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The Journal of Infectious Diseases Nov 2023Filoviruses, including ebolaviruses and marburgviruses, can cause severe and often fatal disease in humans. Over the past several years, antibody therapy has emerged as...
Filoviruses, including ebolaviruses and marburgviruses, can cause severe and often fatal disease in humans. Over the past several years, antibody therapy has emerged as a promising strategy for the treatment of filovirus disease. Here, we describe 2 distinct cross-reactive monoclonal antibodies (mAbs) isolated from mice immunized with recombinant vesicular stomatitis virus-based filovirus vaccines. Both mAbs recognized the glycoproteins of multiple different ebolaviruses and exhibited broad but differential in vitro neutralization activities against these viruses. By themselves, each mAb provided partial to full protection against Ebola virus in mice, and in combination, the mAbs provided 100% protection against Sudan virus challenge in guinea pigs. This study identified novel mAbs that were elicited through immunization and able to provide protection from ebolavirus infection, thus enriching the pool of candidate therapeutics for treating Ebola disease.
Topics: Humans; Animals; Guinea Pigs; Mice; Hemorrhagic Fever, Ebola; Ebolavirus; Antibodies, Monoclonal; Combined Antibody Therapeutics; Antibodies, Neutralizing; Antibodies, Viral
PubMed: 37288609
DOI: 10.1093/infdis/jiad205 -
Current Opinion in Biotechnology Apr 2024Monoclonal antibodies have revolutionized the treatment of human diseases, which has made them the fastest-growing class of therapeutics, with global sales expected to... (Review)
Review
Monoclonal antibodies have revolutionized the treatment of human diseases, which has made them the fastest-growing class of therapeutics, with global sales expected to reach $346.6 billion USD by 2028. Advances in antibody engineering and development have led to the creation of increasingly sophisticated antibody-based therapeutics (e.g. bispecific antibodies and chimeric antigen receptor T cells). However, approaches for antibody discovery have remained comparatively grounded in conventional yet reliable in vitro assays. Breakthrough developments in high-throughput single B-cell sequencing and immunoglobulin proteomic serology, however, have enabled the identification of high-affinity antibodies directly from endogenous B cells or circulating immunoglobulin produced in vivo. Moreover, advances in artificial intelligence offer vast potential for antibody discovery and design with large-scale repertoire datasets positioned as the optimal source of training data for such applications. We highlight advances and recent trends in how these technologies are being applied to antibody repertoire analysis.
Topics: Humans; Proteomics; Artificial Intelligence; Antibodies, Monoclonal; Antibodies, Bispecific
PubMed: 38428225
DOI: 10.1016/j.copbio.2024.103082 -
Expert Review of Anticancer Therapy Jun 2024Modern immunotherapy approaches are revolutionizing the treatment scenario of relapsed/refractory (RR) multiple myeloma (MM) patients, providing an opportunity to reach... (Review)
Review
INTRODUCTION
Modern immunotherapy approaches are revolutionizing the treatment scenario of relapsed/refractory (RR) multiple myeloma (MM) patients, providing an opportunity to reach deep level of responses and extend survival outcomes.
AREAS COVERED
Antibody-drug conjugates (ADCs) and T-cell redirecting treatments, including bispecific antibodies (BsAbs) and chimeric antigen receptor (CAR) T cells therapy, have been recently introduced in the treatment of RRMM. Some agents have already received regulatory approval, while newer constructs, novel combinations, and applications in earlier lines of therapy are currently being explored. This review discusses the current landscape and possible development of ADCs, BsAbs and CAR-T cells immunotherapies.
EXPERT OPINION
ADCs, BsAbs, and CAR-T therapy have demonstrated substantial activity in heavily pretreated, triple-class exposed (TCE) MM patients, and T-cell redirecting treatments represent new standards of care after third (European Medicines Agency, EMA), or fourth (Food and Drug Administration, FDA), line of therapy. All these three immunotherapies carry advantages and disadvantages, with different accessibility and new toxicities that require appropriate management and guidelines. Multiple on-going programs include combinations therapies and applications in earlier lines of treatment, as well as the development of novel agents or construct to enhance potency, reduce toxicity and facilitate administration. Sequencing is a challenge, with few data available and mechanisms of resistance still to be unraveled.
