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1.
J Clin Pharmacol ; 62(11): 1393-1402, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35576521

RESUMO

Atezolizumab is approved as an intravenous (IV) infusion for use as a single agent and in combination with other therapies in a number of indications. The objectives of this publication are to characterize atezolizumab pharmacokinetics (PK) across indications with the available clinical data from one phase I and eight phase III studies, to determine the exposure-response (ER) relationships in combination settings across a variety of tumor types, and to provide the clinical safety to support the extension of the 840 mg q2w, 1200 mg q3w, and 1680 mg q4w IV dosing regimens across various indications in combination settings. Across all clinical studies, atezolizumab PK remained in the dose-linear range and were similar across tumor types when used in combination therapy or as a monotherapy. In the combination studies, efficacy was independent of the exposures tested and there was no significant increase in adverse events with increasing atezolizumab exposure (flat ER). The safety profile of atezolizumab in the individual combination studies was generally consistent with the established safety profile of atezolizumab, the combination partners, and the disease under study. The similar atezolizumab PK across monotherapy and combination therapy settings as well as the flat ER in new tumor types and combination therapies support the use of the 3 interchangeable atezolizumab dosing regimens in the combination setting. Atezolizumab is now approved with 3 interchangeable IV dosing regimens of 840 mg q2w, 1200 mg q3w, and 1680 mg q4w for single-agent and combination therapy use in the USA and EU.


Assuntos
Anticorpos Monoclonais Humanizados , Neoplasias , Simulação por Computador , Humanos , Infusões Intravenosas , Neoplasias/tratamento farmacológico , Neoplasias/patologia
2.
Mol Cancer Ther ; 13(11): 2630-40, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25249555

RESUMO

Mesothelin (MSLN) is an attractive target for antibody-drug conjugate therapy because it is highly expressed in various epithelial cancers, with normal expression limited to nondividing mesothelia. We generated novel antimesothelin antibodies and conjugated an internalizing one (7D9) to the microtubule-disrupting drugs monomethyl auristatin E (MMAE) and MMAF, finding the most effective to be MMAE with a lysosomal protease-cleavable valine-citrulline linker. The humanized (h7D9.v3) version, αMSLN-MMAE, specifically targeted mesothelin-expressing cells and inhibited their proliferation with an IC50 of 0.3 nmol/L. Because the antitumor activity of an antimesothelin immunotoxin (SS1P) in transfected mesothelin models did not translate to the clinic, we carefully selected in vivo efficacy models endogenously expressing clinically relevant levels of mesothelin, after scoring mesothelin levels in ovarian, pancreatic, and mesothelioma tumors by immunohistochemistry. We found that endogenous mesothelin in cancer cells is upregulated in vivo and identified two suitable xenograft models for each of these three indications. A single dose of αMSLN-MMAE profoundly inhibited or regressed tumor growth in a dose-dependent manner in all six models, including two patient-derived tumor xenografts. The robust and durable efficacy of αMSLN-MMAE in preclinical models of ovarian, mesothelioma, and pancreatic cancers justifies the ongoing phase I clinical trial.


Assuntos
Proteínas Ligadas por GPI/imunologia , Imunotoxinas/farmacologia , Mesotelioma/tratamento farmacológico , Oligopeptídeos/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Feminino , Proteínas Ligadas por GPI/biossíntese , Humanos , Imuno-Histoquímica , Imunotoxinas/química , Imunotoxinas/imunologia , Mesotelina , Camundongos , Oligopeptídeos/química , Distribuição Aleatória , Transfecção , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Traffic ; 15(3): 255-72, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24329939

RESUMO

CD22 is a cell surface glycoprotein restricted to normal and malignant B-cells and is the target of several anti-CD22 antibody-based cancer therapies. For therapeutic antibody-payload conjugates, it is important to understand the subcellular trafficking of anti-CD22 antibodies to optimize antibody and/or linker-drug properties to maximize antitumor efficacy. It is agreed that anti-CD22 antibodies rapidly internalize, but controversial whether they recycle or are degraded in lysosomes, and it is unclear if trafficking is antibody or cell-type dependent. No studies examined anti-CD22 trafficking to either pathway in B-cells over time by dual immunofluorescence microscopy, likely partly because multiple samples of suspension cells are tedious to stain. We overcame this by using DropArray™, a novel wall-less 96-well plate technology allowing rapid simultaneous staining of suspension or adherent cells in small (10-20 µL) volumes. We examined the time-course of trafficking of five different anti-CD22 antibodies in eight B-cell lines representing four B-cell cancer types and show that in all cases antibodies internalize within 5 min and recycle, with only small amounts eventually trafficking to lysosomes. CD22 also localizes to recycling endosomes at steady state in the absence of antibody. Our data may help explain the differential efficacies of anti-CD22 antibodies conjugated to different therapeutic payloads.


