-
Nature Cancer Feb 2023Monoclonal antibodies are a growing class of targeted cancer therapeutics, characterized by exquisite specificity, long serum half-life, high affinity and immune... (Review)
Review
Monoclonal antibodies are a growing class of targeted cancer therapeutics, characterized by exquisite specificity, long serum half-life, high affinity and immune effector functions. In this review, we outline key advances in the field with a particular focus on recent and emerging classes of engineered antibody therapeutic candidates, discuss molecular structure and mechanisms of action and provide updates on clinical development and practice.
Topics: Humans; Antibodies, Monoclonal; Neoplasms; Radioimmunotherapy
PubMed: 36806801
DOI: 10.1038/s43018-023-00516-z -
MAbs 2014Antibody therapeutics have revolutionized the treatment of cancer over the past two decades. Antibodies that specifically bind tumor surface antigens can be effective... (Review)
Review
Antibody therapeutics have revolutionized the treatment of cancer over the past two decades. Antibodies that specifically bind tumor surface antigens can be effective therapeutics; however, many unmodified antibodies lack therapeutic activity. These antibodies can instead be applied successfully as guided missiles to deliver potent cytotoxic drugs in the form of antibody drug conjugates (ADCs). The success of ADCs is dependent on four factors--target antigen, antibody, linker, and payload. The field has made great progress in these areas, marked by the recent approval by the US Food and Drug Administration of two ADCs, brentuximab vedotin (Adcetris) and ado-trastuzumab emtansine (Kadcyla). However, the therapeutic window for many ADCs that are currently in pre-clinical or clinical development remains narrow and further improvements may be required to enhance the therapeutic potential of these ADCs. Production of ADCs is an area where improvement is needed because current methods yield heterogeneous mixtures that may include 0-8 drug species per antibody molecule. Site-specific conjugation has been recently shown to eliminate heterogeneity, improve conjugate stability, and increase the therapeutic window. Here, we review and describe various site-specific conjugation strategies that are currently used for the production of ADCs, including use of engineered cysteine residues, unnatural amino acids, and enzymatic conjugation through glycotransferases and transglutaminases. In addition, we also summarize differences among these methods and highlight critical considerations when building next-generation ADC therapeutics.
Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antibody Specificity; Brentuximab Vedotin; Drug Delivery Systems; Humans; Immunoconjugates; Maytansine; Neoplasms; Trastuzumab; United States; United States Food and Drug Administration
PubMed: 24423619
DOI: 10.4161/mabs.27022 -
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 -
Theranostics 2022In recent years, antibody-based cancer therapy has emerged as one of the efficient therapeutic strategies, such as immune checkpoint inhibitors (ICIs), angiogenesis... (Review)
Review
In recent years, antibody-based cancer therapy has emerged as one of the efficient therapeutic strategies, such as immune checkpoint inhibitors (ICIs), angiogenesis inhibitors, antibody-drug conjugates (ADCs), multi-specific antibodies, and chimeric antigen receptor T (CAR-T) cells, among others. To date, various drug delivery platforms have been developed to improve the bioavailability, delivery convenience, and reduced toxicity towards increased therapeutic efficacy of antibodies. Herein, we emphasize the clinical manifestations of various antibody-based tumor therapies, highlighting their mechanisms and applications for cancer therapy. Further, based on the problems to be solved in the current clinical application of antibodies, and combined with the advanced drug delivery technologies, we discuss the roles of antibody-based drug delivery systems (DDSs) in cancer therapy, such as enhanced patient compliance and regulating the tumor microenvironment for combined therapy. By expounding the importance of DDSs and discussing the challenges and prospects of their implementation, we suggest that pharmaceutical enterprises and scientists develop appropriate antibody-based delivery platforms.
