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[This corrects the article DOI: 10.3389/fimmu.2023.1311658.].
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Background: Immune checkpoint therapies have led to significant breakthroughs in cancer patient treatment in recent years. However, their efficiency is variable, and resistance to immunotherapies is common. VISTA is an immune-suppressive checkpoint inhibitor of T cell response belonging to the B7 family and a promising novel therapeutic target. VISTA is expressed in the immuno-suppressive tumor microenvironment, primarily by myeloid lineage cells, and its genetic knockout or antibody blockade restores an efficient antitumor immune response. Methods: Fully human monoclonal antibodies directed against VISTA were produced after immunizing humanized Trianni mice and single B cell sequencing. Anti-VISTA antibodies were evaluated for specificity, cross-reactivity, monocyte and T cell activation, Fc-effector functions, and antitumor efficacy using in vitro and in vivo models to select the KVA12123 antibody lead candidate. The pharmacokinetics and safety profiles of KVA12123 were evaluated in cynomolgus monkeys. Results: Here, we report the development of a clinical candidate anti-VISTA monoclonal antibody, KVA12123. KVA12123 showed high affinity binding to VISTA through a unique epitope distinct from other clinical-stage anti-VISTA monoclonal antibodies. This clinical candidate demonstrated high specificity against VISTA with no cross-reactivity detected against other members of the B7 family. KVA12123 blocked VISTA binding to its binding partners. KVA12123 induced T cell activation and demonstrated NK-mediated monocyte activation. KVA12123 treatment mediated strong single-agent antitumor activity in several syngeneic tumor models and showed enhanced efficacy in combination with anti-PD-1 treatment. This clinical candidate was engineered to improve its pharmacokinetic characteristics and reduce Fc-effector functions. It was well-tolerated in preclinical toxicology studies in cynomolgus monkeys, where hematology, clinical chemistry evaluations, and clinical observations revealed no indicators of toxicity. No cytokines associated with cytokine release syndrome were elevated. Conclusion: These results establish that KVA12123 is a promising drug candidate with a distinct but complementary mechanism of action of the first generation of immune checkpoint inhibitors. This antibody is currently evaluated alone and in combination with pembrolizumab in a Phase 1/2 open-label clinical trial in patients with advanced solid tumors.
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Anticuerpos Monoclonales , Inhibidores de Puntos de Control Inmunológico , Neoplasias , Animales , Humanos , Ratones , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Macaca fascicularis , Neoplasias/terapia , Linfocitos T , Microambiente TumoralRESUMEN
BACKGROUND: Dalazatide is a specific inhibitor of the Kv1.3 potassium channel. The expression and function of Kv1.3 channels are required for the function of chronically activated memory T cells, which have been shown to be key mediators of autoimmune diseases, including psoriasis. OBJECTIVE: The primary objective was to evaluate the safety of repeat doses of dalazatide in adult patients with mild-to-moderate plaque psoriasis. Secondary objectives were to evaluate clinical proof of concept and the effects of dalazatide on mediators of inflammation in the blood and on chronically activated memory T cell populations. METHODS: Patients (n = 24) were randomized 5:5:2 to receive dalazatide at 30 mcg/dose, 60 mcg/dose, or placebo twice weekly by subcutaneous injection (9 doses total). Safety was assessed on the basis of physical and neurological examination and laboratory testing. Clinical assessments included body-surface area affected, Psoriasis Area and Severity Index (PASI), and investigator and patient questionnaires. RESULTS: The most common adverse events were temporary mild (Grade 1) hypoesthesia (n = 20; 75% placebo, 85% dalazatide) and paresthesia (n = 15; 25% placebo, 70% dalazatide) involving the hands, feet, or perioral area. Nine of 10 patients in the 60 mcg/dose group had a reduction in their PASI score between baseline and Day 32, and the mean reduction in PASI score was significant in this group (P < 0.01). Dalazatide treatment reduced the plasma levels of multiple inflammation markers and reduced the expression of T cell activation markers on peripheral blood memory T cells. LIMITATIONS: The study was small and drug treatment was for a short duration (4 weeks). CONCLUSION: This study indicates that dalazatide is generally well tolerated and can improve psoriatic skin lesions by modulating T cell surface and activation marker expression and inhibiting mediators of inflammation in the blood. Larger studies of longer duration are warranted.
