RESUMO
A series of thirty-one new compounds were synthesized and evaluated for their anti-HIV-1 and cytotoxicity activity. Of these, twelve were found to be inhibitors of HIV replications in primary human lymphocytes with median effective concentration (EC50) values < 20 µM. However, most of the compounds demonstrated cytotoxicity in different cells. Our structure activity relationship study identified different patterns. In the series of 2-aryl pyrrolidines, comparing the activity of the compounds containing 2-aryl substituents we observed that compounds 1c, 1f-j, 2f,g with benzyloxyphenyl and isopropoxy groups were more potent. Compounds 1g-j, 2f,g, in which the 1-aryl moiety contained a methyl group in 3,5- or 4-positions also showed high activity. In the series of compounds containing the amide, aminomethyl and nitrile groups we observed an increase in activity with C(O)NH2 < CH2NH2 < CN. In the series of 2-pyrimidinyl pyrrolidines, the best results were demonstrated with derivatives 5e and 5f, in which the presence of a benzyl fragment in 1st and aniline fragment in 6th positions of pyrimidine ring we observed an increase in anti-HIV activity. Molecular docking studies of synthesized compounds with HIV-1 reverse transcriptase enzyme were performed. Binding energies of ligands were estimated, and the interacting amino acids of HIV-1 reverse transcriptase protein were shown. Based on corroborative results of the molecular docking studies and in vitro experiments, we suggest that three groups of synthesized ligands (1c, 1f-i), (2f,g), (5e,f, 7) are of high interest for further research on new drugs against HIV. General structure of synthesized 2-aryl and 2-pyrimidinyl pyrrolidines.
Assuntos
Simulação de Acoplamento MolecularRESUMO
HLA-B27 and HLA-B57 are associated with autoimmunity and long-term viral control and protection against HIV and HCV infection; however, their role in cancer immunity remains unknown. HLA class I molecules interact with innate checkpoint receptors of the LILRA, LILRB and KIR families present in diverse sets of immune cells. Here, we demonstrate that an open format (peptide free conformation) and expression- and stability-optimized HLA-B57-B2m-IgG4_Fc fusion protein (IOS-1002) binds to human leukocyte immunoglobulin-like receptor B1 and B2 (LILRB1 and LILRB2) and to killer immunoglobulin-like receptor 3DL1 (KIR3DL1). In addition, we show that the IgG4 Fc backbone is required for engagement to Fcγ receptors and potent activation of macrophage phagocytosis. IOS-1002 blocks the immunosuppressive ITIM and SHP1/2 phosphatase signaling cascade, reduces the expression of immunosuppressive M2-like polarization markers of macrophages and differentiation of monocytes to myeloid-derived suppressor cells, enhances tumor cell phagocytosis in vitro and potentiates activation of T and NK cells. Lastly, IOS-1002 demonstrates efficacy in an ex vivo patient-derived tumor sample tumoroid model. IOS-1002 is a first-in-class multi-target and multi-functional human-derived HLA molecule that activates anti-tumor immunity and is currently under clinical evaluation.
RESUMO
Angiopoietin-2 (Ang2) exhibits broad expression in the remodeling vasculature of human tumors but very limited expression in normal tissues, making it an attractive candidate target for antiangiogenic cancer therapy. To investigate the functional consequences of blocking Ang2 activity, we generated antibodies and peptide-Fc fusion proteins that potently and selectively neutralize the interaction between Ang2 and its receptor, Tie2. Systemic treatment of tumor-bearing mice with these Ang2-blocking agents resulted in tumor stasis, followed by elimination of all measurable tumor in a subset of animals. These effects were accompanied by reduced endothelial cell proliferation, consistent with an antiangiogenic therapeutic mechanism. Anti-Ang2 therapy also prevented VEGF-stimulated neovascularization in a rat corneal model of angiogenesis. These results imply that specific Ang2 inhibition may represent an effective antiangiogenic strategy for treating patients with solid tumors.
