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BioRxiv : the Preprint Server For... Jun 2024Both endogenous antibodies and a subset of antibody therapeutics engage Fc gamma receptor (FcγR)IIIa / CD16a to stimulate a protective immune response. Increasing the...
Both endogenous antibodies and a subset of antibody therapeutics engage Fc gamma receptor (FcγR)IIIa / CD16a to stimulate a protective immune response. Increasing the FcγRIIIa/IgG1 interaction improves the immune response and thus represents a strategy to improve therapeutic efficacy. FcγRIIIa is a heavily glycosylated receptor and glycan composition affects antibody-binding affinity. Though our laboratory previously demonstrated that natural killer (NK) cell N-glycan composition affected the potency of one key protective mechanism, antibody-dependent cell-mediated cytotoxicity (ADCC), it was unclear if this effect was due to FcγRIIIa glycosylation. Furthermore, the structural mechanism linking glycan composition to affinity and cellular activation remained undescribed. To define the role of individual amino acid and N-glycan residues we measured affinity using multiple FcγRIIIa glycoforms. We observed stepwise affinity increases with each glycan truncation step with the most severely truncated glycoform displaying the highest affinity. Removing the N162 glycan demonstrated its predominant role in regulating antibody-binding affinity, in contrast to four other FcγRIIIa N-glycans. We next evaluated the impact of the N162 glycan on NK cell ADCC. NK cells expressing the FcγRIIIa V158 allotype exhibited increased ADCC following kifunensine treatment to limit N-glycan processing. Notably, an increase was not observed with cells expressing the FcγRIIIa V158 S164A variant that lacks N162 glycosylation, indicating the N162 glycan is required for increased NK cell ADCC. To gain structural insight into the mechanisms of N162 regulation, we applied a novel protein isotope labeling approach in combination with solution NMR spectroscopy. FG loop residues proximal to the N162 glycosylation site showed large chemical shift perturbations following glycan truncation. These data support a model for the regulation of FcγRIIIa affinity and NK cell ADCC whereby composition of the N162 glycan stabilizes the FG loop and thus the antibody-binding site.
PubMed: 38948809
DOI: 10.1101/2024.06.17.599285 -
BioRxiv : the Preprint Server For... Jun 2024SARS-CoV-2 virus has continued to evolve over time necessitating the adaptation of vaccines to maintain efficacy. Monoclonal antibodies (mAbs) against SARS-CoV-2 were a...
UNLABELLED
SARS-CoV-2 virus has continued to evolve over time necessitating the adaptation of vaccines to maintain efficacy. Monoclonal antibodies (mAbs) against SARS-CoV-2 were a key line of defense for unvaccinated or immunocompromised individuals. However, these mAbs are now ineffective against current SARS-CoV-2 variants. Here, we tested three aspects of αSARS-CoV-2 therapeutics. First, we tested whether Fc engagement is necessary for clearance of SARS-CoV-2. Secondly, we tested bi-specific killer engagers (BiKEs) that simultaneously engage SARS-CoV-2 and a specific Fc receptor. Benefits of these engagers include the ease of manufacturing, stability, more cell-specific targeting, and high affinity binding to Fc receptors. Using both mAbs and BiKEs, we found that both neutralization and Fc receptor engagement were necessary for effective SARS-CoV-2 clearance. Thirdly, due to ACE2 being necessary for viral entry, ACE2 will maintain binding to SARS-CoV-2 despite viral evolution. Therefore, we used an ACE2 decoy Fc-fusion or BiKE, instead of an anti-SARS-CoV-2 antibody sequence, as a potential therapeutic that would withstand viral evolution. We found that the ACE2 decoy approach also required Fc receptor engagement and, unlike traditional neutralizing antibodies against specific variants, enabled the clearance of two distinct SARS-CoV-2 variants. These data show the importance of Fc engagement for mAbs, the utility of BiKEs as therapies for infectious disease, and the effectiveness of the ACE2 decoy approach. With further studies, we predict combining neutralization, the cellular response, and this ACE2 decoy approach will benefit individuals with ineffective antibody levels.
ABBREVIATIONS
ACE2, scFv, mAb, BiKE, COVID-19, Fc, CD16, CD32b, CD64, d.p.i.
KEY POINTS
With equal dosing, both neutralization and Fc engagement are necessary for the optimal efficacy of antibodies and bi-specific killer engagers (BiKEs) against SARS-CoV-2. BiKEs can clear SARS-CoV-2 virus and protect against severe infection in the hACE2-K18 mouse model. ACE2 decoys as part of Fc-fusions or BiKEs provide clearance of two disparate SARS-CoV-2 variants.