Topics: Humans; Antibodies, Bispecific; Multiple Myeloma; Immunoconjugates; Immunotherapy, Adoptive; Animals; Receptors, Chimeric Antigen; T-Lymphocytes; Survival Rate; Immunotherapy; Drug Development
PubMed: 38798125
DOI: 10.1080/14737140.2024.2344647 -
Muscle & Nerve Nov 2023Myelin-associated glycoprotein (MAG) is a transmembrane glycoprotein concentrated in periaxonal Schwann cell and oligodendroglial membranes of myelin sheaths that serves... (Review)
Review
Myelin-associated glycoprotein (MAG) is a transmembrane glycoprotein concentrated in periaxonal Schwann cell and oligodendroglial membranes of myelin sheaths that serves as an antigen for immunoglobulin M (IgM) monoclonal antibodies. Individuals who harbor anti-MAG antibodies classically develop a progressive autoimmune peripheral neuropathy characterized clinically by ataxia, distal sensory loss, and gait instability, and electrophysiologically by distally accentuated conduction velocity slowing. Although off-label immunotherapy is common, there are currently no proven effective disease-modifying therapeutics, and most patients experience slow accumulation of disability over years and decades. The typically slowly progressive nature of this neuropathy presents unique challenges when trying to find effective anti-MAG therapeutic agents. Drug development has also been hampered by the lack of validated outcome measures that can detect clinically meaningful changes in a reasonable amount of time as well as by the lack of disease activity biomarkers. In this invited review, we provide an update on the state of clinicometric outcome measures and disease activity biomarkers in anti-MAG neuropathy. We highlight the insensitivity of widely used existing clinicometric outcome measures such as the Inflammatory Neuropathy Cause and Treatment (INCAT) disability score as well as the INCAT sensory subscore in anti-MAG neuropathy, referencing the two previous negative randomized controlled clinical trials evaluating rituximab. We then discuss newly emerging candidate therapeutic agents, including tyrosine kinase inhibitors and enhanced B-cell-depleting agents, among others. We conclude with a practical approach to the evaluation and management of anti-MAG neuropathy patients.
Topics: Humans; Myelin-Associated Glycoprotein; Peripheral Nervous System Diseases; Rituximab; Antibodies, Monoclonal; Immunoglobulin M; Autoantibodies; Neuritis; Biomarkers
PubMed: 37602932
DOI: 10.1002/mus.27954 -
Cellular & Molecular Immunology Feb 2024The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019 prompted scientific, medical, and biotech communities to investigate infection- and... (Review)
Review
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019 prompted scientific, medical, and biotech communities to investigate infection- and vaccine-induced immune responses in the context of this pathogen. B-cell and antibody responses are at the center of these investigations, as neutralizing antibodies (nAbs) are an important correlate of protection (COP) from infection and the primary target of SARS-CoV-2 vaccine modalities. In addition to absolute levels, nAb longevity, neutralization breadth, immunoglobulin isotype and subtype composition, and presence at mucosal sites have become important topics for scientists and health policy makers. The recent pandemic was and still is a unique setting in which to study de novo and memory B-cell (MBC) and antibody responses in the dynamic interplay of infection- and vaccine-induced immunity. It also provided an opportunity to explore new vaccine platforms, such as mRNA or adenoviral vector vaccines, in unprecedented cohort sizes. Combined with the technological advances of recent years, this situation has provided detailed mechanistic insights into the development of B-cell and antibody responses but also revealed some unexpected findings. In this review, we summarize the key findings of the last 2.5 years regarding infection- and vaccine-induced B-cell immunity, which we believe are of significant value not only in the context of SARS-CoV-2 but also for future vaccination approaches in endemic and pandemic settings.
