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1.
Proc Natl Acad Sci U S A ; 119(19): e2123483119, 2022 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-35507878

RESUMO

Immunotherapy approaches focusing on T cells have provided breakthroughs in treating solid tumors. However, there remains an opportunity to drive anticancer immune responses via other cell types, particularly myeloid cells. ATRC-101 was identified via a target-agnostic process evaluating antibodies produced by the plasmablast population of B cells in a patient with non-small cell lung cancer experiencing an antitumor immune response during treatment with checkpoint inhibitor therapy. Here, we describe the target, antitumor activity in preclinical models, and data supporting a mechanism of action of ATRC-101. Immunohistochemistry studies demonstrated tumor-selective binding of ATRC-101 to multiple nonautologous tumor tissues. In biochemical analyses, ATRC-101 appears to target an extracellular, tumor-specific ribonucleoprotein (RNP) complex. In syngeneic murine models, ATRC-101 demonstrated robust antitumor activity and evidence of immune memory following rechallenge of cured mice with fresh tumor cells. ATRC-101 increased the relative abundance of conventional dendritic cell (cDC) type 1 cells in the blood within 24 h of dosing, increased CD8+ T cells and natural killer cells in blood and tumor over time, decreased cDC type 2 cells in the blood, and decreased monocytic myeloid-derived suppressor cells in the tumor. Cellular stress, including that induced by chemotherapy, increased the amount of ATRC-101 target in tumor cells, and ATRC-101 combined with doxorubicin enhanced efficacy compared with either agent alone. Taken together, these data demonstrate that ATRC-101 drives tumor destruction in preclinical models by targeting a tumor-specific RNP complex leading to activation of innate and adaptive immune responses.


Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Neoplasias , Imunidade Adaptativa , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Humanos , Imunidade Inata , Camundongos , Neoplasias/patologia
2.
Clin Immunol ; 187: 37-45, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29031828

RESUMO

There is significant debate regarding whether B cells and their antibodies contribute to effective anti-cancer immune responses. Here we show that patients with metastatic but non-progressing melanoma, lung adenocarcinoma, or renal cell carcinoma exhibited increased levels of blood plasmablasts. We used a cell-barcoding technology to sequence their plasmablast antibody repertoires, revealing clonal families of affinity matured B cells that exhibit progressive class switching and persistence over time. Anti-CTLA4 and other treatments were associated with further increases in somatic hypermutation and clonal family size. Recombinant antibodies from clonal families bound non-autologous tumor tissue and cell lines, and families possessing immunoglobulin paratope sequence motifs shared across patients exhibited increased rates of binding. We identified antibodies that caused regression of, and durable immunity toward, heterologous syngeneic tumors in mice. Our findings demonstrate convergent functional anti-tumor antibody responses targeting public tumor antigens, and provide an approach to identify antibodies with diagnostic or therapeutic utility.


Assuntos
Antígenos de Neoplasias/imunologia , Linfócitos B/imunologia , Neoplasias/imunologia , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos , Sítios de Ligação de Anticorpos/imunologia , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/secundário , Progressão da Doença , Feminino , Humanos , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Masculino , Melanoma/imunologia , Melanoma/secundário , Pessoa de Meia-Idade , Metástase Neoplásica , Plasmócitos/imunologia , Células Precursoras de Linfócitos B , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia
3.
Bioorg Med Chem Lett ; 25(18): 4011-5, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26235950

RESUMO

Antagonists of the TRPV4 receptor were identified using a focused screen, followed by a limited optimization program. The leading compounds obtained from this exercise, RN-1665 23 and RN-9893 26, showed moderate oral bioavailability when dosed to rats. The lead molecule, RN-9893 26, inhibited human, rat and murine variants of TRPV4, and showed excellent selectivity over related TRP receptors, such as TRPV1, TRPV3 and TRPM8. The overall profile for RN-9893 may permit its use as a proof-of-concept probe for in vivo applications.


