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1.
Mol Cancer Ther ; 17(10): 2176-2186, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30065100

RESUMO

Prostate-specific membrane antigen (PSMA) is a membrane-bound glutamate carboxypeptidase that is highly expressed in nearly all prostate cancers with the highest expression in metastatic castration-resistant prostate cancer (mCRPC). The prevalence of increased surface expression and constitutive internalization of PSMA make it an attractive target for an antibody-drug conjugate (ADC) approach to treating patients with mCRPC. MEDI3726 (previously known as ADCT-401) is an ADC consisting of an engineered version of the anti-PSMA antibody J591 site specifically conjugated to the pyrrolobenzodiazepine (PBD) dimer tesirine. MEDI3726 specifically binds the extracellular domain of PSMA and, once internalized, releases the PBD dimer to crosslink DNA and trigger cell death. In vitro, MEDI3726 demonstrated potent and specific cytotoxicity in a panel of PSMA-positive prostate cancer cell lines, consistent with internalization and DNA interstrand crosslinking. In vivo, MEDI3726 showed robust antitumor activity against the LNCaP and the castration-resistant CWR22Rv1 prostate cancer cell line xenografts. MEDI3726 also demonstrated durable antitumor activity in the PSMA-positive human prostate cancer patient-derived xenograft (PDX) LuCaP models. This activity correlated with increased phosphorylated Histone H2AX in tumor xenografts treated with MEDI3726. MEDI3726 is being evaluated in a phase I clinical trial as a treatment for patients with metastatic castrate-resistant prostate cancer (NCT02991911). Mol Cancer Ther; 17(10); 2176-86. ©2018 AACR.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Biomarcadores Tumorais/antagonistas & inibidores , Glutamato Carboxipeptidase II/antagonistas & inibidores , Imunoconjugados/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/imunologia , Animais , Antígenos de Superfície/genética , Antígenos de Superfície/metabolismo , Linhagem Celular Tumoral , Reações Cruzadas/imunologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Expressão Gênica , Glutamato Carboxipeptidase II/genética , Glutamato Carboxipeptidase II/metabolismo , Humanos , Imuno-Histoquímica , Macaca fascicularis , Masculino , Camundongos , Neoplasias da Próstata/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Sci Rep ; 8(1): 10479, 2018 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-29992976

RESUMO

Synthetic pyrrolobenzodiazepine (PBD) dimers, where two PBD monomers are linked through their aromatic A-ring phenolic C8-positions via a flexible propyldioxy tether, are highly efficient DNA minor groove cross-linking agents with potent cytotoxicity. PBD dimer SG3199 is the released warhead component of the antibody-drug conjugate (ADC) payload tesirine (SG3249), currently being evaluated in several ADC clinical trials. SG3199 was potently cytotoxic against a panel of human solid tumour and haematological cancer cell lines with a mean GI50 of 151.5 pM. Cells defective in DNA repair protein ERCC1 or homologous recombination repair showed increased sensitivity to SG3199 and the drug was only moderately susceptible to multidrug resistance mechanisms. SG3199 was highly efficient at producing DNA interstrand cross-links in naked linear plasmid DNA and dose-dependent cross-linking was observed in cells. Cross-links formed rapidly in cells and persisted over 36 hours. Following intravenous (iv) administration to rats SG3199 showed a very rapid clearance with a half life as short as 8 minutes. These combined properties of cytotoxic potency, rapid formation and persistence of DNA interstrand cross-links and very short half-life contribute to the emerging success of SG3199 as a warhead in clinical stage ADCs.


Assuntos
Antineoplásicos/química , Benzodiazepinas/farmacocinética , Imunotoxinas/química , Pirróis/farmacocinética , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Benzodiazepinas/uso terapêutico , Linhagem Celular Tumoral , Reagentes de Ligações Cruzadas , DNA/metabolismo , Reparo do DNA , Dimerização , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Pirróis/uso terapêutico , Ratos
3.
Blood ; 131(10): 1094-1105, 2018 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-29298756

