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Current Opinion in Neurology Jun 2024To provide an overview of the pathogenic mechanisms involved in autoimmune encephalitides mediated by antibodies against neuronal surface antigens, with a focus on NMDAR... (Review)
Review
PURPOSE OF REVIEW
To provide an overview of the pathogenic mechanisms involved in autoimmune encephalitides mediated by antibodies against neuronal surface antigens, with a focus on NMDAR and LGI1 encephalitis.
RECENT FINDINGS
In antibody-mediated encephalitides, binding of IgG antibodies to neuronal surface antigens results in different pathogenic effects depending on the type of antibody, IgG subclass and epitope specificity. NMDAR IgG1 antibodies cause crosslinking and internalization of the target, synaptic and brain circuitry alterations, as well as alterations of NMDAR expressing oligodendrocytes, suggesting a link with white matter lesions observed in MRI studies. LGI1 IgG4 antibodies, instead, induce neuronal dysfunction by disrupting the interaction with cognate proteins and altering AMPAR-mediated signaling. In-vitro findings have been corroborated by memory and behavioral changes in animal models obtained by passive transfer of patients' antibodies or active immunization. These models have been fundamental to identify targets for innovative therapeutic strategies, aimed at counteracting or preventing antibody effects, such as the use of soluble ephrin-B2, NMDAR modulators (e.g., pregnenolone, SGE-301) or chimeric autoantibody receptor T cells (CAART) in models of NMDAR encephalitis.
SUMMARY
A deep understanding of the pathogenic mechanisms underlying antibody-mediated encephalitides is crucial for the development of new therapeutic approaches targeting brain autoimmunity.
Topics: Humans; Encephalitis; Animals; Autoantibodies; Receptors, N-Methyl-D-Aspartate; Hashimoto Disease; Intracellular Signaling Peptides and Proteins; Proteins
PubMed: 38667756
DOI: 10.1097/WCO.0000000000001270 -
The Journal of Allergy and Clinical... Mar 2024The use of human antibodies as biologic therapeutics has revolutionized patient care throughout fields of medicine. As our understanding of the many roles antibodies... (Review)
Review
The use of human antibodies as biologic therapeutics has revolutionized patient care throughout fields of medicine. As our understanding of the many roles antibodies play within our natural immune responses continues to advance, so will the number of therapeutic indications for which an mAb will be developed. The great breadth of function, long half-life, and modular structure allow for nearly limitless therapeutic possibilities. Human antibodies can be rationally engineered to enhance their desired immune functions and eliminate those that may result in unwanted effects. Antibody therapeutics now often start with fully human variable regions, either acquired from genetically engineered humanized mice or from the actual human B cells. These variable genes can be further engineered by widely used methods for optimization of their specificity through affinity maturation, random mutagenesis, targeted mutagenesis, and use of in silico approaches. Antibody isotype selection and deliberate mutations are also used to improve efficacy and tolerability by purposeful fine-tuning of their immune effector functions. Finally, improvements directed at binding to the neonatal Fc receptor can endow therapeutic antibodies with unbelievable extensions in their circulating half-life. The future of engineered antibody therapeutics is bright, with the global mAb market projected to exhibit compound annual growth, forecasted to reach a revenue of nearly half a trillion dollars in 2030.
Topics: Mice; Animals; Humans; Antibodies, Monoclonal; Protein Engineering
PubMed: 37995859
DOI: 10.1016/j.jaci.2023.11.018 -
MAbs 2024Biparatopic antibodies (bpAbs) bind distinct, non-overlapping epitopes on an antigen. This unique binding mode enables new mechanisms of action beyond monospecific and... (Review)
Review
Biparatopic antibodies (bpAbs) bind distinct, non-overlapping epitopes on an antigen. This unique binding mode enables new mechanisms of action beyond monospecific and bispecific antibodies (bsAbs) that can make bpAbs effective therapeutics for various indications, including oncology and infectious diseases. Biparatopic binding can lead to superior affinity and specificity, promote antagonism, lock target conformation, and result in higher-order target clustering. Such antibody-target complexes can elicit strong agonism, increase immune effector function, or result in rapid target downregulation and lysosomal trafficking. These are not only attractive properties for therapeutic antibodies but are increasingly being explored for other modalities such as antibody-drug conjugates, T-cell engagers and chimeric antigen receptors. Recent advances in bpAb engineering have enabled the construction of ever more sophisticated formats that are starting to show promise in the clinic.
