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1.
Cancer Immunol Immunother ; 64(1): 61-73, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25287778

RESUMO

Elotuzumab is a humanized monoclonal antibody specific for signaling lymphocytic activation molecule-F7 (SLAMF7, also known as CS1, CD319, or CRACC) that enhances natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) of SLAMF7-expressing myeloma cells. This study explored the mechanisms underlying enhanced myeloma cell killing with elotuzumab as a single agent and in combination with lenalidomide, to support ongoing phase III trials in patients with relapsed/refractory or newly-diagnosed multiple myeloma (MM). An in vitro peripheral blood lymphocyte (PBL)/myeloma cell co-culture model was developed to evaluate the combination of elotuzumab and lenalidomide. Expression of activation markers and adhesion receptors was evaluated by flow cytometry, cytokine expression by Luminex and ELISPOT assays, and cytotoxicity by myeloma cell counts. Elotuzumab activated NK cells and promoted myeloma cell death in PBL/myeloma cell co-cultures. The combination of elotuzumab plus lenalidomide demonstrated superior anti-myeloma activity on established MM xenografts in vivo and in PBL/myeloma cell co-cultures in vitro than either agent alone. The combination enhanced myeloma cell killing by modulating NK cell function that coincided with the upregulation of adhesion and activation markers, including interleukin (IL)-2Rα expression, IL-2 production by CD3(+)CD56(+) lymphocytes, and tumor necrosis factor (TNF)-α production. In co-culture assays, TNF-α directly increased NK cell activation and myeloma cell death with elotuzumab or elotuzumab plus lenalidomide, and neutralizing TNF-α decreased NK cell activation and myeloma cell death with elotuzumab. These results demonstrate that elotuzumab activates NK cells and induces myeloma cell death via NK cell-mediated ADCC, which is further enhanced when combined with lenalidomide.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Interleucina-2/metabolismo , Células Matadoras Naturais/imunologia , Mieloma Múltiplo/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Citometria de Fluxo , Humanos , Técnicas Imunoenzimáticas , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/metabolismo , Ativação Linfocitária , Camundongos , Camundongos SCID , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
2.
J Exp Med ; 218(8)2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34106206

RESUMO

As indicated by its name, V-domain Ig suppressor of T cell activation (VISTA) is thought to serve primarily as an inhibitory protein that limits immune responses. VISTA antibodies can dampen the effects of several concomitantly elicited activation signals, including TCR and TLR activation, but it is currently unclear if VISTA agonism could singly affect immune cell biology. In this study, we discovered two novel VISTA antibodies and characterized their effects on human peripheral blood mononuclear cells by scRNA/CITE-seq. Both antibodies appeared to agonize VISTA in an Fc-functional manner to elicit transcriptional and functional changes in monocytes consistent with activation. We also used pentameric VISTA to identify Syndecan-2 and several heparan sulfate proteoglycan synthesis genes as novel regulators of VISTA interactions with monocytic cells, adding further evidence of bidirectional signaling. Together, our study highlights several novel aspects of VISTA biology that have yet to be uncovered in myeloid cells and serves as a foundation for future research.


Assuntos
Antígenos B7/metabolismo , Monócitos/metabolismo , Receptores Imunológicos/metabolismo , Anticorpos Monoclonais/metabolismo , Especificidade de Anticorpos/imunologia , Sistemas CRISPR-Cas/genética , Heparitina Sulfato/metabolismo , Humanos , Ligação Proteica , Receptores Fc/metabolismo , Sindecana-2/metabolismo , Transcrição Gênica , Transcriptoma/genética
3.
J Immunother Cancer ; 9(2)2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33608377