Assuntos
Piperazinas/administração & dosagem , Piperazinas/farmacologia , Canais de Cátion TRPV/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Humanos , Camundongos , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Canais de Cátion TRPV/metabolismo
4.
Proc Natl Acad Sci U S A ; 107(15): 7024-9, 2010 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-20351287

RESUMO

The autonomic nervous system regulates fuel availability and energy storage in the liver, adipose tissue, and other organs; however, the molecular components of this neural circuit are poorly understood. We sought to identify neural populations that project from the CNS indirectly through multisynaptic pathways to liver and epididymal white fat in mice using pseudorabies virus strains expressing different reporters together with BAC transgenesis and immunohistochemistry. Neurons common to both circuits were identified in subpopulations of the paraventricular nucleus of the hypothalamus (PVH) by double labeling with markers expressed in viruses injected in both sites. The lateral hypothalamus and arcuate nucleus of the hypothalamus and brainstem regions (nucleus of the solitary tract and A5 region) also project to both tissues but are labeled at later times. Connections from these same sites to the PVH were evident after direct injection of virus into the PVH, suggesting that these regions lie upstream of the PVH in a common pathway to liver and adipose tissue (two metabolically active organs). These common populations of brainstem and hypothalamic neurons express neuropeptide Y and proopiomelanocortin in the arcuate nucleus, melanin-concentrating hormone, and orexin in the lateral hypothalamus and in the corticotrophin-releasing hormone and oxytocin in the PVH. The delineation of this circuitry will facilitate a functional analysis of the possible role of these potential command-like neurons to modulate autonomic outflow and coordinate metabolic responses in liver and adipose tissue.


Assuntos
Tecido Adiposo/patologia , Hipotálamo/patologia , Fígado/patologia , Neurônios/metabolismo , Animais , Tronco Encefálico/metabolismo , Proteínas de Fluorescência Verde/metabolismo , Hormônios Hipotalâmicos/metabolismo , Hipotálamo/metabolismo , Imuno-Histoquímica/métodos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fígado/metabolismo , Masculino , Melaninas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Neuropeptídeo Y/metabolismo , Neuropeptídeos/metabolismo , Orexinas , Hormônios Hipofisários/metabolismo , Pró-Opiomelanocortina/metabolismo
5.
Bioorg Med Chem Lett ; 20(23): 7076-9, 2010 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-20965726

RESUMO

5-Benzyloxytryptamine 19 was found to act as an antagonist of the TRPM8 ion-channel. For example, 19 had an IC(50) of 0.34 µM when menthol was used as the stimulating agonist. Related commercially-available tryptamine derivatives showed diminished, or no antagonist activity at TRPM8. The structural similarity of 5-benzyloxytryptamine to other literature TRPM8 antagonists was noted.


Assuntos
Serotonina/análogos & derivados , Canais de Cátion TRPM/antagonistas & inibidores , Animais , Humanos , Concentração Inibidora 50 , Mentol/farmacologia , Serotonina/farmacologia , Relação Estrutura-Atividade , Canais de Cátion TRPM/agonistas , Triptaminas/farmacologia
6.
Bioorg Med Chem Lett ; 20(1): 276-9, 2010 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-19945872

RESUMO

AP18 1 was recently disclosed as an antagonist of the TRPA1 receptor by the research group of Patapoutian. However, no detailed structure-activity relationships around 1 have been disclosed. Thus, a small number of oximes related to AP18 were examined in order to characterize the determinants of TRPA1 activity. Congeners of AP18 were found to possess both agonist and antagonist activity, suggesting that AP18 may behave as a covalent antagonist of the TRPA1 ion-channel.


Assuntos
Proteínas do Tecido Nervoso/agonistas , Proteínas do Tecido Nervoso/antagonistas & inibidores , Oximas/química , Canais de Potencial de Receptor Transitório/agonistas , Canais de Potencial de Receptor Transitório/antagonistas & inibidores , Canais de Cálcio/metabolismo , Humanos , Proteínas do Tecido Nervoso/metabolismo , Oximas/síntese química , Oximas/farmacologia , Relação Estrutura-Atividade , Canal de Cátion TRPA1 , Canais de Potencial de Receptor Transitório/metabolismo
7.
Biochem Biophys Res Commun ; 389(3): 490-4, 2009 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-19737537

