Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.951
Filtrar
2.
Surgery ; 167(1): 197-203, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31543319

RESUMO

BACKGROUND: As patient-derived xenografts and other preclinical models of neuroendocrine tumors for testing personalized therapeutics are lacking, we have developed a perfused, 3D bioreactor model to culture tumor surrogates from patient-derived neuroendocrine tumors. This work evaluates the duration of surrogate culture and surrogate response to a novel antibody-drug conjugate. METHODS: Twenty-seven patient-derived neuroendocrine tumors were cultured. Histologic sections of a pancreatic neuroendocrine tumor xenograft (BON-1) tumor were assessed for SSTR2 expression before tumor implantation into 2 bioreactors. One surrogate was treated with an antibody-drug conjugate composed of an anti-mitotic Monomethyl auristatin-E linked to a somatostatin receptor 2 antibody. Viability and therapeutic response were assessed by pre-imaging incubation with IR-783 and the RealTime-Glo AnnexinV Apoptosis and Necrosis Assay (Promega Corporation, Madison, WI) over 6 days. A primary human pancreatic neuroendocrine tumor was evaluated similarly. RESULTS: Mean surrogate growth duration was 34.8 days. Treated BON-1 surrogates exhibited less proliferation (1.2 vs 1.9-fold) and greater apoptosis (1.5 vs 1.1-fold) than controls, whereas treated patient-derived neuroendocrine tumor bioreactors exhibited greater degrees of apoptosis (13- vs 9-fold) and necrosis (2.5- vs 1.6-fold). CONCLUSION: Patient-derived neuroendocrine tumor surrogates can be cultured reliably within the bioreactor. This model can be used to evaluate the efficacy of antibody-guided chemotherapy ex vivo and may be useful for predicting clinical responses.


Assuntos
Reatores Biológicos , Ensaios de Seleção de Medicamentos Antitumorais/instrumentação , Imunoconjugados/farmacologia , Tumores Neuroendócrinos/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Cultura Primária de Células/instrumentação , Animais , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Humanos , Imunoconjugados/uso terapêutico , Masculino , Camundongos , Terapia de Alvo Molecular/métodos , Tumores Neuroendócrinos/patologia , Oligopeptídeos/farmacologia , Oligopeptídeos/uso terapêutico , Neoplasias Pancreáticas/patologia , Cultura Primária de Células/métodos , Receptores de Somatostatina/antagonistas & inibidores , Reprodutibilidade dos Testes , Células Tumorais Cultivadas
3.
Chem Commun (Camb) ; 55(96): 14506-14509, 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31735949

RESUMO

Polymers are an attractive anchoring platform for the synthesis of radioimmunoconjugates. They enable independent control over the amount of radioisotope loading and antibody attachment, which is pivotal in developing tailorable formulations for personalised medicine. Herein, we report the synthesis of p(HEMA-ran-GMA) for the conjugation of lutetium ions and rituximab as a functional platform for radioimmunotherapy. We demonstrate the suitability of this platform using non-Hodgkin's lymphoma cells.


Assuntos
Imunoconjugados/química , Linfoma não Hodgkin/radioterapia , Radioimunoterapia , Antineoplásicos Imunológicos/química , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Química Click , Compostos de Epóxi/química , Humanos , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Lutécio/química , Metacrilatos/química , Polímeros/química , Rituximab/química , Rituximab/farmacologia , Rituximab/uso terapêutico
4.
Drugs Today (Barc) ; 55(9): 575-585, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31584574

RESUMO

Patients with metastatic triple-negative breast cancer (mTNBC) that has progressed on first-line therapy have a poor prognosis with limited therapeutic options. Sacituzumab govitecan (SG) is a novel antibody-drug conjugate (ADC) that has shown promising efficacy in mTNBC. SG is comprised of SN-38, the active metabolite of irinotecan, conjugated via a hydrolyzable linker to the humanized RS7 antibody targeting trophoblast cell surface antigen 2 (Trop-2), a glycoprotein that is expressed at high levels in many epithelial solid tumors. It has received breakthrough therapy status by the U.S. Food and Drug Administration (FDA) for the treatment of patients with pretreated mTNBC. In this review, we summarize available data regarding the pharmacology, pharmacokinetics, safety and efficacy of SG and describe ongoing and future clinical studies investigating this agent.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Camptotecina/análogos & derivados , Imunoconjugados/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Antígenos de Neoplasias , Camptotecina/uso terapêutico , Moléculas de Adesão Celular , Feminino , Humanos , Estados Unidos , United States Food and Drug Administration
5.
Dtsch Med Wochenschr ; 144(20): 1400-1404, 2019 10.
Artigo em Alemão | MEDLINE | ID: mdl-31594013