Assuntos
Endocitose , Microscopia de Fluorescência/métodos , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Análise Serial de Tecidos/métodos , Linfócitos B/metabolismo , Linhagem Celular Tumoral , Humanos
4.
Cancer Res ; 69(6): 2358-64, 2009 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-19258515

RESUMO

Antibody-drug conjugates (ADC), potent cytotoxic drugs covalently linked to antibodies via chemical linkers, provide a means to increase the effectiveness of chemotherapy by targeting the drug to neoplastic cells while reducing side effects. Here, we systematically examine the potential targets and linker-drug combinations that could provide an optimal ADC for the treatment for non-Hodgkin's lymphoma. We identified seven antigens (CD19, CD20, CD21, CD22, CD72, CD79b, and CD180) for potential treatment of non-Hodgkin's lymphoma with ADCs. ADCs with cleavable linkers mediated in vivo efficacy via all these targets; ADCs with uncleavable linkers were only effective when targeted to CD22 and CD79b. In target-independent safety studies in rats, the uncleavable linker ADCs showed reduced toxicity, presumably due to the reduced release of free drug or other toxic metabolites into the circulation. Thus, our data suggest that ADCs with cleavable linkers work on a broad range of targets, and for specific targets, ADCs with uncleavable linkers provide a promising opportunity to improve the therapeutic window for ADCs in humans.


Assuntos
Antineoplásicos/administração & dosagem , Imunotoxinas/farmacologia , Linfoma não Hodgkin/tratamento farmacológico , Maitansina/análogos & derivados , Oligopeptídeos/administração & dosagem , Compostos de Sulfidrila/administração & dosagem , Animais , Antígenos CD/biossíntese , Antígenos CD/imunologia , Antineoplásicos/farmacocinética , Linfócitos B/imunologia , Reagentes de Ligações Cruzadas/administração & dosagem , Reagentes de Ligações Cruzadas/farmacocinética , Feminino , Imunotoxinas/imunologia , Imunotoxinas/farmacocinética , Linfoma não Hodgkin/imunologia , Maitansina/administração & dosagem , Maitansina/farmacocinética , Camundongos , Camundongos Endogâmicos ICR , Camundongos SCID , Oligopeptídeos/farmacocinética , Ratos , Compostos de Sulfidrila/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Br J Haematol ; 140(1): 46-58, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17991300

RESUMO

CD19 and CD21 (CR2) are co-receptors found on B-cells and various B-cell lymphomas, including non-Hodgkin lymphoma. To evaluate their suitability as targets for therapy of such lymphomas using internalization-dependent antibody-drug conjugates [such as antibody-4-(N-maleimidomethyl)cyclohexane-1-carboxylate, (N2'-deacetyl-N2'-(3-mercapto-1-oxopropyl)-maytansine) (MCC-DM1) conjugates, which require lysosomal degradation of the antibody moiety for efficacy], we examined uptake of antibodies to CD19 and CD21 in a panel of B-cell lines. Anti-CD21 antibodies were not sufficiently internalized even in the highest CD21-expressing Raji cells, resulting in lack of efficacy with anti-CD21-MCC-DM1 conjugates. Anti-CD19 antibody uptake was variable, and was unexpectedly negatively correlated with CD21 expression. Thus, high CD21-expressing Raji, ARH77 and primary B-cells only very slowly internalized anti-CD19 antibodies, while CD21-negative or low expressing cells, including Ramos and Daudi, rapidly internalized these antibodies in clathrin-coated vesicles followed by lysosomal delivery. Anti-CD19-MCC-DM1 caused greater cytotoxicity in the faster anti-CD19-internalizing cell lines, implying that the rate of lysosomal delivery and subsequent drug release is important. Furthermore, transfection of Ramos cells with CD21 impeded anti-CD19 uptake and decreased anti-CD19-MCC-DM1 efficacy, suggesting that CD21-negative tumours should respond better to such anti-CD19 conjugates. This may have possible clinical implications, as anti-CD21 immunohistochemistry revealed only approximately 30% of 54 diffuse large B-cell lymphoma patients lack CD21 expression.