PubMed: 38948747
DOI: 10.1101/2024.06.20.599956 -
Cancer Management and Research 2024As one of the most important breakthroughs in cancer therapy, immune checkpoint inhibitors have greatly prolonged survival of patients with breast cancer. However, their...
Efficacy and Safety of Chidamide in Combination with PD-1 Inhibitor and Radiotherapy for HER2-Negative Advanced Breast Cancer: Study Protocol of a Single Arm Prospective Study.
PURPOSE
As one of the most important breakthroughs in cancer therapy, immune checkpoint inhibitors have greatly prolonged survival of patients with breast cancer. However, their application and efficacy are limited, especially for advanced HER2-negative breast cancer. It has been reported that epigenetic modulation of the histone deacetylase (HDAC) inhibitor chidamide, as well as immune microenvironment modulation of radiotherapy are potentially synergistic with immunotherapy. Thus, the combination of chidamide, radiotherapy and immunotherapy is expected to improve prognosis of patients with advanced HER2-negative breast cancer.
PATIENTS AND METHODS
This is a single-arm, open, prospective clinical trial investigating the efficacy and safety of the combination of HDAC inhibitor chidamide, anti-PD-1 antibody sintilimab, and the novel immuno-radiotherapy, which aims to enhance efficacy of immunotherapy, in subsequent lines of therapy of HER2-negative breast cancer. Our study will include 35 patients with advanced breast cancer that has failed endocrine therapy and first-line chemotherapy. Participants will receive 30 mg of chidamide twice a week, 200 mg of sintilimab once every 3 weeks, combined with immuno-radiotherapy. Radiotherapy will be centrally 8 Gy for at least one lesion, and at least 1 Gy for the other lesions. We will complete three fractions of radiotherapy in one cycle. The primary endpoint is progression-free survival, and secondary endpoints are objective response rate, disease control rate and safety. Moreover, biomarkers including cytokines and lymphocyte subgroups will be explored.
CONCLUSION
As a single-arm clinical trial, the analysis of the influence of each single treatment is limited. Besides, our study is an open study, which involves neither randomization nor blinding. In spite of the abovementioned limitations, this prospective clinical trial will give an insight into subsequent lines of therapy of HER2-negative advanced breast cancer, prolong the survival or achieve long remission for these participants, and identify potential responders.
PubMed: 38948681
DOI: 10.2147/CMAR.S464677 -
Frontiers in Pharmacology 2024Immune checkpoint inhibitors (ICIs), including anti-PD-1, anti-PD-L1 and anti-CTLA-4 antibodies, have become a standard treatment for multiple cancer types. However,...
Hepatitis-related adverse events associated with immune checkpoint inhibitors in cancer patients: an observational, retrospective, pharmacovigilance study using the FAERS database.
Immune checkpoint inhibitors (ICIs), including anti-PD-1, anti-PD-L1 and anti-CTLA-4 antibodies, have become a standard treatment for multiple cancer types. However, ICIs can induce immune-related adverse events, with hepatitis-related adverse events (HRAEs) being of particular concern. Our objective is to identify and characterize HRAEs that exhibit a significant association with ICIs using real-world data. In this observational and retrospective pharmacovigilance study, we extracted real-world adverse events reports from the FDA Adverse Event Reporting System database spanning from the first quarter of 2004 to the first quarter of 2023. We conducted both Frequentist and Bayesian methodologies in the framework of disproportionality analysis, which included the reporting odds ratios (ROR) and information components (IC) to explore the intricate relationship between ICIs and HRAEs. Through disproportionality analysis, we identified three categories of HRAEs as being significantly related with ICIs, including autoimmune hepatitis (634 cases, ROR 19.34 [95% CI 17.80-21.02]; IC025 2.43), immune-mediated hepatitis (546 cases, ROR 217.24 [189.95-248.45]; IC025 4.75), and hepatitis fulminant (80 cases, ROR 4.56 [3.65-5.70]; IC025 0.49). The median age of patients who report ICI-related HRAEs was 63 years (interquartile range [IQR] 53.8-72), with a fatal outcome observed in 24.9% (313/1,260) of these reports. Cases pertaining to skin cancer, lung cancer, and kidney cancer constituted the majority of these occurrences. Patients treated with anti-PD-1 or anti-PD-L1 antibodies exhibited a higher frequency of immune-mediated hepatitis in comparison to those undergoing anti-CTLA-4 monotherapy, with a ROR of 3.59 (95% CI 1.78-6.18). Moreover, the dual ICI therapy demonstrated higher reporting rates of ICI-related HRAEs compared to ICI monotherapy. Our findings confirm that ICI treatment carries a significant risk of severe HRAEs, in particular autoimmune hepatitis, immune-mediated hepatitis, and hepatitis fulminant. Healthcare providers should exercise heightened vigilance regarding these risks when managing patients receiving ICIs.