RESUMO

Human CD19 antigen is a 95-kDa type I membrane glycoprotein in the immunoglobulin superfamily whose expression is limited to the various stages of B-cell development and differentiation and is maintained in the majority of B-cell malignancies, including leukemias and non-Hodgkin lymphomas of B-cell origin. Coupled with its differential and favorable expression profile, CD19 has rapid internalization kinetics and is not shed into the circulation, making it an ideal target for the development of antibody-drug conjugates (ADCs) to treat B-cell malignancies. ADCT-402 (loncastuximab tesirine) is a novel CD19-targeted ADC delivering SG3199, a highly cytotoxic DNA minor groove interstrand crosslinking pyrrolobenzodiazepine (PDB) dimer warhead. It showed potent and highly targeted in vitro cytotoxicity in CD19-expressing human cell lines. ADCT-402 was specifically bound, internalized, and trafficked to lysosomes in CD19-expressing cells and, following release of the PBD warhead, resulted in formation of DNA crosslinks that persisted for 36 hours. Bystander killing of CD19- cells by ADCT-402 was also observed. In vivo, single doses of ADCT-402 resulted in highly potent, dose-dependent antitumor activity in several subcutaneous and disseminated human tumor models with marked superiority to comparator ADCs delivering tubulin inhibitors. Dose-dependent DNA crosslinks and γ-H2AX DNA damage response were measured in tumors by 24 hours after single dose administration, whereas matched peripheral blood mononuclear cells showed no evidence of DNA damage. Pharmacokinetic analysis in rat and cynomolgus monkey showed excellent stability and tolerability of ADCT-402 in vivo. Together, these impressive data were used to support the clinical testing of this novel ADC in patients with CD19-expressing B-cell malignancies.


Assuntos
Antígenos CD19/biossíntese , Antineoplásicos , Regulação Leucêmica da Expressão Gênica , Imunoconjugados , Leucemia de Células B , Linfoma não Hodgkin , Proteínas de Neoplasias/biossíntese , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Imunoconjugados/farmacocinética , Imunoconjugados/farmacologia , Leucemia de Células B/tratamento farmacológico , Leucemia de Células B/metabolismo , Leucemia de Células B/patologia , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/metabolismo , Linfoma não Hodgkin/patologia , Lisossomos/metabolismo , Lisossomos/patologia
4.
Mol Cancer Ther ; 15(11): 2709-2721, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27535974

RESUMO

Despite the many advances in the treatment of hematologic malignancies over the past decade, outcomes in refractory lymphomas remain poor. One potential strategy in this patient population is the specific targeting of IL2R-α (CD25), which is overexpressed on many lymphoma and leukemic cells, using antibody-drug conjugates (ADC). ADCT-301 is an ADC composed of human IgG1 HuMax-TAC against CD25, stochastically conjugated through a dipeptide cleavable linker to a pyrrolobenzodiazepine (PBD) dimer warhead with a drug-antibody ratio (DAR) of 2.3. ADCT-301 binds human CD25 with picomolar affinity. ADCT-301 has highly potent and selective cytotoxicity against a panel of CD25-expressing human lymphoma cell lines. Once internalized, the released warhead binds in the DNA minor groove and exerts its potent cytotoxic action via the formation of DNA interstrand cross-links. A strong correlation between loss of viability and DNA cross-link formation is demonstrated. DNA damage persists, resulting in phosphorylation of histone H2AX, cell-cycle arrest in G2-M, and apoptosis. Bystander killing of CD25-negative cells by ADCT-301 is also observed. In vivo, a single dose of ADCT-301 results in dose-dependent and targeted antitumor activity against both subcutaneous and disseminated CD25-positive lymphoma models. In xenografts of Karpas 299, which expressed both CD25 and CD30, marked superiority over brentuximab vedotin (Adcetris) is observed. Dose-dependent increases in DNA cross-linking, γ-H2AX, and PBD payload staining were observed in tumors in vivo indicating a role as relevant pharmacodynamic assays. Together, these data support the clinical testing of this novel ADC in patients with CD25-expressing tumors. Mol Cancer Ther; 15(11); 2709-21. ©2016 AACR.


