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Molecular Cancer Aug 2023Recent introduction of monoclonal antibodies targeting immune checkpoints to harness antitumor immunity has revolutionized the cancer treatment landscape. The... (Review)
Review
Recent introduction of monoclonal antibodies targeting immune checkpoints to harness antitumor immunity has revolutionized the cancer treatment landscape. The therapeutic success of immune checkpoint blockade (ICB)-based therapies mainly relies on PD-1/PD-L1 and CTLA-4 blockade. However, the limited overall responses and lack of reliable predictive biomarkers of patient´s response are major pitfalls limiting immunotherapy success. Hence, this reflects the compelling need of unveiling novel targets for immunotherapy that allow to expand the spectrum of ICB-based strategies to achieve optimal therapeutic efficacy and benefit for cancer patients. This review thoroughly dissects current molecular and functional knowledge of BTLA/HVEM axis and the future perspectives to become a target for cancer immunotherapy. BTLA/HVEM dysregulation is commonly found and linked to poor prognosis in solid and hematological malignancies. Moreover, circulating BTLA has been revealed as a blood-based predictive biomarker of immunotherapy response in various cancers. On this basis, BTLA/HVEM axis emerges as a novel promising target for cancer immunotherapy. This prompted rapid development and clinical testing of the anti-BTLA blocking antibody Tifcemalimab/icatolimab as the first BTLA-targeted therapy in various ongoing phase I clinical trials with encouraging results on preliminary efficacy and safety profile as monotherapy and combined with other anti-PD-1/PD-L1 therapies. Nevertheless, it is anticipated that the intricate signaling network constituted by BTLA/HVEM/CD160/LIGHT involved in immune response regulation, tumor development and tumor microenvironment could limit therapeutic success. Therefore, in-depth functional characterization in different cancer settings is highly recommended for adequate design and implementation of BTLA-targeted therapies to guarantee the best clinical outcomes to benefit cancer patients.
Topics: Humans; B7-H1 Antigen; Immunotherapy; Antibodies, Monoclonal; Hematologic Neoplasms; Signal Transduction; Tumor Microenvironment
PubMed: 37649037
DOI: 10.1186/s12943-023-01845-4 -
Molecules (Basel, Switzerland) Sep 2023Antibody engineering has developed into a wide-reaching field, impacting a multitude of industries, most notably healthcare and diagnostics. The seminal work on... (Review)
Review
Antibody engineering has developed into a wide-reaching field, impacting a multitude of industries, most notably healthcare and diagnostics. The seminal work on developing the first monoclonal antibody four decades ago has witnessed exponential growth in the last 10-15 years, where regulators have approved monoclonal antibodies as therapeutics and for several diagnostic applications, including the remarkable attention it garnered during the pandemic. In recent years, antibodies have become the fastest-growing class of biological drugs approved for the treatment of a wide range of diseases, from cancer to autoimmune conditions. This review discusses the field of therapeutic antibodies as it stands today. It summarizes and outlines the clinical relevance and application of therapeutic antibodies in treating a landscape of diseases in different disciplines of medicine. It discusses the nomenclature, various approaches to antibody therapies, and the evolution of antibody therapeutics. It also discusses the risk profile and adverse immune reactions associated with the antibodies and sheds light on future applications and perspectives in antibody drug discovery.
Topics: Humans; Medicine; Antibodies, Monoclonal; Autoimmune Diseases; Biological Products; Clinical Relevance
PubMed: 37764213
DOI: 10.3390/molecules28186438 -
Immunological Reviews Oct 2023Unconjugated monoclonal antibodies (mAb) have revolutionized the treatment of many types of cancer. Some of these mAbs promote the clearance of malignant cells via... (Review)
Review
Unconjugated monoclonal antibodies (mAb) have revolutionized the treatment of many types of cancer. Some of these mAbs promote the clearance of malignant cells via direct cytotoxic effects. More recently, antibody-dependent cellular phagocytosis (ADCP) has been appreciated as a major mechanism of action for a number of widely-used mAbs, including anti-CD20 (rituximab, obinutuzumab), anti-HER2 (trazituzumab), and anti-CD38 (daratumumab). However, as a monotherapy these ADCP-inducing mAbs produce insufficient levels of cytotoxicity in vivo and are not curative. As a result, these mAbs are most effectively used in combination therapies. The efficacy of these mAbs is further hampered by the apparent development of drug resistance by many patients. Here we will explore the role of ADCP in cancer immunotherapy and discuss the key factors that could limit the efficacy of ADCP-inducing mAbs in vivo. Finally, we will discuss current insights and approaches being applied to overcome these limitations.
