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1.
Bioconjug Chem ; 31(4): 1177-1187, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32138509

RESUMO

Antibody-drug conjugates (ADCs) are a class of targeted therapeutics consisting of a monoclonal antibody coupled to a cytotoxic payload. Various bioconjugation methods for producing site-specific ADCs have been reported recently, in efforts to improve immunoreactivity and pharmacokinetics and minimize batch variance-potential issues associated with first-generation ADCs prepared via stochastic peptide coupling of lysines or reduced cysteines. Recently, cell-free protein synthesis of antibodies incorporating para-azidomethyl phenylalanine (pAMF) at specific locations within the protein sequence has emerged as a means to generate antibody-drug conjugates with strictly defined drug-antibody-ratio, leading to ADCs with markedly improved stability, activity, and specificity. The incorporation of pAMF enables the conjugation of payloads functionalized for strain-promoted azide-alkyne cycloaddition. Here, we introduce two dibenzylcyclooctyne-functionalized bifunctional chelators that enable the incorporation of radioisotopes for positron emission tomography with 89Zr (t1/2 = 78.4 h, ß+ = 395 keV (22%), γ = 897 keV) or single photon emission computed tomography with 111In (t1/2 = 67.3 h, γ = 171 keV (91%), 245 keV (94%)) under physiologically compatible conditions. We show that the corresponding radiolabeled conjugates with site-specifically functionalized antibodies targeting HER2 are amenable to targeted molecular imaging of HER2+ expressing tumor xenografts in mice and exhibit a favorable biodistribution profile in comparison with conventional, glycosylated antibody conjugates generated by stochastic bioconjugation.


Assuntos
Alcinos/química , Aminoácidos/química , Azidas/química , Imunoconjugados/química , Radioisótopos de Índio/química , Radioisótopos/química , Zircônio/química , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Reação de Cicloadição , Humanos , Imunoconjugados/uso terapêutico , Marcação por Isótopo , Camundongos
2.
Oncotarget ; 14: 1-13, 2023 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-36634212

RESUMO

Overexpression of CD74, a type II transmembrane glycoprotein involved in MHC class II antigen presentation, has been reported in many B-cell non-Hodgkin lymphomas (NHLs) and in multiple myeloma (MM). STRO-001 is a site-specific, predominantly single-species antibody-drug conjugate (ADC) that targets CD74 and has demonstrated efficacy in xenograft models of MM and tolerability in non-human primates. Here we report results of preclinical studies designed to elucidate the potential role of STRO-001 in B-cell NHL. STRO-001 displayed nanomolar and sub-nanomolar cytotoxicity in 88% (15/17) of cancer cell lines tested. STRO-001 showed potent cytotoxicity on proliferating B cells while limited cytotoxicity was observed on naïve human B cells. A linear dose-response relationship was demonstrated in vivo for DLBCL models SU-DHL-6 and U2932. Tumor regression was induced at doses less than 5 mg/kg, while maximal activity with complete cures were observed starting at 10 mg/kg. In MCL Mino and Jeko-1 xenografts, STRO-001 starting at 3 mg/kg significantly prolonged survival or induced tumor regression, respectively, leading to tumor eradication in both models. In summary, high CD74 expression levels in tumors, nanomolar cellular potency, and significant anti-tumor in DLBCL and MCL xenograft models support the ongoing clinical study of STRO-001 in patients with B-cell NHL.


Assuntos
Antineoplásicos , Imunoconjugados , Linfoma não Hodgkin , Mieloma Múltiplo , Animais , Humanos , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Mieloma Múltiplo/patologia , Linfoma não Hodgkin/tratamento farmacológico , Linhagem Celular Tumoral
3.
Mol Cancer Ther ; 22(2): 155-167, 2023 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-36459691

