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1.
Lancet Haematol ; 8(6): e433-e445, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34048682

RESUMO

BACKGROUND: Novel approaches are required to improve outcomes in relapsed or refractory classical Hodgkin lymphoma and non-Hodgkin lymphoma. We aimed to evaluate camidanlumab tesirine, an anti-CD25 antibody-drug conjugate, in this patient population. METHODS: This was a phase 1, dose-escalation (part 1), dose-expansion (part 2), multicentre trial done in 12 hospital sites (seven in the USA and five in the UK). Adults (≥18 years old) with pathologically confirmed relapsed or refractory classical Hodgkin lymphoma or non-Hodgkin lymphoma, an Eastern Cooperative Oncology Group performance status 0-2, who had no therapies available to them with established clinical benefit for their disease stage were enrolled. Camidanlumab tesirine was administered intravenously (3-150 µg/kg) once every 3 weeks. Primary objectives were to assess dose-limiting toxicity, determine maximum tolerated dose and recommended expansion dose(s), and assess safety of camidanlumab tesirine. Safety was assessed in all treated patients; antitumour activity was assessed in patients with one or more valid baseline and post-baseline disease assessment and in those who had disease progression or died after first study-drug dose. This trial was registered with ClinicalTrials.gov, NCT02432235. FINDINGS: Between Oct 5, 2015, and Jun 30, 2019, 133 patients were enrolled (77 [58%] had classical Hodgkin lymphoma and 56 (42%) had non-Hodgkin lymphoma). Median follow-up was 9·2 months (IQR 4·2-14·3). Eight dose-limiting toxicities were reported in five (6%) of 86 patients who were evaluable; the maximum tolerated dose was not reached. The recommended doses for expansion were 30 µg/kg and 45 µg/kg for patients with classical Hodgkin lymphoma and 80 µg/kg for patients with T-cell non-Hodgkin lymphomas. No recommended doses for expansion were defined for B-cell non-Hodgkin lymphomas. Grade 3 or worse treatment-emergent adverse events (reported by ≥10% of the 133 patients) included increased γ-glutamyltransferase (20 [15%] patients), maculopapular rash (16 [12%]), and anaemia (15 [11%]); 74 (56%) patients had serious treatment-emergent adverse events, most commonly pyrexia (16 [12%]). One (1%) fatal treatment-emergent adverse event and two (2%) deaths outside the reporting period were considered at least possibly study-drug related. Antitumoural activity was seen in classical Hodgkin and non-Hodgkin lymphomas; notably in all patients with classical Hodgkin lymphoma, the overall response was 71% (95% CI 60-81). INTERPRETATION: These results warrant evaluation of camidanlumab tesirine as a potential treatment option for relapsed or refractory lymphoma, particularly in patients with classical Hodgkin lymphoma. FUNDING: ADC Therapeutics.


Assuntos
Imunoconjugados/uso terapêutico , Linfoma/tratamento farmacológico , Administração Intravenosa , Adulto , Idoso , Esquema de Medicação , Exantema/etiologia , Exantema/patologia , Feminino , Febre/etiologia , Febre/patologia , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/patologia , Humanos , Imunoconjugados/efeitos adversos , Subunidade alfa de Receptor de Interleucina-2/imunologia , Estimativa de Kaplan-Meier , Linfoma/mortalidade , Linfoma/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva , Índice de Gravidade de Doença , Resultado do Tratamento
2.
Int J Mol Sci ; 22(9)2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33946310