Topics: Immunoconjugates; Antibodies, Bispecific; Epitopes; Receptors, Chimeric Antigen
PubMed: 38439551
DOI: 10.1080/19420862.2024.2310890 -
Frontiers in Immunology 2023Tuberculosis (TB) is a leading cause of morbidity and mortality worldwide. Global research efforts to improve TB control are hindered by insufficient understanding of... (Review)
Review
Tuberculosis (TB) is a leading cause of morbidity and mortality worldwide. Global research efforts to improve TB control are hindered by insufficient understanding of the role that antibodies play in protective immunity and pathogenesis. This impacts knowledge of rational and optimal vaccine design, appropriate diagnostic biomarkers, and development of therapeutics. Traditional approaches for the prevention and diagnosis of TB may be less efficacious in high prevalence, remote, and resource-poor settings. An improved understanding of the immune response to the causative agent of TB, (), will be crucial for developing better vaccines, therapeutics, and diagnostics. While memory CD4+ T cells and cells and cytokine interferon gamma (IFN-g) have been the main identified correlates of protection in TB, mounting evidence suggests that other types of immunity may also have important roles. TB serology has identified antibodies and functional characteristics that may help diagnose infection and distinguish between different TB disease states. To date, no serological tests meet the World Health Organization (WHO) requirements for TB diagnosis, but multiplex assays show promise for improving the sensitivity and specificity of TB serodiagnosis. Monoclonal antibody (mAb) therapies and serum passive infusion studies in murine models of TB have also demonstrated some protective outcomes. However, animal models that better reflect the human immune response to are necessary to fully assess the clinical utility of antibody-based TB prophylactics and therapeutics. Candidate TB vaccines are not designed to elicit an -specific antibody response, but evidence suggests BCG and novel TB vaccines may induce protective antibodies. The potential of the humoral immune response in TB monitoring and control is being investigated and these studies provide important insight into the functional role of antibody-mediated immunity against TB. In this review, we describe the current state of development of antibody-based clinical tools for TB, with a focus on diagnostic, therapeutic, and vaccine-based applications.
Topics: Humans; Animals; Mice; Tuberculosis; Mycobacterium tuberculosis; Tuberculosis Vaccines; Cytokines; Interferon-gamma; Antibodies
PubMed: 38162666
DOI: 10.3389/fimmu.2023.1278947 -
Current Treatment Options in Oncology Jan 2024Antibody-drug conjugates (ADCs) are a novel class of targeted cancer therapies with the ability to selectively deliver a cytotoxic drug to a tumor cell using a... (Review)
Review
Antibody-drug conjugates (ADCs) are a novel class of targeted cancer therapies with the ability to selectively deliver a cytotoxic drug to a tumor cell using a monoclonal antibody linked to a cytotoxic payload. The technology of ADCs allows for tumor-specificity, improved efficacy, and decreased toxicity compared to standard chemotherapy. Common toxicities associated with ADC use include ocular, pulmonary, hematologic, and neurologic toxicities. Several ADCs have been approved by the United States Food and Drug Administration (FDA) for the management of patients with recurrent or metastatic gynecologic cancers, a population with poor outcomes and limited effective treatment options. The first FDA-approved ADC for recurrent or metastatic cervical cancer was tisotumab vedotin, a tissue factor-targeting agent, after demonstrating response in the innovaTV 204 trial. Mirvetuximab soravtansine targets folate receptor alpha and is approved for use in patients with folate receptor alpha-positive, platinum-resistant, epithelial ovarian cancer based on results from the SORAYA trial. While there are no FDA-approved ADCs for the treatment of uterine cancer, trastuzumab deruxtecan, an anti-human epidermal growth factor receptor 2 (HER2) agent, is actively being investigated. In this review, we will describe the structure and mechanism of action of ADCs, discuss their toxicity profiles, review ADCs both approved and under investigation for the management of gynecologic cancers, and discuss mechanisms of ADC resistance.
Topics: Humans; Female; Folate Receptor 1; Antineoplastic Agents; Genital Neoplasms, Female; Immunoconjugates; Carcinoma, Ovarian Epithelial; Ovarian Neoplasms
PubMed: 38172449
DOI: 10.1007/s11864-023-01166-0 -
Frontiers in Oncology 2023Although the six-transmembrane epithelial antigen of prostate 1 (STEAP1) was first identified in advanced prostate cancer, its overexpression is recognized in multiple... (Review)
Review
Although the six-transmembrane epithelial antigen of prostate 1 (STEAP1) was first identified in advanced prostate cancer, its overexpression is recognized in multiple types of cancer and associated with a poor prognosis. STEAP1 is now drawing attention as a promising therapeutic target because of its tumor specificity and membrane-bound localization. The clinical efficacy of an antibody-drug conjugate targeting STEAP1 in metastatic, castration-resistant, prostate cancer was demonstrated in a phase 1 trial. Furthermore, growing evidence suggests that STEAP1 is an attractive target for immunotherapies such as chimeric antigen receptor-T cell therapy. In this review, we summarize the oncogenic functions of STEAP1 by cancer type. This review also provides new insights into the development of new anticancer strategies targeting STEAP1.