Assuntos
Anticorpos Antineoplásicos/imunologia , Antígenos CD19/imunologia , Imunoconjugados/uso terapêutico , Linfoma de Células B/terapia , Receptores de Complemento 3d/metabolismo , Apoptose/imunologia , Linhagem Celular Tumoral , Clatrina/farmacologia , Citotoxicidade Imunológica/imunologia , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Linfoma de Células B/imunologia
6.
Blood ; 110(2): 616-23, 2007 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-17374736

RESUMO

Targeting cytotoxic drugs to cancer cells using antibody-drug conjugates (ADCs), particularly those with stable linkers between the drug and the antibody, could be an effective cancer treatment with low toxicity. However, for stable-linker ADCs to be effective, they must be internalized and degraded, limiting potential targets to surface antigens that are trafficked to lysosomes. CD79a and CD79b comprise the hetrodimeric signaling component of the B-cell receptor, and are attractive targets for the use of ADCs because they are B-cell-specific, expressed in non-Hodgkin lymphomas (NHL), and are trafficked to a lysosomal-like compartment as part of antigen presentation. We show here that the stable-linker ADCs anti-CD79b-MCC-DM1 and anti-CD79b-MC-MMAF are capable of target-dependent killing of nonHodgkin lymphoma cell lines in vitro. Further, these 2 ADCs are equally effective as low doses in xenograft models of follicular, mantle cell, and Burkitt lymphomas, even though several of these cell lines express relatively low levels of CD79b in vivo. In addition, we demonstrate that anti-CD79b ADCs were more effective than anti-CD79a ADCs and that, as hypothesized, anti-CD79b antibodies downregulated surface B-cell receptor and were trafficked to the lysosomal-like major histocompatibility complex class II-positive compartment MIIC. These results suggest that anti-CD79b-MCC-DM1 and anti-CD79b-MC-MMAF are promising therapeutics for the treatment of NHL.


Assuntos
Anticorpos/uso terapêutico , Antígenos CD79/imunologia , Imunoconjugados/uso terapêutico , Linfoma não Hodgkin/imunologia , Animais , Células CHO , Linhagem Celular Tumoral , Cricetinae , Cricetulus , Feminino , Citometria de Fluxo , Antígenos HLA-D/imunologia , Humanos , Lisossomos/imunologia , Camundongos , Camundongos SCID , Receptores de Antígenos de Linfócitos B/imunologia , Transplante Heterólogo
7.
J Biol Chem ; 278(48): 47654-9, 2003 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-14500721

RESUMO

Stanniocalcin 1 (STC1) is a secreted glycoprotein originally described as a hormone involved in calcium and phosphate homeostasis in bony fishes. We recently identified the mammalian homolog of this molecule to be highly up-regulated in an in vitro model of angiogenesis, as well as focally and intensely expressed at sites of pathological angiogenesis (e.g. tumor vasculature). In the present study, we report that STC1 is a selective modulator of hepatocyte growth factor (HGF)-induced endothelial migration and morphogenesis, but not proliferation. STC1 did not inhibit proliferative or migratory responses to vascular endothelial growth factor or basic fibroblast growth factor. The mechanism of STC1 inhibitory effects on HGF-induced endothelial migration seem to occur secondary to receptor activation because STC1 did not inhibit HGF-induced c-met receptor phosphorylation, but did block HGF-induced focal adhesion kinase activation. In the mouse femoral artery ligation model of angiogenesis, STC1 expression closely paralleled that of the endothelial marker CD31, and the peak level of STC1 expression occurred after an increase in HGF expression. We propose that STC1 may play a selective modulatory role in angiogenesis, possibly serving as a "stop signal" or stabilizing factor contributing to the maturation of newly formed blood vessels. HGF is a mesenchyme-derived pleiotropic factor with mitogenic, motogenic, and morphogenic activities on a number of different cell types. HGF effects are mediated through a specific tyrosine kinase, c-met, and aberrant HGF and c-met expression are frequently observed in a variety of tumors. Recent studies have shown HGF to be a potent growth factor implicated in wound healing, tissue regeneration, and angiogenesis.


