Antibody-Coupled Drugs in HER2-Positive Gastric Cancer

Antibody drug conjugates (ADCs) are a new class of drugs that combine chemosynthetic drugs with antibody drugs through a linker. Antibody drug conjugates combine the targeting characteristics of traditional antibody drugs with the cytotoxic characteristics of small molecule drugs, while reducing the side effects of both drugs, making them a kind of “biological missile” and representing a relatively new and evolving class of anti-cancer drugs. Antibody-coupled drugs are currently used in many solid tumors, and this article reviews the clinical application of antibody-coupled drugs in HER2-positive gastric cancer.

Antibody-platinum(IV)prodrugs conjugates for targeted treatment of cutaneous squamous cell carcinoma

Antibody-drug conjugates(ADCs)are a new type of targeting antibodies that conjugate with highly toxic anticancer drugs via chemical linkers to exert high specificity and efficient killing of tumor cells,thereby attracting considerable attention in precise oncology therapy.Cetuximab(Cet)is a typical antibody that offers the benefits of good targeting and safety for individuals with advanced and inoperable cutaneous squamous cell carcinoma(cSCC);however,its anti-tumor activity is limited to a single use.Cisplatin(CisPt)shows good curative effects;however,its adverse effects and non-tumor-targeting ability are major drawbacks.In this study,we designed and developed a new ADC based on a new cytotoxic platinum(IV)prodrug(C8Pt(IV))and Cet.The so-called antibody-platinum(IV)prodrugs conjugates,named Cet-C8Pt(IV),showed excellent tumor targeting in cSCC.Specifically,it accurately delivered C8Pt(IV)into tumor cells to exert the combined anti-tumor effect of Cet and CisPt.Herein,metabolomic analysis showed that Cet-C8Pt(IV)promoted cellular apoptosis and increased DNA damage in cSCC cells by affecting the vitamin B6 metabolic pathway in tumor cells,thereby further enhancing the tumor-killing ability and providing a new strategy for clinical cancer treatment using antibody-platinum(IV)prodrugs conjugates.

Association between glucose-lowering drugs and circulating insulin antibodies induced by insulin therapy in patients with type 2 diabetes

BACKGROUND Insulin antibodies(IAs)affect blood glucose control in patients receiving insulin therapy.AIM To investigate the relationship between different hypoglycemic treatments and IAs in patients with type 2 diabetes mellitus(T2DM).METHODS This cross-sectional,retrospective study included 1863 patients with T2DM who were receiving exogenous insulin therapy.All patients received stable antidiabetic therapy in the last 3 months and IA levels were measured using an iodine-125 array.RESULTS A total of 1863 patients were enrolled.There were 902(48.4%)patients who had positive IAs(IA level>5%),with a mean IA level of 11.06%(10.39%-11.72%).IA levels were positively correlated with high fasting blood glucose(odds ratio=1.069,P<0.001).The proportion of positive IAs was lowest in patients using glargine only(31.9%)and highest in patients using human insulin only(70.3%),P<0.001.The IA levels in patients using sulfonylureas/glinides(8.3%),metformin(9.6%),and dipeptidyl peptidase-4 inhibitors(8.2%)were all lower than in patients without these drugs(all P<0.05).CONCLUSION Nearly half of patients on insulin therapy have positive IA antibodies,and IA antibody levels are associated with blood glucose control.Insulin glargine and a combination of oral glucose-lowering drugs were correlated with lower IA levels.

