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International Journal of Molecular... Oct 2021Biological therapies have changed the face of oncology by targeting cancerous cells while reducing the effect on normal tissue. This publication focuses mainly on new... (Review)
Review
Biological therapies have changed the face of oncology by targeting cancerous cells while reducing the effect on normal tissue. This publication focuses mainly on new therapies that have contributed to the advances in treatment of certain malignancies. Immunotherapy, which has repeatedly proven to be a breakthrough therapy in melanoma, as well as B-ALL therapy with CAR T cells, are of great merit in this progress. These therapies are currently being developed by modifying bispecific antibodies and CAR T cells to improve their efficiency and bioavailability. Work on improving the therapy with oncolytic viruses is also progressing, and efforts are being made to improve the immunogenicity and stability of cancer vaccines. Combining various biological therapies, immunotherapy with oncolytic viruses or cancer vaccines is gaining importance in cancer therapy. New therapeutic targets are intensively sought among neoantigens, which are not immunocompromised, or antigens associated with tumor stroma cells. An example is fibroblast activation protein α (FAPα), the overexpression of which is observed in the case of tumor progression. Universal therapeutic targets are also sought, such as the neurotrophic receptor tyrosine kinase (NTRK) gene fusion, a key genetic driver present in many types of cancer. This review also raises the problem of the tumor microenvironment. Stromal cells can protect tumor cells from chemotherapy and contribute to relapse and progression. This publication also addresses the problem of cancer stem cells resistance to treatment and presents attempts to avoid this phenomenon. This review focuses on the most important strategies used to improve the selectivity of biological therapies.
Topics: Animals; Antibodies; Biological Therapy; Cancer Vaccines; Humans; Molecular Targeted Therapy; Neoplasms; Recombinant Proteins; T-Lymphocytes
PubMed: 34769123
DOI: 10.3390/ijms222111694 -
Frontiers in Immunology 2019Systemic lupus erythematosus (SLE) is characterized by high-titer serological autoantibodies, including antibodies that bind to double-stranded DNA (dsDNA). The origin,... (Review)
Review
Systemic lupus erythematosus (SLE) is characterized by high-titer serological autoantibodies, including antibodies that bind to double-stranded DNA (dsDNA). The origin, specificity, and pathogenicity of anti-dsDNA antibodies have been studied from a wider perspective. These autoantibodies have been suggested to contribute to multiple end-organ injuries, especially to lupus nephritis, in patients with SLE. Moreover, serum levels of anti-DNA antibodies fluctuate with disease activity in patients with SLE. By directly binding to self-antigens or indirectly forming immune complexes, anti-dsDNA antibodies can accumulate in the glomerular and tubular basement membrane. These autoantibodies can also trigger the complement cascade, penetrate into living cells, modulate gene expression, and even induce profibrotic phenotypes of renal cells. In addition, the expression of suppressor of cytokine signaling 1 is reduced by anti-DNA antibodies simultaneously with upregulation of profibrotic genes. Anti-dsDNA antibodies may even participate in the pathogenesis of SLE by catalyzing hydrolysis of certain DNA molecules or peptides in cells. Recently, anti-dsDNA antibodies have been explored in greater depth as a therapeutic target in the management of SLE. A substantial amount of data indicates that blockade of pathogenic anti-dsDNA antibodies can prevent or even reverse organ damage in murine models of SLE. This review focuses on the recent research advances regarding the origin, specificity, classification, and pathogenicity of anti-dsDNA antibodies and highlights the emerging therapies associated with them.
Topics: Animals; Antibodies, Antinuclear; Autoantibodies; DNA; Humans; Lupus Erythematosus, Systemic; Molecular Targeted Therapy
PubMed: 31379858
DOI: 10.3389/fimmu.2019.01667 -
Drug Delivery Dec 2019ENHANZE drug delivery technology is based on the proprietary recombinant human hyaluronidase PH20 enzyme (rHuPH20; Halozyme Therapeutics, Inc.) that facilitates the... (Review)
Review
ENHANZE drug delivery technology is based on the proprietary recombinant human hyaluronidase PH20 enzyme (rHuPH20; Halozyme Therapeutics, Inc.) that facilitates the subcutaneous (SC) delivery of co-administered therapeutics. rHuPH20 works by degrading the glycosaminoglycan hyaluronan (HA), which plays a role in resistance to bulk fluid flow in the SC space, limiting large volume SC drug delivery, dispersion, and absorption. Co-administration of rHuPH20 with partner therapies can overcome administration time and volume barriers associated with existing SC therapeutic formulations, and has been shown to reduce the burden on patients and healthcare providers compared with intravenous formulations. rHuPH20 (as HYLENEX recombinant) is currently FDA-approved for subcutaneous fluid administration for achieving hydration, to increase the dispersion and absorption of other injected drugs, and in subcutaneous urography for improving resorption of radiopaque agents. rHuPH20 is also co-formulated with two anticancer therapies, trastuzumab (i.e. Herceptin SC) and rituximab (i.e. RITUXAN HYCELA/RITUXAN SC/MabThera SC) and dosed sequentially with human immunoglobin to treat primary immunodeficiency (i.e. HyQvia/HYQVIA). This article reviews pharmaceutical properties of rHuPH20, its current applications with approved therapeutics, and the potential for future developments.
