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Pharmacology & Therapeutics Dec 2022Antibody therapy is effective for treating infectious diseases. Due to the coronavirus disease 2019 (COVID-19) pandemic and the rise of drug-resistant bacteria, rapid... (Review)
Review
Antibody therapy is effective for treating infectious diseases. Due to the coronavirus disease 2019 (COVID-19) pandemic and the rise of drug-resistant bacteria, rapid development of neutralizing monoclonal antibodies (mAbs) to treat infectious diseases is urgently needed. Using a therapeutic human mAb with the lowest immunogenicity is recommended, because chimera and humanized mAbs are occasionally immunogenic. In order to directly obtain naïve human mAbs, there are three methods: phage display, B cell receptor (BCR) cDNA sequencing of a single cell, and antibody-encoding gene and amino acid sequencing of immortalized cells using memory B cells, which are isolated from human peripheral blood mononuclear cells of healthy, vaccinated, infected, or recovered individuals. After screening against the antigen and performing neutralization assays, a human neutralizing mAb is constructed from the antibody-encoding DNA sequences of these memory B cells. This review describes examples of obtaining human neutralizing mAbs against various infectious diseases using these methods. However, a few of these mAbs have been approved for therapy. Therefore, antigen characterization and evaluation of neutralization activity in vitro and in vivo are indispensable for the development of therapeutic mAbs. These results will accelerate the development of antibody drug as therapeutic agents.
Topics: Humans; Antibodies, Monoclonal; Leukocytes, Mononuclear; Antibodies, Neutralizing; Communicable Diseases; COVID-19 Drug Treatment
PubMed: 35738431
DOI: 10.1016/j.pharmthera.2022.108233 -
Annals of the New York Academy of... Jan 2023Therapeutic antibodies have broad indications across diverse disease states, such as oncology, autoimmune diseases, and infectious diseases. New research continues to...
Therapeutic antibodies have broad indications across diverse disease states, such as oncology, autoimmune diseases, and infectious diseases. New research continues to identify antibodies with therapeutic potential as well as methods to improve upon endogenous antibodies and to design antibodies de novo. On April 27-30, 2022, experts in antibody research across academia and industry met for the Keystone symposium "Antibodies as Drugs" to present the state-of-the-art in antibody therapeutics, repertoires and deep learning, bispecific antibodies, and engineering.
Topics: Humans; Antibodies, Bispecific; Immunotherapy
PubMed: 36382536
DOI: 10.1111/nyas.14915 -
Journal For Immunotherapy of Cancer Jun 2023Anticancer immunotherapies, such as immune checkpoint inhibitors, bispecific antibodies, and chimeric antigen receptor T cells, have improved outcomes for patients with...
Anticancer immunotherapies, such as immune checkpoint inhibitors, bispecific antibodies, and chimeric antigen receptor T cells, have improved outcomes for patients with a variety of malignancies. However, most patients either do not initially respond or do not exhibit durable responses due to primary or adaptive/acquired immune resistance mechanisms of the tumor microenvironment. These suppressive programs are myriad, different between patients with ostensibly the same cancer type, and can harness multiple cell types to reinforce their stability. Consequently, the overall benefit of monotherapies remains limited. Cutting-edge technologies now allow for extensive tumor profiling, which can be used to define tumor cell intrinsic and extrinsic pathways of primary and/or acquired immune resistance, herein referred to as features or feature sets of immune resistance to current therapies. We propose that cancers can be characterized by immune resistance archetypes, comprised of five feature sets encompassing known immune resistance mechanisms. Archetypes of resistance may inform new therapeutic strategies that concurrently address multiple cell axes and/or suppressive mechanisms, and clinicians may consequently be able to prioritize targeted therapy combinations for individual patients to improve overall efficacy and outcomes.
Topics: Humans; Neoplasms; Immunotherapy; Antibodies, Bispecific; Tumor Microenvironment
PubMed: 37399356
DOI: 10.1136/jitc-2022-006533 -
Clinical and Experimental Immunology Dec 2014Immunoglobulin (Ig) therapy has been used and studied as a treatment for a variety of neurological conditions for decades. In some of these disorders Ig therapy has a...
Immunoglobulin (Ig) therapy has been used and studied as a treatment for a variety of neurological conditions for decades. In some of these disorders Ig therapy has a significant role as a first-line treatment. This session explores the use of Ig therapy in immune-mediated peripheral neuropathies and various central nervous system (CNS) diseases. Informative practice points relating to the management and treatment of these diseases are discussed. Potential future neurological indications for Ig therapy, as well as data on efficacy and possible mechanisms of action, are also presented. In peripheral immune-mediated neuropathies, data show good response rates to Ig therapy and it is often used as a first-line treatment. Intravenous immunoglobulin (IVIg) and subcutaneous immunoglobulin (SCIg) are both well tolerated, but dose and dosing frequency should be based on individual clinical responses. In Alzheimer's disease, although clinical data show no significant differences between IVIg and placebo, biomarker studies indicate that plasma-derived antibodies may be involved in clearance of amyloid aggregates from the brain. Data suggest that the use of high IVIg doses in early-stage Alzheimer's treatment may warrant further investigation. Ig therapy is considered a valuable option for autoimmune encephalitis, an antibody-mediated CNS disease. Combination treatment with IVIg and corticosteroids shows promising results and is proposed as a first-line treatment in these disorders. Until recently, very little was understood about the pathogenesis of chronic pain disorders. Data now indicate that perpetuation of the pain response may be underpinned by central immune activation. Some data suggest that Ig therapy may mitigate this effect, with good response rates in a number of studies, but these data need confirmation.