PubMed: 38948476
DOI: 10.3389/fphar.2024.1383212 -
Imaging Science in Dentistry Jun 2024Non-secretory multiple myeloma (NSMM) is a rare cancer of plasma cells characterized by the absence of detectable monoclonal M protein in the blood or urine. A...
Non-secretory multiple myeloma (NSMM) is a rare cancer of plasma cells characterized by the absence of detectable monoclonal M protein in the blood or urine. A 57-year-old woman presented with mandibular pain but without intraoral swelling. Imaging studies revealed multiple osteolytic lesions in her mandible and pronounced root resorption of the left mandibular second molar. Biopsy results showed atypical plasmacytoid cells positive for anti-kappa, CD138, MUM1, and CD79a antibodies, but negative for anti-lambda and CD20. These results were indicative of a malignant plasma cell neoplasm. No abnormalities were revealed by free light chain assay or by serum or urine protein electrophoresis, leading to a diagnosis of NSMM. The patient began chemotherapy in conjunction with bisphosphonate therapy and achieved remission following treatment. This case underscores the critical role of dentists in the early detection and prevention of NSMM complications, as the disease can initially present in the oral cavity.
PubMed: 38948192
DOI: 10.5624/isd.20230257 -
Theranostics 2024Immunotherapy has demonstrated its potential to improve the prognosis of patients with hepatocellular carcinoma (HCC); however, patients' responses to immunotherapy...
Immunotherapy has demonstrated its potential to improve the prognosis of patients with hepatocellular carcinoma (HCC); however, patients' responses to immunotherapy vary a lot. A comparative analysis of the tumor microenvironment (TME) in responders and non-responders is expected to unveil the mechanisms responsible for the immunotherapy resistance and provide potential treatment targets. We performed sequencing analyses using 10x Genomics technology on six HCC patients who responded to anti-PD-1 therapy and one HCC patient who did not respond. Additionally, we obtained single cell data from untreated, responsive, and nonresponsive HCC patients from public databases, and used part of the datasets as a validation cohort. These data were integrated using algorithms such as Harmony. An independent validation cohort was established. Furthermore, we performed spatial transcriptomic sequencing on the tumor adjacent tissues of three HCC responsive patients using 10x Genomics spatial transcriptomic technology. Additionally, we analyzed data about three HCC patients obtained from public databases. Finally, we validated our conclusions using immunofluorescence, flow cytometry, and experiments. Our findings confirmed the presence of "immune barrier" partially accounting for the limited efficacy of immunotherapy. Our analysis revealed a significant increase in TREM2 Macrophages among non-responsive patients expressing multiple immunosuppressive signals. anti-Csf1r monoclonal antibodies effectively eliminated these macrophages and augmented the therapeutic effects of anti-PD-1 therapy. TCR Macrophages possessed direct tumor-killing capabilities. IL1B cDC2 was the primary functional subtype of cDC2 cells. Absence of THEMIS CD8 T subtypes might diminish immunotherapeutic effects. Furthermore, CD8 T cells entered a state of stress after anti-PD-1 treatment, which might be associated with CD8 T cell exhaustion and senescence. The profiles of immune TMEs showed differences in HCC patients responsive, non-responsive and untreated. These differences might explain the discounted efficacy of immunotherapy in some HCC patients. The cells and molecules, which we found to carry unique capabilities, may be targeted to enhance immunotherapeutic outcomes in patients with HCC.
PubMed: 38948071
DOI: 10.7150/thno.95971 -
Theranostics 2024Trophoblast cell surface antigen 2 (Trop2) is overexpressed in a range of solid tumors and participants in multiple oncogenic signaling pathways, making it an attractive... (Review)
Review
Trophoblast cell surface antigen 2 (Trop2) is overexpressed in a range of solid tumors and participants in multiple oncogenic signaling pathways, making it an attractive therapeutic target. In the past decade, the rapid development of various Trop2-targeted therapies, notably marked by the advent of the antibody-drug conjugate (ADC), revolutionized the outcome for patients facing Trop2-positive tumors with limited treatment opinions, such as triple-negative breast cancer (TNBC). This review provides a comprehensive summary of advances in Trop2-targeted therapies, including ADCs, antibodies, multispecific agents, immunotherapy, cancer vaccines, and small molecular inhibitors, along with in-depth discussions on their designs, mechanisms of action (MOAs), and limitations. Additionally, we emphasize the clinical research progress of these emerging Trop2-targeted agents, focusing on their clinical application and therapeutic efficacy against tumors. Furthermore, we propose directions for future research, such as enhancing our understanding of Trop2's structure and biology, exploring the best combination strategies, and tailoring precision treatment based on Trop2 testing methodologies.
