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1.
Cell Biochem Biophys ; 81(3): 395-408, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37395856

RESUMO

Several decades of research and clinical trials have conclusively provided proof of concept on the usefulness of monoclonal antibodies in the armamentarium against cancer. There are numerous mAbs approved for both, the treatment of solid tumors as well as hematological malignancies. These have ranked in the top ten best-selling drugs in recent years and one such mAb, pembrolizumab, is slated to be the highest revenue-generating drug by 2024. A large proportion of the mAbs in oncology have been approved by regulatory agencies in just the past decade and many professionals working in the field have been unable to keep abreast with the latest mAbs available and their mechanism of action. In this review, we aim to provide a systematic compilation of the various mAbs in oncology, approved by the US FDA in the past decade. It also elaborates on the mechanism of action of the newly approved mAbs to provide an overall update of the same. For this purpose, we have referred to the Drugs at FDA and relevant articles from PubMed from the year 2010 to date.


Assuntos
Antineoplásicos Imunológicos , Neoplasias , Antineoplásicos Imunológicos/metabolismo , Antineoplásicos Imunológicos/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico , Antígenos de Neoplasias/metabolismo , Microambiente Tumoral , Receptores de Fatores de Crescimento/antagonistas & inibidores , Antígenos CD/metabolismo , Proteínas de Checkpoint Imunológico/metabolismo , Animais
2.
Br J Oral Maxillofac Surg ; 61(4): 320-326, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37061418

RESUMO

The immune checkpoint inhibitor (ICI), nivolumab, has revolutionised the treatment of recurrent and metastatic oral cancer. However, the response rate to ICIs remains low, and identifying predictors of nivolumab response is critical. Although the neutrophil-to-lymphocyte ratio (NLR) has been suggested as a predictive marker of nivolumab response in patients with various types of cancer, its utility in oral squamous cell carcinoma (OSCC) has not been elucidated. In this retrospective multicentre cohort study, we evaluated the association between NLR and outcome of nivolumab treatment in 64 patients with OSCC treated between 2017 and 2020. The objective response and disease control rates were 25.1% and 32.9%, respectively. The rates for complete and partial responses were 15.7% (10/64) and 9.4% (6/64), respectively; stable and progressive disease rates were 7.8% (5/64) and 67.1% (43/64), respectively. Complete and partial responses were classified as responders, and stable and progressive diseases were classified as non-responders. The median (range) pre-treatment NLR among responders was 4.3 (2.8-8.0), which decreased to 4.0 (2.6-6.3) after nivolumab treatment, and the median (range) pre-treatment NLR among non-responders was 5.1 (2.7-7.9), which increased to 6.4 (4.0-14.0) with tumour growth. Moreover, overall survival was significantly worse in the group with a higher post-treatment NLR (≥5) than in the group with a lower NLR (<5). Patients with a post-treatment NLR of ≥6 had worse outcomes for salvage chemotherapy following nivolumab treatment. Thus, post-treatment NLR could be a useful marker for predicting the response to nivolumab treatment or salvage chemotherapy in patients with OSCC.


Assuntos
Antineoplásicos Imunológicos , Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Humanos , Nivolumabe/uso terapêutico , Nivolumabe/metabolismo , Carcinoma de Células Escamosas/patologia , Neutrófilos/metabolismo , Neutrófilos/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Estudos de Coortes , Antineoplásicos Imunológicos/uso terapêutico , Antineoplásicos Imunológicos/metabolismo , Prognóstico , Estudos Retrospectivos , Neoplasias Bucais/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Linfócitos/patologia , Doença Crônica , Neoplasias de Cabeça e Pescoço/patologia
3.
Proc Natl Acad Sci U S A ; 119(1)2022 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-34969858

RESUMO

Brain metastases are a leading cause of death in patients with breast cancer. The lack of clinical trials and the presence of the blood-brain barrier limit therapeutic options. Furthermore, overexpression of the human epidermal growth factor receptor 2 (HER2) increases the incidence of breast cancer brain metastases (BCBM). HER2-targeting agents, such as the monoclonal antibodies trastuzumab and pertuzumab, improved outcomes in patients with breast cancer and extracranial metastases. However, continued BCBM progression in breast cancer patients highlighted the need for novel and effective targeted therapies against intracranial metastases. In this study, we engineered the highly migratory and brain tumor tropic human neural stem cells (NSCs) LM008 to continuously secrete high amounts of functional, stable, full-length antibodies against HER2 (anti-HER2Ab) without compromising the stemness of LM008 cells. The secreted anti-HER2Ab impaired tumor cell proliferation in vitro in HER2+ BCBM cells by inhibiting the PI3K-Akt signaling pathway and resulted in a significant benefit when injected in intracranial xenograft models. In addition, dual HER2 blockade using anti-HER2Ab LM008 NSCs and the tyrosine kinase inhibitor tucatinib significantly improved the survival of mice in a clinically relevant model of multiple HER2+ BCBM. These findings provide compelling evidence for the use of HER2Ab-secreting LM008 NSCs in combination with tucatinib as a promising therapeutic regimen for patients with HER2+ BCBM.