RESUMO

HER2 targeted therapies have significantly improved prognosis of HER2-positive breast and gastric cancer. HER2 overexpression and mutation is the pathogenic driver in non-small cell lung cancer (NSCLC) and colorectal cancer, however, to date, there are no approved HER2-targeted therapies with these indications. Trastuzumab deruxtecan (T-DXd) is a novel HER2-directed antibody drug conjugate showing significant anti-tumor activity in heavily pre-treated HER2-positive breast and gastric cancer patients. Preliminary data have shown promising objective response rates in patients with HER2-positive NSCLC and colorectal cancer. T-DXd has an acceptable safety profile, however with concerns regarding potentially serious treatment-emergent adverse events. In this review we focus on the pharmacologic characteristics and toxicity profile of T-Dxd, and provide an update on the most recent results of clinical trials of T-DXd in solid tumors. The referenced papers were selected through a PubMed search performed on 16 March 2021 with the following searching terms: T-DXd and breast cancer, or gastric cancer, or non-small cell lung cancer (NSCLC), or colorectal cancer. Oral presentation, abstracts, and posters presented at the American Society of Clinical Oncology (ASCO, Alexandria, VA, USA) 2020 and the European Society for Medical Oncology (ESMO, Lugano, Switzerland) 2020 annual meetings were retrieved for data on T-DXd. We also overview ongoing research and data of combination therapies currently under investigation, which will impact on future therapeutic strategies. Clinicaltrials.gov was searched to identify ongoing clinical trials of T-DXd alone or in combination in solid tumors.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Camptotecina/análogos & derivados , Imunoconjugados/uso terapêutico , Neoplasias/tratamento farmacológico , Receptor ErbB-2/análise , Trastuzumab/uso terapêutico , Animais , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/farmacologia , Camptotecina/efeitos adversos , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Ensaios Clínicos como Assunto , Humanos , Imunoconjugados/efeitos adversos , Imunoconjugados/farmacologia , Neoplasias/patologia , Trastuzumab/efeitos adversos , Trastuzumab/farmacologia
3.
N Engl J Med ; 384(16): 1529-1541, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33882206

RESUMO

BACKGROUND: Patients with metastatic triple-negative breast cancer have a poor prognosis. Sacituzumab govitecan is an antibody-drug conjugate composed of an antibody targeting the human trophoblast cell-surface antigen 2 (Trop-2), which is expressed in the majority of breast cancers, coupled to SN-38 (topoisomerase I inhibitor) through a proprietary hydrolyzable linker. METHODS: In this randomized, phase 3 trial, we evaluated sacituzumab govitecan as compared with single-agent chemotherapy of the physician's choice (eribulin, vinorelbine, capecitabine, or gemcitabine) in patients with relapsed or refractory metastatic triple-negative breast cancer. The primary end point was progression-free survival (as determined by blinded independent central review) among patients without brain metastases. RESULTS: A total of 468 patients without brain metastases were randomly assigned to receive sacituzumab govitecan (235 patients) or chemotherapy (233 patients). The median age was 54 years; all the patients had previous use of taxanes. The median progression-free survival was 5.6 months (95% confidence interval [CI], 4.3 to 6.3; 166 events) with sacituzumab govitecan and 1.7 months (95% CI, 1.5 to 2.6; 150 events) with chemotherapy (hazard ratio for disease progression or death, 0.41; 95% CI, 0.32 to 0.52; P<0.001). The median overall survival was 12.1 months (95% CI, 10.7 to 14.0) with sacituzumab govitecan and 6.7 months (95% CI, 5.8 to 7.7) with chemotherapy (hazard ratio for death, 0.48; 95% CI, 0.38 to 0.59; P<0.001). The percentage of patients with an objective response was 35% with sacituzumab govitecan and 5% with chemotherapy. The incidences of key treatment-related adverse events of grade 3 or higher were neutropenia (51% with sacituzumab govitecan and 33% with chemotherapy), leukopenia (10% and 5%), diarrhea (10% and <1%), anemia (8% and 5%), and febrile neutropenia (6% and 2%). There were three deaths owing to adverse events in each group; no deaths were considered to be related to sacituzumab govitecan treatment. CONCLUSIONS: Progression-free and overall survival were significantly longer with sacituzumab govitecan than with single-agent chemotherapy among patients with metastatic triple-negative breast cancer. Myelosuppression and diarrhea were more frequent with sacituzumab govitecan. (Funded by Immunomedics; ASCENT ClinicalTrials.gov number, NCT02574455; EudraCT number, 2017-003019-21.).