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Canal de Potasio Kv1.3/antagonistas & inhibidores , Bloqueadores de los Canales de Potasio/efectos adversos , Proteínas/efectos adversos , Psoriasis/tratamiento farmacológico , Adulto , Método Doble Ciego , Femenino , Humanos , Hipoestesia/inducido químicamente , Masculino , Persona de Mediana Edad , Parestesia/inducido químicamente , Bloqueadores de los Canales de Potasio/farmacología , Bloqueadores de los Canales de Potasio/uso terapéutico , Proteínas/farmacología , Proteínas/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: The Canadian Institutes of Health Research (CIHR) has defined knowledge translation (KT) as a dynamic and iterative process that includes the synthesis, dissemination, exchange, and ethically-sound application of knowledge to improve the health of Canadians, provide more effective health services and products, and strengthen the healthcare system. CIHR, the national health research funding agency in Canada, has undertaken to advance this concept through direct research funding opportunities in KT. Because CIHR is recognized within Canada and internationally for leading and funding the advancement of KT science and practice, it is essential and timely to evaluate this intervention, and specifically, these funding opportunities. DESIGN: The study will employ a novel method of participatory, utilization-focused evaluation inspired by the principles of integrated KT. It will use a mixed methods approach, drawing on both quantitative and qualitative data, and will elicit participation from CIHR funded researchers, knowledge users, KT experts, as well as other health research funding agencies. Lines of inquiry will include an international environmental scan, document/data reviews, in-depth interviews, targeted surveys, case studies, and an expert review panel. The study will investigate how efficiently and effectively the CIHR model of KT funding programs operates, what immediate outcomes these funding mechanisms have produced, and what impact these programs have had on the broader state of health research, health research uptake, and health improvement. DISCUSSION: The protocol and results of this evaluation will be of interest to those engaged in the theory, practice, and evaluation of KT. The dissemination of the study protocol and results to both practitioners and theorists will help to fill a gap in knowledge in three areas: the role of a public research funding agency in facilitating KT, the outcomes and impacts KT funding interventions, and how KT can best be evaluated.
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Agencias Gubernamentales/economía , Educación en Salud/organización & administración , Conocimientos, Actitudes y Práctica en Salud , Difusión de la Información , Canadá , Educación en Salud/economía , HumanosRESUMEN
We experimentally investigate polarization-switched quadrature phase-shift keying (PS-QPSK) with a symbol rate of 37.3 GBd corresponding to a bit rate of 112 Gb/s. In a wavelength-division multiplexing (WDM) experiment with 50 GHz channel spacing, the transmission performance of PS-QPSK is compared to that of polarization-division multiplexed QPSK (PDM-QPSK) over an EDFA amplified ultra-large-effective-area fiber link. For a bit-error ratio (BER) of 3.8 × 10(-3), the achieved transmission distance is 11000 km for PS-QSPK and 10000 km for PDM-QPSK.
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Tecnología de Fibra Óptica/instrumentación , Dispositivos Ópticos , Procesamiento de Señales Asistido por Computador/instrumentación , Telecomunicaciones/instrumentación , Diseño de Equipo , Análisis de Falla de Equipo , Océanos y MaresRESUMEN
Mode-division multiplexing over 33-km few-mode fiber is investigated. It is shown that 6×6 MIMO processing can be used to almost completely compensate for crosstalk and intersymbol interference due to mode coupling in a system that transmits uncorrelated 28-GBaud QPSK signals on the six spatial and polarization modes supported by a novel few-mode fiber.
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B-cell maturation antigen (BCMA) is expressed on normal and malignant plasma cells and represents a potential target for therapeutic intervention. BCMA binds to two ligands that promote tumor cell survival, a proliferation inducing ligand (APRIL) and B-cell activating factor. To selectively target BCMA for plasma cell malignancies, we developed antibodies with ligand blocking activity that could promote cytotoxicity of multiple myeloma (MM) cell lines as naked antibodies or as antibody-drug conjugates. We show that SG1, an inhibitory BCMA antibody, blocks APRIL-dependent activation of nuclear factor-kappaB in a dose-dependent manner in vitro. Cytotoxicity of SG1 was assessed as a naked antibody after chimerization with and without Fc mutations that enhance FcgammaRIIIA binding. The Fc mutations increased the antibody-dependent cell-mediated cytotoxicity potency of BCMA antibodies against MM lines by approximately 100-fold with a > or = 2-fold increase in maximal lysis. As an alternative therapeutic strategy, anti-BCMA antibodies were endowed with direct cytotoxic activity by conjugation to the cytotoxic drug, monomethyl auristatin F. The most potent BCMA antibody-drug conjugate displayed IC(50) values of < or = 130 pmol/L for three different MM lines. Hence, BCMA antibodies show cytotoxic activity both as naked IgG and as drug conjugates and warrant further evaluation as therapeutic candidates for plasma cell malignancies.