Assuntos
Antineoplásicos/farmacologia , Benzodiazepinas , Neoplasias Hematológicas/metabolismo , Imunoconjugados/farmacologia , Subunidade alfa de Receptor de Interleucina-2/antagonistas & inibidores , Pirróis , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Apoptose/genética , Benzodiazepinas/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Histonas/metabolismo , Humanos , Imunoconjugados/química , Subunidade alfa de Receptor de Interleucina-2/genética , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Camundongos , Pirróis/química , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Cancer Res ; 67(20): 9945-53, 2007 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-17942927

RESUMO

Zanolimumab is a human IgG1 antibody against CD4, which is in clinical development for the treatment of cutaneous and nodal T-cell lymphomas. Here, we report on its mechanisms of action. Zanolimumab was found to inhibit CD4+ T cells by combining signaling inhibition with the induction of Fc-dependent effector mechanisms. First, T-cell receptor (TCR) signal transduction is inhibited by zanolimumab through a fast, dual mechanism, which is activated within minutes. Ligation of CD4 by zanolimumab effectively inhibits early TCR signaling events but, interestingly, activates signaling through the CD4-associated tyrosine kinase p56lck. An uncoupling of p56lck from the TCR by anti-CD4 allows the kinase to transmit direct inhibitory signals via the inhibitory adaptor molecules Dok-1 and SHIP-1. Second, CD4+ T cells are killed by induction of antibody-dependent cell-mediated cytotoxicity, to which CD45RO+ cells are more sensitive than CD45RA+ cells. Finally, zanolimumab induces down-modulation of CD4 from cell surfaces via a slow Fc-dependent mechanism. In conclusion, zanolimumab rapidly inhibits T-cell signaling via a dual mechanism of action combined with potent Fc-dependent lysis of CD4+ T cells and may act long-term by down-regulating CD4.


Assuntos
Anticorpos Monoclonais/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfoma Cutâneo de Células T/imunologia , Linfoma Cutâneo de Células T/terapia , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Citotoxicidade Celular Dependente de Anticorpos , Complexo CD3/imunologia , Antígenos CD4/biossíntese , Antígenos CD4/genética , Antígenos CD4/imunologia , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/imunologia , Método Duplo-Cego , Regulação para Baixo , Humanos , Inositol Polifosfato 5-Fosfatases , Ativação Linfocitária/efeitos dos fármacos , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/metabolismo , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases , Monoéster Fosfórico Hidrolases/metabolismo , Fosforilação , Psoríase/imunologia , Psoríase/terapia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais/efeitos dos fármacos
6.
Nature ; 449(7158): 101-4, 2007 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-17805298

RESUMO

Most successful vaccines elicit neutralizing antibodies and this property is a high priority when developing an HIV vaccine. Indeed, passively administered neutralizing antibodies have been shown to protect against HIV challenge in some of the best available animal models. For example, antibodies given intravenously can protect macaques against intravenous or mucosal SHIV (an HIV/SIV chimaera) challenge and topically applied antibodies can protect macaques against vaginal SHIV challenge. However, the mechanism(s) by which neutralizing antibodies afford protection against HIV is not understood and, in particular, the role of antibody Fc-mediated effector functions is unclear. Here we report that there is a dramatic decrease in the ability of a broadly neutralizing antibody to protect macaques against SHIV challenge when Fc receptor and complement-binding activities are engineered out of the antibody. No loss of antibody protective activity is associated with the elimination of complement binding alone. Our in vivo results are consistent with in vitro assays indicating that interaction of Fc-receptor-bearing effector cells with antibody-complexed infected cells is important in reducing virus yield from infected cells. Overall, the data suggest the potential importance of activity against both infected cells and free virus for effective protection against HIV.


Assuntos
Vacinas contra a AIDS/imunologia , Proteínas do Sistema Complemento/imunologia , Anticorpos Anti-HIV/imunologia , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , HIV/imunologia , Receptores Fc/imunologia , Animais , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Complemento C1q/imunologia , Complemento C3/imunologia , Feminino , Anticorpos Anti-HIV/química , Anticorpos Anti-HIV/genética , Antígenos HIV/imunologia , Infecções por HIV/sangue , Infecções por HIV/virologia , Humanos , Imunidade nas Mucosas/imunologia , Macaca mulatta/imunologia , Macaca mulatta/virologia , Testes de Neutralização , Síndrome de Imunodeficiência Adquirida dos Símios/sangue , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/imunologia , Fatores de Tempo , Carga Viral
7.
Perit Dial Int ; 23(4): 323-30, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12968839

