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1.
Curr Drug Deliv ; 8(1): 135-43, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21034418

RESUMO

Vascular-targeting antiangiogenic therapy (VTAT) of cancer can be advantageous over conventional tumor cell targeted cancer therapy if an appropriate target is found. Our hypothesis is that endoglin (ENG; CD105) is an excellent target in VTAT. ENG is selectively expressed on vascular and lymphatic endothelium in tumors. This allows us to target both tumor-associated vasculature and lymphatic vessels to suppress tumor growth and metastasis. ENG is essential for angiogenesis/vascular development and a co-receptor of TGF-ß. Our studies of selected anti-ENG monoclonal antibodies (mAbs) in several animal models and in vitro studies support our hypothesis. These mAbs and/or their immunoconjugates (immunotoxins and radioimmunoconjugates) induced regression of preformed tumors as well as inhibited formation of new tumors. In addition, they suppressed metastasis. Several mechanisms were involved in the suppressive activity of the naked (unconjugated) anti-ENG mAbs. These include direct growth suppression of proliferating endothelial cells, induction of apoptosis, ADCC (antibody-dependent cell-mediated cytotoxicity) and induction of T cell immunity. To facilitate clinical application, we generated a human/mouse chimeric anti-ENG mAb termed c-SN6j and performed studies of pharmacokinetics, toxicology and immunogenicity of c-SN6j in nonhuman primates. No significant toxicity was detected by several criteria and minimal immune response to the murine part of c-SN6j was detected after multiple i.v. injections. The results support our hypothesis that c-SN6j can be safely administered in cancer patients. This hypothesis is supported by the ongoing phase 1 clinical trial of c-SN6j (also known as TRC105) in patients with advanced or metastatic solid cancer in collaboration with Tracon Pharma and several oncologists (NCT00582985).


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Antígenos CD/metabolismo , Imunoconjugados/farmacologia , Imunotoxinas/farmacologia , Neoplasias/tratamento farmacológico , Receptores de Superfície Celular/metabolismo , Animais , Ensaios Clínicos como Assunto , Endoglina , Humanos , Imunoconjugados/imunologia , Imunotoxinas/imunologia , Metástase Neoplásica , Neoplasias/irrigação sanguínea , Neoplasias/metabolismo
3.
Int J Cancer ; 125(6): 1446-53, 2009 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-19533687

RESUMO

Anti-metastatic activity of an antitumor agent is exceedingly important because metastasis is the primary cause of death for most solid cancer patients. In this report, we show that 3 anti-endoglin (ENG) monoclonal antibodies (mAbs) SN6a, SN6j and SN6k which define individually distinct epitopes of ENG of tumor vasculature are capable of suppressing tumor metastases in the multiple metastasis models. The metastasis models were generated by i.v., s.c. (into flank) or mammary gland fat pad injection of 4T1 murine mammary carcinoma cells and splenic injection of two types of colon26 murine colorectal carcinoma cells. Individual mAbs were injected i.v. via the tail vein of mice. SN6a and SN6j effectively suppressed the formation of metastatic colonies of 4T1 in the lung in all of the three 4T1 metastatic models. In addition, these mAbs were effective for suppressing the primary tumors of 4T1 in the skin and mammary fat pad. These mAbs effectively suppressed microvessel density and angiogenesis in tumors as measured by the Matrigel plug assay in mice. No significant side effects of the administered mAbs were detected. Furthermore, SN6a and SN6j extended survival of the tumor-bearing mice. SN6j, SN6k and their immunoconjugates with deglycosylated ricin A-chain were all effective for suppressing hepatic metastasis of colon26. The findings in the present study are clinically relevant in view of the ongoing clinical trial of a humanized (chimerized) form of SN6j.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antígenos CD/imunologia , Metástase Neoplásica/prevenção & controle , Neoplasias Experimentais/irrigação sanguínea , Neovascularização Patológica/prevenção & controle , Receptores de Superfície Celular/imunologia , Animais , Colágeno/metabolismo , Combinação de Medicamentos , Endoglina , Feminino , Humanos , Laminina/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/patologia , Proteoglicanas/metabolismo , Células Tumorais Cultivadas
4.
Int J Cancer ; 122(10): 2266-73, 2008 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-18224682

