative compounds enable precise drug delivery to tumor cells,minimizing harm to normal tissues and offering excellent prospects for cancer treatment.However,monoclonal antibody-based ADCs still present challenges,especially in terms of balancing efficacy and safety.Bispecific antibodies are alternatives to monoclonal antibodies and exhibit superior internalization and selectivity,producing ADCs with increased safety and therapeutic efficacy.In this review,we present available evidence and future prospects regarding the use of bispecific ADCs for cancer treatment,including a comprehensive overview of bispecific ADCs that are currently in clinical trials.We offer insights into the future development of bispecific ADCs to provide novel strategies for cancer treatment.

Trends in Respiratory Infectious Pathogens in Children Under the Age of 14—Xiamen City,Fujian Province,China,2017-2023

Summary What is already known about this topic?Respiratory infections pose a significant burden on public health.Despite recent outbreaks occurring in various locations,there is limited information available on the prevalence trends of multiple common respiratory pathogens in China beyond 2022.What is added by this report?

Stepping forward:T-cell redirecting bispecific antibodies in cancer therapy

T cell-redirecting bispecific antibodies are specifically designed to bind to tumor-associated antigens,thereby engaging with CD3 on the T cell receptor.This linkage between tumor cells and T cells actively triggers T cell activation and initiates targeted killing of the identified tumor cells.These antibodies have emerged as one of the most promising avenues within tumor immunotherapy.However,despite success in treating hematological malignancies,significant advancements in solid tumors have yet to be explored.In this review,we aim to address the critical challenges associated with T cellredirecting bispecific antibodies and explore novel strategies to overcome these obstacles,with the ultimate goal of expanding the application of this therapy to include solid tumors.

Supercritical fluid technology:A game-changer for biomacromolecular nanomedicine preparation and biomedical application

Biomacromolecules are attractive in biomedical applications as therapeutic agents and potential drug carriers due to their natural active components,good biocompatibility,and high targeting.However,their large relative molecular weight,complex structure,susceptibility to degradation,and poor stability limit their usefulness.Nanotechnology can address these issues by improving the therapeutic value,bioavailability,permeability,and absorption of biomacromolecules while regulating their retention time in the body.Especially,compelling evidence has been reported that supercritical fluid(SCF)technology has emerged as an alternative that maintains the integrity of biomacromolecules and reduces environmental contamination.In this review,we highlight a set of unique nanosizing strategies based on SCF technology for biomacromolecular nanomedicine,and extensively discuss their characteristics and mechanisms.In particular,the protein-based,nucleic acid-based,and polysaccharide-based nanomedicine preparations via SCF technology and their biomedical applications are summarized,and the potential for industrial production of biomacromolecular drugs is also considered.We further provide perspectives on the opportunities and challenges in this excellent field of biomacromolecular drugs nanotechnology.

Two antibodies show broad,synergistic neutralization against SARS-CoV-2 variants by inducing conformational change within the RBD

Continual evolution of the severe acute respiratory syndrome coronavirus(SARS-CoV-2)virus has allowed for its gradual evasion of neutralizing antibodies(nAbs)produced in response to natural infection or vaccination.The rapid nature of these changes has incited a need for the development of superior broad nAbs(bnAbs)and/or the rational design of an antibody cocktail that can protect against the mutated virus strain.Here,we report two angiotensin-converting enzyme 2 competing nAbs—8H12 and 3E2—with synergistic neutralization but evaded by some Omicron subvariants.Cryo-electron microscopy reveals the two nAbs synergistic neutralizing virus through a rigorous pairing permitted by rearrangement of the 472-489 loop in the receptor-binding domain to avoid steric clashing.Bispecific antibodies based on these two nAbs tremendously extend the neutralizing breadth and restore neutralization against recent variants including currently dominant XBB.1.5.Together,these findings expand our understanding of the potential strategies for the neutralization of SARS-CoV-2 variants toward the design of broad-acting antibody therapeutics and vaccines.

Carbon-based nanodots for biomedical applications and clinical transformation prospects

Carbon dots(CDs),emerging as a promising class of nanomaterials,have garnered significant interest in the field of biomedicine due to their unique physicochemical properties.This review provides a comprehensive overview of the recent advancements in the biomedical applications of CDs,emphasizing their potential for revolutionizing diagnostics,therapy,and bio-imaging.We discuss the synthesis and functionalization of CDs,which are pivotal in tailoring their properties for specific biomedical applications.The applications of CDs in bioimaging include fluorescence imaging,magnetic resonance imaging,photoacoustic imaging,etc.Additionally,this review delves into the benefits of CDs in the treatment of diseases including cancer,inflammation and Alzheimer's,etc.Finally,we look forward to the future of CDs in the field of biomedicine,emphasizing the necessity of interdisciplinary collaboration to overcome current obstacles and facilitate the clinical translation of CDs-based technologies.This review aims to provide a summary and perspectives on the latest developments of CDs in biomedicine,hoping to inspire further research in this rapidly advancing field.

