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Epigenetic oncogenesis, biomarkers and emerging chemotherapeutics for breast cancer

Ayipo YO, Ajiboye AT, Osunniran WA, Jimoh AA, Mordi MN

Biochim Biophys Acta Gene Regul Mech, 2022 10;1865(7):194873.
PMID: 36064110 DOI: 10.1016/j.bbagrm.2022.194873

Breast cancer remains one of the leading causes of cancer-related deaths globally and the most prominent among females, yet with limited effective therapeutic options. Most of the current medications are challenged by various factors including low efficacy, incessant resistance, immune evasion and frequent recurrence of the disease. Further understanding of the prognosis and identification of plausible therapeutic channels thus requires multimodal approaches. In this review, epigenetics studies of several pathways to BC oncogenesis via the inducement of oncogenic changes on relevant markers have been overviewed. Similarly, the counter-epigenetic mechanisms to reverse such changes as effective therapeutic strategies were surveyed. The epigenetic oncogenesis occurs through several pathways, notably, DNMT-mediated hypermethylation of DNA, dysregulated expression for ERα, HER2/ERBB and PR, histone modification, overexpression of transcription factors including the CDK9-cyclin T1 complex and suppression of tumour suppressor genes. Scientifically, the regulatory reversal of the mechanisms constitutes effective epigenetic approaches for mitigating BC initiation, progression and metastasis. These were exhibited at various experimental levels by classical chemotherapeutic agents including some repurposable drugs, endocrine inhibitors, monoclonal antibodies and miRNAs, natural products, metal complexes and nanoparticles. Dozens of the potential candidates are currently in clinical trials while others are still at preclinical experimental stages showing promising anti-BC efficacy. The review presents a model for a wider understanding of epigenetic oncogenic pathways to BC and reveals plausible channels for reversing the unpleasant changes through epigenetic modifications. It advances the science of therapeutic designs for ameliorating the global burden of BC upon further translational studies.

Matched MeSH terms: Antibodies, Monoclonal/therapeutic use
Counterpoint. Cancer vaccines: single-epitope anti-idiotype vaccine versus multiple-epitope antigen vaccine

Bhattachary-Chatterjee M, Nath Baral R, Chatterjee SK, Das R, Zeytin H, Chakraborty M, et al.

Cancer Immunol Immunother, 2000 Jun;49(3):133-41.
PMID: 10881692

Anti-idiotype (Id) vaccine therapy has been tested and shown to be effective, in several animal models, for triggering the immune system to induce specific and protective immunity against bacterial, viral and parasitic infections. The administration of anti-Id antibodies as surrogate tumor-associated antigens (TAA) also represents another potential application of the concept of the Id network. Limited experience in human trials using anti-Id to stimulate immunity against tumors has shown promising results. In this "counter-point" article, we discuss our own findings showing the potential of anti-Id antibody vaccines to be novel therapeutic approaches to various human cancers and also discuss where anti-Id vaccines may perform better than traditional multiple-epitope antigen vaccines.

Matched MeSH terms: Antibodies, Monoclonal/therapeutic use
The anti-idiotype vaccines for immunotherapy

Bhattacharya-Chatterjee M, Chatterjee SK, Foon KA

Curr. Opin. Mol. Ther., 2001 Feb;3(1):63-9.
PMID: 11249733

Certain anti-idiotypic antibodies that bind to the antigen-combining sites of antibodies can effectively mimic the three-dimensional structures and functions of the external antigens and can be used as surrogate antigens for active specific immunotherapy. Extensive studies in animal models have demonstrated the efficacy of these vaccines for triggering the immune system to induce specific and protective immunity against bacterial, viral and parasitic infections as well as tumors. Several monoclonal anti-idiotype antibodies that mimic distinct human tumor-associated antigens have been developed and characterized. Encouraging results have been obtained in recent clinical trials using these anti-idiotype antibodies as vaccines. In this article, we will review the current literature and discuss the potential of this novel therapeutic approach for various human cancers.