Topics: Humans; Phagocytosis; Antibodies; Extracellular Space; Neoplasms; Immunotherapy
PubMed: 37602915
DOI: 10.1111/imr.13265 -
Advances in Therapy Aug 2023The introduction of novel immunotherapies has transformed the treatment landscape in multiple myeloma (MM). The addition of these agents has significantly improved...
The introduction of novel immunotherapies has transformed the treatment landscape in multiple myeloma (MM). The addition of these agents has significantly improved patient outcomes; however, MM remains largely incurable, with heavily pretreated patients suffering from shorter survival times. To address this unmet need, the focus has shifted toward novel mode of action therapies, such as bispecific antibodies (BsAb), which simultaneously bind to immune effector cells and myeloma cells. Currently, there are several T cell-redirecting BsAb being developed that target BCMA, GPRC5D, and FcRH5. These BsAb show impressive clinical activity for the relapsed/refractory population targeted and will likely become an essential part of MM treatment protocols in the future. In this podcast, the authors summarize and highlight some of the T cell-redirecting BsAb currently in development for the treatment of relapsed/refractory MM with a focus on the data reported at the oral session for BsAb at the American Society of Hematology's 2022 meeting from clinical phase 1 and 2 studies. The six presentations reported the latest safety and efficacy data for the BsAb: talquetamab, elranatamab, teclistamab, forimtamig, and alnuctamab.
Topics: Humans; Antibodies, Bispecific; Multiple Myeloma; T-Lymphocytes; Immunotherapy; Antineoplastic Agents
PubMed: 37328635
DOI: 10.1007/s12325-023-02551-9 -
Immunology Aug 2023Despite the clinical success of monoclonal and bispecific antibodies, there are still limitations in the therapeutic effect of malignant tumours, such as low response... (Review)
Review
Despite the clinical success of monoclonal and bispecific antibodies, there are still limitations in the therapeutic effect of malignant tumours, such as low response rate, treatment resistance, and so on, inspiring the exploration of trispecific antibodies (TsAbs). TsAbs further improve the safety and efficacy and has great clinical potential through three targets combination and formats optimization. This article reviews the development history and the target combination features of TsAbs. Although there are still great challenges in the clinical application of TsAbs, it is undeniable that TsAbs may be a breakthrough in the development of antibody drugs.
Topics: Humans; Immunotherapy; Antibodies, Bispecific; Neoplasms
PubMed: 36855956
DOI: 10.1111/imm.13636 -
Ageing Research Reviews Feb 2024Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by cognitive impairment with few therapeutic options. Despite many failures in... (Review)
Review
Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by cognitive impairment with few therapeutic options. Despite many failures in developing AD treatment during the past 20 years, significant advances have been achieved in passive immunotherapy of AD very recently. Here, we review characteristics, clinical trial data, and mechanisms of action for monoclonal antibodies (mAbs) targeting key players in AD pathogenesis, including amyloid-β (Aβ), tau and neuroinflammation modulators. We emphasized the efficacy of lecanemab and donanemab on cognition and amyloid clearance in AD patients in phase III clinical trials and discussed factors that may contribute to the efficacy and side effects of anti-Aβ mAbs. In addition, we provided important information on mAbs targeting tau or inflammatory regulators in clinical trials, and indicated that mAbs against the mid-region of tau or pathogenic tau have therapeutic potential for AD. In conclusion, passive immunotherapy targeting key players in AD pathogenesis offers a promising strategy for effective AD treatment.
Topics: Humans; Alzheimer Disease; Neurodegenerative Diseases; Amyloid beta-Peptides; Antibodies, Monoclonal; Immunization, Passive; Immunotherapy; tau Proteins; Antibodies, Monoclonal, Humanized
PubMed: 38219962
DOI: 10.1016/j.arr.2024.102192 -
Protein & Cell Sep 2023Although the development of COVID-19 vaccines has been a remarkable success, the heterogeneous individual antibody generation and decline over time are unknown and still...
Although the development of COVID-19 vaccines has been a remarkable success, the heterogeneous individual antibody generation and decline over time are unknown and still hard to predict. In this study, blood samples were collected from 163 participants who next received two doses of an inactivated COVID-19 vaccine (CoronaVac®) at a 28-day interval. Using TMT-based proteomics, we identified 1,715 serum and 7,342 peripheral blood mononuclear cells (PBMCs) proteins. We proposed two sets of potential biomarkers (seven from serum, five from PBMCs) at baseline using machine learning, and predicted the individual seropositivity 57 days after vaccination (AUC = 0.87). Based on the four PBMC's potential biomarkers, we predicted the antibody persistence until 180 days after vaccination (AUC = 0.79). Our data highlighted characteristic hematological host responses, including altered lymphocyte migration regulation, neutrophil degranulation, and humoral immune response. This study proposed potential blood-derived protein biomarkers before vaccination for predicting heterogeneous antibody generation and decline after COVID-19 vaccination, shedding light on immunization mechanisms and individual booster shot planning.
