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Nature Reviews. Drug Discovery Feb 2023The long-sought discovery of HER2 as an actionable and highly sensitive therapeutic target was a major breakthrough for the treatment of highly aggressive HER2-positive... (Review)
Review
The long-sought discovery of HER2 as an actionable and highly sensitive therapeutic target was a major breakthrough for the treatment of highly aggressive HER2-positive breast cancer, leading to approval of the first HER2-targeted drug - the monoclonal antibody trastuzumab - almost 25 years ago. Since then, progress has been swift and the impressive clinical activity across multiple trials with monoclonal antibodies, tyrosine kinase inhibitors and antibody-drug conjugates that target HER2 has spawned extensive efforts to develop newer platforms and more targeted therapies. This Review discusses the current standards of care for HER2-positive breast cancer, mechanisms of resistance to HER2-targeted therapy and new therapeutic approaches and agents, including strategies to harness the immune system.
Topics: Humans; Female; Breast Neoplasms; Antineoplastic Agents; Receptor, ErbB-2; Trastuzumab; Antibodies, Monoclonal
PubMed: 36344672
DOI: 10.1038/s41573-022-00579-0 -
Cell Jul 2022Antibody therapeutics are a large and rapidly expanding drug class providing major health benefits. We provide a snapshot of current antibody therapeutics including... (Review)
Review
Antibody therapeutics are a large and rapidly expanding drug class providing major health benefits. We provide a snapshot of current antibody therapeutics including their formats, common targets, therapeutic areas, and routes of administration. Our focus is on selected emerging directions in antibody design where progress may provide a broad benefit. These topics include enhancing antibodies for cancer, antibody delivery to organs such as the brain, gastrointestinal tract, and lungs, plus antibody developability challenges including immunogenicity risk assessment and mitigation and subcutaneous delivery. Machine learning has the potential, albeit as yet largely unrealized, for a transformative future impact on antibody discovery and engineering.
Topics: Antibodies; Drug Delivery Systems; Humans; Machine Learning; Neoplasms; Protein Engineering
PubMed: 35868279
DOI: 10.1016/j.cell.2022.05.029 -
Journal of Pharmaceutical Sciences Jan 2020Antibody-based proteins have become an important class of biologic therapeutics, due in large part to the stability, specificity, and adaptability of the antibody... (Review)
Review
Antibody-based proteins have become an important class of biologic therapeutics, due in large part to the stability, specificity, and adaptability of the antibody framework. Indeed, antibodies not only have the inherent ability to bind both antigens and endogenous immune receptors but also have proven extremely amenable to protein engineering. Thus, several derivatives of the monoclonal antibody format, including bispecific antibodies, antibody-drug conjugates, and antibody fragments, have demonstrated efficacy for treating human disease, particularly in the fields of immunology and oncology. Reviewed here are considerations for the design of antibody-based therapeutics, including immunological context, therapeutic mechanisms, and engineering strategies. First, characteristics of antibodies are introduced, with emphasis on structural domains, functionally important receptors, isotypic and allotypic differences, and modifications such as glycosylation. Then, aspects of therapeutic antibody design are discussed, including identification of antigen-specific variable regions, choice of expression system, use of multispecific formats, and design of antibody derivatives based on fragmentation, oligomerization, or conjugation to other functional moieties. Finally, strategies to enhance antibody function through protein engineering are reviewed while highlighting the impact of fundamental biophysical properties on protein developability.
Topics: Animals; Antibodies, Monoclonal; Communicable Diseases; Drug Design; Humans; Immunity, Humoral; Immunoconjugates; Immunoglobulin G; Neoplasms; Protein Engineering; Receptors, Fc
PubMed: 31173761
DOI: 10.1016/j.xphs.2019.05.031 -
Frontiers in Immunology 2022Recent advances in cancer immunotherapy using monoclonal antibodies have dramatically revolutionized the therapeutic strategy against advanced malignancies, inspiring... (Review)
Review
Recent advances in cancer immunotherapy using monoclonal antibodies have dramatically revolutionized the therapeutic strategy against advanced malignancies, inspiring the exploration of various types of therapeutic antibodies. Bispecific antibodies (BsAbs) are recombinant molecules containing two different antigens or epitopes identifying binding domains. Bispecific antibody-based tumor immunotherapy has gained broad potential in preclinical and clinical investigations in a variety of tumor types following regulatory approval of newly developed technologies involving bispecific and multispecific antibodies. Meanwhile, a series of challenges such as antibody immunogenicity, tumor heterogeneity, low response rate, treatment resistance, and systemic adverse effects hinder the application of BsAbs. In this review, we provide insights into the various architecture of BsAbs, focus on BsAbs' alternative different mechanisms of action and clinical progression, and discuss relevant approaches to overcome existing challenges in BsAbs clinical application.