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Camptotecina/análogos & derivados , Moléculas de Adesão Celular/antagonistas & inibidores , Imunoconjugados/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antígenos de Neoplasias , Antineoplásicos/efeitos adversos , Camptotecina/efeitos adversos , Camptotecina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Imunoconjugados/efeitos adversos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Intervalo Livre de Progressão , Análise de Sobrevida , Neoplasias de Mama Triplo Negativas/mortalidade , Carga Tumoral
4.
Rev Med Liege ; 76(4): 224-231, 2021 Apr.
Artigo em Francês | MEDLINE | ID: mdl-33830684

RESUMO

Recently, brentuximab vedotin (BV) (Adcetris®) obtained the reimbursement in Belgium for the treatment of the primary cutaneous NKT-cell lymphomas mycosis fungoides (MF), large cell anaplastic lymphoma and lymphomatoid papulosis type A. BV is a monoclonal antibody directed against the CD30 expressed on tumoral T cells. The inhibition of this pathway releases the process of apoptosis leading to the cell death of the tumoral cells. BV is reimbursed after the use of another systemic treatment without success and if the number of CD30 positive atypical T-cells is larger than 10 %. BV is administered intravenously every 3 weeks with a dosing of 1,8 mg/kg with a maximum of 16 courses. The response rates exceed 75 %. In some instances, interesting treatment responses have been observed with BV in CD30 negative patients. The principal adverse effects are neutropenia and peripheral neuropathy. Two patients are presented with longstanding multi-resistant MF that were successfully treated with BV.


Assuntos
Imunoconjugados , Micose Fungoide , Neoplasias Cutâneas , Bélgica , Brentuximab Vedotin , Humanos , Imunoconjugados/uso terapêutico , Micose Fungoide/tratamento farmacológico
5.
Int J Nanomedicine ; 16: 2443-2459, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33814909

RESUMO

Background: Specific modifications to carriers to achieve targeted delivery of chemotherapeutics into malignant tissues are a critical point for efficient diagnosis and therapy. In this case, bovine serum albumin (BSA) was conjugated with cetuximab-valine-citrulline (vc)-doxorubicin (DOX) to target epidermal growth factor receptor (EGFR) and enable the release of drug in EGFR-overexpressed tumor cells. Methods: Maleimidocaproyl-valine-citrulline-p-aminobenzylcarbonyl-p-nitrophenol (MC-Val-Cit-PAB-PNP) and DOX were used to synthesize MC-Val-Cit-PAB-DOX, which was further linked with cetuximab to prepare antibody-drug conjugates (ADCs). Then, the ADCs were adsorbed to the surface of the BSA nanoparticles (NPs), which were prepared by a desolvation method to obtain cetuximab-vc-DOX-BSA-NPs. The cetuximab-vc-DOX conjugates adsorbed on the surface of the BSA nanoparticles were determined and optimized by size exclusion chromatography. An in vitro cytotoxicity study was conducted using a colon carcinoma cell line with different EGFR-expression levels to test the selectivity of cetuximab-vc-DOX-NPs. Results: The vc-DOX and cetuximab-vc-DOX conjugates were both synthesized successfully and their structural characteristics confirmed by 1H-NMR and SDS-PAGE. The MTT assay showed stronger cytotoxicity of cetuximab-vc-DOX-NPs versus control IgG-vc-DOX-NPs in EGFR-overexpressing RKO cells. Cellular binding and intracellular accumulation determined by flow cytometry and confocal laser scanning microscopy revealed the strong binding ability of cetuximab-vc-DOX-NPs to RKO cells. The in vivo imaging study demonstrated that cetuximab-vc-DOX-NPs exhibited higher fluorescent intensity in tumor tissues than non-decorated nanoparticles (IgG-vc-DOX-NPs). In vivo tumor inhibition and survival tests showed that cetuximab-vc-DOX-NPs revealed higher tumor inhibition efficacy and lower systemic toxicity than control IgG-vc-DOX- NPs. Conclusion: The obtained results emphasize that cetuximab-vc-DOX-NPs, with good tumor-targeting ability and low systemic toxicity, are a promising targeting system for drug delivery.