Matched MeSH terms: Antibodies, Monoclonal/therapeutic use
Anti-idiotype vaccine against cancer

Bhattacharya-Chatterjee M, Chatterjee SK, Foon KA

Immunol Lett, 2000 Sep 15;74(1):51-8.
PMID: 10996628

Immunization with anti-idiotype (Id) antibodies represents a novel new approach to active immunotherapy. Extensive studies in animal tumor models have demonstrated the efficacy of anti-Id vaccines in preventing tumor growth and curing mice with established tumor. We have developed and characterized several murine monoclonal anti-Id antibodies (Ab2) which mimic distinct human tumor-associated antigens (TAA) and can be used as surrogate antigens for triggering active anti-tumor immunity in cancer patients. Encouraging results have been obtained in recent clinical trials. In this article, we will review the existing literature and summarize our own findings showing the potential of this approach for various human cancers. We will also discuss where anti-Id vaccines may perform better than traditional antigen vaccines.

Matched MeSH terms: Antibodies, Monoclonal/therapeutic use
Fulltext A treatment for and vaccine against the deadly Hendra and Nipah viruses

Broder CC, Xu K, Nikolov DB, Zhu Z, Dimitrov DS, Middleton D, et al.

Antiviral Res, 2013 Oct;100(1):8-13.
PMID: 23838047 DOI: 10.1016/j.antiviral.2013.06.012

Hendra virus and Nipah virus are bat-borne paramyxoviruses that are the prototypic members of the genus Henipavirus. The henipaviruses emerged in the 1990s, spilling over from their natural bat hosts and causing serious disease outbreaks in humans and livestock. Hendra virus emerged in Australia and since 1994 there have been 7 human infections with 4 case fatalities. Nipah virus first appeared in Malaysia and subsequent outbreaks have occurred in Bangladesh and India. In total, there have been an estimated 582 human cases of Nipah virus and of these, 54% were fatal. Their broad species tropism and ability to cause fatal respiratory and/or neurologic disease in humans and animals make them important transboundary biological threats. Recent experimental findings in animals have demonstrated that a human monoclonal antibody targeting the viral G glycoprotein is an effective post-exposure treatment against Hendra and Nipah virus infection. In addition, a subunit vaccine based on the G glycoprotein of Hendra virus affords protection against Hendra and Nipah virus challenge. The vaccine has been developed for use in horses in Australia and is the first vaccine against a Biosafety Level-4 (BSL-4) agent to be licensed and commercially deployed. Together, these advances offer viable approaches to address Hendra and Nipah virus infection of livestock and people.

Matched MeSH terms: Antibodies, Monoclonal/therapeutic use
Immune Human Antibody Libraries for Infectious Diseases

Chan SK, Lim TS

Adv Exp Med Biol, 2017;1053:61-78.
PMID: 29549635 DOI: 10.1007/978-3-319-72077-7_4

The incident of two children in Europe who died of diphtheria due to a shortage of anti-toxin drugs has highlighted the need for alternative anti-toxins. Historically, antiserum produced from immunised horses have been used to treat diphtheria. Despite the potential of antiserum, the economical and medial concerns associated with the use of animal antiserum has led to its slow market demise. Over the years, new and emerging infectious diseases have grown to be a major global health threat. The emergence of drug-resistant superbugs has also pushed the boundaries of available therapeutics to deal with new infectious diseases. Antibodies have emerged as a possible alternative to combat the continuous onslaught of various infectious agents. The isolation of antibodies against pathogens of infectious diseases isolated from immune libraries utilising phage display has yielded promising results in terms of affinities and neutralizing activities. This chapter focuses on the concept of immune antibody libraries and highlights the application of immune antibody libraries to generate antibodies for various infectious diseases.