RESUMO

TRPV4, a close relative of the vanilloid receptor TRPV1, is activated by diverse modalities such as endogenous lipid ligands, hypotonicity, protein kinases and, possibly, mechanical inputs. While its multiple roles in vivo are being explored with KO mice and selective agonists, there is a dearth of selective antagonists available to examine TRPV4 function. Herein we detail the use of a focused library of commercial compounds in order to identify RN-1747 and RN-1734, a pair of structurally related small molecules endowed with TRPV4 agonist and antagonist properties, respectively. Their activities against human, rat and mouse TRPV4 were characterized using electrophysiology and intracellular calcium influx. Significantly, antagonist RN-1734 was observed to completely inhibit both ligand- and hypotonicity-activated TRPV4. In addition, RN-1734 was found to be selective for TRPV4 in a TRP selectivity panel including TRPV1, TRPV3 and TRPM8, and could thus be a valuable pharmacological probe for TRPV4 studies.


Assuntos
Sulfonamidas/farmacologia , Canais de Cátion TRPV/agonistas , Canais de Cátion TRPV/antagonistas & inibidores , Animais , Humanos , Camundongos , Ratos , Sulfonamidas/química , Sulfonamidas/isolamento & purificação , Xenopus
8.
Curr Top Med Chem ; 11(17): 2237-52, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21671871

RESUMO

TRPM8 belongs to the TRPM Melastatin subfamily of Transient Receptor Potential (TRP) ion channels. Activated by cool temperatures and mimetic ligands, such as menthol and icilin, TRPM8 has been shown to play a role in thermoreception and is expressed in peripheral nerves. TRPM8 is also expressed in other tissues which are not exposed to temperature fluctuations, such as the prostate. The recent advancement of a TRPM8 agonist into the clinic for the treatment of prostate cancer suggests that the channel plays a role in some human pathologies. As more drug-like and selective agonists and antagonists of TRPM8 become available, in vivo pharmacology studies will complement already published knockout data to further our understanding of the role of TRPM8 in human disease.


Assuntos
Canais de Cátion TRPM/agonistas , Canais de Cátion TRPM/antagonistas & inibidores , Química Farmacêutica , Humanos , Ligantes , Estrutura Molecular , Relação Estrutura-Atividade , Canais de Cátion TRPM/metabolismo
9.
Biotechniques ; 47(3): iii-ix, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19852757

RESUMO

The functional activity of a number of ion channels is highly sensitive to large changes in temperature. Foremost among these are the thermosensing TRP channels which include cold- (TRPM8, TRPA1), warmth- (TRPV3, TRPV4), and heat-sensing (TRPV1, TRPV2) members. TRPV1, also known as the vanilloid receptor (VR1), is activated by ligands such as capsaicin, acidic pH, and heat (an increase in temperature to approximately 42 degrees C will lead to channel opening). Screening against the thermal gating of TRPV1 is generally performed using perfusion systems or water baths for temperature control, in conjunction with electrophysiology or Ca2 + influx readouts for direct functional assessment. These approaches are very useful, but have limited throughput or minimal thermo-temporal control. A standard real-time PCR machine with standard microplates allowed us to combine fluorescent Ca2 + detection with precise temperature manipulation to develop a homogeneous (Z' = 0.53), cell-based assay that uses temperature as the agonist. A temperature response curve of TRPV1 was obtained, which provided a T50 of 46.1 degrees C, and IC50 values against heat agonism were determined for known TRPV1 antagonists. Furthermore, we expanded this approach to a cold-activated ion channel, TRPM8. We developed and validated an analytical technique with broad applications for the study and screening of temperature-gated ion channels.


Assuntos
Reação em Cadeia da Polimerase/métodos , Canais de Potencial de Receptor Transitório/análise , Cálcio/metabolismo , Linhagem Celular , Humanos , Concentração Inibidora 50 , Reação em Cadeia da Polimerase/instrumentação , Temperatura , Fatores de Tempo , Canais de Potencial de Receptor Transitório/antagonistas & inibidores , Canais de Potencial de Receptor Transitório/genética , Canais de Potencial de Receptor Transitório/metabolismo
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