Topics: Humans; COVID-19 Vaccines; Leukocytes, Mononuclear; Proteomics; COVID-19; Vaccination; Antibodies; Antibodies, Viral; Antibodies, Neutralizing
PubMed: 36930526
DOI: 10.1093/procel/pwad004 -
Molecules (Basel, Switzerland) Dec 2023Antibodies and their derivatives (scFv, Fabs, etc.) represent a unique class of biomolecules that combine selectivity with the ability to target drug delivery.... (Review)
Review
Antibodies and their derivatives (scFv, Fabs, etc.) represent a unique class of biomolecules that combine selectivity with the ability to target drug delivery. Currently, one of the most promising endeavors in this field is the development of molecular diagnostic tools and antibody-based therapeutic agents, including antibody-drug conjugates (ADCs). To meet this challenge, it is imperative to advance methods for modifying antibodies. A particularly promising strategy involves the introduction of carbonyl groups into the antibody that are amenable to further modification by biorthogonal reactions, namely aliphatic, aromatic, and α-oxo aldehydes, as well as aliphatic and aryl-alkyl ketones. In this review, we summarize the preparation methods and applications of site-specific antibody conjugates that are synthesized using this approach.
Topics: Antibodies; Immunoconjugates; Antigens; Drug Delivery Systems; Antineoplastic Agents
PubMed: 38067618
DOI: 10.3390/molecules28237890 -
Journal of Pharmaceutical and... Sep 2023Monoclonal antibody (mAb)-based therapies have been a major advance in oncology patient care, even though they represent a significant healthcare cost. Biosimilars,... (Review)
Review
Monoclonal antibody (mAb)-based therapies have been a major advance in oncology patient care, even though they represent a significant healthcare cost. Biosimilars, launched in Europe in 2004 are an economically attractive alternative to expensive originator biological drugs. They also increase the competitiveness of pharmaceutical development. This article focuses on the case of Erbitux® (cetuximab). This anti-EGFR (Epidermal Growth Factor Receptor) monoclonal antibody is indicated for metastatic colorectal cancer (2004) and squamous cell carcinoma of the head and neck (2006). However, despite the expiration of the patent in Europe in 2014 and estimated annual sales of 1.681 million US dollars in 2022, Erbitux® has not yet faced any approved biosimilar challenges in the United States or in Europe. Here, we outline the unique structural complexity of this antibody highlighted by advanced orthogonal analytical characterization strategies resulting in risks to demonstrate biosimilarity, which may explain the lack of Erbitux® biosimilars in the European and US markets to date. The development of Erbitux® biobetters are also discussed as alternative strategies to biosimilars. These biologics offer expected additional safety and potency benefits over the reference product but require a full pharmaceutical and clinical development as for New Molecular Entities.
Topics: Humans; United States; Cetuximab; Biosimilar Pharmaceuticals; Antibodies, Monoclonal; Neoplasms; Europe
PubMed: 37418870
DOI: 10.1016/j.jpba.2023.115544 -
Frontiers in Immunology 2023The advent of immunotherapy in lymphomas, beginning with Rituximab, have led to paradigm shifting treatments that are increasingly bringing a greater number of affected... (Review)
Review
The advent of immunotherapy in lymphomas, beginning with Rituximab, have led to paradigm shifting treatments that are increasingly bringing a greater number of affected patients within the ambit of durable disease control and cure. Bispecific antibodies harness the properties of the immunoglobulin antibody structure to design molecules which, apart from engaging with the target tumour associated antigen, engage the host's T-cells to cause tumour cell death. Mosunetuzumab, an anti-CD20 directed bispecific antibody was the first to be approved in follicular lymphoma, this has now been followed by quick approvals of Glofitamab and Epcoritamab in diffuse large B-cell lymphomas. This article reviews contemporary data and ongoing studies evaluating the role of bispecific antibodies in indolent b-cell non Hodgkin lymphomas. This is an area of active research and presents many opportunities in advancing the treatment of indolent lymphomas and potentially forge a chemo-free treatment paradigm in this condition.
Topics: Humans; Antibodies, Monoclonal; Antibodies, Bispecific; Rituximab; Antineoplastic Agents; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse
PubMed: 38274793
DOI: 10.3389/fimmu.2023.1295599