PubMed: 37909017
DOI: 10.3389/fonc.2023.1285661 -
Frontiers in Oncology 2023Urinary tumors primarily consist of kidney, urothelial, and prostate malignancies, which pose significant treatment challenges, particularly in advanced stages.... (Review)
Review
Urinary tumors primarily consist of kidney, urothelial, and prostate malignancies, which pose significant treatment challenges, particularly in advanced stages. Antibody-drug conjugates (ADCs) have emerged as a promising therapeutic approach, combining monoclonal antibody specificity with cytotoxic chemotherapeutic payloads. This review highlights recent advancements, opportunities, and challenges in ADC application for urinary tumors. We discuss the FDA-approved ADCs and other novel ADCs under investigation, emphasizing their potential to improve patient outcomes. Furthermore, we explore strategies to address challenges, such as toxicity management, predictive biomarker identification, and resistance mechanisms. Additionally, we examine the integration of ADCs with other treatment modalities, including immune checkpoint inhibitors, targeted therapies, and radiation therapy. By addressing these challenges and exploring innovative approaches, the development of ADCs may significantly enhance therapeutic options and outcomes for patients with advanced urinary tumor.
PubMed: 38173833
DOI: 10.3389/fonc.2023.1259784 -
Methods in Molecular Biology (Clifton,... 2024Techniques employing monoclonal antibodies (mAbs) are widely used in the initial development phase of biologics. The usefulness of mAbs in basic RA research has been...
Techniques employing monoclonal antibodies (mAbs) are widely used in the initial development phase of biologics. The usefulness of mAbs in basic RA research has been established based on their characteristics, including specificity of binding, homogeneity, and ability to be produced on a large scale. MAb immunoglobulins are the starting material for the generation of smaller antibody fragments and other engineered immunomodulatory antibodies. In this chapter, the basic hybridoma technique, which is a well-established and feasible method for the production of mAbs involving animal immunization, cell fusion, hybridoma screening, expanding positive hybridomas, and purification, is introduced. Aiming at specific affinity to a membrane protein, synthetic proteoliposomes are used in the immunization and screening steps.
Topics: Animals; Antibodies, Neutralizing; Antibodies, Monoclonal; Immunization; Antibodies, Monoclonal, Humanized; Biological Products
PubMed: 38270870
DOI: 10.1007/978-1-0716-3682-4_11 -
Acta Neuropathologica Communications Dec 2023Autosomal dominant pathogenic mutations in Leucine-rich repeat kinase 2 (LRRK2) cause Parkinson's disease (PD). The most common mutation, G2019S-LRRK2, increases the...
Autosomal dominant pathogenic mutations in Leucine-rich repeat kinase 2 (LRRK2) cause Parkinson's disease (PD). The most common mutation, G2019S-LRRK2, increases the kinase activity of LRRK2 causing hyper-phosphorylation of its substrates. One of these substrates, Rab10, is phosphorylated at a conserved Thr73 residue (pRab10), and is one of the most abundant LRRK2 Rab GTPases expressed in various tissues. The involvement of Rab10 in neurodegenerative disease, including both PD and Alzheimer's disease makes pinpointing the cellular and subcellular localization of Rab10 and pRab10 in the brain an important step in understanding its functional role, and how post-translational modifications could impact function. To establish the specificity of antibodies to the phosphorylated form of Rab10 (pRab10), Rab10 specific antisense oligonucleotides were intraventricularly injected into the brains of mice. Further, Rab10 knock out induced neurons, differentiated from human induced pluripotent stem cells were used to test the pRab10 antibody specificity. To amplify the weak immunofluorescence signal of pRab10, tyramide signal amplification was utilized. Rab10 and pRab10 were expressed in the cortex, striatum and the substantia nigra pars compacta. Immunofluorescence for pRab10 was increased in G2019S-LRRK2 knockin mice. Neurons, astrocytes, microglia and oligodendrocytes all showed Rab10 and pRab10 expression. While Rab10 colocalized with endoplasmic reticulum, lysosome and trans-Golgi network markers, pRab10 did not localize to these organelles. However, pRab10, did overlap with markers of the presynaptic terminal in both mouse and human cortex, including α-synuclein. Results from this study suggest Rab10 and pRab10 are expressed in all brain areas and cell types tested in this study, but pRab10 is enriched at the presynaptic terminal. As Rab10 is a LRRK2 kinase substrate, increased kinase activity of G2019S-LRRK2 in PD may affect Rab10 mediated membrane trafficking at the presynaptic terminal in neurons in disease.
Topics: Humans; Mice; Animals; Neurodegenerative Diseases; Induced Pluripotent Stem Cells; Phosphorylation; Parkinson Disease; Mutation; Brain; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; rab GTP-Binding Proteins
PubMed: 38110990
DOI: 10.1186/s40478-023-01704-9