Insights into the structural biology of G-protein coupled receptors impacts drug design for central nervous system neurodegenerative processes

In the last few years, there have been important new insights into the structural biology of G-protein coupled receptors. It is now known that allosteric binding sites are involved in the affinity and selec- tivity of ligands for G-protein coupled receptors, and that signaling by these receptors involves both G-protein dependent and independent pathways. The present review outlines the physiological and pharmacological implications of this perspective for the design of new drugs to treat disorders of the central nervous system. Specifically, new possibilities are explored in relation to allosteric and or- thosteric binding sites on dopamine receptors for the treatment of Parkinson＇s disease, and on muscarinic receptors for Alzheimer＇s disease. Future research can seek to identify ligands that can bind to more than one site on the same receptor, or simultaneously bind to two receptors and form a dimer. For example, the design of bivalent drugs that can reach homo/hetero-dimers of D2 dopa- mine receptor holds promise as a relevant therapeutic strategy for Parkinson＇s disease. Regarding the treatment of Alzheimer＇s disease, the design of dualsteric ligands for mono-oligomeric mus- carinic receptors could increase therapeutic effectiveness by generating potent compounds that could activate more than one signaling pathway.

Excellent effects and possible mechanisms of action of a new antibody–drug conjugate against EGFR-positive triple-negative breast cancer

Background:Triple-negative breast cancer(TNBC)is the most aggressive subtype and occurs in approximately 15%–20%of diagnosed breast cancers.TNBC is characterized by its highly metastatic and recurrent features,as well as a lack of specific targets and targeted therapeutics.Epidermal growth factor receptor(EGFR)is highly expressed in a variety of tumors,especially in TNBC.LR004-VC-MMAE is a new EGFR-targeting antibody–drug conjugate produced by our laboratory.This study aimed to evaluate its antitumor activities against EGFR-positive TNBC and further studied its possible mechanism of antitumor action.Methods:LR004-VC-MMAE was prepared by coupling a cytotoxic payload(MMAE)to an anti-EGFR antibody(LR004)via a linker,and the drug-to-antibody ratio(DAR)was analyzed by HIC-HPLC.The gene expression of EGFR in a series of breast cancer cell lines was assessed using a publicly available microarray dataset(GSE41313)and Western blotting.MDA-MB-468 and MDA-MB-231 cells were treated with LR004-VC-MMAE(0,0.0066,0.066,0.66,6.6 nmol/L),and the inhibitory effects of LR004-VC-MMAE on cell proliferation were examined by CCK-8 and colony formation.The migration and invasion capacity of MDA-MB-468 and MDA-MB-231 cells were tested at different LR004-VCMMAE concentrations(2.5 and 5 nmol/L)with wound healing and Transwell invasion assays.Flow cytometric analysis and tumorsphere-forming assays were used to detect the killing effects of LR004-VC-MMAE on cancer stem cells(MDA-MB-468 and MDA-MB-231 cells).The mouse xenograft models were also used to evaluate the antitumor efficacy of LR004-VC-MMAE in vivo.Briefly,BALB/c nude mice were subcutaneously inoculated with MDA-MB-468 or MDAMB-231 cells.Then they were randomly divided into 4 groups(n=6 per group)and treated with PBS,naked LR004(10 mg/kg),LR004-VC-MMAE(10 mg/kg),or doxorubicin,respectively.Tumor sizes and the body weights of mice were measured every 4 d.The effects of LR004-VC-MMAE on apoptosis and cell cycle distribution were analyzed by flow cytometry.Western blotting was used to detect the effects of LR004-VC-MMAE on EGFR,ERK,MEK phosphorylation and tumor stemness marker gene expression.Results:LR004-VC-MMAE with a DAR of 4.02 were obtained.The expression of EGFR was found to be significantly higher in TNBC cells compared with non-TNBC cells(P<0.01).LR004-VC-MMAE inhibited the proliferation of EGFRpositive TNBC cells,and the ICvalues of MDA-MB-468 and MDA-MB-231 cells treated with LR004-VC-MMAE for 72 h were(0.13±0.02)nmol/L and(0.66±0.06)nmol/L,respectively,which were significantly lower than that of cells treated with MMAE[(3.20±0.60)nmol/L,P<0.01,and(6.60±0.50)nmol/L,P<0.001].LR004-VC-MMAE effectively inhibited migration and invasion of MDA-MB-468 and MDA-MB-231 cells.Moreover,LR004-VC-MMAE also killed tumor stem cells in EGFR-positive TNBC cells and impaired their tumorsphere-forming ability.In TNBC xenograft models,LR004-VC-MMAE at 10 mg/kg significantly suppressed tumor growth and achieved complete tumor regression on day 36.Surprisingly,tumor recurrence was not observed until the end of the experiment on day 52.In a mechanistic study,we found that LR004-VC-MMAE significantly induced cell apoptosis and cell cycle arrest at G/M phase in MDAMB-468[(34±5)%vs.(12±2)%,P<0.001]and MDA-MB-231[(27±4)%vs.(18±3)%,P<0.01]cells.LR004-VC-MMAE also inhibited the activation of EGFR signaling and the expression of cancer stemness marker genes such as Oct4,Sox2,KLF4 and EpCAM.Conclusions:LR004-VC-MMAE showed effective antitumor activity by inhibiting the activation of EGFR signaling and the expression of cancer stemness marker genes.It might be a promising therapeutic candidate and provides a potential therapeutic avenue for the treatment of EGFR-positive TNBC.