RESUMO

BACKGROUND: CD40 agonist immunotherapy can potentially license antigen-presenting cells to promote antitumor T-cell activation and re-educate macrophages to destroy tumor stroma. Systemic administration of CD40 agonists has historically been associated with considerable toxicity, providing the rationale for development of tumor-targeted immunomodulators to improve clinical safety and efficacy. This phase I study assessed the safety, tolerability, preliminary antitumor activity, and preliminary biomarkers of ABBV-428, a first-in-class, mesothelin-targeted, bispecific antibody designed for tumor microenvironment-dependent CD40 activation with limited systemic toxicity. METHODS: ABBV-428 was administered intravenously every 2 weeks to patients with advanced solid tumors. An accelerated titration (starting at a 0.01 mg/kg dose) and a 3+3 dose escalation scheme were used, followed by recommended phase II dose cohort expansions in ovarian cancer and mesothelioma, tumor types associated with high mesothelin expression. RESULTS: Fifty-nine patients were treated at doses between 0.01 and 3.6 mg/kg. The maximum tolerated dose was not reached, and 3.6 mg/kg was selected as the recommended phase II dose. Seven patients (12%) reported infusion-related reactions. Treatment-related grade ≥3 treatment-emergent adverse events were pericardial effusion, colitis, infusion-related reaction, and pleural effusion (n=1 each, 2%), with no cytokine release syndrome reported. The pharmacokinetic profile demonstrated roughly dose-proportional increases in exposure from 0.4 to 3.6 mg/kg. Best response was stable disease in 9/25 patients (36%) treated at the recommended phase II dose. CD40 receptor occupancy >90% was observed on peripheral B-cells starting from 0.8 mg/kg; however, no consistent changes from baseline in intratumoral CD8+ T-cells, programmed death ligand-1 (PD-L1+) cells, or immune-related gene expression were detected post-ABBV-428 treatment (cycle 2, day 1). Mesothelin membrane staining showed greater correlation with progression-free survival in ovarian cancer and mesothelioma than in the broader dose escalation population. CONCLUSIONS: ABBV-428 monotherapy exhibited dose-proportional pharmacokinetics and an acceptable safety profile, particularly for toxicities characteristic of CD40 agonism, illustrating that utilization of a tumor-targeted, bispecific antibody can improve the safety of CD40 agonism as a therapeutic approach. ABBV-428 monotherapy had minimal clinical activity in dose escalation and in a small expansion cohort of patients with advanced mesothelioma or ovarian cancer. TRIAL REGISTRATION NUMBER: NCT02955251.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Antígenos CD40/agonistas , Mesotelina/agonistas , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Biespecíficos/efeitos adversos , Anticorpos Biespecíficos/farmacocinética , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/farmacocinética , Feminino , França , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/imunologia , Neoplasias/mortalidade , Neoplasias/patologia , Intervalo Livre de Progressão , Fatores de Tempo , Microambiente Tumoral , Estados Unidos
4.
Mol Cancer Ther ; 19(4): 1040-1051, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31974274

RESUMO

CD137 (TNFRSF9, 4-1BB) agonist antibodies (mAb) have demonstrated potent antitumor activity with memory response while causing hepatotoxicity in mouse models. In clinical trials, the degrees of liver toxicity of anti-CD137 vary from grade 4 transaminitis (urelumab) to nonexistent (utomilumab). To exploit the antitumor potential of CD137 signaling, we identified a new class of CD137 agonist mAbs with strong antitumor potency without significant transaminitis in vivo compared with CD137 agonists previously reported. These mAbs are cross-reactive to mouse and cynomolgus monkey and showed cross-linking-dependent T-cell costimulation activity in vitro Antitumor efficacy was maintained in Fc gamma receptor (FcγR) III-deficient mice but diminished in FcγRIIB-deficient mice, suggesting the critical role for FcγRIIB to provide cross-linking in vivo Interestingly, a single dose of an affinity-reduced variant was sufficient to control tumor growth, but a higher affinity variant did not improve efficacy. These observations suggest that binding epitope and FcγR interaction, but not necessarily high affinity, are important for antitumor efficacy and reduced liver toxicity of CD137 mAb. Our study suggests the possibility of CD137 agonist therapy with improved safety profile in humans.


Assuntos
Anticorpos Monoclonais/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Neoplasias do Colo/tratamento farmacológico , Reagentes de Ligações Cruzadas/química , Epitopos/imunologia , Melanoma Experimental/tratamento farmacológico , Receptores de IgG/fisiologia , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia , Animais , Apoptose , Proliferação de Células , Neoplasias do Colo/imunologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Reagentes de Ligações Cruzadas/metabolismo , Feminino , Humanos , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Tumorais Cultivadas
5.
Immunol Invest ; 38(1): 76-92, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19172487