Topics: Humans; Antibodies, Bispecific; Immunotherapy; Neoplasms; Antineoplastic Agents, Immunological; Antibodies, Monoclonal
PubMed: 36389699
DOI: 10.3389/fimmu.2022.1035276 -
Cancer Communications (London, England) Sep 2022The efficacy and specificity of conventional monoclonal antibody (mAb) drugs in the clinic require further improvement. Currently, the development and application of... (Review)
Review
The efficacy and specificity of conventional monoclonal antibody (mAb) drugs in the clinic require further improvement. Currently, the development and application of novel antibody formats for improving cancer immunotherapy have attracted much attention. Variable region-retaining antibody fragments, such as antigen-binding fragment (Fab), single-chain variable fragment (scFv), bispecific antibody, and bi/trispecific cell engagers, are engineered with humanization, multivalent antibody construction, affinity optimization and antibody masking for targeting tumor cells and killer cells to improve antibody-based therapy potency, efficacy and specificity. In this review, we summarize the application of antibody variable region engineering and discuss the future direction of antibody engineering for improving cancer therapies.
Topics: Antibodies, Monoclonal; Humans; Immunotherapy; Killer Cells, Natural; Neoplasms; Single-Chain Antibodies
PubMed: 35822503
DOI: 10.1002/cac2.12330 -
Clinical Medicine (London, England) Jun 2017Monoclonal antibody therapeutics have been approved for over 30 targets and diseases, most commonly cancer. Antibodies have become the new backbone of the pharmaceutical... (Review)
Review
Monoclonal antibody therapeutics have been approved for over 30 targets and diseases, most commonly cancer. Antibodies have become the new backbone of the pharmaceutical industry, which previously relied on small molecules. Compared with small molecules, monoclonal antibodies (mAbs) have exquisite target selectivity and hence less toxicity as a result of binding other targets. The clinical value of both mAbs and ligand traps has been proven. New applications of mAbs are being tested and mAbs have now been designed to target two (bi-specific, eg TNF-α and IL-17) or more targets simultaneously, augmenting their therapeutic potential. Because of space limitations and the wide ranging scope of this review there are regrettably, but inevitably, omissions and missing citations. We have chosen to highlight the first successes in inflammatory diseases and cancer, but a broader overview of approved mAbs and related molecules can be found in Table 1.
Topics: Antibodies, Monoclonal; Biological Therapy; Humans
PubMed: 28572223
DOI: 10.7861/clinmedicine.17-3-220 -
Neurotherapeutics : the Journal of the... Apr 2022Autoimmune diseases of the peripheral nervous system have so far been treated mainly with exogenous high-dose intravenous immunoglobulins (IVIg), that act through... (Review)
Review
Autoimmune diseases of the peripheral nervous system have so far been treated mainly with exogenous high-dose intravenous immunoglobulins (IVIg), that act through several mechanisms, including neutralization of pathogenic autoantibodies, modulation of lymphocyte activity, interference with antigen presentation, and interaction with Fc receptors, cytokines, and the complement system. Other therapeutic strategies have recently been developed, in part to address the increasing shortage of IVIg, prime among which is the use of B cell depleting monoclonal antibodies, or small molecule inhibitors targeting the B-cell specific kinases. Rituximab, a chimeric monoclonal antibody against CD20 + B lymphocytes, is currently the most used, especially in anti-MAG antibody neuropathy and autoimmune neuropathies with antibodies to nodal/paranodal antigens that are unresponsive to IVIg. After several reports of its efficacy in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), rituximab is currently under investigation in three Phase 2 trials in CIDP. In addition, the possible role of complement activation in the pathogenesis of chronic autoimmune neuropathies has brought into consideration drugs that can block the complement cascade, such as eculizumab, a monoclonal antibody already assessed in acute polyradiculoneuropathies, and approved for myasthenia gravis. Preliminary data on eculizumab in multifocal motor neuropathy have been published, but randomized controlled studies are pending. Moreover, the neonatal Fc receptor, that recycles IgGs by preventing their lysosome degradation, is an important and attractive pharmacological target. Antibodies against FcRn, which reduce circulating IgG (both pathogenic and non-pathogenic) have been developed. The FcRn blocker efgartigimod, a humanized IgG1-derived Fc fragment, which competitively inhibits the FcRn, has recently been approved for the treatment of myasthenia gravis and is currently under investigation in CIDP. In addition, the anti-human FcRn monoclonal antibody rozanolixizumab is currently being assessed in phase 2 trials in CIDP. However, none of the abovementioned monoclonal antibodies is currently approved for treatment of any immune-mediated neuropathies. While more specific and individualized therapies are being developed, the possibility of combined treatments targeting different pathogenic mechanisms deserves consideration as well.