Matched MeSH terms: Antibodies, Monoclonal/therapeutic use
Fulltext Naïve Human Antibody Libraries for Infectious Diseases

Chan SK, Rahumatullah A, Lai JY, Lim TS

Adv Exp Med Biol, 2017;1053:35-59.
PMID: 29549634 DOI: 10.1007/978-3-319-72077-7_3

Many countries are facing an uphill battle in combating the spread of infectious diseases. The constant evolution of microorganisms magnifies the problem as it facilitates the re-emergence of old infectious diseases as well as promote the introduction of new and more deadly variants. Evidently, infectious diseases have contributed to an alarming rate of mortality worldwide making it a growing concern. Historically, antibodies have been used successfully to prevent and treat infectious diseases since the nineteenth century using antisera collected from immunized animals. The inherent ability of antibodies to trigger effector mechanisms aids the immune system to fight off pathogens that invades the host. Immune libraries have always been an important source of antibodies for infectious diseases due to the skewed repertoire generated post infection. Even so, the role and ability of naïve antibody libraries should not be underestimated. The naïve repertoire has its own unique advantages in generating antibodies against target antigens. This chapter will highlight the concept, advantages and application of human naïve libraries as a source to isolate antibodies against infectious disease target antigens.

Matched MeSH terms: Antibodies, Monoclonal/therapeutic use
Fulltext Delineation of B-cell Epitopes of Salmonella enterica serovar Typhi Hemolysin E: Potential antibody therapeutic target

Chin CF, Lai JY, Choong YS, Anthony AA, Ismail A, Lim TS

Sci Rep, 2017 05 19;7(1):2176.
PMID: 28526816 DOI: 10.1038/s41598-017-01987-8

Hemolysin E (HlyE) is an immunogenic novel pore-forming toxin involved in the pathogenesis of typhoid fever. Thus, mapping of B-cell epitopes of Salmonella enterica serovar Typhi (S. Typhi) is critical to identify key immunogenic regions of HlyE. A random 20-mer peptide library was used for biopanning with enriched anti-HlyE polyclonal antibodies from typhoid patient sera. Bioinformatic tools were used to refine, analyze and map the enriched peptide sequences against the protein to identify the epitopes. The analysis identified both linear and conformational epitopes on the HlyE protein. The predicted linear GAAAGIVAG and conformational epitope PYSQESVLSADSQNQK were further validated against the pooled sera. The identified epitopes were then used to isolate epitope specific monoclonal antibodies by antibody phage display. Monoclonal scFv antibodies were enriched for both linear and conformational epitopes. Molecular docking was performed to elucidate the antigen-antibody interaction of the monoclonal antibodies against the epitopes on the HlyE monomer and oligomer structure. An in-depth view of the mechanistic and positional characteristics of the antibodies and epitope for HlyE was successfully accomplished by a combination of phage display and bioinformatic analysis. The predicted function and structure of the antibodies highlights the possibility of utilizing the antibodies as neutralizing agents for typhoid fever.

Matched MeSH terms: Antibodies, Monoclonal/therapeutic use
Flavivirus infection-A review of immunopathogenesis, immunological response, and immunodiagnosis

Chong HY, Leow CY, Abdul Majeed AB, Leow CH

Virus Res, 2019 12;274:197770.
PMID: 31626874 DOI: 10.1016/j.virusres.2019.197770

Flaviviruses are group of single stranded RNA viruses that cause severe endemic infection and epidemics on a global scale. It presents a significant health impact worldwide and the viruses have the potential to emerge and outbreak in a non-endemic geographical region. Effective vaccines for prophylaxis are only available for several flaviviruses such as Yellow Fever virus, Tick-borne Encephalitis Virus, Dengue Virus and Japanese Encephalitis Virus and there is no antiflaviviral agent being marketed. This review discusses the flavivirus genome, replication cycle, epidemiology, clinical presentation and pathogenesis upon infection. Effective humoral response is critical to confer protective immunity against flaviviruses. Hence, we have also highlighted the immune responses elicited upon infection, various diagnostic facilities available for flaviviral disease and monoclonal antibodies available to date against flavivirus infection.

Matched MeSH terms: Antibodies, Monoclonal/therapeutic use
Computer-Aided Antibody Design: An Overview

Choong YS, Lee YV, Soong JX, Law CT, Lim YY

Adv Exp Med Biol, 2017;1053:221-243.
PMID: 29549642 DOI: 10.1007/978-3-319-72077-7_11

The use of monoclonal antibody as the next generation protein therapeutics with remarkable success has surged the development of antibody engineering to design molecules for optimizing affinity, better efficacy, greater safety and therapeutic function. Therefore, computational methods have become increasingly important to generate hypotheses, interpret and guide experimental works. In this chapter, we discussed the overall antibody design by computational approches.

