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Tag: Monoclonal Antibody

  • Monoclonal antibody Prasinezumab shows promise in slowing rapid Parkinson’s progression

    Monoclonal antibody Prasinezumab shows promise in slowing rapid Parkinson’s progression

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    In a recent study published in the journal Nature Medicine, a large, international team of researchers conducted an exploratory analysis to evaluate whether the monoclonal antibody prasinezumab, which had previously been observed to be effective in slowing the progression of motor-associated signs of Parkinson’s disease, did indeed show benefits in subgroups of Parkinson’s disease patients with faster progression of motor degeneration.

    Study: Prasinezumab slows motor progression in rapidly progressing early-stage Parkinson’s disease. Image Credit: Naeblys / ShutterstockStudy: Prasinezumab slows motor progression in rapidly progressing early-stage Parkinson’s disease. Image Credit: Naeblys / Shutterstock

    Background

    A hallmark of Parkinson’s disease is the aggregation of α-synuclein, which is thought to propagate between neurons and contribute to the pathogenesis of Parkinson’s disease. One of the first therapeutic options to target the aggregated α-synuclein was the monoclonal antibody prasinezumab, which was investigated in phase II clinical trials among patients with early-stage Parkinson’s disease who were part of the PASADENA study.

    The primary endpoint of the phase II trials of the PASADENA study was the Movement Disorder Society Unified Parkinson’s Disease Rating Scale or MDS-UPDRS score. Although the monoclonal antibody was not found to be effective along all the parameters of the MDS-UPDRS, compared to individuals treated with placebo, those who received prasinezumab showed slower progression of motor-associated degeneration. Furthermore, the team also believed that the MDS-UPDRS subscales are unlikely to show changes over short observation periods such as a year.

    About the study

    In the present study, the team examined the impact of prasinezumab on slowing motor degeneration progression in subgroups of Parkinson’s patients who had the rapidly progressing form of the disease. Given that MDS-UPDRS subscales might not show short-term changes associated with treatment, observing subgroups with the rapidly progressing form of Parkinson’s disease could help in improving the signal-to-noise ratio and reveal potential effects of the monoclonal antibody treatment.

    The PASADENA study consisted of three treatments — placebo, 1,500 mg prasinezumab, and 4,500 mg prasinezumab. The patients were randomly assigned to the three groups after being stratified by age (above or below 60), sex, and monoamine oxidase B inhibitor use. Patients using other symptomatic Parkinson’s disease medications, such as dopamine agonists or levodopa at baseline, were excluded. In cases where the use of these medications was considered imperative, the MDS-UPDRS scores were calculated before the initiation of treatment.

    The present study examined the impact of prasinezumab among patients who were on stable doses of monoamine oxidase B inhibitors at baseline and who exhibited other indicators of faster disease progression. The analyses of the six primary prespecified subpopulations included in phases I and II of the PASADENA study only included the results of four subpopulations.

    The subpopulations were based on the use of monoamine oxidase B inhibitors, stage 2 or Hoehn and Yahr stage versus stage 1 Parkinson’s disease, those with and without REM or rapid eye movement sleep behavior disorder, and those with diffuse malignant phenotype versus nondiffuse malignant phenotype.

    The analysis was also stratified along six exploratory subpopulations based on age, sex, duration of disease, age at diagnosis, and motor subphenotypes such as tremor dominant versus akinetic rigid or postural instability gait dysfunction. Furthermore, since previous studies reported no dose response, the two treatment groups consisting of 1,500 mg and 4,500 mg prasinezumab were pooled for the analysis.

    Results

    The findings suggested that prasinezumab was more effective in slowing the progression of motor signs in Parkinson’s disease patients with the rapidly progressing form of the disease. The subpopulation analyses revealed that patients with diffuse malignant phenotypes, or those who were using monoamine oxidase B inhibitors at baseline, which are indicators of rapid disease progression, showed slower signs of motor-associated degeneration compared to the patients with phenotypes that did not indicate rapid progression of Parkinson’s disease.