Assuntos
Endotélio/metabolismo , Glicoproteínas/fisiologia , Fator de Crescimento de Hepatócito/metabolismo , Neovascularização Fisiológica , Animais , Anticorpos Monoclonais/química , Divisão Celular , Movimento Celular , Células Cultivadas , Colágeno/farmacologia , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Endotélio Vascular/citologia , Ativação Enzimática , Fator 2 de Crescimento de Fibroblastos/metabolismo , Quinase 1 de Adesão Focal , Proteína-Tirosina Quinases de Adesão Focal , Vetores Genéticos , Humanos , Laminina/farmacologia , Masculino , Mesoderma/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Proteínas Tirosina Quinases/metabolismo , Proteoglicanas/farmacologia , Proteínas Proto-Oncogênicas c-met/metabolismo , RNA Mensageiro/metabolismo , Fatores de Tempo , Veias Umbilicais/citologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Cicatrização
8.
Microcirculation ; 10(1): 63-81, 2003 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-12610664

RESUMO

The process of endothelial differentiation into a network of tube-like structures with patent lumens requires an integrated program of gene expression. To identify genes upregulated in endothelial cells during the process of tube formation, RNA was prepared from several different time points (0, 4, 8, 24, 40, and 48 hours) and from three different experimental models of human endothelial tube formation: in collagen gels and fibrin gels driven by the combination of PMA (80), bFGF (40 ng/ml) and bFGF (40 ng/ml) or in collagen gels driven by the combination of HGF (40 ng/ml) and VEGF (40 ng/ml). Gene expression was evaluated using Affymetrix Gene Chip oligonucleotide arrays. Over 1000 common genes were upregulated greater than twofold over baseline at one or more time points in the three different models. In the present study, we discuss the identified genes that could be assigned to major functional classes: apoptosis, cytoskeleton, proteases, matrix, and matrix turnover, pumps and transporters, membrane lipid turnover, and junctional molecules or adhesion proteins.


Assuntos
Endotélio Vascular/citologia , Regulação da Expressão Gênica no Desenvolvimento , Neovascularização Fisiológica/fisiologia , Animais , Apoptose/genética , Moléculas de Adesão Celular/biossíntese , Moléculas de Adesão Celular/genética , Diferenciação Celular/genética , Células Cultivadas/metabolismo , Colágeno , Proteínas do Citoesqueleto/biossíntese , Proteínas do Citoesqueleto/genética , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Fibrina , Géis , Perfilação da Expressão Gênica , Substâncias de Crescimento/farmacologia , Humanos , Lipídeos de Membrana/biossíntese , Neovascularização Fisiológica/genética , Análise de Sequência com Séries de Oligonucleotídeos , Acetato de Tetradecanoilforbol/farmacologia
9.
Arterioscler Thromb Vasc Biol ; 22(11): 1797-803, 2002 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-12426207

RESUMO

OBJECTIVE: This study evaluated the relative roles of the vascular endothelial growth factor (VEGF) receptors KDR and Flt-1 in the mediation of altered gene expression elicited by VEGF. METHODS AND RESULTS: We used mutants of VEGF selective for the KDR and Flt-1 receptors to differentiate gene expression patterns mediated by wild-type VEGF (VEGFwt) in human umbilical vein endothelial cells. RNA was extracted from cells treated for 24 hours with 1 nmol/L of each ligand, and gene expression was monitored by using oligonucleotide arrays (Affymetrix U95A). We report that activation of KDR was sufficient to upregulate all the genes induced by VEGFwt. In contrast, there were no genes selectively upregulated by the Flt-selective mutant. However, high concentrations of the Flt-selective mutant could augment the expression of some genes induced by submaximal concentrations of VEGFwt but not the KDR-selective mutant. CONCLUSIONS: The binding of VEGF to its receptor, KDR, is necessary and sufficient to induce the gene expression profile induced by this growth factor. Furthermore, in human umbilical vein endothelial cells, the Flt-1 receptor appears to act as a decoy receptor, tempering the response to lower concentrations of VEGF.