Matched MeSH terms: Antibodies, Monoclonal/therapeutic use*
Bone metabolism and histomorphometric changes in murine models treated with sclerostin antibody: a systematic review

Das S, Sakthiswary R

Curr Drug Targets, 2013 Dec;14(14):1667-74.
PMID: 24354585

Preventing osteoporotic fractures in millions of individuals may significantly reduce the associated morbidity and health-care expenditures incurred. As such, the search for newer anti-osteoporotic agents has been ongoing for years. Genetic studies have proven that the secreted protein sclerostin is one of the main culprits, which negatively regulates the bone formation. Recently, sclerostin-neutralizing monoclonal antibodies (Scl-Ab) in rodent studies have shown positive effects on bone homeostasis. An extensive search of the literature was performed in the BIOSIS, Cinahl, EMBASE, Pub- Med, Web of Science and Cochrane Library databases to evaluate the published murine studies on the effects of Scl-Ab on the bone metabolism and histomorphometric parameters. Our systematic review depicts a significant association between Scl-Ab administration and improvement in bone formation, bone density, bone volume and trabecular thickness.

Matched MeSH terms: Antibodies, Monoclonal/therapeutic use*
A Randomized, Placebo-Controlled Phase 2 Trial of CNTO 6785 in Chronic Obstructive Pulmonary Disease

Eich A, Urban V, Jutel M, Vlcek J, Shim JJ, Trofimov VI, et al.

COPD, 2017 Oct;14(5):476-483.
PMID: 28753067 DOI: 10.1080/15412555.2017.1335697

Interleukin (IL)-17A may be an underlying factor in the pathophysiology of chronic obstructive pulmonary disease (COPD). Anti-IL-17 monoclonal antibodies have been used successfully in treating several immune-mediated inflammatory diseases. This phase 2, randomized, placebo-controlled, double-blind, parallel-group, proof-of-concept study is the first clinical study evaluating the efficacy and safety of the anti-IL-17A monoclonal antibody CNTO 6785 in patients with symptomatic moderate-to-severe COPD. Patients were treated with CNTO 6785 (n = 93) or placebo (n = 94) intravenously at Weeks 0, 2, and 4 (induction), then Weeks 8 and 12, and followed till Week 24. The primary efficacy endpoint was the change from baseline in pre-bronchodilator percent-predicted forced expiratory volume in 1 second at Week 16. Samples were collected at all visits for pharmacokinetic (PK) evaluation, and standard safety assessments were performed. The mean difference in the primary efficacy endpoint between CNTO 6785 and placebo was not statistically significant (-0.49%; p = 0.599). No other efficacy endpoints demonstrated clinically or statistically significant differences with CNTO 6785 compared with placebo. CNTO 6785 was generally well tolerated; no major safety signals were detected. The most frequently reported treatment-emergent adverse events were infections and infestations; however, no notable differences were observed between CNTO 6785 and placebo in terms of rates of infections. PK results suggested that the steady state of serum CNTO 6785 concentration was reached within 16 weeks. These results suggest that IL-17A is unlikely to be a dominant driver in the pathology of, or a viable therapeutic target for, COPD. ClinicalTrials.gov Identifier: NCT01966549; EudraCT Identifier: 2012-003607-36.