Assuntos
Angiopoietina-2/antagonistas & inibidores , Angiopoietina-2/imunologia , Anticorpos/farmacologia , Neoplasias/irrigação sanguínea , Neovascularização Patológica/prevenção & controle , Animais , Proliferação de Células/efeitos dos fármacos , Córnea/irrigação sanguínea , Células Endoteliais/efeitos dos fármacos , Feminino , Camundongos , Camundongos Nus , Transplante de Neoplasias , Testes de Neutralização , Receptores Fc , Proteínas Recombinantes de Fusão/farmacologia , Células Tumorais CultivadasRESUMO
The EphA2 receptor tyrosine kinase is frequently overexpressed and functionally altered in malignant cells and thus provides opportunities for selective targeting of tumor cells. We describe here the development of a novel, bispecific single-chain antibody (bscAb) referred to as bscEphA2xCD3. This molecule simultaneously targets EphA2 on tumor cells and the T-cell receptor/CD3 complex on T cells and possesses structural and functional characteristics of the recently developed BiTE technology. An EphA2-specific single-chain antibody was selected for recognition of an epitope that is preferentially exposed on malignant cells based on the concept of epitope exclusion; this was fused to a CD3-specific single-chain antibody to generate bscEphA2xCD3. The resultant bscAb redirected unstimulated human T cells to lyse EphA2-expressing tumor cells both in vitro and in vivo. In separate experiments, efficient tumor cell lysis was achieved in vitro at drug concentrations Assuntos
Anticorpos Biespecíficos/farmacologia
, Complexo CD3/imunologia
, Imunização Passiva/métodos
, Neoplasias/terapia
, Receptor EphA2/imunologia
, Animais
, Anticorpos Biespecíficos/imunologia
, Especificidade de Anticorpos
, Células CHO
, Processos de Crescimento Celular/imunologia
, Linhagem Celular Tumoral
, Cricetinae
, Cricetulus
, Epitopos/imunologia
, Humanos
, Junções Intercelulares/imunologia
, Ativação Linfocitária
, Camundongos
, Camundongos Endogâmicos NOD
, Camundongos SCID
, Neoplasias/imunologia
, Neoplasias/patologia
, Linfócitos T/imunologia
, Ensaios Antitumorais Modelo de Xenoenxerto
RESUMO
In eukaryotic cells, cyclin-dependent kinase (CDK) complexes regulate the temporal progression of cells through the cell cycle. Deregulation in the cell cycle is an essential component in the evolution of cancer. Here, we validate CDK1 and CDK2 as potential therapeutic targets using novel selective small-molecule inhibitors of cyclin B1/CDK1 and cyclin E2/CDK2 enzyme complexes (CDKi). Flow cytometry-based methods were developed to assess intracellular retinoblastoma (Rb) phosphorylation to show inhibition of the CDK pathway. Tumor cells treated with CDK inhibitors showed an overall decrease in cell proliferation, accumulation of cells in G1 and G2, and apoptosis in a cell line-specific manner. Although CDK inhibitors activate p53, the inhibitors were equipotent in arresting the cell cycle in isogenic breast and colon tumor cells lacking p53, suggesting the response is independent of p53. In vivo, the CDK inhibitors prevented the growth of colon and prostate tumors, blocked proliferation of tumor cells, and inhibited Rb phosphorylation. The discovery and evaluation of novel potent and selective CDK1 and CDK2 inhibitors will help delineate the role that CDK complexes play in regulating tumorigenesis.