RESUMO

In the present study, we investigated the mechanisms by which anti-endoglin (EDG; CD105) monoclonal antibodies (mAbs) suppress angiogenesis and tumor growth. Antihuman EDG mAb SN6j specifically bound to murine endothelial cells and was internalized into the cells in vitro. SN6j effectively suppressed angiogenesis in mice in the Matrigel plug assay. We found that SN6j is more effective for tumor suppression in immunocompetent mice than in SCID mice. We hypothesized that T cell immunity is important for effective antitumor efficacy of SN6j in vivo. To test this hypothesis, we investigated effects of CpG oligodeoxynucleotides (ODN) and depletion of CD4(+) T cells and/or CD8(+) T cells on antitumor efficacy of SN6j in mice. Systemic (i.v.) administration of a relatively small dose (0.6 mug/g body weight/dose) of SN6j suppressed growth of established s.c. tumors of colon-26 in BALB/c mice and improved survival of the tumor-bearing mice. Addition of CpG ODN to SN6j synergistically enhanced antitumor efficacy of SN6j. In contrast, such enhancing effects of CpG ODN were not detected in SCID mice. Antitumor efficacy of SN6j in BALB/c mice was abrogated when CD4(+) T cells and/or CD8(+) T cells were depleted; effect of CD8(+) T cell depletion was stronger. Interestingly, CD4-depletion decreased tumor growth while CD8-depletion enhanced tumor growth in the absence of SN6j. SN6j induced apoptosis in human umbilical vein endothelial cells in a dose-dependent manner which indicates an additional mechanism of antiangiogenesis by SN6j. (c) 2008 Wiley-Liss, Inc.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antígenos CD/imunologia , Neoplasias do Colo/irrigação sanguínea , Neoplasias do Colo/terapia , Neoplasias Mamárias Experimentais/irrigação sanguínea , Neoplasias Mamárias Experimentais/terapia , Receptores de Superfície Celular/imunologia , Animais , Anticorpos Monoclonais/imunologia , Apoptose , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Colágeno/metabolismo , Neoplasias do Colo/imunologia , DNA/uso terapêutico , Combinação de Medicamentos , Sinergismo Farmacológico , Endoglina , Endotélio Vascular/citologia , Endotélio Vascular/imunologia , Endotélio Vascular/metabolismo , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Laminina/metabolismo , Depleção Linfocítica , Neoplasias Mamárias Experimentais/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Células NIH 3T3 , Neovascularização Patológica , Oligodesoxirribonucleotídeos , Proteoglicanas/metabolismo , Telangiectasia Hemorrágica Hereditária , Veias Umbilicais/citologia , Veias Umbilicais/imunologia , Veias Umbilicais/metabolismo
5.
Int J Oncol ; 29(5): 1087-94, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17016638

RESUMO

We investigated anti-angiogenic/vascular targeting therapy of established tumors in immunocompetent mice using an anti-human endoglin (EDG; CD105) monoclonal antibody (mAb) SN6j. SN6j weakly cross-reacted with murine endothelial cells but reacted neither with colon-26 murine colon carcinoma cells nor with 4T1 murine mammary carcinoma cells. Systemic administration of naked (unconjugated) SN6j showed significant growth suppression of established tumors of colon-26 and 4T1 cells in immunocompetent BALB/c mice (P<0.05). Moreover, the overall survival rate of SN6j-treated mice was significantly higher than that of control IgG-treated mice (P<0.01). During these studies, we found that two different types of tumor formed in BALB/c and immunodeficient SCID mice when three different types of tumor cells (colon-26, 4T1 and MCF-7 human breast cancer cells) were inoculated subcutaneously. One type of tumor grew in the skin-side tissue (i.e., epidermis, corium, or subcutis), and mainly invaded into the corium and epidermis. The other type grew in the muscle-side tissue (i.e., fascia, muscle, or peritoneum/pleura). We termed the former SS tumors and the latter MS tumors. MS tumors grew faster than SS tumors. This differential growth of MS and SS tumors was observed in three different animal models, i.e., colon-26 tumors and 4T1 tumors in BALB/c mice, and MCF-7 tumors in SCID mice. In the therapeutic study of colon-26 and 4T1 tumors with SN6j, MS tumors were less responsive to therapy than SS tumors although SN6j showed significant antitumor efficacy against both tumors (P<0.05). The results show that antitumor therapy can yield different therapeutic outcomes depending on the tumor growth sites even for the same tumor. A differential survival between mice with the two types of tumor was also observed when mice were untreated (P<0.01).