Assuntos
Cetuximab/uso terapêutico , Citrulina/química , Neoplasias Colorretais/tratamento farmacológico , Doxorrubicina/uso terapêutico , Receptores ErbB/metabolismo , Nanopartículas/química , Soroalbumina Bovina/química , Valina/química , Adsorção , Animais , Bovinos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/patologia , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Endocitose/efeitos dos fármacos , Humanos , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Camundongos , Tamanho da Partícula , Espectroscopia de Prótons por Ressonância Magnética , Distribuição Tecidual/efeitos dos fármacos
6.
J Med Chem ; 64(7): 4117-4129, 2021 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-33755471

RESUMO

Herein we describe the design and biological evaluation of a novel antitumor therapeutic platform that combines the most favorable properties of small-molecule drug conjugates (SMDCs) and antibody drug conjugates (ADCs). Although the small size of SMDCs, compared to ADCs, is an appealing feature for their application in the treatment of solid tumors, SMDCs usually suffer from poor pharmacokinetics, which severely limits their therapeutic efficacy. To overcome this limitation, in this proof-of-concept study we grafted an α-amanitin-based SMDC that targets prostate cancer cells onto an immunoglobulin Fc domain via a two-step "program and arm" chemoenzymatic strategy. We demonstrated the superior pharmacokinetic properties and therapeutic efficacy of the resulting Fc-SMDC over the SMDC in a prostate cancer xenograft mouse model. This approach may provide a general strategy toward effective antitumor therapeutics combining small size with pharmacokinetic properties close to those of an ADC.


Assuntos
Alfa-Amanitina/uso terapêutico , Antineoplásicos/uso terapêutico , Imunoconjugados/uso terapêutico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Alfa-Amanitina/química , Alfa-Amanitina/farmacocinética , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Humanos , Imunoconjugados/imunologia , Imunoconjugados/farmacocinética , Fragmentos Fc das Imunoglobulinas/imunologia , Imunoglobulina G/imunologia , Imunoglobulina G/uso terapêutico , Masculino , Camundongos SCID , Neoplasias da Próstata/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Ann Oncol ; 32(6): 757-765, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33667670

RESUMO

BACKGROUND: Mirvetuximab soravtansine (MIRV) is an antibody-drug conjugate comprising a folate receptor alpha (FRα)-binding antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent. The randomized, open-label, phase III study FORWARD I compared MIRV and investigator's choice chemotherapy in patients with platinum-resistant epithelial ovarian cancer (EOC). PATIENTS AND METHODS: Eligible patients with 1-3 prior lines of therapy and whose tumors were positive for FRα expression were randomly assigned, in a 2 : 1 ratio, to receive MIRV (6 mg/kg, adjusted ideal body weight) or chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary endpoint was progression-free survival [PFS, Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, blinded independent central review] in the intention-to-treat (ITT) population and in the prespecified FRα high population. RESULTS: A total of 366 patients were randomized; 243 received MIRV and 109 received chemotherapy. The primary endpoint, PFS, did not reach statistical significance in either the ITT [hazard ratio (HR), 0.98, P = 0.897] or the FRα high population (HR, 0.69, P = 0.049). Superior outcomes for MIRV over chemotherapy were observed in all secondary endpoints in the FRα high population including improved objective response rate (24% versus 10%), CA-125 responses (53% versus 25%), and patient-reported outcomes (27% versus 13%). Fewer treatment-related grade 3 or higher adverse events (25.1% versus 44.0%), and fewer events leading to dose reduction (19.8% versus 30.3%) and treatment discontinuation (4.5% versus 8.3%) were seen with MIRV compared with chemotherapy. CONCLUSIONS: In patients with platinum-resistant EOC, MIRV did not result in a significant improvement in PFS compared with chemotherapy. Secondary endpoints consistently favored MIRV, particularly in patients with high FRα expression. MIRV showed a differentiated and more manageable safety profile than chemotherapy.