RESUMO

NEW WHO CLASSIFICATION 2016 FOR LYMPHOMA AND MOLECULAR MARKER: The new WHO 2016 Classification for Lymphomas included more detailed definitions of individual entities, such as: the Anaplastic Large Cell Lymphoma, ALK; the terminus of enteropathy-associated T-cell lymphoma (EATCL, type 1) now is restricted to celiac-associated form. The integration of next Generation sequencing (NGS) enables better differential diagnostics, e. g. angioimmunoblastic lymphoma (AITL) can be characterized by the presence of TET2, RHOA, IDH2 or DNMT3A mutations. Furthermore, certain mutations also have prognostic impact. In ALCL/ALK-, evidence of a DUSP22 / IRF4 re-arrangement is associated with a better and detection of TP63 is associated with a worse prognosis. CLINICAL COURSE AND PROGNOSIS: In addition to B symptoms and nodal manifestation, extranodal manifestations such as skin infiltrates can be observed in up to 20 %. In AITL, polyclonal hypergammaglobulinemia, Coombs-positive hemolytic anemia and immunodeficiency can occur, as a sign of a dysregulated immune system. ADVANCES IN THERAPY: By combining the immunoconjugate brentuximab-vedotin with chemotherapy, improvement in disease-free and overall survival in CD30+-PTCL (especially in ALCL) was observed. FUTURE PERSPECTIVE: At present demethylating agent 5-azacytidine is explored in AITL and PTCL with a T-follicle helper type (TFH).


Assuntos
Linfoma de Células T Periférico , Antineoplásicos/uso terapêutico , Análise Mutacional de DNA , Diagnóstico Diferencial , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunoconjugados/uso terapêutico , Linfoma de Células T Periférico/diagnóstico , Linfoma de Células T Periférico/genética , Linfoma de Células T Periférico/terapia , Mutação/genética
6.
Eur J Med Chem ; 183: 111682, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31563805

RESUMO

Targeted drug delivery has improved cancer treatment significantly in recent years, although it is difficult to achieve. Different approaches have been developed to apply targeted drug delivery. Among which, antibody-drug conjugate (ADC) provides a potentially ideal solution to such a challenge. ADC is an innovative drug treatment model with three key components: payload, monoclonal antibody, and linker. The monoclonal antibody targets the antigen-expressing tumor cells and internalizes the payload linked by the linker to the target cells to reduce the side effects of the traditional chemotherapy drugs. The off-target effect has an excellent therapeutic prospect. Among them, ado-trastuzumab emtansine (T-DM1) is a successful example of targeting human epidermal growth factor receptor-2 (HER2). Its antibody (trastuzumab) is derived from Herceptin with annual sales of more than $6 billion. It has excellent targeting and specific anti-tumor activity against HER2. Its linker is not cleavable and releases the Lys-linker-payload to kill the cells. The two ADCs described here use the same antibody as T-DM1, but the cleavable linker and the more toxic payload allow them to have the not only targeting of T-DM1, but also the reduce T-DM1 resistance and improve efficacy in heterogeneous tumors. This paper describes the mechanism of action and the biochemical characteristics of different parts and preclinical and clinical progress of trastuzumab deruxtecan(DS-8201a) and (vic-)trastuzumab duocarmazine (SYD985).