RESUMO

Several low- or non-FcR binding anti-human CD3 monoclonal antibodies have been under investigation for the treatment of autoimmune diseases. To model the mechanism of action of these anti-human CD3 mAbs in the murine system, an Fc-modified anti-mouse CD3 antibody (N297A) was generated. N297A exhibited similar biological effects as Fc-modified anti-human CD3 antibodies including rapid, reversible reduction in peripheral leukocyte numbers, differential modulation of activated versus resting T cells, and reduced levels of induced cytokine release compared to the non-Fc-modified parent antibody. In an in vivo model of colitis induced by adoptive transfer of IL-10-deficient cells, administration of N297A significantly reduced body weight loss. As N297A shared many functional characteristics of non-FcR binding anti-human CD3 mAbs both in vitro and in vivo, it provides a means to model the mechanisms of action of Fc-modified anti-human CD3 antibodies in mouse.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Complexo CD3/imunologia , Linfócitos T CD4-Positivos/metabolismo , Receptores de IgG/metabolismo , Proteínas Recombinantes de Fusão/administração & dosagem , Transferência Adotiva , Animais , Anticorpos Monoclonais/genética , Anticorpos Monoclonais/metabolismo , Apoptose/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Células CHO , Colite/imunologia , Colo/efeitos dos fármacos , Colo/patologia , Cricetinae , Cricetulus , Citocinas/metabolismo , Humanos , Contagem de Linfócitos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Ovalbumina/imunologia , Ligação Proteica , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Receptores de IgG/imunologia , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo
6.
Cancer Immunol Res ; 7(11): 1864-1875, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31462409

RESUMO

Agonistic CD40 monoclonal antibodies (mAb) have demonstrated some clinical activity, but with dose-limiting toxicity. To reduce systemic toxicity, we developed a bispecific molecule that was maximally active in the presence of a tumor antigen and had limited activity in the absence of the tumor antigen. LB-1 is a bispecific molecule containing single-chain Fv domains targeting mouse CD40 and the tumor antigen mesothelin. LB-1 exhibited enhanced activity upon binding to cell-surface mesothelin but was less potent in the absence of mesothelin binding. In a mouse model implanted with syngeneic 4T1 tumors expressing cell-surface mesothelin, LB-1 demonstrated comparable antitumor activity as an agonistic CD40 mAb but did not cause elevation of serum cytokines and liver enzymes, as was observed in anti-CD40-treated mice. The results from our study of LB-1 were used to develop a human cross-reactive bispecific molecule (ABBV-428) that targeted human CD40 and mesothelin. ABBV-428 demonstrated enhanced activation of antigen-presenting cells and T cells upon binding to cell-surface mesothelin, and inhibition of cultured or implanted PC3 tumor cell growth after immune activation. Although expression of cell-surface mesothelin is necessary, the bispecific molecules induced immune-mediated antitumor activity against both mesothelin+ and mesothelin- tumor cells. ABBV-428 represents a class of bispecific molecules with conditional activity dependent on the binding of a tumor-specific antigen, and such activity could potentially maximize antitumor potency while limiting systemic toxicity in clinical studies.


Assuntos
Anticorpos Biespecíficos/imunologia , Antígenos de Neoplasias/imunologia , Antineoplásicos Imunológicos/imunologia , Antígenos CD40/imunologia , Proteínas Ligadas por GPI/imunologia , Animais , Anticorpos Biespecíficos/química , Anticorpos Biespecíficos/farmacologia , Anticorpos Biespecíficos/uso terapêutico , Células Apresentadoras de Antígenos/efeitos dos fármacos , Células Apresentadoras de Antígenos/imunologia , Antígenos de Neoplasias/metabolismo , Antineoplásicos Imunológicos/química , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Antígenos CD40/agonistas , Linhagem Celular Tumoral , Proteínas Ligadas por GPI/metabolismo , Humanos , Ativação Linfocitária/efeitos dos fármacos , Mesotelina , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Mutantes , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
7.
Cancer Res ; 78(14): 4059-4072, 2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29764866

RESUMO

Progress in understanding tumor stromal biology has been constrained in part because cancer-associated fibroblasts (CAF) are a heterogeneous population with limited cell-type-specific protein markers. Using RNA expression profiling, we identified the membrane protein leucine-rich repeat containing 15 (LRRC15) as highly expressed in multiple solid tumor indications with limited normal tissue expression. LRRC15 was expressed on stromal fibroblasts in many solid tumors (e.g., breast, head and neck, lung, pancreatic) as well as directly on a subset of cancer cells of mesenchymal origin (e.g., sarcoma, melanoma, glioblastoma). LRRC15 expression was induced by TGFß on activated fibroblasts (αSMA+) and on mesenchymal stem cells. These collective findings suggested LRRC15 as a novel CAF and mesenchymal marker with utility as a therapeutic target for the treatment of cancers with LRRC15-positive stromal desmoplasia or cancers of mesenchymal origin. ABBV-085 is a monomethyl auristatin E (MMAE)-containing antibody-drug conjugate (ADC) directed against LRRC15, and it demonstrated robust preclinical efficacy against LRRC15 stromal-positive/cancer-negative, and LRRC15 cancer-positive models as a monotherapy, or in combination with standard-of-care therapies. ABBV-085's unique mechanism of action relied upon the cell-permeable properties of MMAE to preferentially kill cancer cells over LRRC15-positive CAF while also increasing immune infiltrate (e.g., F4/80+ macrophages) in the tumor microenvironment. In summary, these findings validate LRRC15 as a novel therapeutic target in multiple solid tumor indications and support the ongoing clinical development of the LRRC15-targeted ADC ABBV-085.Significance: These findings identify LRRC15 as a new marker of cancer-associated fibroblasts and cancers of mesenchymal origin and provide preclinical evidence for the efficacy of an antibody-drug conjugate targeting the tumor stroma. Cancer Res; 78(14); 4059-72. ©2018 AACR.