Topics: Humans; SARS-CoV-2; Antibody Formation; COVID-19 Vaccines; COVID-19; Vaccination; Antibodies, Neutralizing; Antibodies, Viral
PubMed: 37945737
DOI: 10.1038/s41423-023-01095-w -
Blood Reviews Sep 2023There have been significant advancements in the management of follicular lymphoma (FL), the most common indolent lymphoma. These include immunomodulatory agents such as... (Review)
Review
There have been significant advancements in the management of follicular lymphoma (FL), the most common indolent lymphoma. These include immunomodulatory agents such as lenalidomide, epigenetic modifiers (tazemetostat), and phosphoinotiside-3 kinase inhibitors (copanlisib). The focus of this review is T cell-engager therapies, namely chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies, have recently transformed the treatment landscape of FL. Two CAR T cell products, axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel), and one bispecific antibody, mosunetuzumab, recently received FDA approvals in FL. Several other new immune effector drugs are being evaluated and will expand the treatment armamentarium. This review focuses on CAR T-cell and bispecific antibody therapies, details their safety and efficacy and considers their evolving role in the current treatment landscape of FL.
Topics: Humans; Antibodies, Bispecific; Germinal Center; Immunotherapy, Adoptive; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; T-Lymphocytes
PubMed: 37173225
DOI: 10.1016/j.blre.2023.101099 -
Annals of Hematology Jun 2024Improvement in the therapeutics for multiple myeloma (MM) has been continuously developed owing to the application of novel drugs and technologies in the last 20 years.... (Review)
Review
Improvement in the therapeutics for multiple myeloma (MM) has been continuously developed owing to the application of novel drugs and technologies in the last 20 years. The standard first-line therapy for MM consists of a three-drug induction regimen based on immunomodulatory drugs and proteasome inhibitors combined with autologous stem cell transplantation. However, MM remains incurable; therefore, therapies for relapsed/refractory MM (RRMM) are emerging and evolving rapidly. This study aimed to summarize and review the results of RRMM trials over the past 5 years to provide a holistic overview and insights for practitioners in related fields and to provide additional ideas for clinical trialists. This study shows that daratumumab and isatuximab continue to significantly advance as treatment options. Additionally, novel antibody drugs, such as elotuzumab and selinexor, as well as bispecific antibodies, teclistamab and talquetamab, are currently undergoing clinical research with promising outcomes. However, chimeric antigen receptor-T cell therapy targeting B-cell maturation antigen remains the optimal approach for MM treatment.
Topics: Multiple Myeloma; Humans; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Immunotherapy, Adoptive; Recurrence; Antineoplastic Combined Chemotherapy Protocols; Transplantation, Autologous; Clinical Trials as Topic; Antibodies, Bispecific; Hematopoietic Stem Cell Transplantation
PubMed: 38609727
DOI: 10.1007/s00277-024-05730-y -
Annals of Oncology : Official Journal... Jan 2024The antibody-drug conjugates sacituzumab govitecan (SG) and enfortumab vedotin (EV) are standard monotherapies for metastatic urothelial carcinoma (mUC). Given the...
BACKGROUND
The antibody-drug conjugates sacituzumab govitecan (SG) and enfortumab vedotin (EV) are standard monotherapies for metastatic urothelial carcinoma (mUC). Given the different targets and payloads, we evaluated the safety and efficacy of SG + EV in a phase I trial in mUC (NCT04724018).
PATIENTS AND METHODS
Patients with mUC and Eastern Cooperative Oncology Group performance status ≤1 who had progressed on platinum and/or immunotherapy were enrolled. SG + EV were administered on days 1 + 8 of a 21-day cycle until progression or unacceptable toxicity. Primary endpoint was the incidence of dose-limiting toxicities during cycle 1. The number of patients treated at each of four pre-specified dose levels (DLs) and the maximum tolerated doses in combination (MTD) were determined using a Bayesian Optimal Interval design. Objective response, progression-free survival, and overall survival were secondary endpoints.
RESULTS
Between May 2021 and April 2023, 24 patients were enrolled; 1 patient never started therapy and was excluded from the analysis. Median age was 70 years (range 41-88 years); 11 patients received ≥3 lines of therapy. Seventy-eight percent (18/23) of patients experienced grade ≥3 adverse event (AE) regardless of attribution at any DL, with one grade 5 AE (pneumonitis possibly related to EV). The recommended phase II doses are SG 8 mg/kg with EV 1.25 mg/kg with granulocyte colony-stimulating factor support; MTDs are SG 10 mg/kg with EV 1.25 mg/kg. The objective response rate was 70% (16/23, 95% confidence interval 47% to 87%) with three complete responses; three patients had progressive disease as best response. With a median follow-up of 14 months, 9/23 patients have ongoing response including 6 responses lasting over 12 months.