Assuntos
Imunoconjugados , Maitansina , Neoplasias Ovarianas , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Epitelial do Ovário/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Imunoconjugados/uso terapêutico , Maitansina/efeitos adversos , Maitansina/análogos & derivados , Neoplasias Ovarianas/tratamento farmacológico
8.
Clin Adv Hematol Oncol ; 19(3): 166-174, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33739965

RESUMO

Antibody therapy, which has become a critical option in the treatment of multiple myeloma (MM), includes monoclonal antibodies, antibody-drug conjugates, and bispecific antibodies. Anti-CD38 and anti-SLAMF7 monoclonal antibodies were the first to enter the MM portfolio as treatment options for relapsed/ refractory MM. More recently, daratumumab has become important in the treatment of newly diagnosed MM, and a subcutaneous formulation has been approved. BCMA-targeted antibody-drug conjugates and bispecific antibodies, which are the newest antibody therapies to be investigated, provide additional therapeutic options for patients with heavily pretreated MM. This article reviews how antibody therapy has influenced the treatment of MM, describes the unique adverse event profiles of each relevant drug class, and explains how to incorporate antibody therapy into practice.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Imunoconjugados/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , ADP-Ribosil Ciclase 1/antagonistas & inibidores , ADP-Ribosil Ciclase 1/imunologia , Animais , Anticorpos Biespecíficos/efeitos adversos , Anticorpos Biespecíficos/imunologia , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/imunologia , Antígeno de Maturação de Linfócitos B/antagonistas & inibidores , Antígeno de Maturação de Linfócitos B/imunologia , Humanos , Imunoconjugados/efeitos adversos , Imunoconjugados/imunologia , Mieloma Múltiplo/imunologia , Família de Moléculas de Sinalização da Ativação Linfocitária/antagonistas & inibidores , Família de Moléculas de Sinalização da Ativação Linfocitária/imunologia
10.
BioDrugs ; 35(2): 159-174, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33666903

RESUMO

Metastatic breast cancer remains an incurable disease, and new therapies are needed. One major limitation of chemotherapy is the toxicity associated with higher dose exposure. Antibody-drug conjugates (ADCs) are a complex and evolving class of agents specifically designed with the objective of delivering antineoplastic medicines in the most precise and selectively targeted way. ADCs are composed of four key components: (1) the target antigen, (2) an antibody construct, (3) a payload (most commonly a cytotoxic agent), and (4) a linker moiety that couples the payload and the antibody. In this review, we discuss the clinical development of ADCs for the treatment of breast cancer, focusing on two recently FDA-approved agents, trastuzumab deruxtecan and sacituzumab govitecan, and discuss the ongoing efforts exploring new agents. Finally, we summarize the current portfolio of clinical trials that could change the algorithm of treatment for early and advanced breast cancer.


Assuntos
Antineoplásicos , Neoplasias da Mama , Imunoconjugados , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Humanos , Imunoconjugados/uso terapêutico
11.
Int J Mol Sci ; 22(4)2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33670524

RESUMO

Around 77 new oncology drugs were approved by the FDA in the past five years; however, most cancers remain untreated. Small molecules and antibodies are dominant therapeutic modalities in oncology. Antibody-drug conjugates, bispecific antibodies, peptides, cell, and gene-therapies are emerging to address the unmet patient need. Advancement in the discovery and development platforms, identification of novel targets, and emergence of new technologies have greatly expanded the treatment options for patients. Here, we provide an overview of various therapeutic modalities and the current treatment options in oncology, and an in-depth discussion of the therapeutics in the preclinical stage for the treatment of breast cancer, lung cancer, and multiple myeloma.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Terapia Baseada em Transplante de Células e Tecidos/métodos , Terapia Genética/métodos , Imunoconjugados/uso terapêutico , Neoplasias/terapia , Bibliotecas de Moléculas Pequenas/uso terapêutico , Humanos , Imunoterapia/métodos , Imunoterapia/estatística & dados numéricos , Imunoterapia/tendências , Oncologia/métodos , Oncologia/estatística & dados numéricos , Oncologia/tendências , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/estatística & dados numéricos , Terapia de Alvo Molecular/tendências , Neoplasias/classificação
12.
J Vis Exp ; (168)2021 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-33645559