Roles of G protein-coupled receptors in inflammatory bowel disease

Inflammatory bowel disease(IBD)is a complex disease with multiple pathogenic factors.Although the pathogenesis of IBD is still unclear,a current hypothesis suggests that genetic susceptibility,environmental factors,a dysfunctional immune system,the microbiome,and the interactions of these factors substantially contribute to the occurrence and development of IBD.Although existing and emerging drugs have been proven to be effective in treating IBD,none can cure IBD permanently.G protein-coupled receptors(GPCRs)are critical signaling molecules implicated in the immune response,cell proliferation,inflammation regulation and intestinal barrier maintenance.Breakthroughs in the understanding of the structures and functions of GPCRs have provided a driving force for exploring the roles of GPCRs in the pathogenesis of diseases,thereby leading to the development of GPCR-targeted medication.To date,a number of GPCRs have been shown to be associated with IBD,significantly advancing the drug discovery process for IBD.The associations between GPCRs and disease activity,disease severity,and disease phenotypes have also paved new avenues for the precise management of patients with IBD.In this review,we mainly focus on the roles of the most studied proton-sensing GPCRs,cannabinoid receptors,and estrogen-related GPCRs in the pathogenesis of IBD and their potential clinical values in IBD and some other diseases.

Strategies for overcoming anti-tumor necrosis factor drug antibodies in inflammatory bowel disease:Case series and review of literature

Anti-tumor necrosis factor(TNF) biologics are currentlyamongst the most widely used and efficacious therapies for inflammatory bowel disease(IBD). The development of therapeutic drug monitoring for infliximab and ada-limumab has allowed for measurement of drug levels and antidrug antibodies. This information can allow for manipulation of drug therapy and prediction of response. It has been shown that therapeutic anti-TNF drug levels are associated with maintenance of remission, and development of antidrug antibodies is predictive of loss of response. Studies suggest that a low level of drug antibodies, however, can at times be overcome by dose escalation of anti-TNF therapy or addition of an immunomodulator. We describe a retrospective case series of twelve IBD patients treated at the University of California-Irvine, who were on infliximab or adalimumab therapy and were found to have detectable but low-level antidrug antibodies. These patients underwent dose escalation of the drug or addition of an immunomodulator, with subsequent follow-up drug levels obtained. Eight of the twelve patients(75%) demonstrated resolution of antidrug antibodies, and were noted to have improvement in disease activity. Though data regarding overcoming low-level anti-TNF drug antibodies remains somewhat limited, cases described in the literature as well as our own experience suggest that this may be a viable strategy for preserving the use of an anti-TNF drug. Low-level anti-TNF drug antibodies may be overcome by dose escalation and/or addition of an immunomodulator, and can allow for clinical improvement in disease status. Therapeutic drug monitoring is an important tool to guide this strategy.