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antígenos CD/imunologia , Neoplasias/irrigação sanguínea , Neoplasias/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Receptores de Superfície Celular/imunologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Endoglina , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias/patologia , Neovascularização Patológica/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Cancer Immunol Immunother ; 55(2): 140-50, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15856228

RESUMO

We generated a human/mouse chimeric antibody c-SN6j of human IgG1 isotype from a murine anti-human endoglin (EDG) monoclonal antibody (mAb) SN6j that suppressed angiogenesis, tumor growth and metastasis in mice. We determined pharmacokinetics (PKs) and immunogenicity of c-SN6j in monkeys after multiple i.v. injections. A dose-escalation study was performed by administration of c-SN6j into six monkeys at the dose of 1 mg, 3 mg and 10 mg per kg body weight. In addition, both c-SN6j (3 mg/kg) and doxorubicin (0.275 mg/kg) were injected into two monkeys. c-SN6j and doxorubicin were injected twice a week for 3 weeks. We developed a unique and sensitive ELISA by sequentially targeting the common and idiotypic epitopes of c-SN6j-Fv to quantify plasma c-SN6j. Application of the ELISA showed that increasing the c-SN6j dose resulted in a proportional increase in the circulating c-SN6j after the first injection. In addition, the estimated area under the curve (AUC) for the first injection of c-SN6j is proportional to dose. We carried out detailed analyses of PKs of c-SN6j during and after the repeated injections. Our model of PKs fitted the empirical data well. Addition of doxorubicin modulated the PK parameters. We developed two ELISAs to separately determine the immune responses to the murine part and the human part of c-SN6j in monkeys. Interestingly, the murine part induced a weaker immune response than the human part. Doxorubicin potentiated the immune responses. Increasing the dose of c-SN6j increased plasma levels of c-SN6j but did not increase the immune responses to c-SN6j.


Assuntos
Inibidores da Angiogênese/imunologia , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacocinética , Doxorrubicina/farmacologia , Proteínas Recombinantes de Fusão/imunologia , Molécula 1 de Adesão de Célula Vascular/imunologia , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/farmacocinética , Animais , Anticorpos Monoclonais/administração & dosagem , Antígenos CD , Relação Dose-Resposta Imunológica , Doxorrubicina/administração & dosagem , Doxorrubicina/imunologia , Avaliação Pré-Clínica de Medicamentos , Endoglina , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Injeções Intravenosas , Macaca fascicularis , Modelos Animais , Receptores de Superfície Celular , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/farmacocinética , Distribuição Tecidual
7.
Int J Cancer ; 108(2): 251-7, 2004 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-14639611

RESUMO

Endoglin (CD105) is a proliferation-associated cell membrane antigen of endothelial cells and strongly expressed in the angiogenic vasculature of solid tumors. Endoglin is essential for angiogenesis/vascular development and an ancillary transforming growth factor beta (TGF-beta) receptor. Certain anti-endoglin monoclonal antibodies (mAbs), termed SN6 series mAbs, inhibited angiogenesis, tumor growth and metastasis in mice. We investigated the mechanisms by which anti-endoglin mAbs suppress growth of proliferating endothelial cells. We found that 4 SN6 series mAbs suppressed growth of human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner in the absence of any effector cells or complement. Significant differences in the growth suppression between the 4 anti-endoglin mAbs defining different epitopes were observed. These differences were not determined by antigen-binding avidities of the mAbs. Combination of TGF-beta1 and each of the 4 anti-endoglin mAbs exerted synergistic growth suppression of HUVECs. Binding of anti-endoglin mAbs to endoglin-expressing cells did not block the subsequent binding of TGF-beta1. Conversely, preincubation of HUVECs with TGF-beta1 did not change cell surface expression of endoglin. The present results suggest that direct suppression of the endothelial cell growth by SN6 series mAbs is one of the underlying mechanisms by which anti-endoglin mAbs exert antiangiogenic and tumor-suppressive activity in vivo. The results further suggest that TGF-beta1 plays an important role in the in vivo antiangiogenic efficacy of anti-endoglin mAbs by synergistically enhancing the activity of these mAbs. Further studies of the present novel findings may provide valuable information about the functional roles of endoglin and anti-endoglin mAbs in the TGF-beta-mediated cell regulation.


Assuntos
Anticorpos Monoclonais/farmacologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Fator de Crescimento Transformador beta/farmacologia , Molécula 1 de Adesão de Célula Vascular/imunologia , Antígenos CD , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Sinergismo Farmacológico , Endoglina , Humanos , Prognóstico , Receptores de Superfície Celular
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