RESUMO

STRO-002 is a novel homogeneous folate receptor alpha (FolRα) targeting antibody-drug conjugate (ADC) currently being investigated in the clinic as a treatment for ovarian and endometrial cancers. Here, we describe the discovery, optimization, and antitumor properties of STRO-002. STRO-002 was generated by conjugation of a novel cleavable 3-aminophenyl hemiasterlin linker-warhead (SC239) to the nonnatural amino acid para-azidomethyl-L-phenylalanine incorporated at specific positions within a high affinity anti-FolRα antibody using Sutro's XpressCF+, which resulted in a homogeneous ADC with a drug-antibody ratio (DAR) of 4. STRO-002 binds to FolRα with high affinity, internalizes rapidly into target positive cells, and releases the tubulin-targeting cytotoxin 3-aminophenyl hemiasterlin (SC209). SC209 has reduced potential for drug efflux via P-glycoprotein 1 drug pump compared with other tubulin-targeting payloads. While STRO-002 lacks nonspecific cytotoxicity toward FolRα-negative cell lines, bystander killing of target negative cells was observed when cocultured with target positive cells. STRO-002 is stable in circulation with no change in DAR for up to 21 days and has a half-life of 6.4 days in mice. A single dose of STRO-002 induced significant tumor growth inhibition in FolRα-expressing xenograft models and patient-derived xenograft models. In addition, combination treatment with carboplatin or Avastin further increased STRO-002 efficacy in xenograft models. The potent and specific preclinical efficacy of STRO-002 supports clinical development of STRO-002 for treating patients with FolRα-expressing cancers, including ovarian, endometrial, and non-small cell lung cancer. Phase I dose escalation for STRO-002 is in progress in ovarian cancer and endometrial cancer patients (NCT03748186 and NCT05200364).


Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias do Endométrio , Imunoconjugados , Neoplasias Pulmonares , Feminino , Humanos , Animais , Camundongos , Imunoconjugados/química , Tubulina (Proteína)/metabolismo , Receptor 1 de Folato , Antineoplásicos/farmacologia , Neoplasias do Endométrio/tratamento farmacológico , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
4.
J Immunol ; 183(10): 6733-43, 2009 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-19864592

RESUMO

Roles for monocyte/macrophages (Mphi) in directing the development of tissue fibrosis are increasingly recognized. Macrophages form a heterogeneous group of inflammatory leukocytes, and the mechanisms by which they acquire heterogeneity and its functional significance are unclear. We used the unilateral ureteral obstruction model of progressive kidney fibrosis to explore macrophage heterogeneity and function further. Unilateral ureteral obstruction kidney Mphis form three distinct subpopulations defined by the marker Ly6C, all of which are derived from a single Ly6C(high) bone marrow monocyte population selectively recruited to the kidney. Conditional ablation of these Mphis in vivo in CD11b-DTR mice is potently antifibrotic. The mRNA transcription profile of these populations is consistent with differential functional roles for each subpopulation, with Ly6C(low) macrophages transcribing genes consistent with selective profibrotic or M2-type function. Furthermore, bone marrow chimerism studies indicate that although resident kidney macrophages proliferate markedly to comprise up to 40% of the inflammatory macrophage population, they do not contribute to fibrosis. Our data identify Ly6C as a marker of functionally discrete tissue macrophage subsets and support a model of selective recruitment of Ly6C(high) bone marrow monocytes to the kidney that differentiate into three populations of kidney macrophages, including a profibrotic Ly6C(low) population.


Assuntos
Antígenos Ly/imunologia , Rim/imunologia , Rim/patologia , Macrófagos/imunologia , Monócitos/imunologia , Transferência Adotiva , Animais , Antígenos Ly/metabolismo , Biomarcadores/metabolismo , Medula Óssea/imunologia , Medula Óssea/metabolismo , Modelos Animais de Doenças , Fibrose , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/metabolismo , Baço/imunologia , Baço/metabolismo
5.
Drug News Perspect ; 23(5): 305-15, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20603654

RESUMO

Serum amyloid P or pentraxin 2 (PTX2) is a highly phylogenetically conserved, naturally circulating plasma protein and a soluble pattern recognition receptor of the innate immune system. The unique binding activities of PTX2 suggest that it may localize specifically to sites of injury and function to aid in the removal of damaged tissue. The recent discovery of its ability to regulate certain monocyte differentiation states has identified PTX2 as a novel and potentially powerful antifibrotic agent. A fully recombinant form of the human PTX2 protein, designated PRM-151, has recently initiated human clinical trials. Here we review the molecular, cellular and structural biology of PRM-151/PTX2 in vitro and in several in vivo preclinical models of fibrotic disease that demonstrate its potential as a first-in-class natural modulator of fibrotic pathology with significant potential to treat a wide variety of human diseases.