Antibody-Drug Conjugates (ADCs): Navigating Four Pillars of Safety, Development, Supply Chain and Manufacturing Excellence

Antibody-drug conjugates (ADCs) are pioneering biologics that merge antibodies’ specificity with small molecules’ potency. With a handful of FDA-approved ADCs in the market and many under development, ADCs are poised to revolutionize therapeutics. This paper examines the complexities of ADC production, emphasizing the importance of process characterization and the pivotal role of supply chain characteristics, safety requirements, and Contract Manufacturing Organizations (CMOs) with proficiency. The swift transition of antibody-drug conjugate (ADC) programs from early to advanced clinical stages underscores the urgency for quick and efficient commercial launch preparation. This article delves into strategies to hasten commercial readiness, supply chain strategy, the significance of partnering with adept contract development and manufacturing organizations (CDMOs), and the challenges of ADC production.

Cell Surface Transmembrane Protein Database for Detecting Potential Targets of Antibody Drug in Application of Cancer Therapies

Background： Antibody drug conjugated （ADC） is one kind of very important method of therapy to cancer diseases. In this research, the authors introduce BLAST and some other important algorithms to create transmembrane protein databases. These databases are acquired from well-known databases such as NCBI or Swiss-Prot as template, and then collect all possible transmembrane protein by using BLAST or physical character. After collect these databases, the authors will aim at each nucleotide sequences to design the probes of oligonucleotide microarray, which can detect the high express transmembrane proteins very efficiently. Finally, the authors can accelerate the anti-cancer drug discovery by using these databases. Result： This study constructed a web service, the Transmembrane Protein Database, to researchers that are interested in or need to oligonucleotide microarray probe design for detecting potential targets of antibody drug. With user friendly web based windows containing each necessary selections, users can easily choose the parameters and get the suitable probe design suggestions. Conclusion： Transmembrane protein database is very important and powerful in detecting cancers or other human disease. By using this database, the authors offer a good strategy in transmembrane protein research as well.

Analysis of Detecting HIV-1 Antibody in Paired Urine and Serum Specimens from Drug Users by ELISA

Objective- To compare the consistency of the results from detecting HIV-1 antibody in the paired urine and serum specimens from drug users by ELISA. Methods: The paired urine and serum specimens from 273 drug users detained at a detoxification unit were collected, and the HIV-1 antibodies in the specimens of them were screened by urine and serum ELISA kits, respectively. Results: Of 273 serum specimens, 94 ones showed positive reaction and among 94 counterpart urine specimens, 93 ones also appeared positive reaction. Taking the results together,the consistent rate of HIV-1 antibody screened by urine and serum ELISA kits was 99.6%. Conclusion: The urine ELISA kit, which screened HIV-1 antibody of urine showing almost the same results tested by serum ELISA kit, is reliable. It is proposed that urine ELISA be introduced in many fields.

The ABC of ADCs (Antibody-Drug Conjugates): A Comprehensive Review of Technical, Regulatory, and Clinical Challenges

Over the past several decades, there has been a significant surge in the development of Antibody-Drug Conjugates (ADCs). Designing an ideal ADC presents a multifaceted challenge, requiring the precise orchestration of various elements such as antigens, antibodies, linkers, and payloads. While ADCs aim to target tumor cells specifically, several antigens can also be found in regular tissues, potentially compromising the specificity of ADCs in therapeutic applications. The complexity extends to antibody selection, necessitating effective targeting of the desired antigen and ensuring compatibility with linkers for effective payload delivery. Additionally, the linker and payload combination are critical for the ADC’s therapeutic efficiency, balancing stability in circulation and timely payload release upon target binding. ADC doses must be safe for normal tissues while ensuring the released payloads are effective. The success of ADCs is attributed to their unmatched efficacy compared to traditional chemotherapy agents. The current research article aims to provide a technical review of Antibody-Drug Conjugates (ADCs) for cancer therapies. A brief discussion on the basics of ADCs, regulatory approach, overview, and technical complexities for quantification is presented. This review also summarizes recently approved ADCs and introduces the concepts of antibodies, linkers, and payloads. The article also outlines cancer-specific ADCs currently in late-stage clinical trials for cancer treatment.