RESUMO

OBJECTIVES: Mesothelial cell (MC) injury caused by continuous exposure to unphysiological peritoneal dialysis (PD) fluid and by episodes of peritonitis can eventually lead to peritoneal adhesions and peritoneal fibrosis. In the present study, we evaluated the possibility of using autologous genetically modified MCs for transplantation after the induction of peritoneal injury by acute inflammatory mediators or chronic instillation of PD fluid. METHODS: Rats were injected intraperitoneally either once with N-formyl-methionyl-leucyl-phenylalanine (fMLP), or thioglycollate, or PD fluid [i.e., Dianeal (Baxter Healthcare, Deerfield, Illinois, USA) or Physioneal (Baxter, Nivelles, Belgium)], or chronically (up to 8 weeks) with Dianeal. From 2 to 48 hours later, animals were injected with syngeneic MCs genetically modified to express the LacZ reporter gene. Rats were sacrificed 2 days later and expression of beta-galactosidase (beta-Gal) was visualized by X-Gal staining of excised tissues. Quantification of the percent area of beta-Gal-positive MCs on part of the parietal peritoneum was performed using computerized image analysis. RESULTS: The highest numbers of repopulated genetically modified MCs were observed 8 hours after a single thioglycollate injection, approximately 0.66% of a representative 2-cm2 area selected for study (corresponding to approximately 10% of the peritoneal surface). The number of genetically modified MCs found to repopulate the peritoneal surface following short-term injury varied with inflammatory mediator (thioglycollate > PD fluid > fMLP) and duration of exposure. No obvious differences were observed between the two PD fluids tested. Reimplantation of syngeneic genetically modified MCs was also observed after chronic instillation of PD fluid. CONCLUSIONS: These data demonstrate that transplanted genetically modified MCs repopulate the denuded areas on the peritoneal surface that were caused by acute or chronic inflammation. This technique opens possibilities of MC transplantation and gene therapy in order to prevent complications relevant to the continuous ambulatory PD setting.


Assuntos
Transplante de Células/métodos , Soluções para Diálise/efeitos adversos , Células Epiteliais/transplante , Epitélio/transplante , Inflamação/complicações , Diálise Peritoneal/efeitos adversos , Peritonite/etiologia , Doença Aguda , Animais , Feminino , Terapia Genética/métodos , Falência Renal Crônica/terapia , Modelos Animais , Peritônio/lesões , Peritonite/induzido quimicamente , Peritonite/imunologia , Ratos , Ratos Endogâmicos F344
8.
J Am Soc Nephrol ; 12(12): 2775-2786, 2001 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11729248

RESUMO

The long-term effects of a standard lactate-buffered dialysis fluid and a new, two-chamber, bicarbonate/lactate-buffered dialysis fluid (with fewer glucose degradation products and a neutral pH) were compared in an in vivo peritoneal exposure model. Rats were given daily injections, via an access port, of 10 ml of standard solution or bicarbonate/lactate-buffered solution for 9 to 10 wk. The omentum, peritoneum, and mesothelial cell layer were screened for morphologic changes. In addition, the bacterial clearing capacity of the peritoneal cells was studied. Significantly more milky spots and blood vessels were observed in the omenta of animals treated with standard solution (P < 0.03 for both parameters). Electron-microscopic analysis demonstrated dramatic changes in the appearance of the vascular endothelial cells of the milky spots and a severely damaged or even absent mesothelium on the peritoneal membrane of the standard solution-treated animals. In contrast, the mesothelium was still present in the bicarbonate/lactate-buffered solution group, although the cells lost microvilli. Both peritoneal dialysis fluids significantly increased the density of mesothelial cells (per square millimeter) on the surface of the liver and the thickness of the submesothelial extracellular matrix of the peritoneum (both P < 0.04 for both fluids versus control). A significantly better ex vivo bacterial clearing capacity was observed with peritoneal cells from the bicarbonate/lactate-buffered solution group, compared with the standard solution group (P < 0.05 in both experiments). These results demonstrate that instillation of bicarbonate/lactate-buffered solution into rats for 9 to 10 wk preserves both morphologic and immune parameters much more effectively, compared with standard solution. These findings may be of considerable clinical importance.


Assuntos
Bicarbonatos/administração & dosagem , Soluções para Diálise/farmacologia , Ácido Láctico/administração & dosagem , Diálise Peritoneal , Peritônio/anatomia & histologia , Peritônio/imunologia , Animais , Fenômenos Fisiológicos Bacterianos , Soluções Tampão , Combinação de Medicamentos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Masculino , Microscopia Eletrônica , Omento/efeitos dos fármacos , Omento/patologia , Peritônio/efeitos dos fármacos , Peritônio/patologia , Ratos , Ratos Wistar , Fatores de Tempo
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