    The MDS-UPDRS part III score, which corresponds to clinician-rated motor signs, showed a slower increase or worsening of degeneration in the patients treated with prasinezumab than in those treated with a placebo. Parts I and II of the MDS-UPDRS score correspond to patient-reported motor and nonmotor signs, respectively.

    The researchers believe that since the data indicated a faster progression along MDS-UPDRS part III compared to parts I and II, part III or clinician-rated motor signs might precede parts I and II changes. These findings also indicate that more extended observation periods are required to assess the potential effect of treatments such as prasinezumab accurately.

    Conclusions

    Overall, the results suggested that the monoclonal antibody prasinezumab could potentially be used to slow the progression of motor-associated degeneration in patients with the rapidly progressing form of Parkinson’s disease. Furthermore, more extended observation periods are required to observe the impact of prasinezumab treatment in patients with the slowly progressing form of the disease. Moreover, additional randomized clinical trials need to validate these findings further.

    Journal reference:

    • Pagano, G., Taylor, K. I., Cabrera, A., Simuni, T., Marek, K., Postuma, R. B., Pavese, N., Stocchi, F., Brockmann, K., Svoboda, H., Trundell, D., Monnet, A., Doody, R., Fontoura, P., Kerchner, G. A., Brundin, P., Nikolcheva, T., Bonni, A., PASADENA Investigators, & Prasinezumab Study Group. (2024). Prasinezumab slows motor progression in rapidly progressing early-stage Parkinson’s disease. Nature Medicine. DOI: 10.1038/s4159102402886y, https://www.nature.com/articles/s41591-024-02886-y

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  • Study reveals safety of MS drugs during breastfeeding in child’s early years of life

    Study reveals safety of MS drugs during breastfeeding in child’s early years of life

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    Certain medications for multiple sclerosis (MS) called monoclonal antibodies, taken while breastfeeding, may not affect the development of a child during the first three years of life, according to a preliminary study released today, March 4, 2024. The study will be presented at the American Academy of Neurology’s 76th Annual Meeting taking place April 13–18, 2024, in person in Denver and online. The study examined four monoclonal antibodies for MS: natalizumab, ocrelizumab, rituximab and ofatumumab.

    MS is a disease in which the body’s immune system attacks myelin, the fatty white substance that insulates and protects the nerves. Symptoms may include fatigue, numbness, tingling or difficulty walking.

    Most monoclonal antibody medications for multiple sclerosis are not currently approved for use while a mother is breastfeeding. Yet MS can develop during the childbearing years of life. Since the risk of MS relapses increases after giving birth, some mothers may need or want to restart these therapies, so it is important to determine whether these medications, through breast milk, have a negative impact on a child’s development.”


    Kerstin Hellwig, MD, study author of Ruhr University in Bochum, Germany

    For the study, researchers used the German MS and Pregnancy Registry to identify 183 infants born to mothers taking monoclonal antibodies while breastfeeding. Of this group, 180 had mothers with MS and the three had mothers with neuromyelitis optica spectrum disease (NMOSD). NMOSD is also a demyelinating disease, but it is rare and specifically affects the optic nerve, spinal cord or brain. 

    The infants were compared to another 183 infants, matched for exposure to MS medications shortly before or during pregnancy, born to mothers with the same diseases who did not take monoclonal antibodies while breastfeeding.

    Of those exposed to MS medications, 125 were exposed to natalizumab, 34 to ocrelizumab, 11 to rituximab and 10 to ofatumumab. Two infants were first exposed to natalizumab and then ocrelizumab. One infant was exposed to rituximab and then ocrelizumab.

    The first exposures to the medications through breastfeeding ranged from the day a child was born to the ninth month of life. Infants were breastfed for an average of five-and-a-half months while their mothers took these medications.

    For all infants, researchers then examined the number of hospital stays, antibiotic use, developmental delays such as problems with social and fine motor skills and delayed speech development, and the infants’ weight at follow-up visits during the first three years of life.

    After comparing infants exposed to the medications to infants not exposed, researchers found no differences in their health or development.

    “Our data show infants exposed to these medications through breastfeeding experienced no negative effects on health or development within the first three years of life,” Hellwig said.