PubMed: 38948057
DOI: 10.7150/thno.98178 -
ACS Omega Jun 2024In the rapidly evolving landscape of nanomedicine, aptamers have emerged as powerful molecular tools, demonstrating immense potential in targeted therapeutics,... (Review)
Review
In the rapidly evolving landscape of nanomedicine, aptamers have emerged as powerful molecular tools, demonstrating immense potential in targeted therapeutics, diagnostics, and drug delivery systems. This paper explores the computational features of aptamers in nanomedicine, highlighting their advantages over antibodies, including selectivity, low immunogenicity, and a simple production process. A comprehensive overview of the aptamer development process, specifically the Systematic Evolution of Ligands by Exponential Enrichment (SELEX) process, sheds light on the intricate methodologies behind aptamer selection. The historical evolution of aptamers and their diverse applications in nanomedicine are discussed, emphasizing their pivotal role in targeted drug delivery, precision medicine and therapeutics. Furthermore, we explore the integration of artificial intelligence (AI), machine learning (ML), Internet of Things (IoT), Internet of Medical Things (IoMT), and nanotechnology in aptameric development, illustrating how these cutting-edge technologies are revolutionizing the selection and optimization of aptamers for tailored biomedical applications. This paper also discusses challenges in computational methods for advancing aptamers, including reliable prediction models, extensive data analysis, and multiomics data incorporation. It also addresses ethical concerns and restrictions related to AI and IoT use in aptamer research. The paper examines progress in computer simulations for nanomedicine. By elucidating the importance of aptamers, understanding their superiority over antibodies, and exploring the historical context and challenges, this review serves as a valuable resource for researchers and practitioners aiming to harness the full potential of aptamers in the rapidly evolving field of nanomedicine.
PubMed: 38947800
DOI: 10.1021/acsomega.4c02466 -
Open Forum Infectious Diseases Jul 2024is an opportunistic fungal pathogen that can cause disseminated infection with predominant central nervous system involvement in patients with compromised immunity.... (Review)
Review
is an opportunistic fungal pathogen that can cause disseminated infection with predominant central nervous system involvement in patients with compromised immunity. Biologics are increasingly used in the treatment of neoplasms and autoimmune/inflammatory conditions and the prevention of transplant rejection, which may affect human defense mechanisms against cryptococcosis. In this review, we comprehensively investigate the association between cryptococcosis and various biologics, highlighting their risks of infection, clinical manifestations, and clinical outcomes. Clinicians should remain vigilant for the risk of cryptococcosis in patients receiving biologics that affect the Th1/macrophage activation pathways, such as tumor necrosis factor α antagonists, Bruton tyrosine kinase inhibitors, fingolimod, JAK/STAT inhibitors (Janus kinase/signal transducer and activator of transcription), and monoclonal antibody against CD52. Other risk factors-such as age, underlying condition, and concurrent immunosuppressants, especially corticosteroids-should also be taken into account during risk stratification.
PubMed: 38947739
DOI: 10.1093/ofid/ofae316 -
Cureus May 2024One of the immune-related adverse events from immune checkpoint inhibitors (ICIs) is skin toxicity. Oral corticosteroids are the first-line treatment for severe...
One of the immune-related adverse events from immune checkpoint inhibitors (ICIs) is skin toxicity. Oral corticosteroids are the first-line treatment for severe cutaneous immune-related adverse events. However, corticosteroids may conflict with the efficacy of ICIs. A 55-year-old Japanese man with a history of psoriasis vulgaris was diagnosed with small-cell lung cancer (Stage ⅣA) and administered combined chemoimmunotherapy, including atezolizumab, which resulted in exacerbation of psoriasis. In response, he was treated with biological agents, such as anti-IL-23 and IL-17 antibodies, risankizumab, and secukinumab, respectively, and achieved long-term survival with continued treatment with atezolizumab. This case report suggests that biological agents might be the best course of treatment against autoimmune-related adverse events caused by ICI therapy.
PubMed: 38947665
DOI: 10.7759/cureus.61395