Topics: Antibodies, Monoclonal; Humans; Immunoglobulins, Intravenous; Infant, Newborn; Myasthenia Gravis; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; Rituximab
PubMed: 35349079
DOI: 10.1007/s13311-022-01222-x -
International Journal of Molecular... Feb 2021Around 77 new oncology drugs were approved by the FDA in the past five years; however, most cancers remain untreated. Small molecules and antibodies are dominant... (Review)
Review
Around 77 new oncology drugs were approved by the FDA in the past five years; however, most cancers remain untreated. Small molecules and antibodies are dominant therapeutic modalities in oncology. Antibody-drug conjugates, bispecific antibodies, peptides, cell, and gene-therapies are emerging to address the unmet patient need. Advancement in the discovery and development platforms, identification of novel targets, and emergence of new technologies have greatly expanded the treatment options for patients. Here, we provide an overview of various therapeutic modalities and the current treatment options in oncology, and an in-depth discussion of the therapeutics in the preclinical stage for the treatment of breast cancer, lung cancer, and multiple myeloma.
Topics: Antibodies, Monoclonal; Cell- and Tissue-Based Therapy; Genetic Therapy; Humans; Immunoconjugates; Immunotherapy; Medical Oncology; Molecular Targeted Therapy; Neoplasms; Small Molecule Libraries
PubMed: 33670524
DOI: 10.3390/ijms22042008 -
Current Opinion in Structural Biology Jun 2016The successful introduction of antibody-based protein therapeutics into the arsenal of treatments for patients has within a few decades fostered intense innovation in... (Review)
Review
The successful introduction of antibody-based protein therapeutics into the arsenal of treatments for patients has within a few decades fostered intense innovation in the production and engineering of antibodies. Reviewed here are the methods currently used to produce antibodies along with how our knowledge of the structural and functional characterization of immunoglobulins has resulted in the engineering of antibodies to produce protein therapeutics with unique properties, both biological and biophysical, that are leading to novel therapeutic approaches. Antibody engineering includes the introduction of the antibody combining site (variable regions) into a host of architectures including bi and multi-specific formats that further impact the therapeutic properties leading to further advantages and successes in patient treatment.
Topics: Animals; Antibodies; Humans; Protein Engineering; Tissue Distribution
PubMed: 27525816
DOI: 10.1016/j.sbi.2016.07.012 -
Frontiers in Immunology 2022Chronic kidney disease (CKD) is a major public-health problem that increases the risk of end-stage kidney disease (ESKD), cardiovascular diseases, and other... (Review)
Review
INTRODUCTION
Chronic kidney disease (CKD) is a major public-health problem that increases the risk of end-stage kidney disease (ESKD), cardiovascular diseases, and other complications. Kidney transplantation is a renal-replacement therapy that offers better survival compared to dialysis. Antibody-mediated rejection (ABMR) is a significant complication following kidney transplantation: it contributes to both short- and long-term injury. The standard-of-care (SOC) therapy combines plasmapheresis and Intravenous Immunoglobulins (IVIg) with or without steroids, with or without rituximab: however, despite this combined treatment, ABMR remains the main cause of graft loss. IL-6 is a key cytokine: it regulates inflammation, and the development, maturation, and activation of T cells, B cells, and plasma cells. Tocilizumab (TCZ) is the main humanized monoclonal aimed at IL-6R and appears to be a safe and possible strategy to manage ABMR in sensitized recipients. We conducted a literature review to assess the place of the anti-IL-6R monoclonal antibody TCZ within ABMR protocols.
MATERIALS AND METHODS
We systematically reviewed the PubMed literature and reviewed six studies that included 117 patients and collected data on the utilization of TCZ to treat ABMR.
RESULTS
Most studies report a significant reduction in levels of Donor Specific Antibodies (DSAs) and reduced inflammation and microvascular lesions (as found in biopsies). Stabilization of the renal function was observed. Adverse events were light to moderate, and mortality was not linked with TCZ treatment. The main side effect noted was infection, but infections did not occur more frequently in patients receiving TCZ as compared to those receiving SOC therapy.
CONCLUSION
TCZ may be an alternative to SOC for ABMR kidney-transplant patients, either as a first-line treatment or after failure of SOC. Further randomized and controlled studies are needed to support these results.
Topics: Antibodies, Monoclonal, Humanized; Female; Graft Rejection; Graft Survival; HLA Antigens; Humans; Inflammation; Isoantibodies; Kidney Transplantation; Male
PubMed: 35493469
DOI: 10.3389/fimmu.2022.839380