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Пентозный фосфатный путь ингибиции метаболизма перепрограммирует CD8+T клетки и нарушает автоиммунитет CNS.

Множественный склероз характеризуется проникновением CNS в автоматически реактивные иммунные клетки, которые приводят как к острому подстрекательскому демиэлированию, так и к хронической прогрессирующей аксонной и нейрональной травме. Расширяющиеся доказательства указывают на то, что CD8+ антиневральные Т клетки в нейродегенерации, которая лежит в основе необратимого клинического прогресса в множественном склерозе, но терапия, конкретно ориентированная на эту клеточную популяцию, ограничена. CD8+T клетки пациентов с MS показывают более активное вовлечение пентоза фосфата. Фармакологическое инг

Use of short interfering RNA delivered by cationic liposomes to enable efficient down-regulation of PTPN22 gene in human T lymphocytes.

Type 1 diabetes and thyroid disease are T cell-dependent autoimmune endocrinopathies. The standard substitutive administration of the deficient hormones does not halt the autoimmune process; therefore, development of immunotherapies aiming to preserve the residual hormonal cells, is of crucial importance. PTPN22 C1858T mutation encoding for the R620W lymphoid tyrosine phosphatase variant, plays a potential pathophysiological role in autoimmunity. The PTPN22 encoded protein Lyp is a negative regulator of T cell antigen receptor signaling; R620W variant, leading to a gain of function with parado

Mechanistic Quantitative Pharmacology Strategies for the Early Clinical Development of Bispecific Antibodies in Oncology.

Bispecific antibodies (bsAbs) have become an integral component of the therapeutic research strategy to treat cancer. In addition to clinically validated immune cell re-targeting, bsAbs are being designed for tumor targeting and as dual immune modulators. Explorative preclinical and emerging clinical data indicate potential for enhanced efficacy and reduced systemic toxicity. However, bsAbs are a complex modality with challenges to overcome in early clinical trials, including selection of relevant starting doses using a minimal anticipated biological effect level approach, and predicting effic

Bispecific and multispecific T-cell engagers: advancing the future of immunotherapy.

T-cell engagers (TCEs) represent an emerging class of immunotherapies that harness T cells' cytotoxic power to eliminate diseased cells-a transformative future therapeutic strategy. TCEs form immunological synapses to trigger potent immune responses, with proven efficacy in blood cancers; research expands their use to solid tumors via innovative molecular design and improved safety profiles. Beyond oncology, TCEs hold promise in autoimmune disorders by eliminating autoreactive cells, offering novel avenues for diseases like lupus. However, achieving optimal outcomes without disrupting immune h

Bispecific antibodies and nanotechnology: a strategic alliance in cancer immunotherapy.

Bispecific antibodies (bsAbs), designed to recognize two distinct antigens or epitopes, enable innovative mechanisms of action for emerging generations of cancer immunotherapies. Despite their potential, bsAb therapeutics face several challenges related to their biodistribution and pharmacokinetics, which often result in a suboptimal efficacy/toxicity balance. Starting with a brief description of the relevance of bsAbs in cancer immunotherapy, this review aims to critically analyze the synergistic potential of nanotechnology and bsAb technology oriented to enhance therapeutic efficiency while

Landscape of T-cell engagers in solid tumors.

T-cell engagers (TCEs) are a diverse class of bispecific and multispecific molecules that co-bind CD3 on T cells and tumor-associated antigens to form an immune synapse and induce targeted T-cell-mediated cytotoxicity. While TCEs have demonstrated remarkable efficacy in hematologic malignancies, translation into solid tumors has been more challenging. Recent advances seen with tebentafusp in metastatic uveal melanoma and tarlatamab in small-cell lung cancer have validated the approach and driven a rapidly expanding pipeline targeting other tumor associated antigens such as STEAP1, MUC16, and P

Инженерный антитела TACI × CD3 для перенаправления Т клеток на множественные миэломы.

Вышеупомянутые аббревиатуры, предназначенные для антигена созревания клеток В (BCMA), являющегося членом сверхсемейства суперрецептора некроза опухоли (TNFR), продемонстрировали замечательную клиническую эффективность в лечении рецидива/рефрактора множественной миеломы (MM). Вместе с тем одной из серьезных проблем является частое снижение регулирования или потеря выражения БКМА у пациентов, получающих иммунотерапию, ориентированную на БКМА, что существенно снижает терапевтическую эффективность и способствует прогрессированию и устойчивости к заболеваниям после первоначальной позитивной реакции

Bispecific and multispecific immune engagers for redirecting innate and adaptive immunity against hematologic cancers.