Assuntos
Anticorpos Monoclonais/farmacologia , Imunoconjugados/farmacologia , Proteínas de Membrana/metabolismo , Neoplasias/tratamento farmacológico , Células Estromais/efeitos dos fármacos , Animais , Linhagem Celular , Linhagem Celular Tumoral , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Células HCT116 , Humanos , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , Neoplasias/metabolismo , Oligopeptídeos/farmacologia , Ratos , Ratos Sprague-Dawley , Sarcoma/tratamento farmacológico , Sarcoma/metabolismo , Células Estromais/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
8.
J Transl Med ; 5: 61, 2007 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-18042290

RESUMO

BACKGROUND: Integrins are important adhesion molecules that regulate tumor and endothelial cell survival, proliferation and migration. The integrin alpha5beta1 has been shown to play a critical role during angiogenesis. An inhibitor of this integrin, volociximab (M200), inhibits endothelial cell growth and movement in vitro, independent of the growth factor milieu, and inhibits tumor growth in vivo in the rabbit VX2 carcinoma model. Although volociximab has already been tested in open label, pilot phase II clinical trials in melanoma, pancreatic and renal cell cancer, evaluation of the mechanism of action of volociximab has been limited because this antibody does not cross-react with murine alpha5beta1, precluding its use in standard mouse xenograft models. METHODS: We generated a panel of rat-anti-mouse alpha5beta1 antibodies, with the intent of identifying an antibody that recapitulated the properties of volociximab. Hybridoma clones were screened for analogous function to volociximab, including specificity for alpha5beta1 heterodimer and blocking of integrin binding to fibronectin. A subset of antibodies that met these criteria were further characterized for their capacities to bind to mouse endothelial cells, inhibit cell migration and block angiogenesis in vitro. One antibody that encompassed all of these attributes, 339.1, was selected from this panel and tested in xenograft models. RESULTS: A panel of antibodies was characterized for specificity and potency. The affinity of antibody 339.1 for mouse integrin alpha5beta1 was determined to be 0.59 nM, as measured by BIAcore. This antibody does not significantly cross-react with human integrin, however 339.1 inhibits murine endothelial cell migration and tube formation and elicits cell death in these cells (EC50 = 5.3 nM). In multiple xenograft models, 339.1 inhibited the growth of established tumors by 40-60% (p < 0.05) and this inhibition correlates with a concomitant decrease in vessel density. CONCLUSION: The results herein demonstrate that 339.1, like volociximab, exhibits potent anti-alpha5beta1 activity and confirms that inhibition of integrin alpha5beta1 impedes angiogenesis and slows tumor growth in vivo.


Assuntos
Inibidores da Angiogênese/imunologia , Anticorpos Monoclonais/uso terapêutico , Integrina alfa5beta1/imunologia , Animais , Anexina A5/imunologia , Antineoplásicos/uso terapêutico , Morte Celular , Clonagem Molecular , Ensaio de Imunoadsorção Enzimática , Feminino , Fibronectinas/antagonistas & inibidores , Fibronectinas/imunologia , Citometria de Fluxo , Humanos , Fragmentos Fc das Imunoglobulinas/imunologia , Integrina alfa5beta1/genética , Integrina alfa5beta1/uso terapêutico , Camundongos , Camundongos SCID , Placenta/imunologia , Gravidez , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes de Fusão/imunologia , Transplante Heterólogo
9.
J Immunol Res ; 2017: 5737159, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29075649

