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Margetuximab and trastuzumab deruxtecan: New generation of anti-HER2 immunotherapeutic agents for breast cancer

Nur Husna SM, Wong KK

Mol Immunol, 2022 Dec;152:45-54.
PMID: 36272249 DOI: 10.1016/j.molimm.2022.10.005

Advances in the development of anti-HER2 monoclonal antibodies (mAbs) represent one of the most significant milestones in the treatment of HER2+ breast cancer patients. However, HER2+ metastatic breast cancer (MBC) patients display resistance towards first-generation anti-HER2 mAbs or antibody-drug conjugate (ADC) treatment. In recent years, new generation of anti-HER2 mAb and ADC including margetuximab and trastuzumab deruxtecan (T-DXd), respectively, have been approved for the treatment of previously treated HER2+ MBC patients. The successes of margetuximab and T-DXd have renewed the interest in the research and development of anti-HER2 immunotherapies for both HER2+ and HER2-low breast cancer patients. In this review, we focus on these two immunotherapeutics in terms of their mechanisms of action, preclinical findings and clinical trials leading to their approval, as well as the mechanisms of resistance to conventional anti-HER2 immunotherapies (i.e. trastuzumab, pertuzumab and T-DM1). In the future, combination of either margetuximab or T-DXd with small molecule inhibitors such as tyrosine kinase inhibitors that elicit anticancer immunogenicity may further enhance the efficacy of margetuximab or T-DXd in the treatment of HER2+ MBC patients.

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*
Novel Biologicals for the Treatment of Allergic Diseases and Asthma

Tan HT, Sugita K, Akdis CA

Curr Allergy Asthma Rep, 2016 10;16(10):70.
PMID: 27613653 DOI: 10.1007/s11882-016-0650-5

PURPOSE OF REVIEW: The development of biological therapies has rapidly progressed during the last few years, and major advances were reported for the treatment of allergic diseases, such as atopic dermatitis, allergic rhinitis, urticaria, food allergy, and asthma. Here, we review biologicals targeting the type 2 immune response involving Th2 cells, type 2 innate lymphoid cells, natural killer T cells, mast cells, basophils, and epithelial cells, such as IL-4, IL-5, IL-13, IL-31, tumor necrosis factor alpha (TNF-α), and thymic stromal lymphopoietin (TSLP).
RECENT FINDINGS: The biologicals that have been currently approved for asthma are omalizumab targeting IgE and reslizumab and mepolizumab targeting interleukin (IL)-5. Many other monoclonal antibodies are currently in various phases of clinical development. The new biological therapies for allergic diseases will eventually be tailored to the endotypes of these diseases and the identification of novel biomarkers. Further development of novel biologicals for the treatment of allergic diseases and asthma will be possible upon improved understanding of mechanisms of allergic diseases. Accordingly, further refinement of endotypes of allergen-specific and non-specific type 2 immune response and related inflammatory mediators is needed for optimal treatment of allergic diseases.

Matched MeSH terms: Antibodies, Monoclonal/therapeutic use*
Legacy effect of short-term alirocumab in familial hypercholesterolaemia: A case report

Muhmad Hamidi MH, Chua YA, Mohd Kasim NA, Sani H, Md Nawawi H, Kasim SS

Malays J Pathol, 2022 Dec;44(3):527-531.
PMID: 36591721

Homozygous familial hypercholesterolaemia (FH) is a rare genetic disorder with aberrantly high level of low-density lipoprotein cholesterol (LDL-C) requiring multiple combined aggressive lipidlowering therapy to reduce the progression of atherosclerotic cardiovascular disease. Alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) has been approved for treatment of FH, which requires further lowering of LDL-C in addition to diet modification and maximally tolerated statin therapy. We report the response of short-term alirocumab treatment on a young patient with clinically and genetically confirmed FH, who suffered from acute coronary syndrome, and in particular, discussed the hypothesised legacy effect of PCSK9i. The patient was initially treated with a combination of high-intensity statin and ezetimibe for 12 weeks. Subsequently, alirocumab was added to the patient's lipid-lowering regime and he managed to attain guideline recommended LDL-C target within 10 weeks. However, alirocumab was stopped at week 54 due to financial constraint. Interestingly, despite cessation of PCSK9i therapy for a period of 30 weeks, the patient's LDL-C level rose slightly not returning to his baseline level.

