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1.
Hematology ; 26(1): 652-655, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34474661

RESUMO

OBJECTIVES: Myeloma relapse remains challenging. Daratumumab (dara) with immunomodulatory agents (IMiD) and dexamethasone (dex) was proven highly effective in relapsed or refractory multiple myeloma (RRMM) in randomized controlled trials. The recommended schedule of dara is weekly for eight doses, followed by 2-weekly for eight doses, and then every 4-weekly thereafter. However, the cost of daratumumab is daunting, precluding widespread and prolonged use in some countries. In this study, we aimed to evaluate the efficacy of using a 3-weekly daratumumab regimen in RRMM. METHODS: Thirteen RRMM patients were treated with dara-IMiD-dex till maximal response, followed by single-agent IMiD maintenance until disease progression. Dara (every 6 weekly) would be added upon significant biochemical disease progression. RESULTS: After a median of four daratumumab infusions (range: 3-10), the best responses included complete response (CR) in seven patients (53.8%), very good partial response (VGPR) in four patients (30.8%), and partial response (PR) in two patients (15.4%). The median time to VGPR was four weeks. At 10 months, the overall survival was 90%, and progression-free survival was 54.7%. Two of three patients tested achieved MRD-ve CR. Another patient, who had PET-CT reassessment, showed PET-ve CR. DISCUSSION: Despite less frequent daratumumab use, we reported rapid responses with a median time to VGPR of only four weeks, and a response rate of 100% including CR rate of 54%. Despite less frequent daratumumab use, grade ¾ neutropenia remained common with a frequency comparable to that observed in Pollux. CONCLUSION: This 3-weekly dara-IMiD-dex regimen preserves a high efficacy with rapid, deep responses including MRD-ve and PET-ve CR, hence a cost-effective regimen.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Dexametasona/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Lenalidomida/administração & dosagem , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Recidiva , Taxa de Sobrevida , Talidomida/administração & dosagem , Talidomida/análogos & derivados
2.
Front Immunol ; 12: 709861, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34475873

RESUMO

Background: Immune hyperactivity is an important contributing factor to the morbidity and mortality of COVID-19 infection. Nasal administration of anti-CD3 monoclonal antibody downregulates hyperactive immune responses in animal models of autoimmunity through its immunomodulatory properties. We performed a randomized pilot study of fully-human nasal anti-CD3 (Foralumab) in patients with mild to moderate COVID-19 to determine if its immunomodulatory properties had ameliorating effects on disease. Methods: Thirty-nine outpatients with mild to moderate COVID-19 were recruited at Santa Casa de Misericordia de Santos in Sao Paulo State, Brazil. Patients were randomized to three cohorts: 1) Control, no Foralumab (n=16); 2) Nasal Foralumab (100ug/day) given for 10 consecutive days with 6 mg dexamethasone given on days 1-3 (n=11); and 3) Nasal Foralumab alone (100ug/day) given for 10 consecutive days (n=12). Patients continued standard of care medication. Results: We observed reduction of serum IL-6 and C-reactive protein in Foralumab alone vs. untreated or Foralumab/Dexa treated patients. More rapid clearance of lung infiltrates as measured by chest CT was observed in Foralumab and Foralumab/Dexa treated subjects vs. those that did not receive Foralumab. Foralumab treatment was well-tolerated with no severe adverse events. Conclusions: This pilot study suggests that nasal Foralumab is well tolerated and may be of benefit in treatment of immune hyperactivity and lung involvement in COVID-19 disease and that further studies are warranted.


Assuntos
Anticorpos Monoclonais/uso terapêutico , COVID-19/imunologia , COVID-19/prevenção & controle , Pneumonia/terapia , Administração Intranasal , Adolescente , Adulto , Anticorpos Monoclonais/administração & dosagem , Biomarcadores , Proteína C-Reativa/análise , COVID-19/fisiopatologia , COVID-19/terapia , Estudos de Coortes , Feminino , Humanos , Imunidade/efeitos dos fármacos , Interleucina-6/sangue , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais/estatística & dados numéricos , Projetos Piloto , Pneumonia/prevenção & controle , Adulto Jovem
3.
Viruses ; 13(8)2021 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-34452363