Topics: Animals; Antibodies, Monoclonal; Antigens, Surface; Antineoplastic Agents, Immunological; Cell Adhesion Molecules; Drug Delivery Systems; Drug Therapy, Combination; Humans; Hyaluronoglucosaminidase; Immunoglobulins; Injections, Subcutaneous; Neoplasms; Recombinant Proteins
PubMed: 30744432
DOI: 10.1080/10717544.2018.1551442 -
Current Pharmaceutical Design 2022Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired immune-mediated polyradiculoneuropathy leading to disability via inflammatory demyelination of... (Review)
Review
Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired immune-mediated polyradiculoneuropathy leading to disability via inflammatory demyelination of peripheral nerves. Various therapeutic approaches with different mechanisms of action are established for the treatment of CIDP. Of those, corticosteroids, intravenous or subcutaneous immunoglobulin, or plasma exchange are established first-line therapies as suggested by the recently revised EAN/PNS guidelines for the management of CIDP. In special cases, immunosuppressants or rituximab may be used. Novel therapeutic approaches currently undergoing clinical studies include molecules or monoclonal antibodies interacting with Fc receptors on immune cells to alleviate immune-mediated neuronal damage. Despite various established therapies and the current development of novel therapeutics, treatment of CIDP remains challenging due to an heterogeneous disease course and the lack of surrogate parameters to predict the risk of clinical deterioration. This review summarizes established therapies for CIDP and provides an outlook on future therapeutic approaches.
Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Immunotherapy; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating
PubMed: 35339172
DOI: 10.2174/1381612828666220325102840 -
Life Sciences Jun 2024Antibody-drug conjugates (ADCs) are immunoconjugates that combine the specificity of monoclonal antibodies with a cytotoxic agent. The most appealing aspects of ADCs... (Review)
Review
Antibody-drug conjugates (ADCs) are immunoconjugates that combine the specificity of monoclonal antibodies with a cytotoxic agent. The most appealing aspects of ADCs include their potential additive or synergistic effects of the innate backbone antibody and cytotoxic effects of the payload on tumors without the severe toxic side effects often associated with traditional chemotherapy. Recent advances in identifying new targets with tumor-specific expression, along with improved bioactive payloads and novel linkers, have significantly expanded the scope and optimism for ADCs in cancer therapeutics. In this paper, we will first provide a brief overview of antibody specificity and the structure of ADCs. Next, we will discuss the mechanisms of action and the development of resistance to ADCs. Finally, we will explore opportunities for enhancing ADC efficacy, overcoming drug resistance, and offer future perspectives on leveraging ADCs to improve the outcome of ADC therapy for cancer treatment.
Topics: Humans; Immunoconjugates; Neoplasms; Animals; Antibodies, Monoclonal; Antineoplastic Agents; Drug Resistance, Neoplasm; Antibody Specificity
PubMed: 38688384
DOI: 10.1016/j.lfs.2024.122676 -
Pharmacology & Therapeutics Aug 2020Bispecific therapeutics target two distinct antigens simultaneously and provide novel functionalities that are not attainable with single monospecific molecules or... (Review)
Review
Bispecific therapeutics target two distinct antigens simultaneously and provide novel functionalities that are not attainable with single monospecific molecules or combinations of them. The unique potential of bispecific therapeutics is driving extensive efforts to discover synergistic dual targets, design molecular formats to integrate bispecific elements, and accelerate successful clinical translation. In particular, the past decade has witnessed a boom in the design and development of bispecific antibody formats with more than 100 collections to date. Despite the remarkable progress that has been made to expand the number of formats, qualitative fine-tuning of bispecific formats is needed to achieve optimal dual-target engagement based on understanding of the spatiotemporal interdependence of the two physically linked binding specificities and the complex target biology associated with bispecific approaches. This review provides insights into the design parameters - including affinity, valency, and geometry - that need to be considered at an early stage of development in order to take the best advantage of bispecific therapeutics.