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/farmacologia , Camptotecina/análogos & derivados , Imunoconjugados/farmacologia , Receptor ErbB-2/metabolismo , Trastuzumab/farmacologia , /farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Camptotecina/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Ensaios Clínicos como Assunto , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Imunoconjugados/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológico , Trastuzumab/uso terapêutico
7.
Int J Mol Sci ; 20(18)2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31491952

RESUMO

The prognosis for non-resectable or recurrent osteosarcoma (OS) remains poor. The finding that the majority of OS overexpress the protooncogene HER2 raises the possibility of using HER2 as a therapeutic target. However, clinical trials on the anti-HER2 antibody trastuzumab (TRA) in treating OS find no therapeutic benefit. HER2 overexpression in OS is not generally associated with gene amplification, with low-level expression regarded as HER2 "negative", as per criteria used to classify breast cancer HER2 status. Nevertheless, active HER2-targeting approaches, such as virus-based HER2 vaccines or CAR-T cells have generated promising results. More recently, it has been found that the noncovalent association of TRA with nanomaterial graphene oxide (GO) generates stable TRA/GO complexes capable of rapidly killing OS cells. TRA/GO induces oxidative stress and strong HER2 signaling to elicit immediate degradation of both cIAP (cellular inhibitor of apoptosis protein) and caspase 8, leading to activation of necroptosis. This is an attractive mechanism of cancer cell death as chemo/apoptosis-resistant tumors may remain susceptible to necroptosis. In addition, necroptosis is potentially immunogenic to promote tumor immunity, as opposed to apoptosis that tends to silence tumor immunity. Currently, no established anticancer therapeutics are known to eliminate cancers by necroptosis. The aim of this article is to review the rationale and mechanisms of TRA/GO-mediated cytotoxicity.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Grafite , Imunoconjugados/uso terapêutico , Osteossarcoma/tratamento farmacológico , Osteossarcoma/patologia , Receptor ErbB-2/antagonistas & inibidores , Animais , Antineoplásicos Imunológicos/química , Antineoplásicos Imunológicos/farmacologia , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Grafite/química , Humanos , Imunoconjugados/química , Imunoconjugados/farmacologia , Osteossarcoma/etiologia , Osteossarcoma/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Transdução de Sinais , Trastuzumab/química , Trastuzumab/farmacologia , Trastuzumab/uso terapêutico , Resultado do Tratamento
8.
Mol Carcinog ; 58(12): 2306-2315, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31545001

RESUMO

Syndecan-1 (CD138) is a transmembrane proteoglycan expressed in normal and malignant tissues. It is of interest because of a possible prognostic effect in tumors and as a target for Indatuximab, a monoclonal antibody coupled to a cytotoxic agent. To assess the prognostic role of CD138 expression in breast cancer (BCa), a tissue microarray containing 1535 BCa specimens was analyzed by immunohistochemistry. Cytoplasmic, membranous, and stromal CD138 staining was separately analyzed. In normal breast tissue, CD138 staining was limited to epithelial cell membranes. In cancers, membranous staining tended to become weaker or even disappeared (38.3% of cancers with absence of membranous staining) but cytoplasmic and stromal staining newly appeared in 29.7% and 58.1% of cancers. Loss of membranous epithelial CD138 staining as well as presence of cytoplasmic and stromal CD138 positivity were-to a variable degree-associated with high pT, high grade, nodal metastasis, estrogen receptor-negative, progesterone receptor-negative, human epidermal growth factor receptor 2+, and poor overall patient survival. A combined analysis of epithelial and stromal CD138 expression revealed a link to overall patient survival (P < .0001) with best prognosis for patients with stromal positivity and absence of cytoplasmic staining, the worst prognosis for cancers with cytoplasmic staining and stromal negativity and intermediate prognosis for patients having either cytoplasmic staining or stromal negativity. In multivariate analyses, CD138 was not independent of established prognostic features. In summary, these data reveal a compartment depending prognostic effect of CD138 expression in BCa with cytoplasmic positivity being linked to aggressive cancer and stromal CD138 being linked to a more favorable prognosis.