RESUMO

Enavatuzumab is a humanized IgG1 anti-TWEAK receptor monoclonal antibody that was evaluated in a phase I clinical study for the treatment of solid malignancies. The current study was to determine whether and how myeloid effector cells were involved in postulated mechanisms for its potent antitumor activity in xenograft models. The initial evidence for a role of effector cells was obtained in a subset of tumor xenograft mouse models whose response to enavatuzumab relied on the binding of Fc of the antibody to Fcγ receptor. The involvement of effector cells was further confirmed by immunohistochemistry, which revealed strong infiltration of CD45+ effector cells into tumor xenografts in responding models, but minimal infiltration in nonresponders. Consistent with the xenograft studies, human effector cells preferentially migrated toward in vivo-responsive tumor cells treated by enavatuzumab in vitro, with the majority of migratory cells being monocytes. Conditioned media from enavatuzumab-treated tumor cells contained elevated levels of chemokines, which might be responsible for enavatuzumab-triggered effector cell migration. These preclinical studies demonstrate that enavatuzumab can exert its potent antitumor activity by actively recruiting and activating myeloid effectors to kill tumor cells. Enavatuzumab-induced chemokines warrant further evaluation in clinical studies as potential biomarkers for such activity.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Imunoterapia/métodos , Linfócitos/imunologia , Monócitos/imunologia , Células Mieloides/imunologia , Neoplasias Experimentais/tratamento farmacológico , Animais , Citotoxicidade Celular Dependente de Anticorpos , Movimento Celular , Citocina TWEAK/imunologia , Citocinas/metabolismo , Células HCT116 , Humanos , Imunidade Inata , Camundongos , Camundongos SCID , Receptores Fc/metabolismo , Carga Tumoral , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Front Immunol ; 4: 505, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24409185

RESUMO

TweakR is a TNF receptor family member, whose natural ligand is the multifunctional cytokine TWEAK. The growth inhibitory activity observed following TweakR stimulation in certain cancer cell lines and the overexpression of TweakR in many solid tumor types led to the development of enavatuzumab (PDL192), a humanized IgG1 monoclonal antibody to TweakR. The purpose of this study was to determine the mechanism of action of enavatuzumab's tumor growth inhibition and to provide insight into the biology behind TweakR as a cancer therapeutic target. A panel of 105 cancer lines was treated with enavatuzumab in vitro; and 29 cell lines of varying solid tumor backgrounds had >25% growth inhibition in response to the antibody. Treatment of sensitive cell lines with enavatuzumab resulted in the in vitro and in vivo (xenograft) activation of both classical (p50, p65) and non-classical (p52, RelB) NFκB pathways. Using NFκB DNA binding functional ELISAs and microarray analysis, we observed increased activation of NFκB subunits and NFκB-regulated genes in sensitive cells over that observed in resistant cell lines. Inhibiting NFκB subunits (p50, p65, RelB, p52) and upstream kinases (IKK1, IKK2) with siRNA and chemical inhibitors consistently blocked enavatuzumab's activity. Furthermore, enavatuzumab treatment resulted in NFκB-dependent reduction in cell division as seen by the activation of the cell cycle inhibitor p21 both in vitro and in vivo. The finding that NFκB drives the growth inhibitory activity of enavatuzumab suggests that targeting TweakR with enavatuzumab may represent a novel cancer treatment strategy.

11.
J Cancer Res Clin Oncol ; 139(2): 315-25, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23073510

RESUMO

BACKGROUND: The receptor for the cytokine TWEAK (TweakR) is a cell surface member of the tumor necrosis factor receptor superfamily with diverse biological roles. TNFRSF family members are appealing therapeutic targets in oncology due to their aberrant expression and function in tumor cells. The goal of the current study was to examine the potential of TweakR as a therapeutic target in breast cancer. METHODS: Expression of TweakR in primary breast cancer tissues and metastases was characterized using immunohistochemistry. To determine the functional relevance of TweakR, breast cancer cell lines were treated in vitro and in vivo with enavatuzumab, a humanized mAb against TweakR. RESULTS: Overexpression of TweakR was observed in infiltrating tumors compared to normal adjacent breast tissues, and strong staining of TweakR was observed in all subtypes of invasive ductal breast cancer. In addition, a positive correlation of TweakR and HER2 expression and co-localization were observed, irrespective of ER status. TweakR expression was also observed in bone metastasis samples from primary breast cancer but rarely in benign tumors. Enavatuzumab inhibited the in vitro growth of TweakR-expressing breast cancer cell lines, and this activity was augmented by cross-linking the mAb. In addition, enavatuzumab significantly inhibited the in vivo growth of multiple breast cancer xenograft models including a model of metastasis. CONCLUSIONS: TweakR is highly expressed in all subtypes of invasive ductal breast cancer, and enavatuzumab administration exhibited a dose-dependent inhibition of primary tumor growth and lung metastasis and enhanced the antitumor activity of several chemotherapy agents currently used to treat breast cancer. These data provide the rationale to evaluate enavatuzumab as a potential therapy for the treatment of breast cancer.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma Ductal de Mama/metabolismo , Receptores do Fator de Necrose Tumoral/metabolismo , Animais , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Feminino , Expressão Gênica , Humanos , Camundongos , Invasividade Neoplásica/genética , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores do Fator de Necrose Tumoral/genética , Receptor de TWEAK , Trastuzumab , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Clin Cancer Res ; 16(2): 497-508, 2010 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-20068083