Assuntos
Fatores de Crescimento Endotelial/fisiologia , Endotélio Vascular/química , Endotélio Vascular/metabolismo , Regulação da Expressão Gênica/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Linfocinas/fisiologia , Veias Umbilicais/química , Veias Umbilicais/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/fisiologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/fisiologia , Células Cultivadas , Fatores de Crescimento Endotelial/genética , Fatores de Crescimento Endotelial/farmacologia , Endotélio Vascular/citologia , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Linfocinas/genética , Linfocinas/farmacologia , Mutação/genética , Mutação/fisiologia , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase/métodos , Receptores CXCR4/biossíntese , Fatores de Tempo , Veias Umbilicais/citologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologia , Fator A de Crescimento do Endotélio Vascular , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Fatores de Crescimento do Endotélio Vascular
10.
Endocrinology ; 143(9): 3681-90, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12193584

RESUMO

Fish stanniocalcin (STC) inhibits uptake of calcium and stimulates phosphate reabsorption. To determine the role of the highly homologous mammalian protein, STC-1, we created and characterized transgenic mice that express STC-1 under control of a muscle-specific promoter. STC-1 transgenic mice were smaller than wild-type littermates and had normal growth plate cartilage morphology but increased cartilage matrix synthesis. In STC-1 mice, the rate of bone formation, but not bone mineralization, was decreased. Increased cortical bone thickness and changes in trabeculae number, density, and thickness in STC-1 mice indicated a concomitant suppression of osteoclast activity, which was supported by microcomputed tomography analyses and histochemistry. Skeletal muscles were disproportionately small and showed altered function and response to injury in STC-1 mice. Electron microscopy indicated that muscle mitochondria were dramatically enlarged in STC-1 mice. These changes in STC-1 mice could not be explained by deficits in blood vessel formation, as vascularity in organs and skeletal tissues was increased as was induction of vascularity in response to femoral artery ligation. Our results indicate that STC-1 can affect calcium homeostasis, bone and muscle mass and structure, and angiogenesis through effects on osteoblasts, osteoclasts, myoblasts/myocytes, and endothelial cells.


Assuntos
Osso e Ossos/anatomia & histologia , Osso e Ossos/fisiologia , Glicoproteínas/fisiologia , Hormônios/fisiologia , Músculo Esquelético/anatomia & histologia , Músculo Esquelético/fisiologia , Animais , Composição Corporal , Constituição Corporal , Densidade Óssea , Desenvolvimento Ósseo , Matriz Óssea/metabolismo , Calcificação Fisiológica , Cálcio/sangue , Cartilagem/metabolismo , Feminino , Expressão Gênica , Glicoproteínas/genética , Crescimento/genética , Lâmina de Crescimento/anatomia & histologia , Hormônios/genética , Masculino , Camundongos , Camundongos Transgênicos , Microscopia Eletrônica , Neovascularização Fisiológica , Osteoclastos/fisiologia , Crânio/diagnóstico por imagem , Tomografia Computadorizada por Raios X
11.
Physiol Genomics ; 10(1): 13-20, 2002 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-12118101

RESUMO

The objective of this study was to use gene expression data from well-defined cell culture models, in combination with expression data from diagnostic samples of human diseased tissues, to identify potential therapeutic targets and markers of disease. Using Affymetrix oligonucleotide array technology, we identified a common profile of genes upregulated during endothelial morphogenesis into tubelike structures in three in vitro models of angiogenesis. Rigorous data selection criteria were used to identify a list of over 1,000 genes whose expression was increased more than twofold over baseline at either 4, 8, 24, 40 or 50 h. To further refine and prioritize this list, we used standard bioinformatic algorithms to identify potential transmembrane and secreted proteins. We then overlapped this gene set with genes upregulated in colon tumors vs. normal colon, resulting in a subset of 128 genes in common with our endothelial list. We removed from this list those genes expressed in 6 different colon tumor lines, resulting in a list of 24 putative, vascular-specific angiogenesis-associated genes. Three genes, gp34, stanniocalcin-1 (STC-1), and GA733-1, were expressed at levels 10-fold or more in colon tumors compared with normal mucosa. We validated the vascular-specific expression of one of these genes, STC-1, by in situ hybridization. The ability to combine in vitro and in vivo data sets should permit one to identify putative angiogenesis target genes in various tumors, chronic inflammation, and other disorders where therapeutic manipulation of angiogenesis is a desirable treatment modality.


Assuntos
Bases de Dados Genéticas , Perfilação da Expressão Gênica/métodos , Neovascularização Patológica/genética , Neovascularização Fisiológica/genética , Animais , Linhagem Celular , Endotélio Vascular/química , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiologia , Marcação de Genes/métodos , Humanos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Ratos , Ratos Sprague-Dawley , Células Tumorais Cultivadas , Veias Umbilicais
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