RESUMO

Despite the recent availability of vaccines against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), there is an urgent need for specific anti-SARS-CoV-2 drugs. Monoclonal neutralizing antibodies are an important drug class in the global fight against the SARS-CoV-2 pandemic due to their ability to convey immediate protection and their potential to be used as both prophylactic and therapeutic drugs. Clinically used neutralizing antibodies against respiratory viruses are currently injected intravenously, which can lead to suboptimal pulmonary bioavailability and thus to a lower effectiveness. Here we describe DZIF-10c, a fully human monoclonal neutralizing antibody that binds the receptor-binding domain of the SARS-CoV-2 spike protein. DZIF-10c displays an exceptionally high neutralizing potency against SARS-CoV-2, retains full activity against the variant of concern (VOC) B.1.1.7 and still neutralizes the VOC B.1.351, although with reduced potency. Importantly, not only systemic but also intranasal application of DZIF-10c abolished the presence of infectious particles in the lungs of SARS-CoV-2 infected mice and mitigated lung pathology when administered prophylactically. Along with a favorable pharmacokinetic profile, these results highlight DZIF-10c as a novel human SARS-CoV-2 neutralizing antibody with high in vitro and in vivo antiviral potency. The successful intranasal application of DZIF-10c paves the way for clinical trials investigating topical delivery of anti-SARS-CoV-2 antibodies.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Antivirais/administração & dosagem , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , Administração Intranasal , Animais , COVID-19/virologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/imunologia
5.
Nat Commun ; 12(1): 5000, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34404805

RESUMO

The successive emergences and accelerating spread of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineages and evolved resistance to some ongoing clinical therapeutics increase the risks associated with the coronavirus disease 2019 (COVID-19) pandemic. An urgent intervention for broadly effective therapies to limit the morbidity and mortality of COVID-19 and future transmission events from SARS-related coronaviruses (SARSr-CoVs) is needed. Here, we isolate and humanize an angiotensin-converting enzyme-2 (ACE2)-blocking monoclonal antibody (MAb), named h11B11, which exhibits potent inhibitory activity against SARS-CoV and circulating global SARS-CoV-2 lineages. When administered therapeutically or prophylactically in the hACE2 mouse model, h11B11 alleviates and prevents SARS-CoV-2 replication and virus-induced pathological syndromes. No significant changes in blood pressure and hematology chemistry toxicology were observed after injections of multiple high dosages of h11B11 in cynomolgus monkeys. Analysis of the structures of the h11B11/ACE2 and receptor-binding domain (RBD)/ACE2 complexes shows hindrance and epitope competition of the MAb and RBD for the receptor. Together, these results suggest h11B11 as a potential therapeutic countermeasure against SARS-CoV, SARS-CoV-2, and escape variants.


Assuntos
Enzima de Conversão de Angiotensina 2/efeitos dos fármacos , Enzima de Conversão de Angiotensina 2/imunologia , Anticorpos Neutralizantes/administração & dosagem , COVID-19/tratamento farmacológico , SARS-CoV-2/efeitos dos fármacos , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , COVID-19/imunologia , COVID-19/mortalidade , COVID-19/virologia , Chlorocebus aethiops , Modelos Animais de Doenças , Epitopos , Feminino , Células HEK293 , Haplorrinos , Humanos , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pandemias , SARS-CoV-2/imunologia , SARS-CoV-2/isolamento & purificação , Células Vero , Ativação Viral
6.
Int J Mol Sci ; 22(15)2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34361080

RESUMO

Photoimmunotherapy (PIT) is an upcoming potential cancer treatment modality, the effect of which is improved in combination with chemotherapy. PIT causes a super-enhanced permeability and retention (SUPR) effect. Here, we quantitatively evaluated the SUPR effect using radiolabeled drugs of varying molecular weights (18F-5FU, 111In-DTPA, 99mTc-HSA-D, and 111In-IgG) to determine the appropriate drug size. PIT was conducted with an indocyanine green-labeled anti-HER2 antibody and an 808 nm laser irradiation. Mice were subcutaneously inoculated with HER2-positive cells in both hindlimbs. The tumor on one side was treated with PIT, and the contralateral side was not treated. The differences between tumor accumulations were evaluated using positron emission tomography or single-photon emission computed tomography. Imaging studies found increased tumor accumulation of agents after PIT. PIT-treated tumors showed significantly increased uptake of 18F-5FU (p < 0.001) and 99mTc-HSA-D (p < 0.001). A tendency toward increased accumulation of 111In-DTPA and 111In-IgG was observed. These findings suggest that some low- and medium-molecular-weight agents are promising candidates for combined PIT, as are macromolecules; hence, administration after PIT could enhance their efficacy. Our findings encourage further preclinical and clinical studies to develop a combination therapy of PIT with conventional anticancer drugs.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Sistemas de Liberação de Medicamentos , Imunoterapia/métodos , Neoplasias/terapia , Fototerapia/métodos , Cintilografia/métodos , Animais , Apoptose , Proliferação de Células , Terapia Combinada , Humanos , Verde de Indocianina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/diagnóstico por imagem , Neoplasias/metabolismo , Neoplasias/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Cell Rep ; 36(10): 109679, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34464610