    A limitation of the study was that only about a third of the infants were followed for the full three years. Therefore, Hellwig said, the results for the third year of life are less meaningful than for years one and two.

    Source:

    American Academy of Neurology

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  • Broad-spectrum neutralizing antibody mAb-39 targets conserved S2 epitope in SARS-CoV-2

    Broad-spectrum neutralizing antibody mAb-39 targets conserved S2 epitope in SARS-CoV-2

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    The ongoing COVID-19 pandemic caused by SARS-CoV-2 has caused serious damage to public health and the global economy, and one strategy to combat COVID-19 has been the development of broadly neutralizing antibodies for prophylactic and therapeutic use. The most emergency-use authorized (EUA) therapeutic monoclonal antibodies, are more likely to lose their neutralizing activities as the viral epitopes (e.g. the receptor-binding domain, RBD) within spike protein of SARS-CoV-2 they target are more prone to mutate. By contrast, the S2 subunit of spike protein, has a much lower frequency of mutation than the RBD and exhibits a high degree of homology among human SARS-like CoVs. As such, developing antibodies targeting the more conserved S2 epitopes are able to exert an incredibly broad neutralization spectrum against SARS-like CoV viruses.

    This study is led by Dr. Suping Zhang (Shenzhen University), Dr. Zhenhong Lin (Chongqing University), and Dr Lanfeng Wang (Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences). They isolated one neutralizing mAb, called mAb-39, against SARS-CoV-2 and its variants from convalescent adult. This mAb exhibited good potency in neutralization SARS-CoV2 original strain, previous and current circulating Omicron variants (e.g. Omicron BA.1, BA.2.86, BA.4, BA.5, EG.5.1) in a cell-based assay.

    This antibody binds to a highly conserved new epitope on the glycoprotein from SARS-CoV2.

    This is very exciting! The good activity and highly conserved epitope of this antibody suggested its potential for clinical translation”.


    Dr. Hang Su, Shenzhen University

    The team found the mAb-39 greatly improved the neutralizing activity of anti-RBD antibody, the same type of EUA therapeutic monoclonal antibodies, against the highly neutralization-resistant Omicron variants. The study also extended the knowledge to the neutralizing and protective epitopes of SARS-CoV-2.

    Source:

    Tsinghua University Press

    Journal reference:

    Su, H., et al. (2024). A human monoclonal antibody neutralizes SARS-CoV-2 Omicron variants by targeting the upstream region of spike protein HR2 motif. hLife. doi.org/10.1016/j.hlife.2024.02.001.

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  • Omalizumab boosts tolerance to multiple food allergies, study finds

    Omalizumab boosts tolerance to multiple food allergies, study finds

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    In a recent study published in The New England Journal of Medicine, a group of researchers evaluated the efficacy and safety of omalizumab as a standalone treatment in increasing the allergen tolerance of individuals with multiple food allergies.

    Study: Omalizumab for the Treatment of Multiple Food Allergies. Image Credit: Dejan Stanisavljevic / ShutterstockStudy: Omalizumab for the Treatment of Multiple Food Allergies. Image Credit: Dejan Stanisavljevic / Shutterstock

    Background 

    Food allergies affect a significant portion of the United States (U.S.) population, leading to a high demand for vigilance and negatively impacting individuals’ well-being and healthcare costs. The only Food and Drug Administration (FDA)-approved treatment, oral immunotherapy for peanut allergies, is complex and can cause adverse effects. Omalizumab, an Immunoglobulin-E (IgE)-targeting monoclonal antibody approved for other allergic conditions, shows potential in managing multiple food allergies by improving allergen tolerance, reducing reactions, and enhancing life quality. However, further research is needed to confirm omalizumab’s long-term safety, effectiveness, and the best dosing for treating various food allergies in different demographics.