RESUMO

PURPOSE: Targeted therapeutics have significantly changed the outcome for patients diagnosed with cancer. Still, effective therapeutic intervention does not exist for many cancers and much remains to be done. The objective of this study was to identify novel genes that potentially regulate tumor growth, to target these gene products with monoclonal antibodies, and to examine the therapeutic potential of these antibodies. EXPERIMENTAL DESIGN: Using cDNA microarray analysis, we identified genes overexpressed in several solid malignancies. We generated a mouse monoclonal antibody, 19.2.1, and its humanized counterpart, PDL192, to one such target, TweakR (TWEAK receptor, Fn14, TNFRSF12A, CD266), and characterized the antitumor activities in vitro and in mouse xenograft models. RESULTS: Both 19.2.1 (mouse IgG2a) and PDL192 (human IgG1), like TWEAK, the natural ligand of TweakR, inhibited the growth of several TweakR-expressing cancer cell lines in anchorage-dependent and anchorage-independent assays in vitro. Both antibodies showed significant antitumor activity in multiple mouse xenograft models. PDL192 and 19.2.1 also induced antibody-dependent cellular cytotoxicity (ADCC) of cancer cell lines in vitro. A chimeric version of 19.2.1 containing the mouse IgG1 Fc region (19.2.1 x G1) exhibited significantly less ADCC than 19.2.1. However, 19.2. 1x G1 showed differential activity in vivo, with activity equivalent to 19.2.1 in one model, but significantly less efficacy than 19.2.1 in a second model. These results indicate that PDL192 and 19.2.1 mediate their antitumor effects by signaling through TweakR, resulting in reduced tumor cell proliferation, and by ADCC.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias/patologia , Fatores de Necrose Tumoral/imunologia , Animais , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Citocina TWEAK , Relação Dose-Resposta a Droga , Humanos , Imunoterapia/métodos , Camundongos , Camundongos Endogâmicos BALB C , Células NIH 3T3 , Metástase Neoplásica , Neoplasias/terapia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Carga Tumoral/efeitos dos fármacos , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
13.
J Neuroimmunol ; 212(1-2): 65-73, 2009 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-19477024

RESUMO

Humanization and modification of the Fc region of anti-human CD3 mAbs have greatly expanded their potential use in chronic T cell mediated diseases. However, low levels of cytokine release and immunogenicity may still impact a chronic dosing strategy. We investigated the use of an Fc-modified murine chimeric anti-mouse CD3 (N297A) in the chronic MOG(35-55)-induced EAE mouse model of MS. Two daily doses of 10 microg at the onset of clinical symptoms led to both a reduction in T cell numbers in the blood and a significant, prolonged reduction in the symptoms. Histological examination of the spinal cords at the peak of efficacy confirmed a reduction of infiltrating T cells in the CNS. Analysis of the cerebral spinal fluid from EAE mice showed biologically active levels of N297A. Analysis of the cytokine/chemokine levels in cerebrospinal fluid showed a decrease in GM-CSF, IL-6 and IP-10. The combination of N297A dosing with cyclosporine A (CSA) pretreatment showed a significant decrease of TNFalpha, IL-6 and IP-10 without effect on clinical efficacy. However, pretreatment of CSA significantly reduced the immunogenic response observed following a second course of N297A treatment. Therefore, the side effects of an Fc-modified anti-CD3 mAb may be modulated without affecting efficacy.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Complexo CD3/imunologia , Citocinas/biossíntese , Encefalomielite Autoimune Experimental/terapia , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Animais , Barreira Hematoencefálica , Quimiocinas/biossíntese , Ciclosporina/farmacologia , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/imunologia , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Medula Espinal/imunologia , Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia
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