Assuntos
Biomarcadores Tumorais/biossíntese , Neoplasias da Mama/metabolismo , Membrana Celular/metabolismo , Citoplasma/metabolismo , Células Estromais/metabolismo , Sindecana-1/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Células Epiteliais/metabolismo , Feminino , Humanos , Imunoconjugados/uso terapêutico , Imuno-Histoquímica , Maitansina/análogos & derivados , Maitansina/uso terapêutico , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Prognóstico , Análise de Sobrevida , Sindecana-1/antagonistas & inibidores , Análise Serial de Tecidos/métodos , Adulto Jovem
9.
Blood ; 134(15): 1247-1256, 2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31395601

RESUMO

Minimal residual disease (MRD) has become an increasingly prevalent and important entity in multiple myeloma (MM). Despite deepening responses to frontline therapy, roughly 75% of MM patients never become MRD-negative to ≤10-5, which is concerning because MRD-negative status predicts significantly longer survival. MM is highly heterogeneous, and MRD persistence may reflect survival of isolated single cells and small clusters of treatment-resistant subclones. Virtually all MM clones are exquisitely sensitive to radiation, and the α-emitter astatine-211 (211At) deposits prodigious energy within 3 cell diameters, which is ideal for eliminating MRD if effectively targeted. CD38 is a proven MM target, and we conjugated 211At to an anti-CD38 monoclonal antibody to create an 211At-CD38 therapy. When examined in a bulky xenograft model of MM, single-dose 211At-CD38 at 15 to 45 µCi at least doubled median survival of mice relative to untreated controls (P < .003), but no mice achieved complete remission and all died within 75 days. In contrast, in a disseminated disease model designed to reflect low-burden MRD, 3 studies demonstrated that single-dose 211At-CD38 at 24 to 45 µCi produced sustained remission and long-term survival (>150 days) for 50% to 80% of mice, where all untreated mice died in 20 to 55 days (P < .0001). Treatment toxicities were transient and minimal. These data suggest that 211At-CD38 offers the potential to eliminate residual MM cell clones in low-disease-burden settings, including MRD. We are optimistic that, in a planned clinical trial, addition of 211At-CD38 to an autologous stem cell transplant (ASCT) conditioning regimen may improve ASCT outcomes for MM patients.


Assuntos
ADP-Ribosil Ciclase 1 , Astato/uso terapêutico , Imunoconjugados/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Neoplasia Residual/tratamento farmacológico , ADP-Ribosil Ciclase 1/análise , Astato/administração & dosagem , Astato/farmacocinética , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Imunoconjugados/administração & dosagem , Imunoconjugados/farmacocinética , Masculino , Mieloma Múltiplo/patologia , Neoplasia Residual/patologia
10.
Int J Mol Sci ; 20(16)2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31408937

RESUMO

Wilms tumor 1 (WT1) oncoprotein is an intracellular oncogenic transcription factor which is barely expressed in normal adult tissues but over expressed in a variety of leukemias and solid cancers. WT1-derived HLA-A*02:01 T cell epitope, RMFPNAPYL (RMF), is a validated target for T cell-based immunotherapy. We generated two T cell receptor mimic antibody-drug conjugates (TCRm-ADCs), ESK-MMAE, and Q2L-MMAE, against WT1 RMF/HLA-A*02:01 complex with distinct affinities, which mediate specific antitumor activity. Although ESK-MMAE showed higher tumor growth inhibition ratio in vivo, the efficacy of them was not so promising, which might be due to low expression of peptide/HLA targets. Therefore, we explored a bispecific TCRm-ADC that exerted more potent tumor cytotoxicity compared with TCRm-ADCs. Hence, our findings validate the feasibility of the presenting intracellular peptides as the targets of ADCs, which broadens the antigen selection range of antibody-based drugs and provides new strategies for precision medicine in tumor therapy.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Imunoconjugados/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Proteínas WT1/imunologia , Tumor de Wilms/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Antígenos HLA-A/imunologia , Humanos , Neoplasias Renais/imunologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Receptores de Antígenos de Linfócitos T/imunologia , Tumor de Wilms/imunologia
11.
Nat Commun ; 10(1): 3874, 2019 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-31462678