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*
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*
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*
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
High mobility group box 1 (HMGB1) protein in Multiple Sclerosis (MS): Mechanisms and therapeutic potential

Paudel YN, Angelopoulou E, C BK, Piperi C, Othman I

Life Sci, 2019 Dec 01;238:116924.
PMID: 31606383 DOI: 10.1016/j.lfs.2019.116924

Multiple sclerosis (MS) is an autoimmune chronic inflammatory disease with distinctive features of focal demyelination, axonal loss, activation of glial cells, and immune cells infiltration. The precise molecular mechanism underlying the disease progression remains enigmatic despite of the rapid progression on experimental and clinical MS research. The focus of MS therapy relies on the repression of the pathogenic autoimmune response without compromising an adaptive immune response. High mobility group box-1 (HMGB1) protein is a ubiquitous nuclear protein driving pro-inflammatory responses as well as targeting innate immune signaling that initiates and mediates autoimmunity as well as sterile injury. A considerable amount of experimental and human studies suggests the contribution of HMGB1 in the pathogenesis of MS/experimental autoimmune encephalitis (EAE). In this regard, HMGB1 protein has gained increased attention, as an emerging possible therapeutic target against MS. This is more strengthened by the promising therapeutic outcome demonstrated by HMGB1 neutralizing agents in the experimental EAE model. Herein, we attempt to shed more light on the molecular crosstalk of HMGB1 protein in the pathogenesis of MS/EAE suggesting that HMGB1 blockade could impede the pro-inflammatory loop that drives MS autoimmunity.

Matched MeSH terms: Antibodies, Monoclonal/therapeutic use*
Immunotherapies for Parkinson's Disease: Progression of Clinical Development

Teng JS, Ooi YY, Chye SM, Ling APK, Koh RY

CNS Neurol Disord Drug Targets, 2021;20(9):802-813.
PMID: 34042040 DOI: 10.2174/1871527320666210526160926

Parkinson's disease is a common neurodegenerative disease affecting the movement and well-being of most elderly. The manifestations of Parkinson's disease often include resting tremor, stiffness, bradykinesia, and muscular rigidity. The typical hallmark of Parkinson's disease is the destruction of neurons in the substantia nigra and the presence of Lewy bodies in different compartments of the central nervous system. Due to various limitations to the currently available treatments, immunotherapies have emerged to be the new approach to Parkinson's disease treatment. This approach shows some positive outcomes on the efficacy by removing the aggregated species of alpha-synuclein, which is believed to be one of the causes of Parkinson's disease. In this review, an overview of how alpha-synuclein contributes to Parkinson's disease and the effects of a few new immunotherapeutic treatments, including BIIB054 (cinpanemab), MEDI1341, AFFITOPE, and PRX002 (prasinezumab) that are currently under clinical development, will be discussed.

Matched MeSH terms: Antibodies, Monoclonal/therapeutic use
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
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*
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
Secukinumab therapy for paediatric patients with various phenotypes of congenital ichthyosis

Albela H, Ting IPL, Lee TS, Ooi D, Leong KF

Clin Exp Dermatol, 2024 Jul 19;49(8):920-922.
PMID: 38470562 DOI: 10.1093/ced/llae082
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
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
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*
Fulltext ReoPro Observational Registry (RAPOR): insights from the multicentre use of abciximab in Asia

Poh KK, Tan HC, Yip JW, Lim YT

Singapore Med J, 2005 Aug;46(8):407-13.
PMID: 16049611

The pattern of use of abciximab in real-life clinical patients undergoing percutaneous coronary intervention (PCI) in 11 high-volume centres in Singapore, Malaysia, Thailand, Philippines, India, Pakistan and Korea was prospectively examined.

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
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*

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