Assuntos
Proteína C-Reativa/uso terapêutico , Fibrose/tratamento farmacológico , Proteínas de Homeodomínio/uso terapêutico , Proteínas do Tecido Nervoso/uso terapêutico , Componente Amiloide P Sérico/uso terapêutico , Amiloidose/patologia , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem da Célula/efeitos dos fármacos , Fibrose/patologia , Humanos , Proteínas Recombinantes/uso terapêutico
6.
Adv Immunol ; 89: 245-88, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16682276

RESUMO

Inflammation and fibrosis are two inter-related conditions with many overlapping mechanisms. Three specific cell types, macrophages, T helper cells, and myofibroblasts, each play important roles in regulating both processes. Following tissue injury, an inflammatory stimulus is often necessary to initiate tissue repair, where cytokines released from resident and infiltrating leukocytes stimulate proliferation and activation of myofibroblasts. However, in many cases this drive stimulates an inappropriate pro-fibrotic response. In addition, activated myofibroblasts can take on the role of traditional APCs, secrete pro-inflammatory cytokines, and recruit inflammatory cells to fibrotic foci, amplifying the fibrotic response in a vicious cycle. Moreover, inflammatory cells have been shown to play contradictory roles in initiation, amplification, and resolution of fibrotic disease processes. The central role of the macrophage in contributing to the fibrotic response and fibrotic resolution is only beginning to be fully appreciated. In the following review, we discuss the fibrotic disease process from the context of the immune response to injury. We review the major cellular and soluble factors controlling these responses and suggest ways in which more specific and, hopefully, more effective therapies may be derived.


Assuntos
Fibrose/imunologia , Sistema Imunitário/imunologia , Sistema Imunitário/patologia , Mediadores da Inflamação/fisiologia , Animais , Quimiocinas/metabolismo , Fibrose/metabolismo , Fibrose/terapia , Humanos , Sistema Imunitário/metabolismo , Mediadores da Inflamação/metabolismo , Integrinas/metabolismo
7.
Adv Immunol ; 91: 111-57, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16938539

RESUMO

Initially linked to the pathogenesis of inflammatory and hematologic diseases, integrins have become validated drug targets with the approval of five drugs. Moreover, there are several promising drug candidates in preclinical and clinical stages of development for multiple clinical indications. Integrins are attractive drug targets as their antagonism can block several steps in disease progression or maintenance. Integrin inhibitors can block the proliferation, migration, or tissue localization of inflammatory, angiogenic, and tumor cells, as well as signaling and gene expression contributing to disease. There has been a rapid increase in the elucidation of integrin structure, their allosteric mechanisms of bidirectional signaling, and the structure of complexes with drugs. This information brings greater focus to how integrins support various cellular functions and how they have been and may be targeted to develop novel drugs. Here we review conformational switches, including an internal ligand, which allosterically regulate the transition from low- to high-affinity ligand binding. We address some of the successes, disappointments, and challenges in targeting competitive or allosteric sites to develop therapeutics. We also discuss new opportunities, including a structure-based approach to discover novel drugs to treat inflammatory and other diseases. This approach targets structural relatives of the von Willebrand factor A-domain present in integrins and many functionally diverse proteins.


Assuntos
Integrinas/química , Integrinas/metabolismo , Animais , Doenças Hematológicas/imunologia , Doenças Hematológicas/metabolismo , Humanos , Inflamação/imunologia , Inflamação/metabolismo
8.
Oncotarget ; 9(102): 37700-37714, 2018 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-30701025