RESUMO

While IL-2 can potently activate both NK and T cells, its short in vivo half-life, severe toxicity, and propensity to amplify Treg cells are major barriers that prevent IL-2 from being widely used for cancer therapy. In this study, we construct a recombinant IL-2 immunocytokine comprising a tumor-targeting antibody (Ab) and a super mutant IL-2 (sumIL-2) with decreased CD25 binding and increased CD122 binding. The Ab-sumIL2 significantly enhances antitumor activity through tumor targeting and specific binding to cytotoxic T lymphocytes (CTLs). We also observe that pre-existing CTLs within the tumor are sufficient and essential for sumIL-2 therapy. This next-generation IL-2 can also overcome targeted therapy-associated resistance. In addition, preoperative sumIL-2 treatment extends survival much longer than standard adjuvant therapy. Finally, Ab-sumIL2 overcomes resistance to immune checkpoint blockade through concurrent immunotherapies. Therefore, this next-generation IL-2 reduces toxicity while increasing TILs that potentiate combined cancer therapies.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Imunoconjugados/farmacologia , Interleucina-2/farmacologia , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Linhagem Celular Tumoral/transplante , Cetuximab/farmacologia , Cetuximab/uso terapêutico , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/imunologia , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Humanos , Imunoconjugados/genética , Imunoconjugados/uso terapêutico , Interleucina-2/genética , Interleucina-2/uso terapêutico , Subunidade alfa de Receptor de Interleucina-2/imunologia , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Subunidade beta de Receptor de Interleucina-2/imunologia , Subunidade beta de Receptor de Interleucina-2/metabolismo , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Mutação , Neoplasias/imunologia , Neoplasias/patologia , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/imunologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Resultado do Tratamento
12.
ACS Appl Mater Interfaces ; 11(30): 26637-26647, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31276378

RESUMO

Stimulation of Toll-like receptors (TLRs) and/or NOD-like receptors on immune cells initiates and directs immune responses that are essential for vaccine adjuvants. The small-molecule TLR7 agonist, imiquimod, has been approved by the FDA as an immune response modifier but is limited to topical application due to its poor pharmacokinetics that causes undesired adverse effects. Nanoparticles are increasingly used with innate immune stimulators to mitigate side effects and enhance adjuvant efficacy. In this study, a potent small-molecule TLR7 agonist, 2-methoxyethoxy-8-oxo-9-(4-carboxybenzyl)adenine (1V209), was conjugated to hollow silica nanoshells (NS). Proinflammatory cytokine (IL-6, IL-12) release by mouse bone-marrow-derived dendritic cells and human peripheral blood mononuclear cells revealed that the potency of silica nanoshells-TLR7 conjugates (NS-TLR) depends on nanoshell size and ligand coating density. Silica nanoshells of 100 nm diameter coated with a minimum of ∼6000 1V209 ligands/particle displayed 3-fold higher potency with no observed cytotoxicity when compared to an unconjugated TLR7 agonist. NS-TLR activated the TLR7-signaling pathway, triggered caspase activity, and stimulated IL-1ß release, while neither unconjugated TLR7 ligands nor silica shells alone produced IL-1ß. An in vivo murine immunization study, using the model antigen ovalbumin, demonstrated that NS-TLR increased antigen-specific IgG antibody induction by 1000× with a Th1-biased immune response, compared to unconjugated TLR7 agonists. The results show that the TLR7 ligand conjugated to silica nanoshells is capable of activating an inflammasome pathway to enhance both innate immune-stimulatory and adjuvant potencies of the TLR7 agonist, thereby broadening applications of innate immune stimulators.


Assuntos
Imiquimode/imunologia , Imunidade Inata/efeitos dos fármacos , Imunoconjugados/imunologia , Receptor 7 Toll-Like/imunologia , Adjuvantes Imunológicos/química , Adjuvantes Imunológicos/farmacologia , Animais , Células da Medula Óssea/efeitos dos fármacos , Humanos , Imiquimode/química , Imiquimode/uso terapêutico , Imunidade Inata/genética , Imunoconjugados/química , Imunoconjugados/uso terapêutico , Interleucina-12/genética , Interleucina-12/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Camundongos , Nanoconchas/química , Transdução de Sinais/efeitos dos fármacos , Dióxido de Silício/química , Receptor 7 Toll-Like/agonistas , Receptor 7 Toll-Like/genética
13.
BioDrugs ; 33(4): 401-409, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31302863