Assuntos
Proteína Quinase CDC2/antagonistas & inibidores , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Inibidores de Proteínas Quinases/farmacologia , Animais , Apoptose/efeitos dos fármacos , Proteína Quinase CDC2/metabolismo , Processos de Crescimento Celular/efeitos dos fármacos , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Ciclina B/antagonistas & inibidores , Ciclina B/metabolismo , Ciclina B1 , Ciclina E/antagonistas & inibidores , Ciclina E/metabolismo , Quinase 2 Dependente de Ciclina/metabolismo , Feminino , Fase G1/efeitos dos fármacos , Fase G2/efeitos dos fármacos , Humanos , Camundongos , Camundongos Nus , Neoplasias/patologia , Fosforilação/efeitos dos fármacos , Proteína do Retinoblastoma/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
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 XenoenxertoRESUMO
The humanized monoclonal antibody Abegrin, currently in phase II trials for treatment of solid tumors, specifically recognizes the integrin alphavbeta3. Due to its high expression on mature osteoclasts, angiogenic endothelial cells, and tumor cells, integrin alphavbeta3 functions in several pathologic processes important to tumor growth and metastasis. Targeting of this integrin with Abegrin results in antitumor, antiangiogenic, and antiosteolytic activities. Here, we exploit the species specificity of Abegrin to evaluate the effects of direct targeting of tumor cells (independent of targeting of endothelia or osteoclasts). Flow cytometry analysis of human tumor cell lines shows high levels of alphavbeta3 on many solid tumors, including cancers of the prostate, skin, ovary, kidney, lung, and breast. We also show that tumor growth of alphavbeta3-expressing tumor cells is inhibited by Abegrin in a dose-dependent manner. We present a novel finding that high-dose administration can actively impair the antitumor activity of Abegrin. We also provide evidence that antibody-dependent cellular cytotoxicity contributes to in vitro and in vivo antitumor activity. Finally, it was observed that peak biological activity of Abegrin arises at serum levels that are consistent with those achieved in clinical trials. These results support a concept that Abegrin can be used to achieve selective targeting of the many tumor cells that express alphavbeta3 integrin. In combination with the well-established concept that alphavbeta3 plays a key role in cancer-associated angiogenesis and osteolytic activities, this triad of activity could provide new opportunities for therapeutic targeting of cancer.
Assuntos
Anticorpos Monoclonais/farmacologia , Integrina alfaVbeta3/imunologia , Neoplasias/terapia , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais Humanizados , Citotoxicidade Celular Dependente de Anticorpos , Linhagem Celular Tumoral , Relação Dose-Resposta Imunológica , Feminino , Humanos , Integrina alfaVbeta3/biossíntese , Camundongos , Camundongos Nus , Camundongos SCID , Neoplasias/imunologia , Especificidade da Espécie , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The increased expression of G(1) cyclins has been associated with the many types of human tumors. In primary solid tumors however, the expression and activity of cyclin E2, the newest member of the G(1) cyclin family, is largely unknown. In this study we have analysed the expression of the E-type cyclins in primary solid tumors from breast, lung, uterus, ovary, colon, and rectal tissues. Relative gene expression was analysed by quantitative real-time reverse transcription polymerase chain reaction (Taqman). The levels of cyclin E1 and cyclin E2 were significantly elevated (23 vs 38%, respectively) in primary breast tumor samples relative to normal breast tissue controls. We also observed an inverse correlation between the expression of cyclin E1/E2 and estrogen receptor in breast tumors. Our results demonstrate that the expression and associated catalytic activity for both cyclin E1 and cyclin E2 is elevated in primary breast tumors when compared to normal breast tissue. The increased level of cyclin E2 in breast tumors suggests that, similar to cyclin E1, it may contribute to the pathogenesis of breast cancer.