Therapeutic targeting of cellular prion protein: toward the development of dual mechanism anti-prion compounds

PrPSc,a misfolded,aggregation-prone isoform of the cellular prion protein(PrPC),is the infectious prion agent responsible for fatal neurodegenerative diseases of humans and other mammals.PrPSccan adopt different pathogenic conformations(prion strains),which can be resistant to potential drugs,or acquire drug resistance,posing challenges for the development of effective therapies.Since PrPCis the obligate precursor of any prion strain and serves as the mediator of prion neurotoxicity,it represents an attractive therapeutic target fo r prion diseases.In this minireview,we briefly outline the approaches to target PrPCand discuss our recent identification of Zn(Ⅱ)-Bn PyP,a PrPC-targeting porphyrin with an unprecedented bimodal mechanism of action.We argue that in-depth understanding of the molecular mechanism by which Zn(Ⅱ)-Bn PyP targets PrPCmay lead toward the development of a new class of dual mechanism anti-prion compounds.

Clinical efficacy and drug resistance of anti-epidermal growth factor receptor therapy in colorectal cancer

Colorectal cancer(CRC) ranked third in cancer related death and its incidence has been increasing worldwide. In recent decades important therapeutic advances have been developed in treatment of metastatic CRC(mCRC), such as monoclonal antibodies against epidermal growth factor receptor(anti-EGFR), which provided additional clinical benefits in mCRC. However, anti-EGFR therapies have limited usage due to approximately 95% of patients with KRAS mutated mCRC do not response to anti-EGFR treatment. Thus, KRAS mutation is predictive of nonresponse to anti-EGFR therapies but it alone is not a sufficient basis to decide who should not be received such therapies because; approximately fifty percent(40%-60%) of CRC patients with wild-type KRAS mutation also have poor response to anti-EGFR based treatment. This fact leads us to suspect that there must be other molecular determinants of response to anti-EGFR therapies which have not been identified yet. Current article summarizes the clinical efficacy of anti-EGFR therapies and also evaluates its resistance mechanisms.

Prevalence of hepatitis C infection among intravenous drug users in Shanghai

AIM:To characterize the prevalence of hepatitis C virus(HCV)infection among Chinese intravenous drug users(IDUs).METHODS:A total of 432 adult IDUs(95 women and337 men)in Shanghai were included in the study.The third-generation Elecsys Anti-HCV assay(Roche Diagnostics GmbH,Sandhofer Strasse 116,D-68305,Mannheim,Germany)was used to screen for antibodies against HCV.The RIBA strip,a supplemental antiHCV test with high specificity,was performed on all of the samples that tested positive during the initial screening.All of the anti-HCV positive samples were analyzed with a Cobas TaqMan 48 Analyzer(Roche Diagnostics)for direct detection of HCV RNA.All of the HCV RNA-positive samples were sequenced for genotype determination.RESULTS:The preliminary screening identified 262(60.6%)subjects who were seropositive for HCV.Of the 62 females and 200 males seropositive subjects,16(16.7%)and 65(19.3%),respectively,were confirmed by RIBA,yielding an overall HCV seropositive rate of18.8%.Four female(6.5%)and 14 male(7.0%)subjects tested positive for HCV RNA,indicating an active infection rate of 4.2%for the entire study population.The 18 HCV RNA-positive serum samples were genotyped.Seven individuals were genotype 1b,and four were genotype 1a.One individual each was infected with genotypes 2a,2b and 3a.Four subjects were coinfected with multiple strains:two with genotypes 1a and 2a,and two with genotypes 1b and 2a.The active infection rate among HCV-seropositive individuals was22.2%,which was significantly lower than most estimates.CONCLUSION:The prevalence of HCV is relatively low among IDUs in Shanghai,with a spontaneous recovery rate much higher than previous estimates.