Advancements in Defining and Estimating the Reproduction Number in Infectious Disease Epidemiology

The reproduction number(R)serves as a fundamental metric in the examination of infectious disease outbreaks,epidemics,and pandemics.Despite an array of available methods for estimating,both newcomers and established public health professionals often encounter difficulties in comprehending the circumstances for their use and their constrictions.Consequently,this review intends to offer elementary guidance on’s selection and estimation approaches.To facilitate our review,we executed an extensive search on PubMed and Web of Science applying the following search approach:[“Basic Reproduction Number/classification”(Mesh)]AND[“Basic Reproduction Number/prevention and control”(Mesh)]OR[“Basic Reproduction Number/statistics and numerical data”(Mesh)].

Radio-granular hydrogels for image-guided tumor brachytherapy

Transarterial radioembolization(TARE),derived from transarterial chemoembolization,embolizes tumor blood vessels and elicits tumor brachytherapy by using radionuclide-loaded microspheres,a promising therapeutic modality for locally advanced hepatocellular carcinoma(HCC)[1,2].However,the implementation of TARE in the clinic has been hampered by the lack of efficient radioembolization agents[3,4].

Basic Research Advances in China on Embryo Implantation,Placentation,and Parturition

This review aimed to summarize the major progress in maternal-fetal medicine achieved by Chinese scientists in recent years.PubMed was systematically searched from January 2020 to November 2023.Publications that reported the progress in embryo implantation,placentation,and parturition made by Chinese scientists in the last 3 years were selected.The milestone events during gestation,embryo implantation,endometrial decidualization,placentation,and parturition are pivotal to a successful pregnancy.Embryo implantation requires intricate interactions between implantation-competent blastocysts and receptive endometrium.To adapt to pregnancy,endometrial stromal cells transform into specialized decidual cells,which occur spontaneously under the influence of ovarian hormones in humans but require the presence of embryos in mice.With embryonic development,the placenta forms to support fetal growth until parturition.The maternal-fetal interface is composed of diverse cell types,including endometrial decidual cells,placental trophoblast cells,endothelial cells,and various immune cells,a sophisticated interplay among which contributes to the maintenance of pregnancy.Near term,the uterus transitions from quiescence to contractility,in preparation for delivery.Disruptions to these events lead to pregnancy-related disorders such as repeated implantation failure,recurrent pregnancy loss,preeclampsia,fetal growth restriction,preterm birth,and infertility.In recent years,Chinese scientists have made prominent achievements in basic research on the aforementioned pregnancy events.Chinese scientists have made remarkable contributions to reproductive biology and maternal-fetal medicine research in recent years,highlighting future research directions in this field.

Immune landscape and response to oncolytic virus-based immunotherapy

Oncolytic virus(OV)-based immunotherapy has emerged as a promising strategy for cancer treatment,offering a unique potential to selectively target malignant cells while sparing normal tissues.However,the immunosuppressive nature of tumor microenvironment(TME)poses a substantial hurdle to the development of OVs as effective immunotherapeutic agents,as it restricts the activation and recruitment of immune cells.This review elucidates the potential of OV-based immunotherapy in modulating the immune landscape within the TME to overcome immune resistance and enhance antitumor immune responses.We examine the role of OVs in targeting specific immune cell populations,including dendritic cells,T cells,natural killer cells,and macrophages,and their ability to alter the TME by inhibiting angiogenesis and reducing tumor fibrosis.Additionally,we explore strategies to optimize OV-based drug delivery and improve the efficiency of OV-mediated immunotherapy.In conclusion,this review offers a concise and comprehensive synopsis of the current status and future prospects of OV-based immunotherapy,underscoring its remarkable potential as an effective immunotherapeutic agent for cancer treatment.

表位结构指导免疫优势转移的HPV交叉疫苗的理性设计

In vaccine development,broadly or cross-type neutralizing antibodies(bnAbs or cnAbs)are frequently targeted to enhance protection.Utilizing immunodominant antibodies could help fine-tune vaccine immunogenicity and augment the precision of immunization strategies.However,the methodologies to capitalize on the attributes of bnAbs in vaccine design have not been clearly elucidated.In this study,we discovered a cross-type neutralizing monoclonal antibody,13H5,against human papillomavirus 6(HPV6)and HPV11.This nAb exhibited a marked preference for HPV6,demonstrating superior binding activity to virus-like particles(VLPs)and significantly higher prevalence in anti-HPV6 human serum as compared to HPV11 antiserum(90%vs.31%).Through co-crystal structural analysis of the HPV6 L1 pentamer:13H5 complex,we delineated the epitope as spanning four segments of amino acids(Phe42-Ala47,Gly172-Asp173,Glu255-Val275,and Val337-Tyr351)on the L1 surface loops.Further interaction analysis and site-directed mutagenesis revealed that the Ser341 residue in the HPV6 HI loop plays a critical role in the interaction between 13H5 and L1.Substituting Ser341 with alanine,which is the residue type present in HPV11 L1,almost completely abolished binding activity to 13H5.By swapping amino acids in the HPV11 HI loop with corresponding residues in HPV6 L1(Ser341,Thr338,and Thr339),we engineered chimeric HPV11-6HI VLPs.Remarkably,the chimeric HPV11-6HI VLPs shifted the high immunodominance of 13H5 from HPV6 to the engineered VLPs and yielded comparable neutralization titers for both HPV6 and HPV11 in mice and non-human primates.This approach paves the way for the design of broadly protective vaccines from antibodies within the main immunization reservoir.