    About the study 

    The Omalizumab as Monotherapy and as Adjunct Therapy to Multi-Allergen Oral Immunotherapy (OIT) in Food Allergic Children and Adults (OUtMATCH) 

    The OUtMATCH trial, a multi-stage, double-blind, placebo-controlled study at ten U.S. centers, explores omalizumab’s efficacy against food allergies. Developed in collaboration with the Consortium for Food Allergy Research and pharmaceutical giants, its protocols ensure rigorous evaluation and safety, overseen by Johns Hopkins University’s review board. After completing its initial phase, the trial progresses to assess long-term outcomes and dietary reintroduction post-treatment.

    Participants, ranging from 1 to 55 years old and allergic to peanuts and at least two other specified foods, underwent thorough screening and challenges to ascertain eligibility. The initial phase involved a 2:1 randomization to either omalizumab or placebo, followed by reevaluation through food challenges. An interim analysis, prompted by the coronavirus disease 2019 (COVID-19) pandemic’s impact on enrollment, affirmed omalizumab potential, leading to an adjusted final sample size.

    The statistical analysis utilized a two-sided Fisher’s exact test to assess the efficacy of the treatment by comparing the percentage of participants who could ingest targeted food doses without adverse symptoms. To address multiple comparison issues, gatekeeping and sequential testing strategies were employed, ensuring a family-wise error rate below 0.05. The interim analysis, indicating positive outcomes, led to the cessation of enrollment. Secondary endpoints are presented with 95% confidence intervals, specifically focusing on the pediatric cohort, which constituted the primary analysis group.

    Study results 

    In the comprehensive evaluation spanning from September 2019 through November 2022, the trial screened 435 children and adolescents for eligibility. Of these, 177 were randomized to either the omalizumab or placebo group, with the majority of exclusions resulting from insufficient allergic responses to the tested foods. The demographic makeup of participants was predominantly male, with a median age of seven years. These individuals were notably atopic, suffering from conditions such as asthma, atopic dermatitis, and allergic rhinitis, and had a median total IgE level of 700 IU per milliliter. Baseline food challenge tests showed similar maximum tolerated doses across the board for the allergens in question.

    The trial’s omalizumab group saw a significant percentage (67%) of participants able to consume at least 600 mg of peanut protein without dose-limiting symptoms, starkly contrasting with only 7% in the placebo group. This efficacy extended to other specified foods, demonstrating omalizumab’s potential to significantly raise allergen tolerance levels among recipients. The dosage varied among participants, with a notable division in administration frequency based on individual requirements.

    Further analysis within the trial assessed the capability of participants to ingest one, two, or three of the specified allergens in varying doses without adverse effects. Results from the omalizumab group were promising, showing a substantial capacity for increased allergen consumption. An open-label extension of the trial aimed to investigate the durability of omalizumab’s efficacy over a more extended period (40 to 44 weeks), revealing that most participants maintained or improved their allergen tolerance levels.

    Quality of life assessments for both participants and caregivers, conducted via validated questionnaires, indicated no significant change by the end of the initial trial stage. However, improvements were noted during the open-label extension. Safety profiles were similar across both groups, with the exception of more frequent injection-site reactions among omalizumab recipients. One serious adverse event was reported, considered possible but unlikely related to omalizumab.

    The trial faced challenges due to the COVID-19 pandemic, which temporarily disrupted participant recruitment and treatment administration. Additionally, mold contamination in some food challenge products necessitated a brief pause in testing, although subsequent analyses confirmed that these issues did not impact the trial’s overall results. 

    Conclusions 

    To summarize, omalizumab significantly raised the tolerance threshold for multiple food allergens, including peanuts, cashews, eggs, and milk, among individuals from as young as 1 year old over 16 weeks. A majority of those treated with omalizumab could safely ingest quantities of allergens far exceeding typical accidental exposure levels, indicating its potential as an effective monotherapy for food allergies. The treatment also demonstrated the ability to simultaneously protect against reactions from multiple allergens. Extended treatment in a 24-week follow-up showed sustained tolerance.

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  • Novel monoclonal antibody shows promise in targeting HER2-positive breast cancer cells

    Novel monoclonal antibody shows promise in targeting HER2-positive breast cancer cells

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    In a step forward for breast cancer treatment, researchers at Tohoku University have developed a novel monoclonal antibody which specifically targets a certain type of breast cancer cell. Their findings, published in the International Journal of Molecular Sciences, offer a new tool for treating this disease.