Assuntos
Neoplasias da Mama/genética , Quinases Ciclina-Dependentes/genética , Ciclinas/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Neoplasias Colorretais , Ciclina E , Feminino , Regulação Enzimológica da Expressão Gênica , Neoplasias dos Genitais Femininos , Humanos , Neoplasias Pulmonares , Especificidade de Órgãos , Valores de Referência , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais CultivadasRESUMO
The eukaryotic cell cycle is regulated by a family of serine/threonine protein kinases known as cyclin-dependent kinases (CDKs). The activation of a CDK is dependent on its association with a cyclin regulatory subunit. The formation of distinct cyclin-CDK complexes controls the progression through the first gap phase (G(1)) and initiation of DNA synthesis (S phase). These complexes are in turn regulated by protein phosphorylation and cyclin-dependent kinase inhibitors (CKIs). Cyclin E2 has emerged as the second member of the E-type cyclin family. Cyclin E2-associated kinase activity is regulated in a cell cycle dependent manner with peak activity at the G(1) to S transition. Ectopic expression of cyclin E2 in human cells accelerates G(1), suggesting that cyclin E2 is rate limiting for G(1) progression. Although the pattern and level of cyclin E2 expression in some primary tumor and normal tissue RNAs are distinct from cyclin E1, both E-type cyclins appear to have inherent functional redundancies. This functional redundancy has facilitated the rapid characterization of cyclin E2 and uncovered unique features associated with each E-type cyclin.
Assuntos
Ciclo Celular , Ciclinas/fisiologia , Motivos de Aminoácidos , Sequência de Aminoácidos , Animais , Sequência Conservada , Quinases Ciclina-Dependentes/fisiologia , Ciclinas/química , Previsões , Humanos , Dados de Sequência Molecular , Neoplasias/etiologia , Estrutura Terciária de Proteína , RNA Mensageiro/metabolismo , Alinhamento de SequênciaRESUMO
Individual or combinations of somatic mutations found in genes from colorectal cancers can redirect the effects of chemotherapy and targeted agents on cancer cell survival and, consequently, on clinical outcome. Novel therapeutics with mechanisms of action that are independent of mutational status would therefore fulfill a current unmet clinical need. Here the CEA and CD3 bispecific single-chain antibody MEDI-565 (also known as MT111 and AMG 211) was evaluated for its ability to activate T cells both in vitro and in vivo and to kill human tumor cell lines harboring various somatic mutations commonly found in colorectal cancers. MEDI-565 specifically bound to normal and malignant tissues in a CEA-specific manner, and only killed CEA positive cells. The BiTE® antibody construct mediated T cell-directed killing of CEA positive tumor cells within 6 hours, at low effector-to-target ratios which were independent of high concentrations of soluble CEA. The potency of in vitro lysis was dependent on CEA antigen density but independent of the mutational status in cancer cell lines. Importantly, individual or combinations of mutated KRAS and BRAF oncogenes, activating PI3KCA mutations, loss of PTEN expression, and loss-of-function mutations in TP53 did not reduce the activity in vitro. MEDI-565 also prevented growth of human xenograft tumors which harbored various mutations. These findings suggest that MEDI-565 represents a potential treatment option for patients with CEA positive tumors of diverse origin, including those with individual or combinations of somatic mutations that may be less responsive to chemotherapy and other targeted agents.
Assuntos
Anticorpos Biespecíficos/farmacologia , Citotoxicidade Imunológica/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Linfócitos T/efeitos dos fármacos , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Animais , Anticorpos Biespecíficos/imunologia , Complexo CD3/imunologia , Células CHO , Antígeno Carcinoembrionário/imunologia , Linhagem Celular Tumoral , Células Cultivadas , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Cricetinae , Cricetulus , Citotoxicidade Imunológica/imunologia , Feminino , Células HT29 , Células HeLa , Humanos , Ativação Linfocitária/imunologia , Masculino , Camundongos SCID , Mutação , Neoplasias/genética , Neoplasias/imunologia , Ligação Proteica/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
EphB4 is a member of the Eph receptor tyrosine kinase family shown to act in neuronal guidance and mediate venal/arterial separation. In contrast to these more established roles, EphB4's function in cancer is much less clear. Here we illustrate both tumor promoting as well as suppressing roles of EphB4, by showing that its activation resulted in inhibition of the Ras/ERK pathway in endothelial cells but activation of the same pathway in MCF-7 breast cancer cells. This was true if EphB4 was stimulated with EphrinB2, its natural ligand, or an agonistic monoclonal antibody for EphB4. Correspondingly, EphB4 activation stimulated MCF7 growth while inhibiting HUVEC cell proliferation. The reason for these dramatic differences is due to functional coupling of EphB4 to different downstream effectors. Reduction of p120 RasGAP in HUVEC cells attenuated the inhibitory effect of EphB4 activation on the ERK pathway, whereas knockdown of PP2A in MCF7 cells attenuated EphB4 activation of the ERK pathway. This represents the first time a functional coupling between Eph receptor and PP2A has been demonstrated leading to activation of an oncogenic pathway. Our study illustrates the caveats and potential challenges of targeting EphB4 for cancer therapy due to the conflicting effects on cancer cell and endothelial cell compartments.
Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Sistema de Sinalização das MAP Quinases , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Neoplasias/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Receptor EphB4/metabolismo , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Efrina-B2/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neoplasias/enzimologia , Receptor EphB4/agonistas , Receptor EphB4/imunologiaRESUMO
Angiopoietin 2 (Ang2) is an important regulator of angiogenesis, blood vessel maturation and integrity of the vascular endothelium. The correlation between the dynamic expression of Ang2 in tumors with regions of high angiogenic activity and a poor prognosis in many tumor types makes Ang2 an ideal drug target. We have generated MEDI3617, a human anti-Ang2 monoclonal antibody that neutralizes Ang2 by preventing its binding to the Tie2 receptor in vitro, and inhibits angiogenesis and tumor growth in vivo. Treatment of mice with MEDI3617 resulted in inhibition of angiogenesis in several mouse models including: FGF2-induced angiogenesis in a basement extract plug model, tumor and retinal angiogenesis. In xenograft tumor models, treatment with MEDI3617 resulted in a reduction in tumor angiogenesis and an increase in tumor hypoxia. The administration of MEDI3617 as a single agent to mice bearing human tumor xenografts resulted in tumor growth inhibition against a broad spectrum of tumor types. Combining MEDI3617 with chemotherapy or bevacizumab resulted in a delay in tumor growth and no body weight loss was observed in the combination groups. These results, combined with pharmacodynamic studies, demonstrate that treatment of tumor-bearing mice with MEDI3617 significantly inhibited tumor growth as a single agent by blocking tumor angiogenesis. Together, these data show that MEDI3617 is a robust antiangiogenic agent and support the clinical evaluation and biomarker development of MEDI3617 in cancer patients.
Assuntos
Inibidores da Angiogênese/farmacologia , Angiopoietina-2/antagonistas & inibidores , Anticorpos Monoclonais/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias/tratamento farmacológico , Neovascularização Patológica/prevenção & controle , Inibidores da Angiogênese/administração & dosagem , Angiopoietina-2/imunologia , Angiopoietina-2/metabolismo , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Bevacizumab , Linhagem Celular Tumoral , Molde por Corrosão , Relação Dose-Resposta a Droga , Feminino , Fluorescência , Células HEK293 , Humanos , Camundongos , Camundongos Nus , Neoplasias/irrigação sanguínea , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/patologia , Neovascularização Patológica/imunologia , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Neovascularização Fisiológica/efeitos dos fármacos , Paclitaxel/administração & dosagem , Fosforilação , Receptor TIE-2/genética , Receptor TIE-2/metabolismo , Neovascularização Retiniana/imunologia , Neovascularização Retiniana/metabolismo , Neovascularização Retiniana/prevenção & controle , Fatores de Tempo , Transfecção , Carga Tumoral/efeitos dos fármacos , Microtomografia por Raio-X , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The discovery of aurora kinases as essential regulators of cell division has led to intense interest in identifying small molecule aurora kinase inhibitors for the potential treatment of cancer. A high-throughput screening effort identified pyridinyl-pyrimidine 6a as a moderately potent dual inhibitor of aurora kinases -A and -B. Optimization of this hit resulted in an anthranilamide lead (6j) that possessed improved enzyme and cellular activity and exhibited a high level of kinase selectivity. However, this anthranilamide and subsequent analogues suffered from a lack of oral bioavailability. Converting the internally hydrogen-bonded six-membered pseudo-ring of the anthranilamide to a phthalazine (8a-b) led to a dramatic improvement in oral bioavailability (38-61%F) while maintaining the potency and selectivity characteristics of the anthranilamide series. In a COLO 205 tumor pharmacodynamic assay measuring phosphorylation of the aurora-B substrate histone H3 at serine 10 (p-histone H3), oral administration of 8b at 50 mg/kg demonstrated significant reduction in tumor p-histone H3 for at least 6 h.