RESUMO

A wide range of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing monoclonal antibodies (mAbs) have been reported, most of which target the spike glycoprotein. Therapeutic implementation of these antibodies has been challenged by emerging SARS-CoV-2 variants harboring mutated spike versions. Consequently, re-assessment of previously identified mAbs is of high priority. Four previously selected mAbs targeting non-overlapping epitopes are now evaluated for binding potency to mutated RBD versions, reported to mediate escape from antibody neutralization. In vitro neutralization potencies of these mAbs, and two NTD-specific mAbs, are evaluated against two frequent SARS-CoV-2 variants of concern, the B.1.1.7 Alpha and the B.1.351 Beta. Furthermore, we demonstrate therapeutic potential of three selected mAbs by treatment of K18-human angiotensin-converting enzyme 2 (hACE2) transgenic mice 2 days post-infection with each virus variant. Thus, despite the accumulation of spike mutations, the highly potent MD65 and BL6 mAbs retain their ability to bind the prevalent viral mutants, effectively protecting against B.1.1.7 and B.1.351 variants.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , SARS-CoV-2/imunologia , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/química , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/química , Afinidade de Anticorpos , COVID-19/terapia , COVID-19/virologia , Epitopos/genética , Epitopos/imunologia , Humanos , Imunização Passiva , Camundongos , Camundongos Transgênicos , Modelos Moleculares , Testes de Neutralização , Domínios Proteicos , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Resultado do Tratamento
8.
N Engl J Med ; 385(9): 803-814, 2021 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-34379916

RESUMO

BACKGROUND: Additional interventions are needed to reduce the morbidity and mortality caused by malaria. METHODS: We conducted a two-part, phase 1 clinical trial to assess the safety and pharmacokinetics of CIS43LS, an antimalarial monoclonal antibody with an extended half-life, and its efficacy against infection with Plasmodium falciparum. Part A of the trial assessed the safety, initial side-effect profile, and pharmacokinetics of CIS43LS in healthy adults who had never had malaria. Participants received CIS43LS subcutaneously or intravenously at one of three escalating dose levels. A subgroup of participants from Part A continued to Part B, and some received a second CIS43LS infusion. Additional participants were enrolled in Part B and received CIS43LS intravenously. To assess the protective efficacy of CIS43LS, some participants underwent controlled human malaria infection in which they were exposed to mosquitoes carrying P. falciparum sporozoites 4 to 36 weeks after administration of CIS43LS. RESULTS: A total of 25 participants received CIS43LS at a dose of 5 mg per kilogram of body weight, 20 mg per kilogram, or 40 mg per kilogram, and 4 of the 25 participants received a second dose (20 mg per kilogram regardless of initial dose). No safety concerns were identified. We observed dose-dependent increases in CIS43LS serum concentrations, with a half-life of 56 days. None of the 9 participants who received CIS43LS, as compared with 5 of 6 control participants who did not receive CIS43LS, had parasitemia according to polymerase-chain-reaction testing through 21 days after controlled human malaria infection. Two participants who received 40 mg per kilogram of CIS43LS and underwent controlled human malaria infection approximately 36 weeks later had no parasitemia, with serum concentrations of CIS43LS of 46 and 57 µg per milliliter at the time of controlled human malaria infection. CONCLUSIONS: Among adults who had never had malaria infection or vaccination, administration of the long-acting monoclonal antibody CIS43LS prevented malaria after controlled infection. (Funded by the National Institute of Allergy and Infectious Diseases; VRC 612 ClinicalTrials.gov number, NCT04206332.).


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antimaláricos/uso terapêutico , Malária Falciparum/prevenção & controle , Adulto , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Anticorpos Antiprotozoários/sangue , Antimaláricos/administração & dosagem , Antimaláricos/efeitos adversos , Antimaláricos/farmacocinética , Relação Dose-Resposta a Droga , Voluntários Saudáveis , Humanos , Infusões Intravenosas/efeitos adversos , Injeções Subcutâneas/efeitos adversos , Pessoa de Meia-Idade , Plasmodium falciparum/imunologia , Plasmodium falciparum/isolamento & purificação
9.
Int J Mol Sci ; 22(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208575

RESUMO

Due to their high specificity, monoclonal antibodies have been widely investigated for their application in drug delivery to the central nervous system (CNS) for the treatment of neurological diseases such as stroke, Alzheimer's, and Parkinson's disease. Research in the past few decades has revealed that one of the biggest challenges in the development of antibodies for drug delivery to the CNS is the presence of blood-brain barrier (BBB), which acts to restrict drug delivery and contributes to the limited uptake (0.1-0.2% of injected dose) of circulating antibodies into the brain. This article reviews the various methods currently used for antibody delivery to the CNS at the preclinical stage of development and the underlying mechanisms of BBB penetration. It also describes efforts to improve or modulate the physicochemical and biochemical properties of antibodies (e.g., charge, Fc receptor binding affinity, and target affinity), to adapt their pharmacokinetics (PK), and to influence their distribution and disposition into the brain. Finally, a distinction is made between approaches that seek to modify BBB permeability and those that use a physiological approach or antibody engineering to increase uptake in the CNS. Although there are currently inherent difficulties in developing safe and efficacious antibodies that will cross the BBB, the future prospects of brain-targeted delivery of antibody-based agents are believed to be excellent.