RESUMO

Three prospective controlled clinical trials and numerous small series and case reports have confirmed that durable, drug-free remission in systemic sclerosis is possible via an autologous hematopoietic stem cell transplantation. Similar results have been seen in other autoimmune diseases. The exact mechanism by which this immune "reset" was achieved in some but not all cases remains elusive, but includes major reduction of autoreactive immune competent cells, re-establishment of T- and B cell regulatory networks and normalization of tissue niche function, particularly vascular. Some aspects regarding mobilization, conditioning and graft manipulation still remain open, but clearly a significant toxicity is associated with all effective regimens at present, and therefore patient selection remains a key issue. In the hematology/oncology arena, major efforts are being made to reduce genotoxic and other collateral toxicity induced by current mobilization and conditioning protocols, which may also translate to autoimmune disease. These include developments in rapid mobilization and antibody drug conjugate conditioning technology. If effective, such low-toxicity regimens might be applied to autoimmune disease at an earlier stage before chronicity of autoimmunity has been established, thus changing the therapeutic paradigm.


Assuntos
Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/métodos , Imunoconjugados/uso terapêutico , Escleroderma Sistêmico/terapia , Condicionamento Pré-Transplante/métodos , Ensaios Clínicos Controlados como Assunto , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Estudos Prospectivos , Escleroderma Sistêmico/imunologia , Transplante Autólogo/efeitos adversos , Transplante Autólogo/métodos , Transplante Homólogo/efeitos adversos , Transplante Homólogo/métodos , Resultado do Tratamento
14.
Int J Med Sci ; 16(7): 1032-1041, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31341417

RESUMO

AP25 is an anti-tumor peptide with a high affinity for integrins. It exerts its anti-tumor activity by inhibiting angiogenesis and by directly inhibiting the growth of tumor cells. Its half-life time in vivo is only about 50 minutes, which limits its clinical application. In order to prolong the half-life time of AP25 while preserving its anti-tumor activity, several fusion proteins of AP25 and IgG4 Fc were designed and expressed; their anti-tumor activity and pharmacokinetics properties were evaluated. Firstly, four AP25-Fc fusion protein sequences were designed, and the corresponding proteins were expressed and purified. Based on the results of HUVEC migration inhibition assay, HUVEC and tumor cell proliferation inhibition assay and yields of expression by HEK293 cells, the fusion protein designated PSG4R was selected for further evaluation. The anti-tumor effect of PSG4R was then evaluated in vivo on HCT-116 nude mice xenograft model. And the pharmacokinetics properties of PSG4R were investigated in rats. The results showed that PSG4R could inhibit the growth of xenografts of human colon cancer cell line HCT-116 in nude mice by intravenous administration of 40 mg/kg once every two days. The half-life time of PSG4R was 56.270 ± 15.398 h. This study showed that the construction of AP25-Fc fusion protein could significantly prolong the half-life of AP25 while retaining its anti-tumor activity, which provides a new direction for new drug development of AP25.


Assuntos
Endostatinas/farmacologia , Imunoconjugados/farmacologia , Imunoglobulina G/farmacologia , Neoplasias/tratamento farmacológico , Fragmentos de Peptídeos/farmacologia , Proteínas Recombinantes de Fusão/farmacologia , Administração Intravenosa , Animais , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Endostatinas/genética , Endostatinas/uso terapêutico , Feminino , Células HCT116 , Células HEK293 , Meia-Vida , Células Endoteliais da Veia Umbilical Humana , Humanos , Imunoconjugados/genética , Imunoconjugados/uso terapêutico , Imunoglobulina G/genética , Imunoglobulina G/uso terapêutico , Masculino , Camundongos , Modelos Animais , Neoplasias/patologia , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/uso terapêutico , Ratos , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/uso terapêutico , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Int J Radiat Oncol Biol Phys ; 105(2): 410-422, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31255687