Assuntos
Antineoplásicos Imunológicos/metabolismo , Neoplasias Encefálicas , Neoplasias Experimentais , Células-Tronco Neurais , Oxazóis/farmacologia , Piridinas/farmacologia , Quinazolinas/farmacologia , Receptor ErbB-2 , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Nus , Metástase Neoplásica , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia , Células-Tronco Neurais/transplante , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Nat Med ; 27(12): 2200-2211, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34893775

RESUMO

In a recent phase 3 randomized trial of 700 patients with advanced urothelial cancer (JAVELIN Bladder 100; NCT02603432 ), avelumab/best supportive care (BSC) significantly prolonged overall survival relative to BSC alone as maintenance therapy after first-line chemotherapy. Exploratory biomarker analyses were performed to identify biological pathways that might affect survival benefit. Tumor molecular profiling by immunohistochemistry, whole-exome sequencing and whole-transcriptome sequencing revealed that avelumab survival benefit was positively associated with PD-L1 expression by tumor cells, tumor mutational burden, APOBEC mutation signatures, expression of genes underlying innate and adaptive immune activity and the number of alleles encoding high-affinity variants of activating Fcγ receptors. Pathways connected to tissue growth and angiogenesis might have been associated with reduced survival benefit. Individual biomarkers did not comprehensively identify patients who could benefit from therapy; however, multi-parameter models incorporating genomic alteration, immune responses and tumor growth showed promising predictive utility. These results characterize the complex biologic pathways underlying survival benefit from immune checkpoint inhibition in advanced urothelial cancer and suggest that multiple biomarkers might be needed to identify patients who would benefit from treatment.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Humanos , Mutação , Neoplasias da Bexiga Urinária/patologia
5.
Cell Rep ; 37(5): 109953, 2021 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-34731630

RESUMO

Receptor clustering is the first and critical step to activate apoptosis by death receptor-5 (DR5). The recent discovery of the autoinhibitory DR5 ectodomain has challenged the long-standing view of its mechanistic activation by the natural ligand Apo2L. Because the autoinhibitory residues have remained unknown, here we characterize a crucial patch of positively charged residues (PPCR) in the highly variable domain of DR5. The PPCR electrostatically separates DR5 receptors to autoinhibit their clustering in the absence of ligand and antibody binding. Mutational substitution and antibody-mediated PPCR interference resulted in increased apoptotic cytotoxic function. A dually specific antibody that enables sustained tampering with PPCR function exceptionally enhanced DR5 clustering and apoptotic activation and distinctively improved the survival of animals bearing aggressive metastatic and recurrent tumors, whereas clinically tested DR5 antibodies without PPCR blockade function were largely ineffective. Our study provides mechanistic insights into DR5 activation and a therapeutic analytical design for potential clinical success.


Assuntos
Anticorpos Monoclonais/farmacologia , Antineoplásicos Imunológicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/antagonistas & inibidores , Células A549 , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/metabolismo , Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais Humanizados/metabolismo , Anticorpos Monoclonais Humanizados/farmacologia , Especificidade de Anticorpos , Antineoplásicos Imunológicos/imunologia , Antineoplásicos Imunológicos/metabolismo , Epitopos , Humanos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias/imunologia , Neoplasias/metabolismo , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/imunologia , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Transdução de Sinais , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Sci Rep ; 11(1): 22966, 2021 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-34824364

RESUMO

High tumor regulatory T (Treg) cell infiltration is associated with poor prognosis of many cancers. CD25 is highly expressed on tumor Treg cells and is a potential target for Treg deletion. Previously characterized anti-CD25 antibodies appear to have limited efficacy in tumor inhibition. Here we identified two human anti-CD25 antibodies, BA9 and BT942, which did not prevent the activation of IL-2R signaling pathway by IL-2. BT942 had weaker binding and cytotoxic activity to human CD25-expressing cell lines than BA9. But both demonstrated significant tumor growth inhibition in early and late-stage animal cancer models. BT942 resulted in a higher expansion of CD8+ T cells and CD4+ T cells in tumor microenvironment in mouse MC38 model compared to BA9. BT942 also demonstrated significant higher tumor growth inhibition and higher expansion of CD8+ T cells and CD4+ T cells in combination with an anti-PD1 antibody. Pharmacokinetic study of BT942 in cynomolgus monkeys demonstrated a half-life of 206.97 ± 19.03 h. Structural analysis by cryo-EM revealed that BT942 recognizes an epitope on opposite side of the CD25-IL-2 binding site, consistent with no IL-2 signaling blockade in vitro. BT942 appears to be an excellent candidate for cancer immunotherapy.


Assuntos
Antineoplásicos Imunológicos , Subunidade alfa de Receptor de Interleucina-2/imunologia , Neoplasias , Animais , Antineoplásicos Imunológicos/química , Antineoplásicos Imunológicos/imunologia , Antineoplásicos Imunológicos/metabolismo , Antineoplásicos Imunológicos/farmacologia , Linhagem Celular , Microscopia Crioeletrônica , Modelos Animais de Doenças , Humanos , Imunoterapia/métodos , Interleucina-2/metabolismo , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Macaca fascicularis , Camundongos , Neoplasias/imunologia , Neoplasias/terapia , Linfócitos T Reguladores/imunologia , Microambiente Tumoral/imunologia
7.
Acta Biochim Biophys Sin (Shanghai) ; 53(12): 1625-1639, 2021 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-34586349

RESUMO

Mucin 1 (MUC1) has been regarded as an ideal target for cancer treatment, since it is overexpressed in a variety of different cancers including the majority of breast cancer. However, there are still no approved monoclonal antibody drugs targeting MUC1. In this study, we generated a humanized MUC1 (HzMUC1) antibody from our previously developed MUC1 mouse monoclonal antibody that only recognizes MUC1 on the surface of tumor cells. Furthermore, an antibody-drug conjugate (ADC) was generated by conjugating HzMUC1 with monomethyl auristatin (MMAE), and the efficacy of HzMUC1-MMAE on the MUC1-positive HER2+ breast cancer in vitro and in 'Xenograft' model was tested. Results from western blot analysis and immunoprecipitation revealed that the HzMUC1 antibody did not recognize cell-free MUC1-N in sera from breast cancer patients. Confocal microscopy analysis showed that HzMUC1 antibody bound to MUC1 on the surface of breast cancer cells. Results from mapping experiments suggested that HzMUC1 may recognize an epitope present in the interaction region between MUC1-N and MUC1-C. Results from colony formation assay and flow cytometry demonstrated that HzMUC1-MMAE significantly inhibited cell growth by inducing G2/M cell cycle arrest and apoptosis in trastuzumab-resistant HER2-positive breast cancer cells. Meanwhile, HzMUC1-MMAE significantly reduced the growth of HCC1954 xenograft tumors by inhibiting cell proliferation and enhancing cell death. In conclusion, our results indicate that HzMUC1-ADC is a novel therapeutic drug that can overcome trastuzumab resistance of breast cancer. HzMUC1-ADC should also be an effective therapeutic drug for the treatment of different MUC1-positive cancers in clinic.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos Imunológicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Imunoconjugados/farmacologia , Mucina-1/metabolismo , Trastuzumab/farmacologia , Animais , Anticorpos Monoclonais Humanizados/metabolismo , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/metabolismo , Antineoplásicos Imunológicos/uso terapêutico , Apoptose/efeitos dos fármacos , Neoplasias da Mama/sangue , Neoplasias da Mama/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/imunologia , Epitopos , Humanos , Imunoconjugados/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mucina-1/sangue , Mucina-1/química , Mucina-1/imunologia , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Oligopeptídeos/uso terapêutico , Receptor ErbB-2/imunologia , Receptor ErbB-2/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Int Immunopharmacol ; 100: 108112, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34521023

RESUMO

More than 100 monoclonal antibodies (mAbs) have been approved by FDA. The mechanism of action (MoA) involves in neutralization of a specific target via the Fab region and Fc effector functions through Fc region, while the latter include complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). ADCP has been recognized one of the most important MoAs, especially for anti-cancer mAbs in recent years. However, traditional bioassays measuring ADCP always introduced primary macrophages and flow cytometry, which are difficult to handle and highly variable. In this study, we engineered a monoclonal Jurkat/NFAT/CD32a-FcεRIγ effector cell line that stably expresses CD32a-FcεRIγ chimeric receptor and NFAT-controlled luciferase. The corresponding mAb could bind with the membrane antigens on the target cells with its Fab fragment and CD32a-FcεRIγ on the effector cells with its Fc fragment, leading to the crosslinking of CD32a-FcεRIγ and the resultant expression of subsequent NFAT-controlled luciferase, which represents the bioactivity of ADCP based on the MoA of the mAb. With rituximab as the model mAb, Raji cells as the target cells, and Jurkat/NFAT/CD32a-FcεRIγ cells as the effector cells, we adopted the strategy of Design of Experiment (DoE) to optimize the bioassay. Then we fully validated the established bioassay according to ICH-Q2(R1), which proved the good assay performance characteristics of the bioassay, including specificity, accuracy, precision, linearity, stability and robustness. This RGA can be applied to evaluate the -ADCP bioactivity for anti-CD20 mAbs in lot release, stability testing as well as biosimilar comparability. The engineered cells may also potentially be used to evaluate the ADCP bioactivity of mAbs with other targets.


Assuntos
Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Antineoplásicos Imunológicos/farmacologia , Bioensaio , Genes Reporter , Linfoma de Células B/tratamento farmacológico , Fagocitose/efeitos dos fármacos , Rituximab/farmacologia , Antineoplásicos Imunológicos/metabolismo , Humanos , Células Jurkat , Luciferases/genética , Luciferases/metabolismo , Linfoma de Células B/imunologia , Linfoma de Células B/metabolismo , Fatores de Transcrição NFATC/genética , Fatores de Transcrição NFATC/metabolismo , Receptores de IgE/genética , Receptores de IgE/metabolismo , Receptores de IgG/genética , Receptores de IgG/metabolismo , Reprodutibilidade dos Testes , Rituximab/metabolismo
9.
Biomed Pharmacother ; 141: 111913, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34328096

RESUMO

BACKGROUND: B7-H4 is a member of the B7 superfamily that is expressed on the surface of tumors and exhibits limited expression on normal tissue. B7-H4 negatively regulates tumor immunity by interacting with the B7-H4 receptor, which is expressed by activated CD8 + T cells. Hence, we sought to generate an immunomodulatory antibody that targets B7-H4 and blocks the immunosuppressive activity of B7-H4. METHODS: Anti-B7-H4 antibodies were generated using the hybridoma technique and screened by a binding assay based on B7-H4-expressing tumor cells. The B7-H4 antagonistic antibodies were further screened based on their checkpoint blockade activity using a SEB-stimulated peripheral blood mononuclear cell (PBMC) assay, which comprised B7-H4-expressing antigen presenting cells (APCs) and activated T cells. To assess the immunomodulatory activity of anti-B7-H4 antibodies, activated human CD8+ T cells were cultured in B7-H4 protein-coated plates, and the production of IL-2 and the proliferation rate of CD8+ T cells were measured. In addition, we evaluated the ADCC effect of anti-B7-H4 antibodies against tumor cell lines. The in vivo antitumor efficacy of the anti-B7-H4 antibody was also evaluated in human T cell-engrafted NOG mice. RESULTS: A panel of anti-B7-H4 antibodies was generated. The top 23 antibodies were screened to identify antibodies that disabled B7-H4-mediated inhibition. Antibody 17 exhibited the greatest induction of the production of IL-2 and IFN-gamma in SEB-stimulated PBMCs. Antibody 17 was constructed as a chimeric antibody (CH17) with a human IgG1 constant domain. CH17 showed high affinity for human B7-H4 and fully cross-reacted with cynomolgus B7-H4. Additionally, CH17 mediated potent antibody-dependent cell cytotoxicity (ADCC) against different B7-H4-positive tumor cell lines. More importantly, CH17 relieved B7-H4-mediated T cell suppression by enhancing IL2 production and promoting T cell proliferation. In an MDA-MB-468-bearing mouse model in which human pan-T cells were engrafted, CH17 delayed tumor growth by engaging T cells and exerted a synergistic effect in combination with an anti-human PD-1 antibody. CONCLUSIONS: We successfully generated an immunomodulatory antibody targeting B7-H4 that possesses both T cell immune checkpoint inhibitory activity and ADCC activity in B7-H4-positive tumors. B7-H4-targeting antibodies might represent a promising immunotherapy for B7-H4-expressing tumors.


Assuntos
Antineoplásicos Imunológicos/imunologia , Antineoplásicos Imunológicos/farmacologia , Linfócitos T CD8-Positivos/imunologia , Imunidade Celular/imunologia , Inibidor 1 da Ativação de Células T com Domínio V-Set/antagonistas & inibidores , Inibidor 1 da Ativação de Células T com Domínio V-Set/imunologia , Animais , Antineoplásicos Imunológicos/metabolismo , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Células CHO , Linhagem Celular Tumoral , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Humanos , Imunidade Celular/efeitos dos fármacos , Imunoterapia/métodos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Inibidor 1 da Ativação de Células T com Domínio V-Set/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
10.
Mol Biotechnol ; 63(11): 1016-1029, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34185248

RESUMO

Plants are promising drug-production platforms with high economic efficiency, stability, and convenience in mass production. However, studies comparing the equivalency between the original antibodies and those produced in plants are limited. Amino acid sequences that constitute the Fab region of an antibody are diverse, and the post-transcriptional modifications that occur according to these sequences in animals and plants are also highly variable. In this study, rituximab, a blockbuster antibody drug used in the treatment of non-Hodgkin's lymphoma, was produced in Nicotiana benthamiana leaves and Arabidopsis thaliana callus, and was compared to the original rituximab produced in CHO cells. Interestingly, the epitope recognition and antigen-binding abilities of rituximab from N. benthamiana leaves were almost lost. In the case of rituximab produced in A. thaliana callus, the specific binding ability and CD20 capping activity were maintained, but the binding affinity was less than 50% of that of original rituximab from CHO cells. These results suggest that different plant species exhibit different binding affinities. Accordingly, in addition to the differences in PTMs between mammals and plants, the differences between the species must also be considered in the process of producing antibodies in plants.


Assuntos
Antígenos CD20/metabolismo , Arabidopsis/metabolismo , Nicotiana/metabolismo , Folhas de Planta/química , Rituximab/metabolismo , Animais , Afinidade de Anticorpos , Antígenos CD20/química , Antineoplásicos Imunológicos/isolamento & purificação , Antineoplásicos Imunológicos/metabolismo , Arabidopsis/genética , Cricetinae , Humanos , Folhas de Planta/metabolismo , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Rituximab/biossíntese , Rituximab/genética , Rituximab/isolamento & purificação , Nicotiana/genética
11.
Theranostics ; 11(13): 6293-6314, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995659

RESUMO

Radioimmunotherapy (RIT) is FDA-approved for the clinical management of liquid malignancies, however, its use for solid malignancies remains a challenge. The putative benefit of RIT lies in selective targeting of antigens expressed on the tumor surface using monoclonal antibodies, to systemically deliver cytotoxic radionuclides. The past several decades yielded dramatic improvements in the quality, quantity, recent commercial availability of alpha-, beta- and Auger Electron-emitting therapeutic radiometals. Investigators have created new or improved existing bifunctional chelators. These bifunctional chelators bind radiometals and can be coupled to antigen-specific antibodies. In this review, we discuss approaches to develop radiometal-based RITs, including the selection of radiometals, chelators and antibody platforms (i.e. full-length, F(ab')2, Fab, minibodies, diabodies, scFv-Fc and nanobodies). We cite examples of the performance of RIT in the clinic, describe challenges to its implementation, and offer insights to address gaps toward translation.


Assuntos
Radioimunoterapia/métodos , Compostos Radiofarmacêuticos/uso terapêutico , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Antígenos de Neoplasias/imunologia , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/metabolismo , Antineoplásicos Imunológicos/uso terapêutico , Quelantes/administração & dosagem , Quelantes/metabolismo , Química Click , Ensaios Clínicos como Assunto , Fracionamento da Dose de Radiação , Sistemas de Liberação de Medicamentos , Previsões , Humanos , Fragmentos Fab das Imunoglobulinas/administração & dosagem , Fragmentos Fab das Imunoglobulinas/uso terapêutico , Linfoma não Hodgkin/radioterapia , Camundongos , Terapia de Alvo Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/radioterapia , Especificidade de Órgãos , Medicina de Precisão , Tolerância a Radiação , Compostos Radiofarmacêuticos/administração & dosagem , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Anticorpos de Cadeia Única/administração & dosagem , Anticorpos de Cadeia Única/uso terapêutico , Anticorpos de Domínio Único/administração & dosagem , Anticorpos de Domínio Único/uso terapêutico , Radioisótopos de Ítrio/administração & dosagem , Radioisótopos de Ítrio/uso terapêutico
12.
FEBS Lett ; 595(11): 1587-1603, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33792041

RESUMO

OX40 is a costimulatory molecule that belongs to the tumor necrosis factor receptor (TNFR) superfamily. OX40 agonist-based combinations are emerging as promising candidates for novel cancer immunotherapy. Clinical trials have shown that OX40 agonist antibodies could lead to better results in cancer patients. Using a hybridoma platform and three different types of immunization strategies, namely recombinant protein, DNA, and overexpressing cells, we identified a chimeric anti-OX40 antibody (mAb035-hIgG1 from DNA immunization) that shows excellent binding specificity, and slightly stronger activation of human memory CD4+ T cells and similar potent antitumor activity compared with BMS 986178, an anti-OX40 antibody currently being evaluated for the treatment of solid tumors. This paper further systematically investigates the antigen-specific immune response, the number of binders, epitope bins, and functional activities of antibodies among different immunization strategies. Interestingly, we found that different immunization strategies affect the biological activity of monoclonal antibodies.


Assuntos
Anticorpos Monoclonais/farmacologia , Antineoplásicos Imunológicos/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Imunização/métodos , Receptores OX40/imunologia , Proteínas Recombinantes de Fusão/farmacologia , Animais , Anticorpos Monoclonais/biossíntese , Anticorpos Monoclonais/isolamento & purificação , Afinidade de Anticorpos , Especificidade de Anticorpos , Antineoplásicos Imunológicos/isolamento & purificação , Antineoplásicos Imunológicos/metabolismo , Bioensaio , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Células CHO , Cricetulus , Feminino , Adjuvante de Freund/administração & dosagem , Expressão Gênica , Genes Reporter , Células HEK293 , Humanos , Hibridomas/química , Hibridomas/imunologia , Fragmentos Fc das Imunoglobulinas/biossíntese , Fragmentos Fc das Imunoglobulinas/isolamento & purificação , Fragmentos Fc das Imunoglobulinas/farmacologia , Células Jurkat , Luciferases/genética , Luciferases/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/genética , NF-kappa B/imunologia , Receptores OX40/antagonistas & inibidores , Receptores OX40/genética , Proteínas Recombinantes de Fusão/biossíntese , Proteínas Recombinantes de Fusão/isolamento & purificação
13.
Commun Biol ; 4(1): 310, 2021 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-33686177

RESUMO

Fc-less bispecific T-cell engagers have reached the immuno-oncology market but necessitate continual infusion due to rapid clearance from the circulation. This work introduces a programmable serum half-life extension platform based on fusion of human albumin sequences engineered with either null (NB), wild type (WT) or high binding (HB) FcRn affinity combined with a bispecific T-cell engager. We demonstrate in a humanised FcRn/albumin double transgenic mouse model (AlbuMus) the ability to tune half-life based on the albumin sequence fused with a BiTE-like bispecific (anti-EGFR nanobody x anti-CD3 scFv) light T-cell engager (LiTE) construct [(t½ 0.6 h (Fc-less LiTE), t½ 19 hours (Albu-LiTE-NB), t½ 26 hours (Albu-LiTE-WT), t½ 37 hours (Albu-LiTE-HB)]. We show in vitro cognate target engagement, T-cell activation and discrimination in cellular cytotoxicity dependent on EGFR expression levels. Furthermore, greater growth inhibition of EGFR-positive BRAF mutated tumours was measured following a single dose of Albu-LiTE-HB construct compared to the Fc-less LiTE format and a full-length anti-EGFR monoclonal antibody in a new AlbuMus RAG1 knockout model introduced in this work. Programmable half-life extension facilitated by this albumin platform potentially offers long-lasting effects, better patient compliance and a method to tailor pharmacokinetics to maximise therapeutic efficacy and safety of immuno-oncology targeted biologics.


Assuntos
Anticorpos Biespecíficos/farmacocinética , Antineoplásicos Imunológicos/farmacocinética , Antígenos de Histocompatibilidade Classe I/metabolismo , Neoplasias/tratamento farmacológico , Receptores Fc/metabolismo , Albumina Sérica Humana/farmacocinética , Linfócitos T/efeitos dos fármacos , Células 3T3 , Animais , Anticorpos Biespecíficos/metabolismo , Antineoplásicos Imunológicos/metabolismo , Células CHO , Cricetulus , Composição de Medicamentos , Feminino , Células HEK293 , Células HT29 , Meia-Vida , Proteínas de Homeodomínio/genética , Humanos , Células Jurkat , Ativação Linfocitária/efeitos dos fármacos , Células MCF-7 , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias/imunologia , Neoplasias/patologia , Estudo de Prova de Conceito , Ligação Proteica , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Recombinantes de Fusão/farmacocinética , Albumina Sérica Humana/genética , Albumina Sérica Humana/metabolismo , Linfócitos T/imunologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Chem Commun (Camb) ; 57(28): 3457-3460, 2021 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-33687404

RESUMO

A novel enzyme cleavable linker for antibody-drug conjugates is reported. The 3-O-sulfo-ß-galactose linker is cleaved sequentially by two lysosomal enzymes - arylsulfatase A and ß-galactosidase - to release the payload in targeted cells. An α-HER2 antibody-drug conjugate synthesised using this highly hydrophilic dual-cleavable linker exhibited excellent cytotoxicity and selectivity.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Cerebrosídeo Sulfatase/química , Imunoconjugados/química , Trastuzumab/farmacologia , beta-Galactosidase/química , Antineoplásicos Imunológicos/química , Antineoplásicos Imunológicos/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Cerebrosídeo Sulfatase/metabolismo , Relação Dose-Resposta a Droga , Humanos , Interações Hidrofóbicas e Hidrofílicas , Imunoconjugados/metabolismo , Estrutura Molecular , Trastuzumab/química , Trastuzumab/metabolismo , beta-Galactosidase/metabolismo
15.
Cancer Med ; 10(6): 2125-2136, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33629544

RESUMO

BACKGROUND: CD47 is a widely expressed transmembrane protein located on the surface of somatic cells. It mediates a variety of cellular processes including apoptosis, proliferation, adhesion, and migration. An important role for CD47 is the transmission of a "Don't eat me" signal by interacting with SIRPα on the macrophage surface membrane, thereby preventing the phagocytosis of normal cells. However, cancer cells can take advantage of this autogenous signal to protect themselves from phagocytosis, thus enabling immune escape. Blocking the interaction between CD47 and SIRPα has proven to be effective in removing cancer cells. The treatment of various cancers with CD47 monoclonal antibodies has also been validated. METHODS: We designed and synthesized a peptide (RS17), which can specifically bind to CD47 and block CD47-SIRPα signaling. The affinity of RS17 for CD47-expressing tumor cells was determined, while the inhibition of CD47-SIRPα signaling was evaluated in vitro and in vivo. RESULTS: The results indicated that RS17 significantly promotes the phagocytosis of tumor cells by macrophages and had a similar therapeutic effect compared with a positive control (CD47 monoclonal antibodies). In addition, a cancer xenograft mouse model was established using CD47-expressing HepG2 cells to evaluate the effect of RS17 on tumor growth in vivo. Using ex vivo and in vivo mouse models, RS17 demonstrated a high inhibitory effect on tumor growth. CONCLUSIONS: Based on our results, RS17 may represent a novel therapeutic peptide for cancer therapy.


Assuntos
Antígenos de Diferenciação/metabolismo , Antineoplásicos Imunológicos/metabolismo , Antígeno CD47/metabolismo , Macrófagos/metabolismo , Peptídeos/metabolismo , Fagocitose , Receptores Imunológicos/metabolismo , Aminoácidos/metabolismo , Animais , Anticorpos Monoclonais , Antineoplásicos Imunológicos/síntese química , Antineoplásicos Imunológicos/uso terapêutico , Antígeno CD47/antagonistas & inibidores , Antígeno CD47/química , Carcinoma de Células Escamosas/metabolismo , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Feminino , Citometria de Fluxo , Células Hep G2/metabolismo , Humanos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Simulação de Acoplamento Molecular , Terapia de Alvo Molecular/métodos , Peptídeos/síntese química , Peptídeos/uso terapêutico , Fagocitose/imunologia , Neoplasias Cutâneas/metabolismo , Software , Evasão Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
16.
J Cell Physiol ; 236(6): 4303-4312, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33421131

RESUMO

The overexpression of epidermal growth factor receptor (EGFR) could result in the development of solid tumors of prostate, breast, gastric, colorectal, ovarian, and head and neck, leading to carcinoma. Antibody therapies are ideal methods to overcome malignant diseases. However, immunoribonucleases are a new generation of antibodies in which an RNase binds to a specific antibody and shows a stronger ability to terminate cancer cells. In this study, we engineered Rana pipiens RNase to bind to the scFv of human antiepidermal growth factor receptor antibody. The molecular dynamic simulations confirmed protein stability and the ability of scFv-ranpirnase (rantoxin) to bind to epidermal growth factor receptor protein. Then, the rantoxin construct was synthesized in a pCDNA 3.1 Neo vector. CHO-K1 cells were used as expression hosts and the construct was transfected. Cells were selected by antibiotic therapies using neomycin, 120 mg/ml, and the high-yield colony was screened by real-time polymerase chain reaction (PCR) methods. Then, the recombinant protein production was confirmed using the sodium dodecyl sulfate polyacrylamide gel electrophoresis and western blot analyses. The molecular dynamic simulation (MDS) confirmed that the I467, S468, Q408, and H409 amino acids of EGFR bonded well to rantoxin. As revealed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and western blot analyses, the rantoxin production and PCR analysis showed that the T3 colony can produce rantoxin messenger RNA fourfold higher than the GAPDH gene. The immunotoxin function was assessed in A431 cancer cells and EGFR-negative HEK293 cells, and IC50  values were estimated to be 22.4 ± 3 and >620.4 ± 5 nM, respectively. The results indicated that the immunotoxins produced in this study had the potential for use as anticancer drugs.


Assuntos
Proteínas de Anfíbios/farmacologia , Antineoplásicos Imunológicos/farmacologia , Imunotoxinas/farmacologia , Engenharia de Proteínas , Ribonucleases/farmacologia , Anticorpos de Cadeia Única/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Proteínas de Anfíbios/genética , Proteínas de Anfíbios/metabolismo , Animais , Antineoplásicos Imunológicos/metabolismo , Apoptose/efeitos dos fármacos , Sítios de Ligação de Anticorpos , Células CHO , Linhagem Celular Tumoral , Cricetulus , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/imunologia , Receptores ErbB/metabolismo , Células HEK293 , Humanos , Imunotoxinas/genética , Imunotoxinas/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Rana pipiens , Ribonucleases/genética , Ribonucleases/metabolismo , Anticorpos de Cadeia Única/metabolismo , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia
17.
Med Sci (Paris) ; 37(1): 47-52, 2021 Jan.
Artigo em Francês | MEDLINE | ID: mdl-33492218

RESUMO

Research on viruses, bacteria and protozoa-based immunotherapy has been on the rise for several years. The antitumoral efficacy of these microorganisms relies on three main mechanisms: Destruction of tumor cells, stimulation of the immune response and reprogramming of the tumor microenvironment. In order to optimize their immunotherapeutic action, these microorganisms can be genetically engineered to enhance their tumor-targeting efficacy or to vectorize immunostimulating molecules and/or antibodies. To this aim, molecular engineering allows the design of new antibody formats optimizing their functions. From whole antibodies to tandem single-chain variable fragments, various antibody formats can be vectorized by microorganisms to target receptors such as immune checkpoints or recruit immune effector cells within the tumor. Such possibilities broaden the arsenal of immunotherapeutic cancer treatment. This review focuses on these innovations and their advantages for immunotherapy.


TITLE: Micro-organismes anti-cancéreux et armement - Le couteau suisse de l'immunothérapie. ABSTRACT: Depuis plusieurs années, la recherche sur les micro-organismes pour une utilisation à des fins d'immunothérapie antitumorale est en plein essor. L'efficacité antitumorale de ces micro-organismes repose sur trois mécanismes principaux : la destruction des cellules tumorales, la stimulation du système immunitaire et la reprogrammation du microenvironnement tumoral. Afin d'optimiser leur action immunothérapeutique, ces micro-organismes peuvent être génétiquement modifiés pour les rendre capables de vectoriser des molécules immunostimulantes ou des anticorps. Par ingénierie moléculaire, il est désormais possible de diversifier les formats et fonctions de ces anticorps afin d'inhiber les points de contrôle immunitaire ou encore de recruter les cellules immunitaires effectrices au site de la tumeur. Cette Synthèse s'intéresse particulièrement à ces innovations et à leurs avantages en immunothérapie.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Imunoterapia , Microrganismos Geneticamente Modificados/fisiologia , Animais , Antineoplásicos Imunológicos/metabolismo , Terapia Genética/métodos , Terapia Genética/tendências , Vetores Genéticos/uso terapêutico , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/genética , Fatores Imunológicos/metabolismo , Imunoterapia/métodos , Imunoterapia/tendências , Microrganismos Geneticamente Modificados/genética , Neoplasias/imunologia , Neoplasias/microbiologia , Neoplasias/terapia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
18.
Biomed Pharmacother ; 133: 111053, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33378959

RESUMO

Trastuzumab is considered to be a fundamental drug for treatment of breast cancer with Her-2 overexpression (Her-2 positive cells). Trastuzumab is a monoclonal antibody that targets the Her-2 receptor. Trastuzumab treatment used in breast cancer therapy require a visualization to validate their delivery and response. The objective of this study was to investigate Trastuzumab-dendrimer-fluorine drug delivery system by synthesis and characterization of a series of fluorinated dendrimers. MATERIALS AND METHODS: Trastuzumab-dendrimer-fluorine drug delivery system is a covalent attachment of Trastuzumab to fluorinated dendrimers. We design synthesis and evaluate main product by using electrophoresis, HPLC and LC-MS techniques. We prepared three-dimensional breast cancer cell culture in bioreactor device. For the cell culture we used MCF-7 cells with Her-2 overexpression to study Trastuzumab-dendrimer-fluorine drug delivery system efficacy. We evaluate efficacy by Magnetic Resonance Imaging (MRI) relaxation time. RESULTS: An analytical analysis showed that synthesis of Trastuzumab-dendrimer-fluorine drug delivery system is possible to obtain with a good yield. The results obtained indicated potential of Trastuzumab-dendrimer-fluorine drug delivery system is more efficient than trastuzumab alone. Chromatographic and electrophoretic separations showed that the synthetized conjugates were a Trastuzumab-dendrimer-fluorine drug delivery systems. The hight synthesis efficiency was found. The presence of molecules with lower masses than trastuzumab can have influence on efficiency. CONCLUSIONS: Trastuzumab-dendrimer-fluorine drug delivery system is a new form of Trastuzumab to treat breast cancer cells in vitro. Due to presence of 19F nuclei the system can be monitored by MRI measurements.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Dendrímeros/química , Portadores de Fármacos , Flúor/química , Trastuzumab/farmacologia , Antineoplásicos Imunológicos/química , Antineoplásicos Imunológicos/metabolismo , Reatores Biológicos , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Cocultura , Composição de Medicamentos , Feminino , Humanos , Células MCF-7 , Imageamento por Ressonância Magnética , Trastuzumab/química , Trastuzumab/metabolismo
19.
Front Immunol ; 11: 604318, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33365032

RESUMO

Boosting the production of recombinant therapeutic antibodies is crucial in both academic and industry settings. In this work, we investigated the usage of varying signal peptides by antibody V-genes and their roles in recombinant transient production, systematically comparing myeloma and the native signal peptides of both heavy and light chains in 168 antibody permutation variants. We found that amino acids count and types (essential or non-essential) were important factors in a logistic regression equation model for predicting transient co-transfection protein production rates. Deeper analysis revealed that the culture media were often incomplete and that the supplementation of essential amino acids can improve the recombinant protein yield. While these findings are derived from transient HEK293 expression, they also provide insights to the usage of the large repertoire of antibody signal peptides, where by varying the number of specific amino acids in the signal peptides attached to the variable regions, bottlenecks in amino acid availability can be mitigated.


Assuntos
Aminoácidos/metabolismo , Anticorpos Monoclonais Humanizados/biossíntese , Antineoplásicos Imunológicos/metabolismo , Biotecnologia , Imunoglobulina E/biossíntese , Região Variável de Imunoglobulina , Engenharia de Proteínas , Sinais Direcionadores de Proteínas , Trastuzumab/biossíntese , Anticorpos Monoclonais Humanizados/genética , Meios de Cultura/metabolismo , Células HEK293 , Humanos , Imunoglobulina E/genética , Região Variável de Imunoglobulina/genética , Mieloma Múltiplo/genética , Mieloma Múltiplo/imunologia , Sinais Direcionadores de Proteínas/genética , Proteínas Recombinantes/biossíntese , Trastuzumab/genética , Fluxo de Trabalho
20.
Cancer Biol Med ; 17(4): 1026-1038, 2020 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-33299651

RESUMO

Objective: Natural killer (NK) cells have gained considerable attention due to their potential in treating "cold tumors," and are therefore considered as one of the new strategies for curing cancer, by using worldwide development of their new possibilities and interventions with NK cell-related therapeutic products. Methods: We constructed a trispecific killer engager (TriKE) consisting of anti-CD16, IL-15, and anti-CD19. This TriKE was designed to attract CD19+ tumor cells to CD16+ NK cells, whereas IL-15 sustained the proliferation, development, and survival of NK cells. Results: Treatment with 161519 TriKE in the presence of CD19+ targets upregulated expression of CD69, CD107a, TRAIL, IFN-γ, and TNF-α in NK cells, and significantly improved the proliferation and cytotoxicity of NK cells. NK cells "armed" with 161519 TriKE showed stronger cytolysis against CD19+ targets compared with that of "unarmed" NK cells. A preclinical model of B-cell lymphoma in human peripheral blood mononuclear cell-reconstituted xenograft mice showed significant inhibition of tumor growth and prolonged overall survival after treatment with 161519 TriKE, when compared with that in control mice or mice treated with 1619 BiKE. Combined use of IL-2 was a more effective treatment with 1619 BiKE, when compared with that using 161519 TriKE. Conclusions: The newly generated 161519 TriKE enhanced the proliferation, activation, cytokine secretion, and cytotoxicity of NK cells in the presence of CD19+ tumor cells. The 161519 TriKE aided inhibition of tumor growth and prolonged the overall survival of murine xenografts, and could be used to treat CD19-positive cancers.


Assuntos
Antígenos CD19/metabolismo , Antineoplásicos Imunológicos/uso terapêutico , Imunoterapia/métodos , Células Matadoras Naturais/imunologia , Animais , Antineoplásicos Imunológicos/metabolismo , Linhagem Celular Tumoral , Citotoxicidade Imunológica , Feminino , Humanos , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos NOD , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Receptores de IgG/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
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