RESUMO

STRO-001 is a site-specific, predominantly single-species, fully human, aglycosylated anti-CD74 antibody-drug conjugate incorporating a non-cleavable linker-maytansinoid warhead with a drug-antibody ratio of 2 which was produced by a novel cell-free antibody synthesis platform. We examined the potential pharmacodynamics and anti-tumor effects of STRO-001 in multiple myeloma (MM). CD74 expression was assessed in MM cell lines and primary bone marrow (BM) MM biopsies. CD74 mRNA was detectable in CD138+ enriched plasma cells from 100% (892/892) of patients with newly diagnosed MM. Immunohistochemistry confirmed CD74 expression in 35/36 BM biopsies from patients with newly diagnosed and relapsed/refractory MM. Cytotoxicity assays demonstrated nanomolar STRO-001 potency in 4/6 MM cell lines. In ARP-1 and MM.1S tumor-bearing mice, repeat STRO-001 dosing provided significant antitumor activity with eradication of malignant hCD138+ BM plasma cells and prolonged survival. In a luciferase-expressing MM.1S xenograft model, dose-dependent STRO-001 efficacy was confirmed using bioluminescent imaging and BM tumor burden quantification. Consistent with the intended pharmacodynamic effect, STRO-001 induced dose-responsive, reversible B-cell and monocyte depletion in cynomolgus monkeys, up to a maximum tolerated 10 mg/kg, with no evidence of off-target toxicity. Collectively, these data suggest that STRO-001 is a promising therapeutic agent for the treatment of MM.

9.
Structure ; 12(3): 371-8, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15016353

RESUMO

Complement factor B is a 90 kDa protein consisting of three domains: a three-module complement control protein, a von Willebrand factor A domain, and a C-terminal serine protease (SP) domain that adopts a default inactive (zymogen) conformation. The interaction between factor B and pathogen-bound C3b is mediated by its A domain, triggering a conformational change in factor B that ultimately creates the "C3 convertase" of the alternative complement pathway. We report the crystal structure of the A domain from factor B and show that it contains an integrin-like MIDAS motif that adopts the "open" conformation typical of integrin-ligand complexes, with an acidic residue (provided by a fortuitous crystal contact) completing the coordination of the metal ion. Modeling studies indicate that the factor B A domain can also adopt the closed conformation, supporting the hypothesis that an "integrin-like switch" is conserved in complement proteins and perhaps in 60 other A domains found within the human proteome.


Assuntos
Fator B do Complemento/química , Sequência de Aminoácidos , Sítios de Ligação , Complemento C2/genética , Fator B do Complemento/genética , Cristalografia por Raios X , Integrinas/genética , Ligantes , Dados de Sequência Molecular , Estrutura Terciária de Proteína , Alinhamento de Sequência , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
10.
JCI Insight ; 1(20): e87446, 2016 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-27942582

RESUMO

Pentraxin-2 (PTX-2), also known as serum amyloid P component (SAP/APCS), is a constitutive, antiinflammatory, innate immune plasma protein whose circulating level is decreased in chronic human fibrotic diseases. Here we show that recombinant human PTX-2 (rhPTX-2) retards progression of chronic kidney disease in Col4a3 mutant mice with Alport syndrome, reducing blood markers of kidney failure, enhancing lifespan by 20%, and improving histological signs of disease. Exogenously delivered rhPTX-2 was detected in macrophages but also in tubular epithelial cells, where it counteracted macrophage activation and was cytoprotective for the epithelium. Computational analysis of genes regulated by rhPTX-2 identified the transcriptional regulator c-Jun along with its activator protein-1 (AP-1) binding partners as a central target for the function of rhPTX-2. Accordingly, PTX-2 attenuates c-Jun and AP-1 activity, and reduces expression of AP-1-dependent inflammatory genes in both monocytes and epithelium. Our studies therefore identify rhPTX-2 as a potential therapy for chronic fibrotic disease of the kidney and an important inhibitor of pathological c-Jun signaling in this setting.


Assuntos
Proteína C-Reativa/farmacologia , Rim/patologia , Nefrite Hereditária/terapia , Proteínas do Tecido Nervoso/farmacologia , Proteínas Proto-Oncogênicas c-jun/antagonistas & inibidores , Transdução de Sinais , Fator de Transcrição AP-1/antagonistas & inibidores , Animais , Células Cultivadas , Fibrose , Humanos , Ativação de Macrófagos , Camundongos , Camundongos da Linhagem 129 , Camundongos Knockout , Monócitos , Nefrite Hereditária/patologia , Proteínas Recombinantes/farmacologia
11.
Annu Rev Pathol ; 8: 241-76, 2013 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-23092186