RESUMO

PURPOSE: Fibroblast growth factor receptor 2 (FGFR2) has been previously reported to be overexpressed in several types of cancer, whereas the expression in normal tissue is considered to be moderate to low. Thus, FGFR2 is regarded as an attractive tumor antigen for targeted alpha therapy. This study reports the evaluation of an FGFR2-targeted thorium-227 conjugate (FGFR2-TTC, BAY 2304058) comprising an anti-FGFR2 antibody, a chelator moiety covalently conjugated to the antibody, and the alpha particle-emitting radionuclide thorium-227. FGFR2-TTC was assessed as a monotherapy and in combination with the DNA damage response inhibitor ATRi BAY 1895344. METHODS AND MATERIALS: The in vitro cytotoxicity and mechanism of action were evaluated by determining cell viability, the DNA damage response marker γH2A.X, and cell cycle analyses. The in vivo efficacy was determined using human tumor xenograft models in nude mice. RESULTS: In vitro mechanistic assays demonstrated upregulation of γH2A.X and induction of cell cycle arrest in several FGFR2-expressing cancer cell lines after treatment with FGFR2-TTC. In vivo, FGFR2-TTC significantly inhibited tumor growth at a dose of 500 kBq/kg in the xenograft models NCI-H716, SNU-16, and MFM-223. By combining FGFR2-TTC with the ATR inhibitor BAY 1895344, an increased potency was observed in vitro, as were elevated levels of γH2A.X and inhibition of FGFR2-TTC-mediated cell cycle arrest. In the MFM-223 tumor xenograft model, combination of the ATRi BAY 1895344 with FGFR2-TTC resulted in significant tumor growth inhibition at doses at which the single agents had no effect. CONCLUSIONS: The data provide a mechanism-based rationale for combining the FGFR2-TTC with the ATRi BAY 1895344 as a new therapeutic approach for treatment of FGFR2-positive tumors from different cancer indications.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Neoplasias da Mama/radioterapia , Inibidores de Proteínas Quinases/uso terapêutico , Radioimunoterapia/métodos , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/uso terapêutico , Tório/uso terapêutico , Animais , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quelantes/uso terapêutico , Dano ao DNA , Combinação de Medicamentos , Sinergismo Farmacológico , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos da radiação , Histonas/metabolismo , Humanos , Imunoconjugados/química , Imunoconjugados/farmacocinética , Imunoconjugados/uso terapêutico , Camundongos , Camundongos Nus , Terapia de Alvo Molecular/métodos , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Tório/farmacocinética , Compostos de Tório/uso terapêutico , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Presse Med ; 48(10): 1131-1137, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31151842

RESUMO

Managing endocrine resistance and resistance to endocrine therapy for ER+ HER2- breast cancer with the CDK 4/6 inhibitors in the metastatic setting. New antibodies drug conjugates for HER2+ and TNBC. Targeting DNA damage and synthetic lethality strategies with PARP inhibitors for breast cancer patients harboring BRCA mutation. Immunotherapies in 1st line metastatic setting of TNBC.


Assuntos
Neoplasias da Mama/terapia , Neoplasias da Mama/química , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Feminino , Humanos , Imunoconjugados/uso terapêutico , Imunoterapia/métodos , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto
17.
MAbs ; 11(6): 987-995, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31208270

RESUMO

Antibody-drug conjugates (ADCs) that exploit the active metabolite SN-38, which is derived from the popular anticancer drug, irinotecan (a camptothecin that inhibits the nuclear topoisomerase I enzyme, inducing double-stranded DNA breaks during the mitotic S-phase of affected cells), represent a substantial advance in the ADC field. SN-38 has been conjugated to a humanized antibody against trophoblast cell surface antigen 2 (TROP-2), which is involved in cancer signaling pathways and has increased expression by many cancer cell types, yielding the ADC sacituzumab govitecan. By conjugating a higher number of SN-38 molecules to the immunoglobulin (drug-to-antibody ratio = 7-8:1), and giving higher (10 mg/kg) and repeated therapy cycles (Days 1 and 8 of 21-day cycles), enhanced drug uptake by the targeted cancer cells is achieved. Based on a unique conjugation method, the lactone ring of the SN-38 molecule is stabilized and the molecule is protected from glucuronidation, a process that contributes to the untoward late diarrhea experienced with irinotecan. Finally, while the ADC is internalized, the use of a moderately stable linker permits release of SN-38 in an acidic environment of the tumor cell and its microenvironment, contributing to a bystander effect on neighboring cancer cells. Here, we discuss the development of sacituzumab govitecan and clinical results obtained using it for the management of patients with advanced, refractive breast, lung, and urinary bladder cancers. Sacituzumab govitecan, which is undergoing accelerated approval review by the US Food and Drug Administration while also being studied in Phase 3 clinical studies, was granted Breakthrough Therapy status from the FDA for advanced, refractory, metastatic triple-negative breast cancer patients.