Impact of donor-specific antibodies on the outcomes of kidney graft:Pathophysiology, clinical, therapy

Allo-antibodies, particularly when donor specific, are one of the most important factors that cause both early and late graft dysfunction. The authors review the current state of the art concerning this important issue in renal transplantation. Many antibodies have been recognized as mediators of renal injury. In particular donorspecific-Human Leukocyte Antigens antibodies appear to play a major role. New techniques, such as solid phase techniques and Luminex, have revealed these antibodies from patient sera. Other new techniques have uncovered alloantibodies and signs of complement activation in renal biopsy specimens. It has been acknowledged that the old concept of chronic renal injury caused by calcineurine inhibitors toxicity should be replaced in many cases by alloantibodies acting against the graft. In addition, the number of patients on waiting lists with preformed anti-human leukocyte antigens(HLA) antibodies is increasing, primarily from patients with a history of renal transplant failure already been sensitized. We should distinguish early and late acute antibody-mediated rejection from chronic antibody-mediated rejection. The latter often manifets late during the course of the posttransplant period and may be difficult to recognize if specific techniques are not applied. Different therapeutic strategies are used to control antibody-induced damage.These strategies may be applied prior to transplantation or, in the case of acute antibody-mediated rejection, after transplantation. Many new drugs are appearing at the horizon; however, these drugs are far from the clinic because they are in phase Ⅰ-Ⅱ of clinical trials. Thus the pipeline for the near future appears almost empty.

Human immunodeficiency virus/acquired immune deficiency syndrome: Using drug from mathematical perceptive

Entry of acquired immune deficiency syndrome virus into the host immune cell involves the participation of various components of host and viral cell unit. These components may be categorized as attachment of the viral surface envelope protein subunit, gp120, to the CD4+ receptor and chemokine coreceptors, CCR5 and CXCR4, present on T cell surface. The viral fusion protein, gp41, the second cleaved subunit of Env undergoes reconfiguration and the membrane fusion reaction itself. Since the CD4+ T cell population is actively involved; the ultimate outcome of human immunodeficiency virus infection is total collapse of the host immune system. Mathematical modeling of the stages in viral membrane protein-host cell receptor-coreceptor interaction and the effect of antibody vaccine on the viral entry into the susceptible host cell has been carried out using as impulsive differential equations. We have studied the effect of antibody vaccination and determined analytically the threshold value of drug dosage and dosing interval for optimum levels of infection. We have also investigated the effect of perfect adherence of drug dose on the immune cell count in extreme cases and observed that systematic drug dosage of the immune cells leads to longer and improved lives.

Clinical correlations of infliximab trough levels and antibodies to infliximab in South Korean patients with Crohn's disease

To investigate the clinical implications of infliximab trough levels (IFX-TLs) and antibodies to infliximab (ATI) levels in Crohn’s disease (CD) patients in Asian countries.METHODSIFX-TL and ATI level were measured using prospectively collected samples obtained with informed consent from CD patients being treated at Asan Medical Center, South Korea. We analyzed the correlations between IFX-TLs/ATI levels and the clinical activity of CD (quiescent vs active disease) based on the CD activity index, C-reactive protein level, and physician’s judgment of patients’ clinical status at enrollment. The impact of concomitant immunomodulators was also investigated.RESULTSThis study enrolled 138 patients with CD (84 with quiescent and 54 with active disease). In patients with quiescent and active diseases, the median IFX-TLs were 1.423 μg/mL and 0.163 μg/mL, respectively (P < 0.001) and the median ATI levels were 8.064 AU/mL and 11.209 AU/mL, respectively (P < 0.001). In the ATI-negative and -positive groups, the median IFX-TLs were 1.415 μg/mL and 0.141 μg/mL, respectively (P < 0.001). In patients with and without concomitant immunomodulator use, there were no differences in IFX-TLs (0.632 μg/mL and 1.150 μg/mL, respectively; P = 0.274) or ATI levels (8.655 AU/mL and 9.017 AU/mL, respectively; P = 0.083).CONCLUSIONIFX-TL/ATI levels were well correlated with the clinical activity in South Korean CD patients. Our findings support the usefulness of IFX-TLs/ATI levels in treating CD patients receiving IFX in clinical practice.