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Anticuerpos Monoclonales/farmacología , Antígeno de Maduración de Linfocitos B/antagonistas & inhibidores , Células Plasmáticas/patología , Animales , Citotoxicidad Celular Dependiente de Anticuerpos/efectos de los fármacos , Antígenos de Neoplasias/inmunología , Línea Celular Tumoral , Depsipéptidos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Ratones , FN-kappa B/metabolismo , Células Plasmáticas/inmunología , Unión Proteica/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Transfección , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/metabolismoRESUMEN
Monoclonal antibodies have begun to show great clinical promise for the treatment of cancer. Antibodies that can directly affect a tumor cell's growth and/or survival are of particular interest for immunotherapy. Previously, we described monoclonal antibody DMF10.62.3 that had antiproliferative and proapoptotic effects when it bound an antigen of unknown identity on tumor cells in vitro. In this report, we determined that DMF10.62.3 and a clonally related antibody DMF10.167.4 recognize the ganglioside GM2. These antibodies react with a GM2 epitope that is expressed on a large number of tumor cell lines, including human melanoma and small cell lung carcinoma, but not on normal primary lines or most normal tissues. Interestingly, this pattern of cellular reactivity is distinct from that reported for other previously described GM2 antibodies, a difference that is presumably due to DMF10.167.4's binding to a unique GM2-associated epitope. Additional characterization of DMF10.167.4 revealed that this antibody was able to induce apoptosis and/or block cellular proliferation when cultured in vitro with the human Jurkat T lymphoma, CHL-1 melanoma, and SBC-3 small cell lung carcinoma lines. In vivo, DMF10.167.4 antibody was well tolerated in mice and did not detectably bind to or damage normal tissues. However, this antibody was able to prevent murine E710.2.3 lymphoma, human CHL-1 melanoma, and SBC-3 small cell lung carcinoma lines from establishing tumors in vivo and blocked progression of established CHL-1 and SBC-3 tumors in vivo. Therefore, monoclonal antibody DMF10.167.4 has immunotherapeutic potential.
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Anticuerpos Monoclonales/inmunología , Carcinoma de Células Pequeñas/terapia , Gangliósido G(M2)/inmunología , Inmunización Pasiva/métodos , Neoplasias Pulmonares/terapia , Melanoma/terapia , Animales , Anticuerpos Monoclonales/farmacología , Especificidad de Anticuerpos , Apoptosis/inmunología , Carcinoma de Células Pequeñas/inmunología , Carcinoma de Células Pequeñas/patología , Cricetinae , Epítopos/inmunología , Femenino , Humanos , Células Jurkat , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Melanoma/inmunología , Melanoma/patología , Ratones , Ratones Endogámicos AKR , Ratones SCIDRESUMEN
Reaction to certain motifs in bacterial DNA is an important function of natural immunity. For example, single stranded oligonucleotides (ODN) containing the motif "not C, unmethylated C, G, not G" are powerful mitogens and apoptosis inhibitors for mouse spleen B cells. But replacing GCGTT or ACGTT with GCGGG or ACGGG converted a stimulatory 15-mer ODN into an inhibitory ODN. All inhibitory ODN had three consecutive G, and a fourth G increased inhibitory activity, but a deazaguanosine substitution to prevent planar stacking did not affect activity. Inhibitory ODN blocked apoptosis protection and cell-cycle entry induced by stimulatory ODN, but not that induced by lipopolysaccharide, anti-CD40 or anti-IgM+IL-4. ODN-driven up-regulation of cyclin D(2), c-Myc, c-Fos, c-Jun and Bcl(XL) and down-regulation of cyclin kinase inhibitor p27(kip1) were all blocked by inhibitory ODN. The relative potency of a series of stimulatory and inhibitory ODN was the same for all readouts measured. Interference with uptake of stimulatory ODN could not account for their inhibitory effects. Even if addition of inhibitory ODN was delayed several hours, partial inhibition of stimulatory ODN effects occurred. Inhibitory ODN hold potential as antidotes for excessive ODN stimulation in the clinical setting and provide an important tool for studying ODN recognition.