RESUMO

The efficacy of photoimmunotherapy can be evaluated more accurately with an orthotopic mouse model than with a subcutaneous one. A pleural dissemination model can be used for the evaluation of treatment methods for intrathoracic diseases such as lung cancer or malignant pleural mesothelioma. Near-infrared photoimmunotherapy (NIR-PIT) is a recently developed cancer treatment strategy that combines the specificity of tumor-targeting antibodies with toxicity caused by a photoabsorber (IR700Dye) after exposure to NIR light. The efficacy of NIR-PIT has been reported using various antibodies; however, only a few reports have shown the therapeutic effect of this strategy in an orthotopic model. In the present study, we demonstrate an example of efficacy evaluation of the pleural disseminated lung cancer model, which was treated using NIR-PIT.


Assuntos
Imunoterapia/métodos , Neoplasias Pulmonares/terapia , Fármacos Fotossensibilizantes/uso terapêutico , Fototerapia/métodos , Neoplasias Pleurais/terapia , Animais , Terapia Combinada , Modelos Animais de Doenças , Feminino , Humanos , Imunoconjugados/uso terapêutico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Neoplasias Pleurais/imunologia , Neoplasias Pleurais/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Int J Mol Sci ; 22(4)2021 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-33669431

RESUMO

Several immune checkpoint molecules and immune targets in leukemic cells have been investigated. Recent studies have suggested the potential clinical benefits of immuno-oncology (IO) therapy against acute myeloid leukemia (AML), especially targeting CD33, CD123, and CLL-1, as well as immune checkpoint inhibitors (e.g., anti-PD (programmed cell death)-1 and anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) antibodies) with or without conventional chemotherapy. Early-phase clinical trials of chimeric antigen receptor (CAR)-T or natural killer (NK) cells for relapsed/refractory AML showed complete remission (CR) or marked reduction of marrow blasts in a few enrolled patients. Bi-/tri-specific antibodies (e.g., bispecific T-cell engager (BiTE) and dual-affinity retargeting (DART)) exhibited 11-67% CR rates with 13-78% risk of cytokine-releasing syndrome (CRS). Conventional chemotherapy in combination with anti-PD-1/anti-CTLA4 antibody for relapsed/refractory AML showed 10-36% CR rates with 7-24 month-long median survival. The current advantages of IO therapy in the field of AML are summarized herein. However, although cancer vaccination should be included in the concept of IO therapy, it is not mentioned in this review because of the paucity of relevant evidence.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Imunoconjugados/uso terapêutico , Fatores Imunológicos/uso terapêutico , Imunoterapia Adotiva/métodos , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Receptores de Antígenos Quiméricos/uso terapêutico , Animais , Ensaios Clínicos como Assunto , Humanos , Leucemia Mieloide Aguda/metabolismo , Taxa de Sobrevida
14.
BMC Cancer ; 21(1): 321, 2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33765976