CONCLUSIONS
The combination of SG + EV was assessed at different DLs and a safe dose for phase II was identified. The combination had encouraging activity in patients with mUC with high response rates, including clinically significant complete responses. Additional study of this combination is warranted.
Topics: Humans; Adult; Middle Aged; Aged; Aged, 80 and over; Carcinoma, Transitional Cell; Bayes Theorem; Urinary Bladder Neoplasms; Immunoconjugates; Antibodies, Monoclonal; Camptothecin; Antibodies, Monoclonal, Humanized
PubMed: 37871703
DOI: 10.1016/j.annonc.2023.09.3114 -
Nature Communications Aug 2023Infant antibody responses to viral infection can differ from those in adults. However, data on the specificity and function of severe acute respiratory syndrome...
Infant antibody responses to viral infection can differ from those in adults. However, data on the specificity and function of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in infants, and direct comparisons between infants and adults are limited. Here, we characterize antibody binding and functionality against Wuhan-Hu-1 (B lineage) strain SARS-CoV-2 in convalescent plasma from 36 postpartum women and 14 of their infants infected with SARS-CoV-2 from a vaccine-naïve prospective cohort in Nairobi, Kenya. We find significantly higher antibody titers against SARS-CoV-2 Spike, receptor binding domain and N-terminal domain, and Spike-expressing cell-surface staining levels in infants versus mothers. Plasma antibodies from mothers and infants bind to similar regions of the Spike S2 subunit, including the fusion peptide (FP) and stem helix-heptad repeat 2. However, infants display higher antibody levels and more consistent antibody escape pathways in the FP region compared to mothers. Finally, infants have significantly higher levels of antibody-dependent cellular cytotoxicity (ADCC), though, surprisingly, Spike pseudovirus neutralization titers between infants and mothers are similar. These results suggest infants develop distinct SARS-CoV-2 binding and functional antibody activities and reveal age-related differences in humoral immunity to SARS-CoV-2 infection that could be relevant to protection and COVID-19 disease outcomes.
Topics: Adult; Humans; Infant; Female; SARS-CoV-2; Mothers; COVID-19; Antibody Formation; Prospective Studies; COVID-19 Serotherapy; Kenya; Antibodies; Spike Glycoprotein, Coronavirus; Antibodies, Viral; Antibodies, Neutralizing
PubMed: 37567924
DOI: 10.1038/s41467-023-40554-w -
Frontiers in Immunology 2023Natural Killer (NK) cells are a type of innate lymphoid cells that play a crucial role in immunity by killing virally infected or tumor cells and secreting cytokines and... (Review)
Review
Natural Killer (NK) cells are a type of innate lymphoid cells that play a crucial role in immunity by killing virally infected or tumor cells and secreting cytokines and chemokines. NK cell-mediated immunotherapy has emerged as a promising approach for cancer treatment due to its safety and effectiveness. NK cell engagers (NKCEs), such as BiKE (bispecific killer cell engager) or TriKE (trispecific killer cell engager), are a novel class of antibody-based therapeutics that exhibit several advantages over other cancer immunotherapies harnessing NK cells. By bridging NK and tumor cells, NKCEs activate NK cells and lead to tumor cell lysis. A growing number of NKCEs are currently undergoing development, with some already in clinical trials. However, there is a need for more comprehensive studies to determine how the molecular design of NKCEs affects their functionality and manufacturability, which are crucial for their development as off-the-shelf drugs for cancer treatment. In this review, we summarize current knowledge on NKCE development and discuss critical factors required for the production of effective NKCEs.
Topics: Humans; Immunity, Innate; Neoplasms; Immunotherapy; Killer Cells, Natural; Antibodies
PubMed: 37638058
DOI: 10.3389/fimmu.2023.1207276