Matched MeSH terms: Antibodies, Monoclonal/therapeutic use*
The current status of checkpoint inhibitors in metastatic bladder cancer

Fahmy O, Khairul-Asri MG, Stenzl A, Gakis G

Clin. Exp. Metastasis, 2016 10;33(7):629-35.
PMID: 27380916 DOI: 10.1007/s10585-016-9807-9

For many decades, no significant improvements could be achieved to prolong the survival in metastatic bladder cancer. Recently, systemic immunotherapy with checkpoint inhibitors (anti-PD-L1/anti-CTLA-4) has been introduced as a novel treatment modality for patients with metastatic bladder cancer. We conducted a systematic review according to the PRISMA statement for data published on the clinical efficacy of checkpoint inhibitors in metastatic bladder cancer. Clinical efficacy of anti PD-L1 therapy was investigated in prospective trials in a total of 155 patients. Patients with positive expression for PD-L1 tended towards better overall response rates (ORR) compared to those with negative expression (34/76 vs 10/73, 45 vs 14 %; p = 0.21). Among patients with PD-L1 positive tumors, those with non-visceral metastases exhibited significantly higher ORR compared to those with visceral metastases (82 vs 28 %; p = 0.001). For anti-CTLA4 therapy, there were no data retrievable on clinical efficacy. Although data on clinical efficacy of checkpoint inhibitors in metastatic bladder cancer are currently limited, the efficacy of these drugs might depend mainly on the metastatic volume and immune system integrity. Patients with PD-L1 positive tumors and non-visceral metastases seem to derive the highest benefit from therapy.

Matched MeSH terms: Antibodies, Monoclonal/therapeutic use
Fulltext The use of neutralizing monoclonal antibodies and risk of hospital admission and mortality in patients with COVID-19: a systematic review and meta-analysis of randomized trials

Kow CS, Ramachandram DS, Hasan SS

Immunopharmacol Immunotoxicol, 2022 Feb;44(1):28-34.
PMID: 34762561 DOI: 10.1080/08923973.2021.1993894

AIM: Several randomized trials have evaluated the effect of neutralizing monoclonal antibodies on the risk of hospital admission and risk of mortality in patients with COVID-19. We aimed to summarize the overall evidence in the form of a systematic review and meta-analysis.
METHODS: A systematic literature search with no language restriction was performed in electronic databases and preprint repositories to identify eligible studies published up to 29 June 2021. The outcomes of interest were hospital admission and all-cause mortality. A random-effects model was used to estimate the pooled odds ratio (OR) for outcomes of interest with the use of neutralizing monoclonal antibodies relative to nonuse of neutralizing monoclonal antibodies, at 95% confidence intervals (CI).
RESULTS: Our systematic literature search identified nine randomized controlled trials. Three trials had an overall low risk of bias, while four trials had some concerns in the overall risk of bias. The meta-analysis revealed no statistically significant difference in the odds of mortality (pooled OR = 0.69; 95% CI 0.33-1.47), but a statistically significant reduction in the odds of hospital admission (pooled OR = 0.29; 95% CI 0.21-0.42), with the administration of a neutralizing monoclonal antibody among patients with COVID-19, relative to non-administration of a neutralizing monoclonal antibody, at the current sample size.
CONCLUSION: The reduced risk of hospital admission with neutralizing monoclonal antibodies use suggests that the timing of neutralizing antibodies administration is key in preventing hospital admission and, ultimately, death. Future randomized trials should aim to determine if the clinical outcomes with neutralizing monoclonal antibodies differ based on serostatus.

Matched MeSH terms: Antibodies, Monoclonal/therapeutic use*
Potential application of Leishmania tarentolae as an alternative platform for antibody expression

Lai JY, Klatt S, Lim TS

Crit Rev Biotechnol, 2019 May;39(3):380-394.
PMID: 30720351 DOI: 10.1080/07388551.2019.1566206

Through the discovery of monoclonal antibody (mAb) technology, profound successes in medical treatment against a wide range of diseases have been achieved. This has led antibodies to emerge as a new class of biodrugs. As the "rising star" in the pharmaceutical market, extensive research and development in antibody production has been carried out in various expression systems including bacteria, insects, plants, yeasts, and mammalian cell lines. The major benefit of eukaryotic expression systems is the ability to carry out posttranslational modifications of the antibody. Glycosylation of therapeutic antibodies is one of these important modifications, due to its influence on antibody structure, stability, serum half-life, and complement recruitment. In recent years, the protozoan parasite Leishmania tarentolae has been introduced as a new eukaryotic expression system. L. tarentolae is rich in glycoproteins with oligosaccharide structures that are very similar to humans. Therefore, it is touted as a potential alternative to mammalian expression systems for therapeutic antibody production. Here, we present a comparative review on the features of the L. tarentolae expression system with other expression platforms such as bacteria, insect cells, yeasts, transgenic plants, and mammalian cells with a focus on mAb production.