RESUMO

BACKGROUND: We prepared an anti-p21Ras scFv which could specifically bind with mutant and wild-type p21Ras. However, it cannot penetrate the cell membrane, which prevents it from binding to p21Ras in the cytoplasm. Here, the RGD4C peptide was used to mediate the scFv penetration into tumor cells and produce antitumor effects. METHODS: RGD4C-EGFP and RGD4C-p21Ras-scFv recombinant expression plasmids were constructed to express fusion proteins in E. coli, then the fusion proteins were purified with HisPur Ni-NTA. RGD4C-EGFP was used as reporter to test the factors affecting RGD4C penetration into tumor cell. The immunoreactivity of RGD4C-p21Ras-scFv toward p21Ras was identified by ELISA and western blotting. The ability of RGD4C-p21Ras-scFv to penetrate SW480 cells and colocalization with Ras protein was detected by immunocytochemistry and immunofluorescence. The antitumor activity of the RGD4C-p21Ras-scFv was assessed with the MTT, TUNEL, colony formation and cell migration assays. Chloroquine (CQ) was used an endosomal escape enhancing agent to enhance endosomal escape of RGD4C-scFv. RESULTS: RGD4C-p21Ras-scFv fusion protein were successfully expressed and purified. We found that the RGD4C fusion protein could penetrate into tumor cells, but the tumor cell entry of was time and concentration dependent. Endocytosis inhibitors and a low temperature inhibited RGD4C fusion protein endocytosis into cells. The change of the cell membrane potential did not affect penetrability. RGD4C-p21Ras-scFv could penetrate SW480 cells, effectively inhibit the growth, proliferation and migration of SW480 cells and promote this cells apoptosis. In addition, chloroquine (CQ) could increase endosomal escape and improve antitumor activity of RGD4C-scFv in SW480 cells. CONCLUSION: The RGD4C peptide can mediate anti-p21Ras scFv entry into SW480 cells and produce an inhibitory effect, which indicates that RGD4C-p21Ras-scFv may be a potential therapeutic antibody for the treatment of ras-driven cancers.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Neoplasias do Colo/tratamento farmacológico , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Proteínas Recombinantes de Fusão/farmacologia , Antineoplásicos Imunológicos/isolamento & purificação , Antineoplásicos Imunológicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Permeabilidade da Membrana Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Humanos , Imunoconjugados/genética , Imunoconjugados/isolamento & purificação , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/isolamento & purificação , Proteínas Recombinantes de Fusão/uso terapêutico , Anticorpos de Cadeia Única/genética , Anticorpos de Cadeia Única/isolamento & purificação , Anticorpos de Cadeia Única/farmacologia , Anticorpos de Cadeia Única/uso terapêutico
16.
Eur J Med Chem ; 216: 113297, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33677351

RESUMO

Antibody-drug conjugates (ADCs) are currently among the most successful and important strategies for treating patients with solid tumors. ADCs are composed of a monoclonal antibody and warhead, which are conjugated via a linker. Currently, monomethyl auristatin E (MMAE) is the most widely applied warhead in the development of ADCs. However, MMAE-based ADCs are generally constructed using the MC-VC-PABC linker, and this design has limited structural diversity and some disadvantages. Accordingly, in this study, we generated three types of novel linker-MMAE (with alterations in the spacer, catabolizing area, and self-immolative compared with MC-VC-PABC-MMAE) in ADCs, termed SCT200-linker-MMAE conjugates, and then evaluated the linker-drug plasma stability and the rate of drug release by cathepsin B. The binding ability, internalization rates, and efficacy of all SCT200-linker-MMAE ADCs were systematically studied, and the expression of apoptosis-associated proteins and the therapeutic efficacies of SCT200-M-2, -C-2, and -C-4 were evaluated. The results showed that the activities of some of these ADCs were increased for epidermal growth factor receptor-positive tumors. Moreover, the novel linkers designed in this study can be linked with other antibodies to treat other types of cancer. Overall, these findings provide important insights into the application of SCT200-based linkers in ADCs.


Assuntos
Anticorpos Monoclonais/química , Antineoplásicos/síntese química , Imunoconjugados/química , Oligopeptídeos/química , Animais , Antineoplásicos/sangue , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Catepsina B/metabolismo , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Receptores ErbB/genética , Receptores ErbB/imunologia , Receptores ErbB/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Imunoconjugados/sangue , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Camundongos , Camundongos Nus , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Oligopeptídeos/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Eur J Med Chem ; 216: 113355, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33721668

RESUMO

We describe the use of natural product combretastatin A4 (CA4) as a versatile new payload for the construction of antibody-drug conjugates (ADCs). Cetuximab conjugates consisting of CA4 derivatives were site-specially prepared by disulfide re-bridging approach using cleavable and non-cleavable linkers. These ADCs retained antigen binding and internalization efficiency and exhibited high potencies against cancer cell lines in vitro. The conjugates also demonstrated significant antitumor activities in EGFR-positive xenograft models without observed toxicities. CA4 appears to be a viable payload option for ADCs research and development.


