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1.
Mol Cancer Ther ; 23(4): 421-435, 2024 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-38030380

RESUMEN

IL12 is a proinflammatory cytokine, that has shown promising antitumor activity in humans by promoting the recruitment and activation of immune cells in tumors. However, the systemic administration of IL12 has been accompanied by considerable toxicity, prompting interest in researching alternatives to drive preferential IL12 bioactivity in the tumor. Here, we have generated XTX301, a tumor-activated IL12 linked to the human Fc protein via a protease cleavable linker that is pharmacologically inactivated by an IL12 receptor subunit beta 2 masking domain. In vitro characterization demonstrates multiple matrix metalloproteases, as well as human primary tumors cultured as cell suspensions, can effectively activate XTX301. Intravenous administration of a mouse surrogate mXTX301 demonstrated significant tumor growth inhibition (TGI) in inflamed and non-inflamed mouse models without causing systemic toxicities. The superiority of mXTX301 in mediating TGI compared with non-activatable control molecules and the greater percentage of active mXTX301 in tumors versus other organs further confirms activation by the tumor microenvironment-associated proteases in vivo. Pharmacodynamic characterization shows tumor selective increases in inflammation and upregulation of immune-related genes involved in IFNγ cell signaling, antigen processing, presentation, and adaptive immune response. XTX301 was tolerated following four repeat doses up to 2.0 mg/kg in a nonhuman primate study; XTX301 exposures were substantially higher than those at the minimally efficacious dose in mice. Thus, XTX301 has the potential to achieve potent antitumor activity while widening the therapeutic index of IL12 treatment and is currently being evaluated in a phase I clinical trial.


Asunto(s)
Interleucina-12 , Neoplasias , Humanos , Ratones , Animales , Interleucina-12/metabolismo , Neoplasias/tratamiento farmacológico , Citocinas , Transducción de Señal , Índice Terapéutico , Microambiente Tumoral
2.
J Immunother Cancer ; 11(12)2023 12 12.
Artículo en Inglés | MEDLINE | ID: mdl-38164757

RESUMEN

INTRODUCTION: The clinical benefit of the anti-CTLA-4 monoclonal antibody (mAb) ipilimumab has been well established but limited by immune-related adverse events, especially when ipilimumab is used in combination with anti-PD-(L)1 mAb therapy. To overcome these limitations, we have developed XTX101, a tumor-activated, Fc-enhanced anti-CTLA-4 mAb. METHODS: XTX101 consists of an anti-human CTLA-4 mAb covalently linked to masking peptides that block the complementarity-determining regions, thereby minimizing the mAb binding to CTLA-4. The masking peptides are designed to be released by proteases that are typically dysregulated within the tumor microenvironment (TME), resulting in activation of XTX101 intratumorally. Mutations within the Fc region of XTX101 were included to enhance affinity for FcγRIII, which is expected to enhance potency through antibody-dependent cellular cytotoxicity. RESULTS: Biophysical, biochemical, and cell-based assays demonstrate that the function of XTX101 depends on proteolytic activation. In human CTLA-4 transgenic mice, XTX101 monotherapy demonstrated significant tumor growth inhibition (TGI) including complete responses, increased intratumoral CD8+T cells, and regulatory T cell depletion within the TME while maintaining minimal pharmacodynamic effects in the periphery. XTX101 in combination with anti-PD-1 mAb treatment resulted in significant TGI and was well tolerated in mice. XTX101 was activated in primary human tumors across a range of tumor types including melanoma, renal cell carcinoma, colon cancer and lung cancer in an ex vivo assay system. CONCLUSIONS: These data demonstrate that XTX101 retains the full potency of an Fc-enhanced CTLA-4 antagonist within the TME while minimizing the activity in non-tumor tissue, supporting the further evaluation of XTX101 in clinical studies.


Asunto(s)
Antineoplásicos , Melanoma , Humanos , Ratones , Animales , Antígeno CTLA-4 , Ipilimumab/uso terapéutico , Antineoplásicos/uso terapéutico , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Melanoma/tratamiento farmacológico , Modelos Animales de Enfermedad , Ratones Transgénicos , Péptidos/uso terapéutico , Microambiente Tumoral
3.
J Immunother Cancer ; 10(6)2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35728874

RESUMEN

BACKGROUND: Chimeric antigen receptor (CAR) T cells engineered to recognize and target tumor associated antigens have made a profound impact on the quality of life for many patients with cancer. However, tumor heterogeneity and intratumoral immune suppression reduce the efficacy of this approach, allowing for tumor cells devoid of the target antigen to seed disease recurrence. Here, we address the complexity of tumor heterogeneity by developing a universal CAR. METHOD: We constructed a universal Fabrack-CAR with an extracellular domain composed of the non-tumor targeted, cyclic, twelve residue meditope peptide that binds specifically to an engineered binding pocket within the Fab arm of monoclonal antibodies (mAbs). As this site is readily grafted onto therapeutic mAbs, the antigen specificity of these universal Fabrack-CAR T cells is simply conferred by administering mAbs with specificity to the heterogeneous tumor. RESULTS: Using in vitro and in vivo studies with multiple meditope-engineered mAbs, we show the feasibility, specificity, and robustness of this approach. These studies demonstrate antigen- and antibody-specific T cell activation, proliferation, and IFNγ production, selective killing of target cells in a mixed population, and tumor regression in animal models. CONCLUSION: Collectively, these findings support the feasibility of this universal Fabrack-CAR T cell approach and provide the rationale for future clinical use in cancer immunotherapy.