Topics: Antibodies; Drug Delivery Systems; Humans; Immune Checkpoint Inhibitors; Immunotherapy; Neoplasms; Tumor Microenvironment
PubMed: 35664074
DOI: 10.7150/thno.72594 -
Frontiers in Bioscience : a Journal and... May 2006The concept of targeted therapy was conceived through increased understanding of the biological pathways involved in the pathogenesis of cancer and subsequently... (Review)
Review
The concept of targeted therapy was conceived through increased understanding of the biological pathways involved in the pathogenesis of cancer and subsequently identification of the most appropriate antigens to target. Monoclonal antibody therapy harnesses host defense mechanisms through activation of the antibody dependent cytotoxic pathway and complement mediated cytotoxicity. However, these two processes alone do not explain the therapeutic efficacy of antibody therapy; they also act by apoptotic signaling and growth inhibitory pathways. Conjugation of monoclonal antibody therapy, with radionuclides or toxins, offers more therapeutic approaches. Initial data demonstrates efficacy of single agent use, although combination therapy appears potentially more beneficial. Monoclonal antibody therapy is having a significant impact on many disease processes, particularly malignancies of solid and hematological origin. In this article, we shall review and discuss the monoclonal antibodies approved by the US Food and Drug Administration (FDA). in the management of cancer.
Topics: Alemtuzumab; Aminoglycosides; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antibodies, Neoplasm; Antineoplastic Agents; Bevacizumab; Cetuximab; Clinical Trials as Topic; Gemtuzumab; Hematologic Neoplasms; Humans; Immunotherapy; Immunotoxins; Neoplasms; Rituximab; Signal Transduction; Trastuzumab
PubMed: 16368542
DOI: 10.2741/1909 -
Journal of Drug Targeting Jul 2020Cancer has become one of the major threats to human survival. Because of antibodies specificity and low toxicity, it is the primary choice to diagnose and treat cancer.... (Review)
Review
Cancer has become one of the major threats to human survival. Because of antibodies specificity and low toxicity, it is the primary choice to diagnose and treat cancer. It is easy to be cleared from the blood circulation or distributing throughout the body and causes unnecessary side effects. It is necessary to delivery antibodies to the tumour region in a stable, safe and effective manner. In this review, we discuss the latest studies that aimed to delivery antibodies to tumour sites several vector forms, such as liposomes, carbon nanomaterials, and gold nanomaterials. How to deliver antibodies to the target site is a difficulty for antibody therapy. This review summarises the antibody's therapeutic forms and carrier materials in recent years, and to explore how antibodies can be safely and stably delivered to the target site.
Topics: Animals; Antibodies, Neoplasm; Drug Carriers; Drug Delivery Systems; Humans; Neoplasms
PubMed: 32037905
DOI: 10.1080/1061186X.2020.1728537 -
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 -
Expert Opinion on Pharmacotherapy Jun 2001The availability of rituximab and the possible imminent availability of two new radiolabelled monoclonal anti-CD20 antibodies (Yttrium-90 (90Y)-ibritumomab and... (Review)
Review
The availability of rituximab and the possible imminent availability of two new radiolabelled monoclonal anti-CD20 antibodies (Yttrium-90 (90Y)-ibritumomab and Iodine-131(131I)-tositumomab) have captured much attention in the treatment of lymphoma. The chimeric monoclonal anti-CD20 antibody, rituximab has truly heralded a new era for the treatment of lymphoma and human malignancies. The full potential of antibody-based therapy to improve the outcome in patients with B-cell non-Hodgkin's lymphoma has yet to be defined, but recent data suggests that the combination of chemotherapy plus rituximab may significantly improve outcome for patients with aggressive lymphoma over chemotherapy alone. Highly promising data are also emerging for the use of rituximab in combination with chemotherapy in other types of lymphoma. New advances in antibody therapy, driven by new technologies and defining novel antigen targets, offer the promise of more effective tumour specific therapies. Combinations of antibodies, either conjugated with radioisotopes or unlabelled, used with chemotherapy are likely to provide definitive advances in the treatment of lymphoma in the immediate future.
Topics: Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antibodies, Neoplasm; Antigens, CD20; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Combined Modality Therapy; Guidelines as Topic; Humans; Immunoconjugates; Iodine Radioisotopes; Lymphoma; Radioimmunotherapy; Rituximab
PubMed: 11585011
DOI: 10.1517/14656566.2.6.953 -
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 -
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