Topics: Alzheimer Disease; Antibodies; Autoimmune Diseases of the Nervous System; Central Nervous System Diseases; Humans; Immunization, Passive; Immunoglobulins, Intravenous; Neurology; Peripheral Nervous System Diseases
PubMed: 25546749
DOI: 10.1111/cei.12498 -
Scientific Reports Jun 2023The landscape of current cancer immunotherapy is dominated by antibodies targeting PD-1/PD-L1 and CTLA-4 that have transformed cancer therapy, yet their efficacy is...
The landscape of current cancer immunotherapy is dominated by antibodies targeting PD-1/PD-L1 and CTLA-4 that have transformed cancer therapy, yet their efficacy is limited by primary and acquired resistance. The blockade of additional immune checkpoints, especially TIGIT and LAG-3, has been extensively explored, but so far only a LAG-3 antibody has been approved for combination with nivolumab to treat unresectable or metastatic melanoma. Here we report the development of a PDL1 × TIGIT bi-specific antibody (bsAb) GB265, a PDL1 × LAG3 bsAb GB266, and a PDL1 × TIGIT × LAG3 tri-specific antibody (tsAb) GB266T, all with intact Fc function. In in vitro cell-based assays, these antibodies promote greater T cell expansion and tumor cell killing than benchmark antibodies and antibody combinations in an Fc-dependent manner, likely by facilitating T cell interactions (bridging) with cancer cells and monocytes, in addition to blocking immune checkpoints. In animal models, GB265 and GB266T antibodies outperformed benchmarks in tumor suppression. This study demonstrates the potential of a new generation of multispecific checkpoint inhibitors to overcome resistance to current monospecific checkpoint antibodies or their combinations for the treatment of human cancers.
Topics: Animals; Humans; Neoplasms; Melanoma; Nivolumab; Receptors, Immunologic; Immunotherapy; T-Lymphocytes
PubMed: 37332070
DOI: 10.1038/s41598-023-36942-3 -
Frontiers in Immunology 2022Development of disease-modifying therapies including monoclonal antibody (mAb)-based therapeutics for the treatment of multiple sclerosis (MS) has been extremely... (Review)
Review
Development of disease-modifying therapies including monoclonal antibody (mAb)-based therapeutics for the treatment of multiple sclerosis (MS) has been extremely successful over the past decades. Most of the mAb-based therapies approved for MS deplete immune cell subsets and act through activation of cellular Fc-gamma receptors expressed by cytotoxic lymphocytes and phagocytes, resulting in antibody-dependent cellular cytotoxicity or by initiation of complement-mediated cytotoxicity. The therapeutic goal is to eliminate pathogenic immune cell components and to potentially foster the reconstitution of a new and healthy immune system. Ab-mediated immune cell depletion therapies include the CD52-targeting mAb alemtuzumab, CD20-specific therapeutics, and new Ab-based treatments which are currently being developed and tested in clinical trials. Here, we review recent developments in effector mechanisms and clinical applications of Ab-based cell depletion therapies, compare their immunological and clinical effects with the prototypic immune reconstitution treatment strategy, autologous hematopoietic stem cell transplantation, and discuss their potential to restore immunological tolerance and to achieve durable remission in people with MS.
Topics: Alemtuzumab; Antibodies, Monoclonal; Antigens, CD20; Humans; Immunotherapy; Multiple Sclerosis
PubMed: 36172350
DOI: 10.3389/fimmu.2022.953649 -
Trends in Molecular Medicine Dec 2019The use of antibodies as targeting molecules or cell-penetrating tools has emerged at the forefront of pharmaceutical research. Antibody-directed therapies in the form... (Review)
Review
The use of antibodies as targeting molecules or cell-penetrating tools has emerged at the forefront of pharmaceutical research. Antibody-directed therapies in the form of antibody-drug conjugates, immune modulators, and antibody-directed enzyme prodrugs have been most extensively utilized as hematological, rheumatological, and oncological therapies, but recent developments are identifying additional applications of antibody-mediated delivery systems. A novel application of this technology is for the treatment of glycogen storage disorders (GSDs) via an antibody-enzyme fusion (AEF) platform to penetrate cells and deliver an enzyme to the cytoplasm, nucleus, and/or other organelles. Exciting developments are currently underway for AEFs in the treatment of the GSDs Pompe disease and Lafora disease (LD). Antibody-based therapies are quickly becoming an integral part of modern disease therapeutics.