Therapeutic drug monitoring in patients with inflammatory bowel disease

Thiopurine analogs and anti-tumor necrosis factor (TNF) agents have dramatically changed the therapeutics of inflammatory bowel diseases (IBD), improving short and long-term outcomes. Unfortunately some patients do not respond to therapy and others lose response over time. The pharmacokinetic properties of these drugs are complex, with high inter-patient variability. Thiopurine analogs are metabolized through a series of pathways, which vary according to the patients&#x02019; pharmacogenetic profile. This profile largely determines the ratios of metabolites, which are in turn associated with likelihoods of clinical efficacy and/or toxicity. Understanding these mechanisms allows for manipulation of drug dose, aiming to reduce the development of toxicity while improving the efficacy of treatment. The efficacy of anti-TNF drugs is influenced by many pharmacodynamic variables. Several factors may alter drug clearance, including the concomitant use of immunomodulators (thiopurine analogs and methotrexate), systemic inflammation, the presence of anti-drug antibodies, and body mass. The treatment of IBD has evolved with the understanding of the pharmacologic profiles of immunomodulating and TNF-inhibiting medications, with good evidence for improvement in patient outcomes observed when measuring metabolic pathway indices. The role of routine measurement of metabolite/drug levels and antibodies warrants further prospective studies as we enter the era of personalized IBD care.

Current status of novel biologics and small molecule drugs in the individualized treatment of inflammatory bowel disease

Treatment strategies for inflammatory bowel disease(IBD)are rapidly evolving with the development of biologics and small molecule drugs(SMDs).However,these drugs are not guaranteed to be effective in all patients,and a“ceiling effect”of biologic monotherapy may occur.This issue highlights an unmet need for optimizing the use of biologics and predicting therapeutic responses.Thus,the development of new drugs with novel mechanisms of action is urgently needed for patients with primary nonresponse and secondary loss of response to conventional biologics and SMDs.In addition,combining different biologics or SMDs has been proposed as a novel strategy to enhance treatment efficacy in IBD,which theoretically has multidimensional anti-inflammatory potential.Based on the current evidence available for IBD,dual targeted therapy may be a promising strategy for refractory IBD patients who have failed in multiple biologic treatments or who have extraintestinal manifestation.Additionally,identifying the subgroup of IBD patients who are responding to biological combination therapies is also equally important in stable disease remission.In this review,we summarize the newly developed biologics and SMDs and the current status of biologics/SMDs to highlight the development of individualized treatment in IBD.

Strategies for Precise Engineering and Conjugation of Antibody Targeted-nanoparticles for Cancer Therapy

Improvements in the diagnosis and treatment of cancer are urgently needed for use in nanotechnology.Nanoparticles(NPs)can reduce the side effects of traditional chemotherapy by sustained release of loaded drugs and increase therapeutic efficiency.NPs can also enhance endothelial permeation retention by size effect and its accumulation in tumor cells through passive targeting.Furthermore,it is critical to treat cancer with a controlled targeted drug which can be specifically delivered into tumor cells and released there,resulting in a targeted therapy to eradicate tumor cells while sparing normal cells.To this end,antibody-mediated targeting therapy has been developed,but imperfections in antibodies(Abs)limit this therapy.Therefore,the combination of NPs and Abs has been highly valued in recent years,because conjugating special Abs on the surface of NPs can increase targeting efficiency,enabling selective delivery of anti-cancer drugs to tumor cells.In this mini-review,we would like to enumerate the strategies for the conjugation of Abs to the surface of the NPs as well as the precise engineering of targeted NPs.The application of targeting antibody fragments in this drug delivery system will also be discussed.