Assuntos
Cetuximab/química , Imunoconjugados/química , Estilbenos/química , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dissulfetos , Desenho de Fármacos , Humanos , Imunoconjugados/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos NOD , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Transplante Heterólogo
18.
J Med Chem ; 64(5): 2576-2607, 2021 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-33596073

RESUMO

Heterobifunctional compounds that direct the ubiquitination of intracellular proteins in a targeted manner via co-opted ubiquitin ligases have enormous potential to transform the field of medicinal chemistry. These chimeric molecules, often termed proteolysis-targeting chimeras (PROTACs) in the chemical literature, enable the controlled degradation of specific proteins via their direction to the cellular proteasome. In this report, we describe the second phase of our research focused on exploring antibody-drug conjugates (ADCs), which incorporate BRD4-targeting chimeric degrader entities. We employ a new BRD4-binding fragment in the construction of the chimeric ADC payloads that is significantly more potent than the corresponding entity utilized in our initial studies. The resulting BRD4-degrader antibody conjugates exhibit potent and antigen-dependent BRD4 degradation and antiproliferation activities in cell-based experiments. Multiple ADCs bearing chimeric BRD4-degrader payloads also exhibit strong, antigen-dependent antitumor efficacy in mouse xenograft assessments that employ several different tumor models.


Assuntos
Antineoplásicos/uso terapêutico , Proteínas de Ciclo Celular/antagonistas & inibidores , Proliferação de Células/efeitos dos fármacos , Imunoconjugados/uso terapêutico , Neoplasias/tratamento farmacológico , Proteólise/efeitos dos fármacos , Fatores de Transcrição/antagonistas & inibidores , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/uso terapêutico , Antígenos de Neoplasias/imunologia , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Dipeptídeos/síntese química , Dipeptídeos/farmacocinética , Dipeptídeos/uso terapêutico , Feminino , Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Imunoconjugados/imunologia , Imunoconjugados/farmacocinética , Camundongos SCID , Oxirredutases/imunologia , Fatores de Transcrição/metabolismo , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Int J Mol Sci ; 22(4)2021 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-33557050

RESUMO

Prostate cancer is the most frequent malignancy in the worldwide male population; it is also one of the most common among all the leading cancer-related death causes. In the last two decades, the therapeutic scenario of metastatic castration-resistant prostate cancer has been enriched by the use of chemotherapy and androgen receptor signaling inhibitors (ARSI) and, more recently, by immunotherapy and poly(ADP-ribose) polymerase (PARP) inhibitors. At the same time, several trials have shown the survival benefits related to the administration of novel ARSIs among patients with non-castration-resistant metastatic disease along with nonmetastatic castration-resistant cancer too. Consequently, the therapeutic course of this malignancy has been radically expanded, ensuring survival benefits never seen before. Among the more recently emerging agents, the so-called "antibody-drug conjugates" (ADCs) are noteworthy because of their clinical practice changing outcomes obtained in the management of other malignancies (including breast cancer). The ADCs are novel compounds consisting of cytotoxic agents (also known as the payload) linked to specific antibodies able to recognize antigens expressed over cancer cells' surfaces. As for prostate cancer, researchers are focusing on STEAP1, TROP2, PSMA, CD46 and B7-H3 as optimal antigens which may be targeted by ADCs. In this paper, we review the pivotal trials that have currently changed the therapeutic approach to prostate cancer, both in the nonmetastatic castration-resistant and metastatic settings. Therefore, we focus on recently published and ongoing trials designed to investigate the clinical activity of ADCs against prostate malignancy, characterizing these agents. Lastly, we briefly discuss some ADCs-related issues with corresponding strategies to overwhelm them, along with future perspectives for these promising novel compounds.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Imunoconjugados/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Animais , Antineoplásicos Imunológicos/farmacologia , Biomarcadores Tumorais , Ensaios Clínicos como Assunto , Gerenciamento Clínico , Suscetibilidade a Doenças , Humanos , Imunoconjugados/farmacologia , Masculino , Terapia de Alvo Molecular , Prognóstico , Neoplasias da Próstata/etiologia , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/etiologia , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/patologia , Padrão de Cuidado , Resultado do Tratamento
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