Asunto(s)
Inmunoterapia Adoptiva , Neoplasias , Animales , Anticuerpos Monoclonales/uso terapéutico , Humanos , Neoplasias/terapia , Calidad de Vida , Receptores de Antígenos de Linfocitos T , Linfocitos T
4.
Cancer Res ; 77(18): 5118-5128, 2017 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-28716895

RESUMEN

CTL-associated antigen 4 (CTLA4) is a well-established immune checkpoint for antitumor immune responses. The protumorigenic function of CTLA4 is believed to be limited to T-cell inhibition by countering the activity of the T-cell costimulating receptor CD28. However, as we demonstrate here, there are two additional roles for CTLA4 in cancer, including via CTLA4 overexpression in diverse B-cell lymphomas and in melanoma-associated B cells. CTLA4-CD86 ligation recruited and activated the JAK family member Tyk2, resulting in STAT3 activation and expression of genes critical for cancer immunosuppression and tumor growth and survival. CTLA4 activation resulted in lymphoma cell proliferation and tumor growth, whereas silencing or antibody-blockade of CTLA4 in B-cell lymphoma tumor cells in the absence of T cells inhibits tumor growth. This inhibition was accompanied by reduction of Tyk2/STAT3 activity, tumor cell proliferation, and induction of tumor cell apoptosis. The CTLA4-Tyk2-STAT3 signal pathway was also active in tumor-associated nonmalignant B cells in mouse models of melanoma and lymphoma. Overall, our results show how CTLA4-induced immune suppression occurs primarily via an intrinsic STAT3 pathway and that CTLA4 is critical for B-cell lymphoma proliferation and survival. Cancer Res; 77(18); 5118-28. ©2017 AACR.


Asunto(s)
Linfocitos B/patología , Biomarcadores de Tumor/metabolismo , Antígeno CTLA-4/metabolismo , Linfoma de Células B/patología , Factor de Transcripción STAT3/metabolismo , TYK2 Quinasa/metabolismo , Adulto , Anciano , Animales , Apoptosis , Linfocitos B/inmunología , Linfocitos B/metabolismo , Antígenos CD28/metabolismo , Proliferación Celular , Femenino , Humanos , Activación de Linfocitos , Linfoma de Células B/inmunología , Linfoma de Células B/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Transducción de Señal , Linfocitos T/inmunología , Células Tumorales Cultivadas
5.
Cell Stress Chaperones ; 21(4): 717-25, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27188431

RESUMEN

Increasing heat shock protein 70 (HSP70) in aged and/or insulin-resistant animal models confers benefits to healthspan and lifespan. Heat application to increase core temperature induces HSPs in metabolically important tissues, and preliminary human and animal data suggest that heated hydrotherapy is an effective method to achieve increased HSPs. However, safety concerns exist, particularly in geriatric medicine where organ and cardiovascular disease commonly will preexist. We evaluated young vervet monkeys compared to old, insulin-resistant vervet monkeys (Chlorocebus aethiops sabaeus) in their core temperatures, glucose tolerance, muscle HSP70 level, and selected safety biomarkers after 10 sessions of hot water immersions administered twice weekly. Hot water immersion robustly induced the heat shock response in muscles. We observed that heat-treated old and young monkeys have significantly higher muscle HSP70 than control monkeys and treatment was without significant adverse effects on organ or cardiovascular health. Heat therapy improved pancreatic responses to glucose challenge and tended to normalize glucose excursions. A trend for worsened blood pressure and glucose values in the control monkeys and improved values in heat-treated monkeys were seen to support further investigation into the safety and efficacy of this intervention for metabolic syndrome or diabetes in young or old persons unable to exercise.