Bispecific antibodies (BsAbs) and multispecific antibodies (MsAbs) represent a transformative class of immunotherapeutics in oncology. These engineered molecules possess the unique ability to simultaneously target two or more distinct antigens, thereby facilitating precise immune cell engagement and disrupting multiple signaling pathways. This comprehensive review focuses on their pivotal role in redirecting both innate (natural killer cells, phagocytes) and adaptive (T cells) immunity, with a particular emphasis on their application against hematologic cancers. Significant clinical successes,

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… One scFv typically binds to the T cell-specific CD3 complex, while the second targets a tumor-associated antigen (TAA) [ 25 – 27 ]. Blinatumomab, targeting CD19 and CD3, is a seminal example of this class [ 25 , 28 ]. … complex on T cells as their central immune effector target[ 21 ]. …

Включаю T-камеры для очистки.

Те, кто занимается клетками, представляют собой преобразующий подход к иммунотерапии рака, стимулирующий использование двухуровневых и многообразных антителных конструкций для перенаправления китотоксичности Т-клеток на злокачественные клетки. Эти молекулы соединяют клетки Т и клетки опухоли, одновременно связывая CD3 с Т клетками и связанными с опухолью антигенами на раковые клетки, что позволяет точно определить иммунную направленность даже в иммунологических "холодных" опухолях. Последние достижения включают в себя условное использование Т-клеток, активированное микроэкологическими протезам

Emerging new therapeutic antibody derivatives for cancer treatment.

Monoclonal antibodies constitute a promising class of targeted anticancer agents that enhance natural immune system functions to suppress cancer cell activity and eliminate cancer cells. The successful application of IgG monoclonal antibodies has inspired the development of various types of therapeutic antibodies, such as antibody fragments, bispecific antibodies, and antibody derivatives (e.g., antibody-drug conjugates and immunocytokines). The miniaturization and multifunctionalization of antibodies are flexible and viable strategies for diagnosing or treating malignant tumors in a complex t

T-cell engagers in cancer immunotherapy: mechanisms, challenges, and future perspectives.

T-cell engagers (TCEs) are a rapidly evolving class of cancer immunotherapies that redirect cytotoxic T cells to tumor-associated antigens independently of MHC presentation. This review outlines the development, structural formats, and therapeutic potential of various TCE platforms, including bispecific (BiTEs) and trispecific T-cell engagers (TriTEs), dual affinity re-targeting (DART), and other emerging formats. We also highlight the clinical success in treating hematologic malignancies as demonstrated by agents such as blinatumomab and teclistamab. We also discussed the ongoing challenges i

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… Mechanism of action of TCEs TCE activity depends on the engagement and activation of the TCR/CD3 complex. … TCEs bypass native antigen recognition by directly engaging the CD3 complex and simultaneously redirecting T cells toward tumor-associated antigens in an MHC-independent manner. …

Функциональное иммунное профилирование переводит динамику Т-клеток в прогнозируемые биомаркеры для иммунотерапии миеломы.

Биспектифические Т-клеточные энджеры (TCE), мишенирующие к BCMA или GPRC5D, улучшили исходы у пациентов с резидуальным/рефракторным множественным миеломой (ММ), однако до 40% пациентов являются первичными рефракторными, и предиктивные биомаркеры крайне ограничены. Чтобы решить эту неудовлетворенную клиническую потребность, мы разработали изображение-ориентированную высокопроизводительную эквивалентную вне организма пробу, используя мононуклеаты костного мозга, полученные от пациентов, подвергнутые воздействию теclistamаба или талкетамаба. Мультиплексная иммунофлуоресценция позволила количестве

Совпадение в полном тексте источника
… On the dynamics of TCR: CD3 complex cell surface expression and downmodulation. Immunity. 2000;13:665–75. 41. Shilts J, Severin Y, Galaway F, Müller-Sienerth N, Chong ZS, Pritchard S, et al. A physical wiring diagram for the human immune system. Nature. 2022;608:397–404. 42. …

Drug Conjugated and Bispecific Antibodies for Multiple Myeloma: Improving Immunotherapies off the Shelf.

The impressive improvement of overall survival in multiple myeloma (MM) patients in the last years has been mostly related to the availability of new classes of drugs with different mechanisms of action, including proteasome inhibitors (PI), immunomodulating agents (IMiDs), and monoclonal antibodies. However, even with this increased potence of fire, MM still remains an incurable condition, due to clonal selection and evolution of neoplastic clone. This concept underlines the importance of immunotherapy as one of the most relevant tools to try to eradicate the disease. In line with this concep

Therapeutic Antibodies in Hematology: Advances in Malignant and Non-Malignant Disorders.