    Breast cancer remains a significant global health concern that afflicts millions of people each year. The HER2-positive subtype of breast cancer is one of the most aggressive and challenging to treat. Approximately 20% of breast cancer cases are classified as HER2-positive, meaning that there is an urgent need for therapies targeted to this specific subtype.

    A research team led by Yukinari Kato rose to this challenge by developing a monoclonal antibody that precisely targets HER2-positive breast cancer cells. Monoclonal antibodies are specialized proteins engineered to recognize and bind to specific targets with exceptional precision.

    HER2-positive breast cancer cells have more of the HER2 protein on their surface than healthy cells. This protein plays an important role in cell growth and division, and the excess of HER2 is one reason HER2-positive tumors are aggressive. By specifically targeting HER2-positive cells, the antibody disrupts their growth and proliferation while minimizing harm to surrounding healthy tissue.

    The development of this antibody represents a significant milestone in our ongoing efforts to advance breast cancer treatment. By targeting HER2-positive breast cancer cells with precision, we can offer patients a more effective and less toxic treatment option.”

    Yukinari Kato, Tohoku University

    The new antibody offers a more targeted and selective approach than conventional treatments, such as chemotherapy, which can cause significant collateral damage to healthy cells. This precision not only enhances the efficacy of treatment but also reduces the incidence and severity of side effects, greatly improving the quality of life of breast cancer patients.

    The project is set to move to the next phase, which will include clinical trials and regulatory approval processes. The researchers will also explore potential applications of other novel antibodies in various therapeutic areas, assessing whether they can improve outcomes for people battling other types of cancer.

    The research was supported by grants from the Japan Agency for Medical Research and Development (AMED), including the “Science and Technology Platform Program for Advanced Biological Medicine” and “Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)”.

    Source:

    Journal reference:

    Kaneko, M. K., et al. (2024). A Cancer-Specific Monoclonal Antibody against HER2 Exerts Antitumor Activities in Human Breast Cancer Xenograft Models. International Journal of Molecular Sciences. doi.org/10.3390/ijms25031941.

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  • FDA approves omalizumab for food allergy reactions based on NIH research

    FDA approves omalizumab for food allergy reactions based on NIH research

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    Today’s Food and Drug Administration approval of a supplemental biologics license for the monoclonal antibody omalizumab (Xolair) highlights the vital role of the National Institutes of Health-supported research that underpins the FDA decision.

    FDA has approved omalizumab for the reduction of allergic reactions, including anaphylaxis, that may occur with an accidental exposure to one or more foods in adults and children aged 1 year and older with food allergy. People taking omalizumab still need to avoid exposure to foods to which they are allergic. Omalizumab previously received FDA approval for three other indications, including the treatment of moderate-to-severe persistent allergic asthma in certain patients.

    The new FDA approval is based on data from a planned interim analysis of a Phase 3 clinical trial sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of NIH. The trial is called Omalizumab as Monotherapy and as Adjunct Therapy to Multi-Allergen OIT in Food Allergic Children and Adults, or OUtMATCH. Investigators in the NIAID-funded Consortium for Food Allergy Research conducted the trial.

    Detailed final results from the first stage of the trial will be presented at the American Academy of Allergy, Asthma & Immunology Annual Meeting in Washington, D.C. during a late-breaking symposium titled, “Omalizumab for the Treatment of Food Allergy: The OUtMATCH Study” on Sunday, Feb. 25, 2024, at 1:45 pm ET. An online supplement of the Journal of Allergy and Clinical Immunology published an abstract outlining the final results on Feb. 5, 2024. 

    NIAID funds the trial with additional support from and collaboration with Genentech, a member of the Roche Group, and Novartis Pharmaceuticals Corporation. The two companies collaborate to develop and promote omalizumab and are supplying it for the trial. 

    Additional information about the ongoing OUtMATCH trial is available at ClinicalTrials.gov under study identifier NCT03881696.

    Source:

    NIH/National Institute of Allergy and Infectious Diseases

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