Topics: Animals; Antibodies, Bispecific; Blood-Brain Barrier; Drug Design; Humans
PubMed: 32450189
DOI: 10.1016/j.pharmthera.2020.107582 -
Brain : a Journal of Neurology May 2022Antibody-based therapeutics are now standard in the treatment of neuroinflammatory diseases, and the spectrum of neurological diseases targeted by those approaches... (Review)
Review
Antibody-based therapeutics are now standard in the treatment of neuroinflammatory diseases, and the spectrum of neurological diseases targeted by those approaches continues to grow. The efficacy of antibody-based drug platforms is largely determined by the specificity-conferring antigen-binding fragment (Fab) and the crystallizable fragment (Fc) driving antibody function. The latter provides specific instructions to the immune system by interacting with cellular Fc receptors and complement components. Extensive engineering efforts have enabled tuning of Fc functions to modulate effector functions and to prolong or reduce antibody serum half-lives. Technologies that improve bioavailability of antibody-based treatment platforms within the CNS parenchyma are being developed and could invigorate drug discovery for a number of brain diseases for which current therapeutic options are limited. These powerful approaches are currently being tested in clinical trials or have been successfully translated into the clinic. Here, we review recent developments in the design and implementation of antibody-based treatment modalities in neurological diseases.
Topics: Antibodies; Humans; Immunoglobulin Fab Fragments; Immunologic Factors; Neurology; Receptors, Fc
PubMed: 34928330
DOI: 10.1093/brain/awab465 -
Chemical Record (New York, N.Y.) Nov 2021Antibody-drug conjugates (ADCs) are a class of biopharmaceuticals in which cytotoxic agents are conjugated to monoclonal antibodies (mAbs), allowing targeted drug... (Review)
Review
Antibody-drug conjugates (ADCs) are a class of biopharmaceuticals in which cytotoxic agents are conjugated to monoclonal antibodies (mAbs), allowing targeted drug delivery. Present heterogeneous ADCs (conjugated in random variable positions) suffered from issues of stability, reproducibility, efficacy, etc. Recent advances have led to the development of homogeneous ADC preparations by site-specific conjugation, allowing the control of the drug-to-antibody ratio. These approaches have increased the therapeutic window, efficacy, and batch-to-batch consistency of the ADC preparations. Antibodies carry a pair of heterogeneous N-glycans in the Fc regions, which are critical for antibody function. Drug conjugation through glycoengineering has been achieved with different approaches, including the use of endo-β-N-acetylglucosaminidase (ENGases) and monosaccharyl transferase mutants. In this article, we summarize different glycoengineering approaches for antibody-drug conjugation, and discuss their advantages for the development of next-generation homogeneous ADCs.
Topics: Antibodies, Monoclonal; Drug Delivery Systems; Immunoconjugates; Polysaccharides; Reproducibility of Results
PubMed: 33886147
DOI: 10.1002/tcr.202100054 -
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 Controlled Release :... Dec 2020Antibody has become the most rapidly expanding class of pharmaceuticals for treating a wide variety of human diseases including cancers. Especially, with the fast... (Review)
Review
Antibody has become the most rapidly expanding class of pharmaceuticals for treating a wide variety of human diseases including cancers. Especially, with the fast development of cancer immunotherapy, antibody drugs have become the most promising therapeutic for curing cancers. Immune-mediated cell killing by antibodies including antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cell phagocytosis (ADCP) and complement-dependent cytotoxicity (CDC) as well as regulation of T cell function through immune checkpoint blockade. Due to the absence of Fc fragment, antibody fragments including single-chain variable fragments (scFvs) and single-domain antibodies (sdAds) are mainly applied in chimeric antigen receptors (CAR) T cell therapy for redirecting T cells to tumors and T cell activation by immune checkpoint blockade. In this review, the cancer immunity is first discussed. Then the principal mechanisms of antibody-based immunotherapy will be reviewed. Next, the antibody and antibody fragments applied for cancer immunotherapy will be summarized. Bispecific and multispecific antibodies and a combination of cancer immunotherapy with other tumor treatments will also be mentioned. Finally, an outlook and perspective of antibody-based cancer immunotherapy will be given. This review would provide a comprehensive guidance for the researchers who are interested in and intended to involve in the antibodies- or antibody fragments-based tumor immunity.
Topics: Antibodies, Bispecific; Antibody-Dependent Cell Cytotoxicity; Humans; Immunoglobulin Fc Fragments; Immunotherapy; Neoplasms
PubMed: 32853733
DOI: 10.1016/j.jconrel.2020.08.021