Combination therapy with oncolytic virus and T cells or mRNA vaccine amplifies antitumor effects

Antitumor therapies based on adoptively transferred T cells or oncolytic viruses have made significant progress in recent years,but the limited efficiency of their infiltration into solid tumors makes it difficult to achieve desired antitumor effects when used alone.In this study,an oncolytic virus(rVSV-LCMVG)that is not prone to induce virus-neutralizing antibodies was designed and combined with adoptively transferred T cells.By transforming the immunosuppressive tumor microenvironment into an immunosensitive one,in B16 tumor-bearing mice,combination therapy showed superior antitumor effects than monotherapy.This occurred whether the OV was administered intratumorally or intravenously.Combination therapy significantly increased cytokine and chemokine levels within tumors and recruited CD8^(+)T cells to the TME to trigger antitumor immune responses.Pretreatment with adoptively transferred T cells and subsequent oncolytic virotherapy sensitizes refractory tumors by boosting T-cell recruitment,downregulating the expression of PD-1,and restoring effector T-cell function.To offer a combination therapy with greater translational value,mRNA vaccines were introduced to induce tumor-specific T cells instead of adoptively transferred T cells.The combination of OVs and mRNA vaccine also displays a significant reduction in tumor burden and prolonged survival.This study proposed a rational combination therapy of OVs with adoptive T-cell transfer or mRNA vaccines encoding tumor-associated antigens,in terms of synergistic efficacy and mechanism.

Theoretical Epidemiology Needs Urgent Attention in China

The mathematical method to which theoretical epidemiology belongs is one of the three major methodologies in epidemiology.It is of great value in diagnosing infectious disease epidemic trends and evaluating the effectiveness of prevention and control measures.This paper aims to summarize the brief history of the development of theoretical epidemiology,common types of mathematical models,and key steps to develop a mathematical model.It also provides some thoughts and perspectives on the development and application of theoretical epidemiology in China.

Tuberculosis Prevalence Trends from a Predictive Modelling Study-10 High-Burden Countries,1980-2035

What is already known about this topic?Given the challenges presented by drug-resistant strains of tuberculosis(TB)and the rising mobility of the population,achieving the objective of eradicating TB appears uncertain.What is added by this report?The examination of TB incidence trends in 10 highburden countries(HBCs)indicated a steady rise in cases,with India and China jointly accounting for nearly 70%of the burden.Projections for the future show diverse trajectories in these countries,with potential difficulties in reaching the TB elimination target,especially in Nigeria,Congo,and South Africa.What are the implications for public health practice?The number of TB cases is on the rise.It is crucial to learn from successful strategies to improve TB prevention and control worldwide through collaborative efforts.

MODELS:a six-step framework for developing an infectious disease model

Since the COVID-19 pandemic began,a plethora of modeling studies relatedto COVID-19 have been released.While some models stand out due to their innovative approaches,others are flawed in their methodology.To assist novices,frontline healthcare workers,and public health policymakers in navigating the complex landscape of these models,we introduced a structured framework named MODELS.This framework is designed to detail the essential steps and considerations for creating a dependable epidemic model,offering direction to researchers engaged in epidemic modeling endeavors.

基于大肠杆菌表达的重组九价人乳头瘤病毒(HPV 6/11/16/18/31/33/45/52/58型)疫苗免疫原性和安全性的Ⅱ期临床试验

人乳头瘤病毒(HPV)16/18型双价疫苗(大肠埃希菌)已上市并通过世界卫生组织预认证.本研究通过一项随机双盲Ⅱ期临床试验评估其第二代HPV6/11/16/18/31/33/45/52/58型九价疫苗在18~45岁健康女性中的免疫原性和安全性.来自江苏省东台市的627名女性志愿者1:1随机分配至九价疫苗组(313人)或对照组(314人),并按照0、1、6月接种程序分别接种三剂1.0 mL(270μg)九价疫苗或空白佐剂,主要终点为第7月时血清抗体阳转率和抗体水平.结果显示,几乎所有疫苗组符合方案人群在第7月时出现针对9种HPV型别的血清中和抗体阳转,仅2人未发生HPV11型阳转,1人未发生HPV52型阳转.九价疫苗组和对照组的总体不良事件发生率分别为80.8%和72.9%,绝大多数不良事件症状轻微并很快恢复,未发生疫苗相关严重不良事件.该研究证明候选九价疫苗具有良好的安全性和免疫原性,支持在更大人群中进一步进行效力研究.