RESUMO

Myofibroblasts accumulate in the spaces between organ structures and produce extracellular matrix (ECM) proteins, including collagen I. They are the primary "effector" cells in tissue remodeling and fibrosis. Previously, leukocyte progenitors termed fibrocytes and myofibroblasts generated from epithelial cells through epithelial-to-mesenchymal transition (EMT) were considered the primary sources of ECM-producing myofibroblasts in injured tissues. However, genetic fate mapping experiments suggest that mesenchyme-derived cells, known as resident fibroblasts, and pericytes are the primary precursors of scar-forming myofibroblasts, whereas epithelial cells, endothelial cells, and myeloid leukocytes contribute to fibrogenesis predominantly by producing key fibrogenic cytokines and by promoting cell-to-cell communication. Numerous cytokines derived from T cells, macrophages, and other myeloid cell populations are important drivers of myofibroblast differentiation. Monocyte-derived cell populations are key regulators of the fibrotic process: They act as a brake on the processes driving fibrogenesis, and they dismantle and degrade established fibrosis. We discuss the origins, modes of activation, and fate of myofibroblasts in various important fibrotic diseases and describe how manipulation of macrophage activation could help ameliorate fibrosis.


Assuntos
Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Cicatrização/fisiologia , Animais , Comunicação Celular/fisiologia , Fibrose , Humanos , Pericitos/metabolismo , Pericitos/patologia
12.
Expert Opin Investig Drugs ; 19(6): 737-45, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20443753

RESUMO

IMPORTANCE OF THE FIELD: In fibrosing diseases, scar tissue begins to replace normal tissue, causing tissue dysfunction. For instance, in lung fibrosis, foci of what resembles scar tissue form in the lungs, impeding the ability of patients to breathe. These conditions represent a significant source of morbidity and mortality. More than 150,000 people in the USA have some form of fibrotic lung disease, and the 5-year mortality rate for these diseases can be as high as 80%. Despite this large unmet medical need, there are no FDA-approved therapies. Although our understanding of the causes and the biology of fibrosing diseases remains relatively poor, we have made impressive advances in identifying the major cell populations and many biochemical mediators that can drive this process. As a result, novel therapeutics are being developed based upon these discoveries. AREAS COVERED IN THIS REVIEW: This review examines the experimental therapies currently under investigation as of late 2009 for a major class of lung fibrosis called idiopathic pulmonary fibrosis (IPF). WHAT THE READER WILL GAIN: The reader will gain an overview of current experimental therapies for IPF. TAKE HOME MESSAGE: With the recent approval of Pirfenidone in Japan for use in IPF, and a rich pipeline of experimental therapies in various stages of clinical development, the future looks bright for new treatment options.


Assuntos
Desenho de Fármacos , Drogas em Investigação/uso terapêutico , Fibrose Pulmonar/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Humanos , Fibrose Pulmonar/mortalidade , Fibrose Pulmonar/fisiopatologia , Piridonas/uso terapêutico
13.
Sci Transl Med ; 1(5): 5ra13, 2009 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-20368175

RESUMO

New therapies that target chronic inflammation with fibrosis are urgently required. Increasing evidence points to innate activation of inflammatory cells in driving chronic organ fibrosis. Serum amyloid P is a naturally circulating soluble pattern recognition receptor, a member of the family of pentraxin proteins. It links danger-associated molecular pattern recognition to Fc gamma receptor-mediated phagocytosis. Here we show that fibrosis progression in the mouse kidney is significantly inhibited by therapeutic administration of human serum amyloid P, regulated by activating Fc gamma receptors, and dependent on inflammatory monocytes and macrophages, but not fibrocytes. Human serum amyloid P-mediated inhibition of mouse kidney fibrosis correlated with specific binding of human serum amyloid P to cell debris and with subsequent suppression of inflammatory monocytes and kidney macrophages in vitro and in vivo, and was dependent on regulated binding to activating Fc gamma receptors and interleukin-10 expression. These studies uncover previously unidentified roles for Fc gamma receptors in sterile inflammation and highlight serum amyloid P as a potential antifibrotic therapy through local generation of interleukin-10.


Assuntos
Fibrose/prevenção & controle , Macrófagos/química , Macrófagos/citologia , Monócitos/citologia , Receptores de IgG/fisiologia , Componente Amiloide P Sérico/fisiologia , Animais , Humanos , Camundongos
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