Assuntos
Antineoplásicos/síntese química , Ftalazinas/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Piridinas/síntese química , Pirimidinas/síntese química , Administração Oral , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Aurora Quinase B , Aurora Quinases , Disponibilidade Biológica , Proteínas Sanguíneas/metabolismo , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Histonas/metabolismo , Humanos , Técnicas In Vitro , Masculino , Camundongos , Camundongos Nus , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Transplante de Neoplasias , Ftalazinas/farmacocinética , Ftalazinas/farmacologia , Ligação Proteica , Piridinas/farmacocinética , Piridinas/farmacologia , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Transplante HeterólogoRESUMO
In recent decades, mAbs have been used increasingly as targeted therapeutics for various diseases. However, the selective nature of antibodies can often lead to mAbs that do not recognize the target antigen in a preclinical model species used in studies of in vivo efficacy and safety. This feature review article focuses on the use of alternative animal models and surrogate antibodies for studies of efficacy for cases in which the primary therapeutic antibody does not recognize the antigen in a relevant species. In addition, the use of rodent and non-human primate models for preclinical safety studies with mAbs is discussed.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Avaliação Pré-Clínica de Medicamentos/métodos , Modelos Biológicos , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/toxicidade , Antígenos/imunologia , Humanos , Modelos Animais , Especificidade da Espécie , Testes de Toxicidade/métodosRESUMO
IPI-504 is a novel, highly soluble small-molecule inhibitor of heat shock protein 90 (Hsp90), a protein chaperone essential for regulating homeostasis of oncoproteins and cell signaling proteins. Human epidermal growth factor receptor 2 (HER2; ErbB2) oncoprotein, expressed in a subset of metastatic breast cancers, is a Hsp90 client protein. In this study, we investigated the antitumor activity and the mechanism of action of IPI-504 in HER2(+), trastuzumab-sensitive and trastuzumab-refractory cell lines in vitro and in vivo. IPI-504 exhibited potent antiproliferative activities (range of IC(50), 10-40 nmol/L) against several tumor cell lines examined, whereby mechanism of action was mediated through HER2 and Akt degradation. Both intravenous and oral administration of IPI-504 assessed in multiple schedules showed potent tumor growth inhibition in vivo with corresponding degradation of HER2. The tolerability and efficacy of IPI-504 combined with either trastuzumab or lapatinib were also investigated in HER2(+) tumor xenograft models. Combination of IPI-504 with trastuzumab significantly enhanced tumor growth delay and induced greater responses when compared with either agent alone. Although, as expected, trastuzumab alone did not exhibit any significant antitumor activity in the trastuzumab-resistant JIMT-1 model, IPI-504 administered in combination with trastuzumab yielded greater antitumor efficacy than either agent alone. Finally, combination of IPI-504 and lapatinib was well tolerated up to 50 mg/kg IPI-504 and 100 mg/kg lapatinib and resulted in significant delay in tumor growth, including partial and complete tumor responses. These lines of evidence support the development of IPI-504 in HER2-positive breast cancers as a single agent and in combination with either trastuzumab or lapatinib