Assuntos
Anticorpos Monoclonais Humanizados , Camptotecina/análogos & derivados , Moléculas de Adesão Celular/antagonistas & inibidores , Sistemas de Liberação de Medicamentos , Imunoconjugados , Irinotecano , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Microambiente Tumoral/efeitos dos fármacos , Anticorpos Monoclonais Humanizados/química , Anticorpos Monoclonais Humanizados/uso terapêutico , Antígenos de Neoplasias , Camptotecina/química , Camptotecina/uso terapêutico , Ensaios Clínicos Fase III como Assunto , Feminino , Humanos , Imunoconjugados/química , Imunoconjugados/uso terapêutico , Irinotecano/química , Irinotecano/uso terapêutico , Masculino , Neoplasias/metabolismo , Neoplasias/patologia
18.
Hematol Oncol ; 37 Suppl 1: 101-104, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31187537

RESUMO

In recent years, many new antibodies, either naked or armed with toxin or radionuclides have been investigated to enhance the field of active agents directed against already identified ("old") targets. This was particularly the case for the antigens CD19 and CD20 but also some other ones. The success of these developments has been variable and underlines the need to better characterize the mode of action of these molecules. Combinations studies of these new agents with other molecules, in particular those with an immunomodulatory potential, are also currently developed with some promising results.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Animais , Antígenos CD19 , Antígenos CD20 , Antígenos de Neoplasias , Antineoplásicos/farmacologia , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Humanos , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Imunomodulação/efeitos dos fármacos , Neoplasias/etiologia , Neoplasias/metabolismo , Tetraspaninas
19.
Mar Drugs ; 17(6)2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31159276

RESUMO

Currently a few compounds isolated from marine sources have become drugs, mainly directed towards cancer and pain. Compounds from marine sources have exquisite potencies against eukaryotic cells, as they act as protective agents against attack by predators in the marine environment. Their toxicities act as a "double-edged sword" as they are often too toxic for direct use in humans and thus have to be chemically modified. By linking suitably modified compounds to monoclonal antibodies directed against specific epitopes in mammalian cancer cells, they can be delivered to a specific cell type in humans. This review updates and extends an article published in early 2017, demonstrating how by careful chemical modifications, highly toxic compounds, frequently peptidic in nature, can be utilized as antitumor drug candidates. The antibody-drug- conjugates (ADCs) discussed are those that are currently in clinical trials listed in the NIH Clinical Trials Registry as, "currently active, recruiting or in some cases, recently completed". There are also some ADCs discussed that are at the advanced preclinical stage, that in some cases, are repurposing current drug entities, and the review finishes with a short discussion of the aplyronines as potential candidate warheads as a result of scalable synthetic processes.


Assuntos
Toxinas Marinhas/química , Toxinas Marinhas/uso terapêutico , Neoplasias/tratamento farmacológico , Analgésicos/química , Analgésicos/uso terapêutico , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Humanos , Imunoconjugados/uso terapêutico , Dor/tratamento farmacológico
20.
Rinsho Ketsueki ; 60(5): 447-452, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31168012

RESUMO

Hodgkin lymphoma is characterized by CD30 overexpression and downstream NF-κB pathway activation in Hodgkin/Reed-Sternberg (H/RS) cells. Accordingly, CD30 and its aberrant downstream signaling have been investigated as potential treatment targets for the disease. Given that H/RS cells are surrounded by a variety of immune cells that constitute a unique inflammatory and immunoinhibitory microenvironment, efforts have also been made to treat the disease by reversing the abnormal tumor immune milieu. In recent years, a CD30 antibody-drug conjugate and immune checkpoint inhibitors have been approved for the treatment of Hodgkin lymphoma and have demonstrated remarkable treatment efficacy. These new agents have not only contributed to improved survival of patients refractory to conventional chemotherapy but have also enabled further understanding on the molecular pathogenesis of Hodgkin lymphoma in relation to the key signaling of the PD-1 and JAK/STAT pathways.


Assuntos
Doença de Hodgkin/diagnóstico , Doença de Hodgkin/tratamento farmacológico , Humanos , Imunoconjugados/uso terapêutico , Antígeno Ki-1 , Células de Reed-Sternberg , Transdução de Sinais , Microambiente Tumoral
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA