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1.
Oncotarget ; 14: 1-13, 2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36634212

RESUMO

Overexpression of CD74, a type II transmembrane glycoprotein involved in MHC class II antigen presentation, has been reported in many B-cell non-Hodgkin lymphomas (NHLs) and in multiple myeloma (MM). STRO-001 is a site-specific, predominantly single-species antibody-drug conjugate (ADC) that targets CD74 and has demonstrated efficacy in xenograft models of MM and tolerability in non-human primates. Here we report results of preclinical studies designed to elucidate the potential role of STRO-001 in B-cell NHL. STRO-001 displayed nanomolar and sub-nanomolar cytotoxicity in 88% (15/17) of cancer cell lines tested. STRO-001 showed potent cytotoxicity on proliferating B cells while limited cytotoxicity was observed on naïve human B cells. A linear dose-response relationship was demonstrated in vivo for DLBCL models SU-DHL-6 and U2932. Tumor regression was induced at doses less than 5 mg/kg, while maximal activity with complete cures were observed starting at 10 mg/kg. In MCL Mino and Jeko-1 xenografts, STRO-001 starting at 3 mg/kg significantly prolonged survival or induced tumor regression, respectively, leading to tumor eradication in both models. In summary, high CD74 expression levels in tumors, nanomolar cellular potency, and significant anti-tumor in DLBCL and MCL xenograft models support the ongoing clinical study of STRO-001 in patients with B-cell NHL.


Assuntos
Antineoplásicos , Imunoconjugados , Linfoma não Hodgkin , Mieloma Múltiplo , Animais , Humanos , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Mieloma Múltiplo/patologia , Linfoma não Hodgkin/tratamento farmacológico , Linhagem Celular Tumoral
2.
Antiviral Res ; 210: 105513, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36592670

RESUMO

Antibody-based therapy is emerging as a critical therapeutic countermeasure to treat acute viral infections by offering rapid protection against clinical disease. The advancements in structural biology made it feasible to rationalize monoclonal antibodies (mAbs) by identifying key and, possibly, neutralizing epitopes of viral proteins for therapeutic purposes. A critical component in assessing mAbs during pandemics requires the development of rapid but detailed methods to detect and quantitate the neutralization activity. In this study, we developed and optimized two high-content image (HCI)-based assays: one to detect viral proteins by staining and the second to quantify cytopathic viral effects by a label-free phenotypic assay. These assays were employed to screen for therapeutic antibodies against the monkeypox virus (MPXV) using surrogate poxviruses such as vaccinia virus (VACV). Plaque-based neutralization results confirmed the HCI data. The phenotypic assay found pox virus-induced syncytia formation in various cells, and we were able to quantitate and use this phenotype to screen mAbs. The HCI identified several potent VACV-neutralizing antibodies that showed in vitro efficacy against both clades of MPXV. In addition, a combination study of ST-246/tecovirimat/TPOXX a single neutralizing antibody Ab-40, showed synergistic activity against VACV in an in-vitro neutralization assay. This rapid high-content method utilizing state-of-the-art technologies enabled the evaluation of hundreds of mAbs quickly to identify several potent anti-MPXV neutralizing mAbs for further development.


Assuntos
Anticorpos Antivirais , Vírus da Varíola dos Macacos , Anticorpos Neutralizantes , Vírus Vaccinia/genética , Proteínas Virais , Anticorpos Monoclonais/farmacologia , Testes de Neutralização
3.
J Immunother Cancer ; 11(1)2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36720496

RESUMO

BACKGROUND: Our previous study showed that transmembrane tumor necrosis factor alpha (tmTNF-α) is overexpressed in primary breast cancers including triple-negative breast cancers (TNBCs). Chimeric antigen receptor engineered-T (CAR-T) cells have been successfully used mainly in B-cell malignancies. METHODS: We generated CAR-T cells targeting tmTNF-α but not secreted tumor necrosis factor alpha and assessed the antitumor effect of the CAR-T cells on tmTNF-α-expressing breast cancer cells in vitro and in vivo. RESULTS: Our tmTNF-α CAR-T cells showed potent cytotoxicity against tmTNF-α-expressing breast cancer cells but not tmTNF-α-negative tumor cells with increased secretion of interferon gamma (IFN-γ) and interleukin (IL)-2 in vitro. In tmTNF-α-overexpressing TNBC-bearing mice, the tmTNF-α CAR-T therapy induced evident tumor regression, prolonged survival and increased serum concentrations of IFN-γ and IL-2. However, we found thattmTNF-α induced programmed death-ligand 1 (PD-L1) expression through the p38 pathway via TNF receptor (TNFR) and through the NF-κB and AKT pathways via outside-to-inside (reverse) signaling, which might limit the efficacy of the CAR-T cell therapy. Blockage of the PD-L1/programmed death-1 (PD-1) pathway by PD-1 monoclonal antibody significantly enhanced the antitumor effect of the tmTNF-α CAR-T cell therapy in vitro and in vivo, and the combination was effective for antiprimary tumors and had a tendency to increase the antimetastasis effect of the CAR-T cell therapy. CONCLUSION: Our findings suggest a potent antitumor efficacy of the tmTNF-α CAR-T cells that can be enhanced by anti-PD-L1/PD-1 because high PD-L1 expression in TNBC was induced by the tmTNF-α signaling, indicating a promising individual therapy for tmTNF-α-positive breast cancers including TNBC.


Assuntos
Receptores de Antígenos Quiméricos , Neoplasias de Mama Triplo Negativas , Humanos , Animais , Camundongos , Fator de Necrose Tumoral alfa/metabolismo , Receptor de Morte Celular Programada 1 , Neoplasias de Mama Triplo Negativas/terapia , Anticorpos Monoclonais/farmacologia , Interferon gama , Linfócitos T
4.
AAPS J ; 25(1): 21, 2023 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-36703086

RESUMO

MTBT 1466A is a monoclonal antibody designed to bind to mature human TGFß3 in human tissue and systemic circulation. To evaluate binding of this therapeutic, a mature TGFß3 assay was needed to be able to monitor pharmacodynamic responses in non-human primate (NHP) studies. However, mature TGFß3 levels in systemic circulation are very low and require development of a highly sensitive assay for detection. This study describes the development of a highly sensitive, drug-tolerant pharmacodynamic biomarker assay for demonstrating target engagement in a pre-clinical study using MTBT1466A. Since mature TGFß3 is a dimer, a single MAb was used as both the capture and detection antibodies. This assay was developed on the SMCxPRO platform and qualified based on current accepted criteria for biomarker assays. The assay demonstrated specificity to mature TGFß3, with a lower limit of quantification of 31.3pg/mL. Although baseline levels of mature TGFß3 were below the assay detection limit in 40% of animals within our study, 2- to 16-fold increases were observed in many of the animals following multiple-dosing regimen.


Assuntos
Anticorpos Monoclonais , Fator de Crescimento Transformador beta3 , Animais , Anticorpos Monoclonais/farmacologia , Primatas
5.
Anticancer Res ; 43(2): 613-620, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36697107

RESUMO

BACKGROUND/AIM: Chemotherapy combined with anti-EGFR or anti-VEGF monoclonal antibodies (mAb) is widely used to treat patients with metastatic colorectal cancer (mCRC). Here, we investigated the effects of these antibodies on T-cell infiltration and T-cell receptor (TCR) repertoire variation in CRC liver metastases. MATERIALS AND METHODS: Ten patients with mCRC received chemotherapy in combination with anti-EGFR (n=6) or anti-VEGF (n=4) mAb. T-cell infiltration was examined for CD3 and CD8 by carrying out immunohistochemistry on biopsy or surgical specimens from liver metastases before and after treatment. TCR repertoire analysis was carried out on specimens with post-treatment CD3+ T-cell infiltration. RESULTS: T-cell infiltrations were approximately 83% (5/6) and 50% (2/4), following treatment with anti-EGFR or anti-VEGF mAb, respectively. TCR repertoire analysis revealed higher clonality and lower diversity of TCR alpha and beta (TRA and TRB) in the anti-VEGF mAb group than that in the anti-EGFR group mAb. Furthermore, the percentage of the common TCR clones between infiltrating T cells and T cells in peripheral blood was significantly lower in the anti-VEGF mAb group compared to that in the anti-EGFR mAb group. CONCLUSION: The population of T cells infiltrating liver metastases in the anti-VEGF mAb group differed from that in the anti-EGFR mAb group.


Assuntos
Antineoplásicos , Neoplasias Colorretais , Neoplasias Hepáticas , Humanos , Linfócitos T , Anticorpos Monoclonais/farmacologia , Receptores de Antígenos de Linfócitos T alfa-beta , Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Receptores de Antígenos de Linfócitos T
6.
Sci Rep ; 13(1): 582, 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36631511

RESUMO

B-cell Non-Hodgkin lymphomas are the malignancies of lymphocytes. CD20 is a membrane protein, which is highly expressed on the cell surface of the B-cells in NHL. Treatments using monoclonal antibodies (mAbs) have resulted in failure in some cases. Nanobodies (NBs), single-domain antibodies with low molecular weights and a high specificity in antigen recognition, could be practical alternatives for traditional mAbs with superior characteristics. To design an optimized NB as a candidate CD20 inhibitor with raised binding affinity to CD20, the structure of anti-CD20 NB was optimized to selectively target CD20. The 3D structure of the NB was constructed based on the optimal templates (6C5W and 5JQH), and the key residues were determined by applying a molecular docking study. After identifying the key residues, some mutations were introduced using a rational protocol to improve the binding affinity of the NB to CD20. The rational mutations were conducted using the experimental design (Taguchi method). Six residues (Ser27, Thr28, Phe29, Ile31, Asp99, and Asn100) were selected as the key residues, and five residues were targeted for rational mutation (Trp, Phe, His, Asp, and Tyr). Based on the mutations suggested by the experimental design, two optimized NB structures were constructed. NB2 showed a remarkable binding affinity to CD20 in docking studies with a binding energy of - 853 kcal/mol. The optimized NB was further evaluated using molecular dynamics simulation. The results revealed that CDR1 (complementarity determining regions1) and CDR3 are essential loops for recognizing the antigen. NB2 could be considered as a potential inhibitor of CD20, though experimental evaluations are needed to confirm it.


Assuntos
Anticorpos Monoclonais , Anticorpos de Domínio Único , Simulação de Acoplamento Molecular , Anticorpos Monoclonais/farmacologia , Anticorpos de Domínio Único/farmacologia , Linfócitos B , Antígenos CD20
7.
Oncoimmunology ; 12(1): 2163784, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36632565

RESUMO

Primary effusion lymphoma (PEL), an aggressive non-Hodgkin lymphoma caused by Kaposi sarcoma-associated herpesvirus (KSHV), lacks standard therapy and has a median survival of 10-22 months with combination chemotherapy. PEL is a tumor of plasmablast-like B cells generally expressing CD38, the target of daratumumab (Dara). Initially, we assessed PEL cells from eight patients and established that each expressed high levels of CD38 by flow cytometry. PEL cell lines were also evaluated and most had high CD38 expression. We then assessed Dara's effects on complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) of PEL cell lines as well as its clinical benefits on two patients with PEL. Despite high CD38 expression, Dara did not induce CDC of PEL cell lines, due in part to high levels of the complement-inhibitory proteins, CD55 and CD59. However, Dara induced significant and dose-dependent increases in ADCC, particularly in those lines with high CD38 levels. Two FDA-approved drugs, all trans-retinoic acid (ATRA) and pomalidomide (Pom), significantly increased surface CD38 levels in low-CD38 expressing PEL cell lines, resulting in increased Dara-induced ADCC. Two patients with refractory PEL were treated with Dara alone or in combination with Pom. One patient with leptomeningeal PEL had a complete response to Dara and Pom combination treatment. Others had improvement in performance status and resolution of malignant ascites with Dara alone. Together, these data support the use of Dara monotherapy or in combination with ATRA or Pom as a potential therapeutic option for PEL.


Assuntos
Linfoma de Efusão Primária , Humanos , Linfoma de Efusão Primária/tratamento farmacológico , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Citotoxicidade Imunológica , Tretinoína/farmacologia , Tretinoína/uso terapêutico
8.
Sci Immunol ; 8(79): eadd4947, 2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36638191

RESUMO

The PD-1 receptor triggers a negative immunoregulatory mechanism that prevents overactivation of immune cells and subsequent inflammatory diseases. Because of its biological significance, PD-1 has been a drug target for modulating immune responses. Immunoenhancing anti-PD-1 blocking antibodies have become a widely used cancer treatment; however, little is known about the required characteristics for anti-PD-1 antibodies to be capable of stimulating immunosuppressive activity. Here, we show that PD-1 agonists exist in the group of anti-PD-1 antibodies recognizing the membrane-proximal extracellular region in sharp contrast to the binding of the membrane-distal region by blocking antibodies. This trend was consistent in an analysis of 81 anti-human PD-1 monoclonal antibodies. Because PD-1 agonist antibodies trigger immunosuppressive signaling by cross-linking PD-1 molecules, Fc engineering to enhance FcγRIIB binding of PD-1 agonist antibodies notably improved human T cell inhibition. A PD-1 agonist antibody suppressed inflammation in murine disease models, indicating its clinical potential for treatment of various inflammatory disorders, including autoimmune diseases.


Assuntos
Anticorpos Monoclonais , Linfócitos T , Animais , Camundongos , Anticorpos Bloqueadores/metabolismo , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/metabolismo , Humanos
9.
Drugs ; 83(1): 87-92, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36509938

RESUMO

Ozoralizumab (Nanozora®), a trivalent anti-tumour necrosis factor alpha (TNFα) NANOBODYⓇ compound, has been developed by Taisho Pharmaceutical Co. Ltd (under license from Ablynx, an affiliate of Sanofi) for the treatment of rheumatoid arthritis (RA). In September 2022, ozoralizumab was approved in Japan for the treatment of RA that is inadequately managed by current available treatments. This article summarizes the milestones in the development of ozoralizumab leading to this first approval.


Assuntos
Artrite Reumatoide , Humanos , Artrite Reumatoide/tratamento farmacológico , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Fator de Necrose Tumoral alfa , Japão
10.
Trends Pharmacol Sci ; 44(2): 85-97, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36566131

RESUMO

Monoclonal antibodies represent an exciting class of therapeutics against respiratory viral infections. Notwithstanding their specificity and affinity, the conventional parenteral administration is suboptimal in delivering antibodies for neutralizing activity in the airways due to the poor distribution of macromolecules to the respiratory tract. Inhaled therapy is a promising approach to overcome this hurdle in a noninvasive manner, while advances in antibody engineering have led to the development of unique antibody formats which exhibit properties desirable for inhalation. In this Opinion, we examine the major challenges surrounding the development of inhaled antibodies, identify knowledge gaps that need to be addressed and provide strategies from a drug delivery perspective to enhance the efficacy and safety of neutralizing antibodies against respiratory viral infections.


Assuntos
Anticorpos Neutralizantes , COVID-19 , Humanos , Anticorpos Neutralizantes/farmacologia , Anticorpos Neutralizantes/uso terapêutico , SARS-CoV-2 , Anticorpos Antivirais/uso terapêutico , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico
12.
MAbs ; 15(1): 2153409, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36511654

RESUMO

Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a critical inhibitory checkpoint molecule, and monoclonal antibodies (mAbs) targeting CTLA-4 that restore anti-tumor T cell immunity have achieved clinical success. Here, we report a humanized IgG1 mAb, namely JS007, with high binding affinity to CTLA-4. JS007 shows superior binding affinity and T-cell activating efficiency over ipilimumab. Moreover, it demonstrates substantial in vivo tumor suppression efficacy at low doses. The crystal structure of JS007/CTLA-4 complex (PDB: 8HIT) shows JS007 adopts a heavy-chain-dominant binding mode, and mainly contacts the BC loop, DE loop and FG loop of CTLA-4. Notably, two Tyr residues (VH-Y100 and VL-Y32) from the complementarity-determining region loops insert into the two cavities formed by the residues from the loops of CTLA-4, which may contribute to the stabilization of the binding. Comparative analysis with other anti-CTLA-4 mAbs indicates that the double "wedge-into-hole" binding mode is unique for JS007 and may be responsible for the high-affinity binding to CTLA-4. These findings have provided an important molecular understanding of the high-affinity CTLA-4 blockade mAbs and shed light on future development of agents targeting CTLA-4.


Assuntos
Neoplasias , Humanos , Ipilimumab/uso terapêutico , Ipilimumab/farmacologia , Neoplasias/terapia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/farmacologia , Anticorpos Bloqueadores , Regiões Determinantes de Complementaridade
13.
MAbs ; 15(1): 2156317, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36524835

RESUMO

Receptor occupancy assays applied in clinical studies provide insights into pharmacokinetic-pharmacodynamic relationships for therapeutic antibodies. When measured by different assays, however, receptor occupancy results can be controversial, as was observed for nivolumab, a monoclonal antibody targeting programmed cell death 1 (PD-1) receptor. We suggested an explanation of results obtained and a mechanistic approach based on specific features of the receptor occupancy assays: measurement of the free or bound receptor, normalized to the baseline or at each time point. The approach was evaluated against controversial clinical data on PD-1 receptor occupancy by nivolumab. It was shown that receptor occupancy measured by different assays might vary substantially if the internalization rate of the bound receptor is higher than the rate of degradation of the free receptor. Equations proposed in this work can be applied in quantitative systems pharmacology models to describe target receptor occupancy by different therapeutic antibodies.


Assuntos
Farmacologia em Rede , Nivolumabe , Nivolumabe/farmacologia , Receptor de Morte Celular Programada 1/metabolismo , Anticorpos Monoclonais/farmacologia
14.
J Am Chem Soc ; 145(1): 322-333, 2023 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-36542493

RESUMO

Alternative antibacterial therapies refractory to existing mechanisms of antibiotic resistance are urgently needed. One such attractive therapy is to inhibit bacterial adhesion and colonization. Ser O-heptosylation (Ser O-Hep) on autotransporters of Gram-negative bacteria is a novel glycosylation and has been proven to be essential for bacterial colonization. Herein, we chemically synthesized glycopeptides containing this atypical glycan structure and an absolute C6 configuration through the assembly of Ser O-Hep building blocks. Using glycopeptides as haptens, we generated first-in-class poly- and monoclonal antibodies, termed Anti-SerHep1a and Anti-SerHep1b, that stereoselectively recognize Ser O-heptosylation (d/l-glycero) with high specificity in vitro and in vivo. Importantly, these antibodies effectively blocked diffusely adhering Escherichia coli 2787 adhesion to HeLa cells and in mice in a dose- and Ser O-Hep-dependent manner. Together, these antibodies represent not only useful tools for the discovery of unknown serine O-heptosylated proteins bearing various C6 chiral centers but also a novel class of antiadhesion therapeutic agents for the treatment of bacterial infection.


Assuntos
Anticorpos Monoclonais , Polissacarídeos , Humanos , Animais , Camundongos , Células HeLa , Glicosilação , Polissacarídeos/química , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Escherichia coli , Glicopeptídeos/química
15.
Pharmacol Res ; 187: 106631, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36586644

RESUMO

According to the ß-amyloid (Aß) hypothesis of Alzheimer's disease (AD), brain Aß accumulation is the primary cascade event leading to cognitive deficit and dementia. Numerous anti-Aß drugs either inhibiting production or aggregation of Aß or stimulating its clearance have failed to show clinical benefit in large scale AD trials, with ß- and γ-secretase inhibitors consistently worsening cognitive and clinical decline. In June 2021, the FDA approved aducanumab, an anti-Aß monoclonal antibody for early AD based on its ability to reduce brain amyloid plaques, while two other amyloid-clearing antibodies (lecanemab and donanemab) have recently produced encouraging cognitive and clinical results. We reviewed AD trials using PubMed, meeting abstracts and ClinicalTrials.gov and evaluated the effects of such drugs on cerebrospinal fluid (CSF) Aß levels, correlating them with cognitive effects. We found that ß-secretase and γ-secretase inhibitors produce detrimental cognitive effects by significantly reducing CSF Aß levels. We speculate that monoclonal antibodies targeting Aß protofibrils, fibrils or plaques may improve cognitive performance in early AD by increasing soluble Aß levels through Aß aggregate disassembly and/or stabilization of existing Aß monomers.These findings suggest that the real culprit in AD may be decreased levels of soluble monomeric Aß due to sequestration into brain Aß aggregates and plaques.


Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Peptídeos beta-Amiloides , Cognição
16.
Drug Discov Today ; 27(1): 354-361, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34597756

RESUMO

In antibody-drug conjugates (ADCs), monoclonal antibodies (mAbs) act as carriers for a cytotoxic payload providing the therapy with targeted action against cells expressing a target cell surface antigen. An appropriate choice of mAb is crucial to developing a successful ADC for clinical development. However, problems such as immunogenicity, poor pharmacokinetic (PK) and pharmacodynamic (PD) profiles and variable drug-antibody ratios (DARs) plague ADCs. In this review, we detail recent mAb-based innovations and factors that should be considered to overcome these problems to achieve a new generation of more effective ADC therapeutics.


Assuntos
Anticorpos Monoclonais/farmacologia , Desenvolvimento de Medicamentos , Imunoconjugados/farmacologia , Neoplasias/tratamento farmacológico , Antineoplásicos Imunológicos/farmacologia , Desenvolvimento de Medicamentos/métodos , Desenvolvimento de Medicamentos/normas , Desenvolvimento de Medicamentos/tendências , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Melhoria de Qualidade
17.
Cancer Immunol Immunother ; 71(5): 1017-1031, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-34545416

RESUMO

Primary effusion lymphoma (PEL) is a rare, aggressive B cell non-Hodgkin's lymphoma of the body cavities with malignant effusions. The prognosis is poor, and no optimal treatment has been established. CD38 is a type II transmembrane glycoprotein known to overexpress in multiple myeloma (MM). Daratumumab (DARA), a human CD38-targeting monoclonal antibody (mAb), is approved for MM treatment. In this study, we found expression of CD38 on PEL cells and assessed the anti-PEL activity of DARA. We found that both KHYG-1 and N6 (CD16-transfected KHYG-1) NK cell lines showed direct killing activity against PEL cells with induction of CD107a, and NK-mediated cytotoxicity by N6NK (CD16+) cells increased with DARA treatment. We confirmed direct NK activity and antibody-dependent cell cytotoxicity (ADCC) by expanded NK cells, indicating that DARA has high ADCC activity. We elucidated the antibody-dependent cell phagocytosis (ADCP) by using human monocyte-derived macrophages (MDMs) and mouse peritoneal macrophages. DARA also showed potent complement-dependent cytolysis (CDC) toward PEL. DARA also induced PEL cell death in the presence of a cross-linking antibody. Moreover, treatment with DARA inhibited tumor growth in a PEL xenograft mouse model. These results provide preclinical evidence that Ab targeting of CD38 could be an effective therapeutic strategy for the treatment of PEL.


Assuntos
Antineoplásicos , Linfoma de Efusão Primária , Mieloma Múltiplo , ADP-Ribosil Ciclase 1 , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Citotoxicidade Celular Dependente de Anticorpos , Antineoplásicos/uso terapêutico , Humanos , Linfoma de Efusão Primária/tratamento farmacológico , Camundongos
18.
Leukemia ; 36(2): 525-531, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34545183

RESUMO

Chronic eosinophilic leukemia-not otherwise specified (CEL-NOS) is a rare, aggressive, fatal disease characterized by blood eosinophilia and dysfunction of organs infiltrated with eosinophils. Clinically, the disease manifests with weight loss, cough, weakness, diarrhea, and multi-organ dysfunction that is unresponsive to therapy. We developed a one-time gene therapy for CEL-NOS using an adeno-associated virus (AAV) expressing an anti-eosinophil monoclonal antibody (AAVrh.10mAnti-Eos) to provide sustained suppression of eosinophil numbers in blood, thus reducing eosinophil tissue invasion and organ dysfunction. A novel CEL-NOS model was developed in NOD-scid IL2rγnull (NSG) mice by administration of AAV expressing the cytokine IL5 (AAVrh.10mIL5), resulting in marked peripheral and tissue eosinophilia of the heart, lung, liver, and spleen, and eventually death. Mice were administered AAVrh.10mAnti-Eos (1011 genome copies) 4 wk after administration of AAVrh.10mIL5 and evaluated for anti-eosinophil antibody expression, blood eosinophil counts, organ eosinophil invasion, and survival. AAVrh.10mAnti-Eos expressed persistent levels of the anti-eosinophil antibody for >24 wk. Strikingly, CEL-NOS treated mice had markedly lower blood eosinophil levels and reduced mortality when compared with control treated mice. These results suggest that a single treatment with AAVrh.10mAnti-Eos has the potential to provide substantial therapeutic benefit to patients with CEL-NOS, a fatal malignant disorder.


Assuntos
Anticorpos Monoclonais/farmacologia , Dependovirus/genética , Modelos Animais de Doenças , Eosinófilos/imunologia , Terapia Genética , Síndrome Hipereosinofílica/terapia , Interleucina-5/genética , Leucemia/terapia , Animais , Eosinófilos/efeitos dos fármacos , Feminino , Síndrome Hipereosinofílica/genética , Síndrome Hipereosinofílica/imunologia , Leucemia/genética , Leucemia/imunologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID
19.
PLoS One ; 17(12): e0277956, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36525420

RESUMO

Standard treatment for patients with high-risk neuroblastoma remains multimodal therapy including chemoradiation, surgical resection, and autologous stem cell rescue. Immunotherapy has demonstrated success in treating many types of cancers; however, its use in pediatric solid tumors has been limited by low tumor mutation burdens. Gastrin-releasing peptide receptor (GRP-R) is overexpressed in numerous malignancies, including poorly-differentiated neuroblastoma. Monoclonal antibodies (mAbs) to GRP-R have yet to be developed but could serve as a potential novel immunotherapy. This preclinical study aims to evaluate the efficacy of a novel GRP-R mAb immunotherapy against neuroblastoma. We established four candidate anti-GRP-R mAbs by screening a single-chain variable fragment (scFv) library. GRP-R mAb-1 demonstrated the highest efficacy with the lowest EC50 at 4.607 ng/ml against GRP-R expressing neuroblastoma cells, blocked the GRP-ligand activation of GRP-R and its downstream PI3K/AKT signaling. This resulted in functional inhibition of cell proliferation and anchorage-independent growth, indicating that mAb-1 has an antagonist inhibitory role on GRP-R. To examine the antibody-dependent cellular cytotoxicity (ADCC) of GRP-R mAb-1 on neuroblastoma, we co-cultured neuroblastoma cells with natural killer (NK) cells versus GRP-R mAb-1 treatment alone. GRP-R mAb-1 mediated ADCC effects on neuroblastoma cells and induced release of IFNγ by NK cells under co-culture conditions in vitro. The cytotoxic effects of mAb-1 were confirmed with the secretion of cytotoxic granzyme B from NK cells and the reduction of mitotic tumor cells in vivo using a murine tumor xenograft model. In summary, GRP-R mAb-1 demonstrated efficacious anti-tumor effects on neuroblastoma cells in preclinical models. Importantly, GRP-R mAb-1 may be an efficacious, novel immunotherapy in the treatment of high-risk neuroblastoma patients.


Assuntos
Neuroblastoma , Receptores da Bombesina , Criança , Humanos , Camundongos , Animais , Receptores da Bombesina/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Linhagem Celular Tumoral , Neuroblastoma/metabolismo , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico
20.
Expert Opin Drug Metab Toxicol ; 18(11): 755-767, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36582117

RESUMO

INTRODUCTION: The introduction of monoclonal antibodies to the chemotherapy backbone treatment has challenged the paradigm of metastatic colorectal cancer (mCRC) treatment. Their mechanism of action and pharmacokinetics are complex but important to understand in order to improve patient selection and treatment outcomes for mCRC population. AREAS COVERED: This review examines the scientific data, pharmacodynamics, and pharmacokinetics of approved monoclonal antibodies used to treat mCRC patients, including agents targeting signaling via VEGFR (bevacizumab and ramucirumab), EGFR (cetuximab and panitumumab), HER2/3 target therapy, and immunotherapy agents such as pembrolizumab or nivolumab. Efficacy and mechanism of action of bispecific antibodies are also covered. EXPERT OPINION: mCRC is a heterogeneous disease and the optimal selection and sequence of treatments is challenging. Monoclonal antibodies have complex pharmacokinetics and pharmacodynamics, with important interactions between them. The arrival of bioequivalent molecules to the market increases the need for the characterization of pharmacokinetics and pharmacodynamics of classic monoclonal antibodies to reach bioequivalent novel molecules.


Assuntos
Antineoplásicos , Neoplasias Colorretais , Humanos , Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Receptores ErbB/uso terapêutico , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Cetuximab/uso terapêutico , Imunoterapia
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