Matched MeSH terms: Antibodies, Monoclonal/therapeutic use
The use of infliximab in South-east Asian children with severe Crohn's disease

Lee WS

Pediatr Int, 2004 Apr;46(2):198-201.
PMID: 15056252
Matched MeSH terms: Antibodies, Monoclonal/therapeutic use*
Are we ready for combination therapy in moderate-to-severe ulcerative colitis?

Lee YY, Gangireddy V, Khurana S, Rao SS

Gastroenterology, 2014 Aug;147(2):544.
PMID: 24976027 DOI: 10.1053/j.gastro.2014.03.053
Matched MeSH terms: Antibodies, Monoclonal/therapeutic use*
Fulltext A comparison of thrombotic thrombocytopenic purpura in an inception cohort of patients with and without systemic lupus erythematosus

Letchumanan P, Ng HJ, Lee LH, Thumboo J

Rheumatology (Oxford), 2009 Apr;48(4):399-403.
PMID: 19202160 DOI: 10.1093/rheumatology/ken510

To compare the clinical presentation, response to therapy and outcome of thrombotic thrombocytopenic purpura (TTP) in an inception cohort of patients with and without SLE.

Matched MeSH terms: Antibodies, Monoclonal/therapeutic use
Principles and application of antibody libraries for infectious diseases

Lim BN, Tye GJ, Choong YS, Ong EB, Ismail A, Lim TS

Biotechnol Lett, 2014 Dec;36(12):2381-92.
PMID: 25214212 DOI: 10.1007/s10529-014-1635-x

Antibodies have been used efficiently for the treatment and diagnosis of many diseases. Recombinant antibody technology allows the generation of fully human antibodies. Phage display is the gold standard for the production of human antibodies in vitro. To generate monoclonal antibodies by phage display, the generation of antibody libraries is crucial. Antibody libraries are classified according to the source where the antibody gene sequences were obtained. The most useful library for infectious diseases is the immunized library. Immunized libraries would allow better and selective enrichment of antibodies against disease antigens. The antibodies generated from these libraries can be translated for both diagnostic and therapeutic applications. This review focuses on the generation of immunized antibody libraries and the potential applications of the antibodies derived from these libraries.

Matched MeSH terms: Antibodies, Monoclonal/therapeutic use*
Fulltext Pathogenic Differences between Nipah Virus Bangladesh and Malaysia Strains in Primates: Implications for Antibody Therapy

Mire CE, Satterfield BA, Geisbert JB, Agans KN, Borisevich V, Yan L, et al.

Sci Rep, 2016 08 03;6:30916.
PMID: 27484128 DOI: 10.1038/srep30916

Nipah virus (NiV) is a paramyxovirus that causes severe disease in humans and animals. There are two distinct strains of NiV, Malaysia (NiVM) and Bangladesh (NiVB). Differences in transmission patterns and mortality rates suggest that NiVB may be more pathogenic than NiVM. To investigate pathogenic differences between strains, 4 African green monkeys (AGM) were exposed to NiVM and 4 AGMs were exposed to NiVB. While NiVB was uniformly lethal, only 50% of NiVM-infected animals succumbed to infection. Histopathology of lungs and spleens from NiVB-infected AGMs was significantly more severe than NiVM-infected animals. Importantly, a second study utilizing 11 AGMs showed that the therapeutic window for human monoclonal antibody m102.4, previously shown to rescue AGMs from NiVM infection, was much shorter in NiVB-infected AGMs. Together, these data show that NiVB is more pathogenic in AGMs under identical experimental conditions and suggests that postexposure treatments may need to be NiV strain specific for optimal efficacy.

Matched MeSH terms: Antibodies, Monoclonal/therapeutic use

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