Asunto(s)
Envejecimiento/metabolismo , Glucosa/metabolismo , Proteínas HSP70 de Choque Térmico/metabolismo , Calor , Hidroterapia , Músculos/metabolismo , Animales , Área Bajo la Curva , Biomarcadores/metabolismo , Sistema Cardiovascular/metabolismo , Chlorocebus aethiops , Ayuno/sangre , Prueba de Tolerancia a la Glucosa
6.
Am J Physiol Endocrinol Metab ; 300(5): E894-901, 2011 May.
Artículo en Inglés | MEDLINE | ID: mdl-21325107

RESUMEN

We evaluated heat shock protein 70 (HSP70) changes in diabetes mellitus (DM) in a nonhuman primate model. To this end, two studies were conducted in DM vervet monkeys. 1) Normal control and streptozotocin-induced DM monkeys (Stz-DM) that were differentiated into moderately or poorly controlled DM by judicious insulin administration were evaluated. Liver was collected at 4, 8, 12, 16, and 20 wk after streptozotocin, exposed to ex vivo heat shock at 42°C, and immunoblotted for heat shock factor 1 (HSF1), HSP70, and phosphorylated HSF1. 2) Spontaneous DM monkeys that were not pharmacologically induced were included in a crossover study of the HSP70-inducing drug geranylgeranylacetone (GGA). GGA at 20 mg/kg was given for 14 days with a 6-wk washout period. Glucose tolerance testing and plasma and muscle HSP70 were the primary outcome measurements. In Stz-DM, hyperglycemia reduced hepatic HSP70 in a dose-dependent fashion. HSF1 was increased in livers of monkeys with Stz-DM, but responses to ex vivo heat shock were impaired vs. normal monkeys. Activation of HSF1 appears to be important, because the phosphorylation change with heat stress was nearly perfectly correlated with HSP70 increases. Impaired HSF1 activation was also seen in Stz-DM after chronic hyperglycemia (>12 wk). In naturally occurring DM, increased circulating HSP70 resulted in significantly improved glucose tolerance and significant, positive trends in other measurements of insulin resistance. No change in muscle HSP70 content was observed. We conclude that increasing HSP70, potentially through targeting hyperglycemia-related deficits in HSF1 induction and activation in the liver, is a potent and viable strategy to improve glucose tolerance.


Asunto(s)
Diabetes Mellitus Experimental/terapia , Intolerancia a la Glucosa/terapia , Proteínas HSP70 de Choque Térmico/fisiología , Análisis de Varianza , Animales , Peso Corporal/fisiología , Chlorocebus aethiops , Proteínas de Unión al ADN/sangre , Diabetes Mellitus Experimental/metabolismo , Diterpenos/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Hemoglobina Glucada/metabolismo , Proteínas HSP70 de Choque Térmico/genética , Factores de Transcripción del Choque Térmico , Trastornos de Estrés por Calor/metabolismo , Hiperglucemia/sangre , Metabolismo de los Lípidos/fisiología , Hígado/metabolismo , Masculino , Fosforilación , Factores de Transcripción/sangre
7.
Nutr Res ; 30(6): 418-26, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20650350

RESUMEN

Industrially produced trans-fatty acids (TFAs) consumed in Western diets are incorporated into maternal and fetal tissues and are passed linearly to offspring via breast milk. We hypothesized that TFA exposure in utero and during lactation in infants would promote obesity and poor glycemic control as compared with unmodified fatty acids. We further hypothesized that in utero exposure alone may program for these outcomes in adulthood. To test this hypothesis, we fed female C57/BL6 mice identical Western diets that differed only in cis- or trans-isomers of C18:1 and then aimed to determine whether maternal transfer of TFAs through pregnancy and lactation alters growth, body composition, and glucose metabolism. Mice were unexposed, exposed during pregnancy, during lactation, or throughout pregnancy and lactation to TFA. Body weight and composition (by computed tomography) and glucose metabolism were assessed at weaning and adulthood. Trans-fatty acid exposure through breast milk caused significant early growth retardation (P < .001) and higher fasting glucose (P = .01), but insulin sensitivity was not different. Elevated plasma insulin-like growth factor-1 in mice consuming TFA-enriched milk (P = .02) may contribute to later catch-up growth and leanness and preserved peripheral insulin sensitivity observed in these mice. Mice exposed to TFA in utero underwent rapid early neonatal growth with TFA-free breast milk and had significantly impaired insulin sensitivity (P < .05) and greater abdominal fat (P = .01). We conclude that very early catch-up growth resulted in impaired peripheral insulin sensitivity in this model of diet-related fetal and neonatal programming. Trans-fatty acid surprisingly retarded growth and adiposity while still adversely affecting glucose metabolism.


Asunto(s)
Glucemia/metabolismo , Grasas de la Dieta/administración & dosificación , Trastornos del Crecimiento/etiología , Crecimiento/efectos de los fármacos , Obesidad/prevención & control , Efectos Tardíos de la Exposición Prenatal , Ácidos Grasos trans/farmacología , Grasa Abdominal/metabolismo , Adiposidad/efectos de los fármacos , Animales , Animales Recién Nacidos , Femenino , Trastornos del Crecimiento/metabolismo , Resistencia a la Insulina , Factor I del Crecimiento Similar a la Insulina/metabolismo , Lactancia , Masculino , Ratones , Ratones Endogámicos C57BL , Leche Humana/química , Obesidad/metabolismo , Embarazo , Efectos Tardíos de la Exposición Prenatal/metabolismo
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