Topics: Animals; Antibodies; Enzyme Therapy; Glycogen Storage Disease; Humans; Immunoconjugates; Recombinant Fusion Proteins
PubMed: 31522955
DOI: 10.1016/j.molmed.2019.08.005 -
British Journal of Haematology Feb 2015Despite the significant advances in modern chemotherapy, it remains challenging to treat adult patients with acute lymphoblastic leukaemia (ALL). The relapse rate... (Review)
Review
Despite the significant advances in modern chemotherapy, it remains challenging to treat adult patients with acute lymphoblastic leukaemia (ALL). The relapse rate remains high, and the outcome at the time of relapse is dismal. Antibody-based therapies have demonstrated promising results in this patient group. Variable mechanisms have been applied to target surface antigens (CD20 [also termed MS4A1], CD22, CD52 and CD19) that are commonly expressed on malignant leukaemia cells. In this review, we will focus on the clinical application of such therapies in adult ALL, including the naked antibodies: Rituximab, Ofatumumab, Epratuzumab and Alemtuzumab; the immunotoxins: BL22 and Combotox; the immunoconjugates: inotuzumab and SAR 3419; as well as the Bi-specific T cell engaging (BiTE)-specific antibody, Blinatumomab.
Topics: Adult; Antibodies, Monoclonal; Antibodies, Neoplasm; Antibody Specificity; Antigens, CD; Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Child; Cytotoxicity, Immunologic; Humans; Immunization, Passive; Immunoconjugates; Lymphocytes; Molecular Targeted Therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction
PubMed: 25382151
DOI: 10.1111/bjh.13205 -
Microbiology Spectrum Apr 2015Antibodies and passive antibody therapy in the treatment of infectious diseases is the story of a treatment concept which dates back more than 120 years, to the 1890s,... (Review)
Review
Antibodies and passive antibody therapy in the treatment of infectious diseases is the story of a treatment concept which dates back more than 120 years, to the 1890s, when the use of serum from immunized animals provided the first effective treatment options against infections with Clostridium tetani and Corynebacterium diphtheriae. However, after the discovery of penicillin by Fleming in 1928, and the subsequent introduction of the much cheaper and safer antibiotics in the 1930s, serum therapy was largely abandoned. However, the broad and general use of antibiotics in human and veterinary medicine has resulted in the development of multi-resistant strains of bacteria with limited to no response to existing treatments and the need for alternative treatment options. The combined specificity and flexibility of antibody-based treatments makes them very valuable tools for designing specific antibody treatments to infectious agents. These attributes have already caused a revolution in new antibody-based treatments in oncology and inflammatory diseases, with many approved products. However, only one monoclonal antibody, palivizumab, for the prevention and treatment of respiratory syncytial virus, is approved for infectious diseases. The high cost of monoclonal antibody therapies, the need for parallel development of diagnostics, and the relatively small markets are major barriers for their development in the presence of cheap antibiotics. It is time to take a new and revised look into the future to find appropriate niches in infectious diseases where new antibody-based treatments or combinations with existing antibiotics, could prove their value and serve as stepping stones for broader acceptance of the potential for and value of these treatments.
Topics: Animals; Antibodies; Communicable Diseases; History, 19th Century; History, 20th Century; History, 21st Century; Humans; Immunization, Passive
PubMed: 26104697
DOI: 10.1128/microbiolspec.AID-0026-2014 -
Drug Discovery Today. Technologies Dec 2018The field of targeted therapeutics has benefitted immeasurably from the development of high-affinity antibodies. These important ligands have facilitated the development... (Review)
Review
The field of targeted therapeutics has benefitted immeasurably from the development of high-affinity antibodies. These important ligands have facilitated the development of effective therapies, particularly when conjugated to potent cytotoxic payloads i.e. in antibody-drug conjugates (ADCs). The success of ADCs is evidenced by rapid adoption within the pharmaceuticals community; many major companies have dedicated ADC research programmes. However, despite the advantages, the field of ADCs has failed to live up to its full potential. Studies have emerged suggesting that traditional IgG scaffolds may not be the optimal format for targeted payload delivery. In response, the protein engineering community has begun to explore alternative high-binding protein scaffolds as antibody mimics. In this short review I will summarise the generation, modification, and application of emerging antibody fragments and synthetic antibody mimics, with a focus on their use as drug carriers. The review aims to highlight the advantages of antibody mimics, and how they could be employed to overcome the issues and limitations of traditional ADCs.
Topics: Antibodies; Drug Delivery Systems; Humans; Immunoconjugates
PubMed: 30553519
DOI: 10.1016/j.ddtec.2018.10.005