Therapeutic antibodies have revolutionized hematology, offering targeted and effective treatments for both malignant and non-malignant diseases. In hematologic malignancies, anti-CD20, anti-CD19, anti-CD38, and anti-B-cell maturation antigen (BCMA) antibodies have markedly improved survival outcomes, whereas antibody-drug conjugates and bispecific antibodies continue to expand therapeutic possibilities. Besides cancer, complement inhibitors such as eculizumab, ravulizumab, and the recently approved crovalimab have redefined paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic synd

Bispecific Antibodies for Multiple Myeloma: A Review of Targets, Drugs, Clinical Trials, and Future Directions.

Multiple myeloma (MM) is a plasma cell malignancy and the second most common hematological neoplasm in adults, comprising 1.8% of all cancers. With an annual incidence of ~30,770 cases in the United States, MM has a high mortality rate, leading to 12,770 deaths per year. MM is a genetically complex, highly heterogeneous malignancy, with significant inter- and intra-patient clonal variability. Recent years have witnessed dramatic improvements in the diagnostics, classification, and treatment of MM. However, patients with high-risk disease have not yet benefited from therapeutic advances. High-r

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… Proposed mechanisms for this include clustering of the TCR-CD3 complexes to induce signaling in the absence of co-stimulation and the predominance of acting on memory T cells that require less stimulation to become activated ( 13 ). …

Clinical application of cytokine-induced killer cells in cancer immunotherapy.

Cytokine-induced killer (CIK) cells exhibit potent antitumor activity with reduced dependence on strict MHC compatibility, mediated by a combination of T-cell receptor (TCR)-dependent recognition and natural killer (NK)-like, MHC-unrestricted cytotoxicity. This narrative review synthesizes evidence from clinical trial evaluations, including 48 published studies. We examine strategies to enhance CIK function, such as engineering, combination with checkpoint inhibitors, and co-administration with dendritic cells. CIK cell therapy effectively reduces post-treatment recurrence in the adjuvant sett

Current State of the Art and Prospects of T Cell-Redirecting Bispecific Antibodies in Multiple Myeloma.

Multiple myeloma (MM) patients eventually develop multi-drug-resistant disease with poor survival. Hence, the development of novel treatment strategies is of great importance. Recently, different classes of immunotherapeutic agents have shown great promise in heavily pre-treated MM, including T cell-redirecting bispecific antibodies (BsAbs). These BsAbs simultaneously interact with CD3 on effector T cells and a tumor-associated antigen on MM cells, resulting in redirection of T cells to MM cells. This leads to the formation of an immunologic synapse, the release of granzymes/perforins, and sub

Bispecific Antibody-Based Immune-Cell Engagers and Their Emerging Therapeutic Targets in Cancer Immunotherapy.

Cancer is the second leading cause of death worldwide after cardiovascular diseases. Harnessing the power of immune cells is a promising strategy to improve the antitumor effect of cancer immunotherapy. Recent progress in recombinant DNA technology and antibody engineering has ushered in a new era of bispecific antibody (bsAb)-based immune-cell engagers (ICEs), including T- and natural-killer-cell engagers. Since the first approval of blinatumomab by the United States Food and Drug Administration (US FDA), various bsAb-based ICEs have been developed for the effective treatment of patients with

Innovative Clinical Perspectives for CIK Cells in Cancer Patients.

Cytokine-induced killer (CIK) cells are T lymphocytes that have acquired, in vitro, following extensive manipulation by Interferon gamma (IFN-γ), OKT3 and Interleukin 2 (IL-2) addition, the expression of several Natural Killer (NK) cell-surface markers. CIK cells have a dual "nature", due to the presence of functional TCR as well as NK molecules, even if the antitumoral activity can be traced back only to the NK-like structures (DNAM-1, NKG2D, NKp30 and CD56). In addition to antineoplastic activity in vitro and in several in-vivo models, CIK cells show very limited, if any, GvHD toxicity as we

Kidney-Tonifying, Phlegm-Resolving, and Blood Stasis-Removing Therapy for Multiple Myeloma: Protocol for a Randomized Controlled Trial on Epigenetic and Immune Modulation.

BACKGROUND: Multiple myeloma (MM) is characterized by kidney deficiency, phlegm, and blood stasis as core findings, specifically in Traditional Chinese Medicine (TCM), and the kidney-tonifying, phlegm-resolving, and blood stasis-removing (KPR) method is a fundamental therapeutic approach for MM in TCM. Western medicine primarily focuses on targeted immunotherapy or chemotherapy for MM treatment, whereas TCM characterizes MM through distinct pathological patterns that directly correspond to immune microenvironment dysregulation. Emerging evidence implicates the PHD finger protein 19 (PHF19)/enh