Assuntos
Anticorpos Monoclonais/metabolismo , Anticorpos/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Animais , Anticorpos/administração & dosagem , Anticorpos/efeitos adversos , Anticorpos/uso terapêutico , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Transporte Biológico , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Encéfalo/efeitos dos fármacos , Vias de Administração de Medicamentos , Humanos , Imunoconjugados/administração & dosagem , Imunoconjugados/efeitos adversos , Imunoconjugados/metabolismo , Imunoconjugados/uso terapêutico , Permeabilidade , Agregados Proteicos , Agregação Patológica de Proteínas , Engenharia de Proteínas , Distribuição Tecidual
10.
N Engl J Med ; 385(1): 46-58, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34192431

RESUMO

BACKGROUND: Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+ plasma cells. Daratumumab, a human CD38-targeting antibody, may improve outcomes for this disease. METHODS: We randomly assigned patients with newly diagnosed AL amyloidosis to receive six cycles of bortezomib, cyclophosphamide, and dexamethasone either alone (control group) or with subcutaneous daratumumab followed by single-agent daratumumab every 4 weeks for up to 24 cycles (daratumumab group). The primary end point was a hematologic complete response. RESULTS: A total of 388 patients underwent randomization. The median follow-up was 11.4 months. The percentage of patients who had a hematologic complete response was significantly higher in the daratumumab group than in the control group (53.3% vs. 18.1%) (relative risk ratio, 2.9; 95% confidence interval [CI], 2.1 to 4.1; P<0.001). Survival free from major organ deterioration or hematologic progression favored the daratumumab group (hazard ratio for major organ deterioration, hematologic progression, or death, 0.58; 95% CI, 0.36 to 0.93; P = 0.02). At 6 months, more cardiac and renal responses occurred in the daratumumab group than in the control group (41.5% vs. 22.2% and 53.0% vs. 23.9%, respectively). The four most common grade 3 or 4 adverse events were lymphopenia (13.0% in the daratumumab group and 10.1% in the control group), pneumonia (7.8% and 4.3%, respectively), cardiac failure (6.2% and 4.8%), and diarrhea (5.7% and 3.7%). Systemic administration-related reactions to daratumumab occurred in 7.3% of the patients. A total of 56 patients died (27 in the daratumumab group and 29 in the control group), most due to amyloidosis-related cardiomyopathy. CONCLUSIONS: Among patients with newly diagnosed AL amyloidosis, the addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone was associated with higher frequencies of hematologic complete response and survival free from major organ deterioration or hematologic progression. (Funded by Janssen Research and Development; ANDROMEDA ClinicalTrials.gov number, NCT03201965.).


Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Amiloidose de Cadeia Leve de Imunoglobulina/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/administração & dosagem , Ciclofosfamida/administração & dosagem , Dexametasona/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/mortalidade , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
11.
Lancet Oncol ; 22(6): 801-812, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34087126

RESUMO

BACKGROUND: In a phase 1b study, intravenous daratumumab plus pomalidomide and dexamethasone induced a very good partial response or better rate of 42% and was well tolerated in patients with heavily pretreated multiple myeloma. We aimed to evaluate whether daratumumab plus pomalidomide and dexamethasone would improve progression-free survival versus pomalidomide and dexamethasone alone in patients with previously treated multiple myeloma. METHODS: In this ongoing, open-label, randomised, phase 3 trial (APOLLO) done at 48 academic centres and hospitals across 12 European countries, eligible patients were aged 18 years or older, had relapsed or refractory multiple myeloma with measurable disease, had an Eastern Cooperative Oncology Group performance status of 0-2, had at least one previous line of therapy, including lenalidomide and a proteasome inhibitor, had a partial response or better to one or more previous lines of antimyeloma therapy, and were refractory to lenalidomide if only one previous line of therapy was received. Patients were randomly assigned (1:1) by an interactive web-response system in a random block size of two or four to receive pomalidomide and dexamethasone alone or daratumumab plus pomalidomide and dexamethasone. Randomisation was stratified by number of previous lines of therapy and International Staging System disease stage. All patients received oral pomalidomide (4 mg, once daily on days 1-21) and oral dexamethasone (40 mg once daily on days 1, 8, 15, and 22; 20 mg for those aged 75 years or older) at each 28-day cycle. The daratumumab plus pomalidomide and dexamethasone group received daratumumab (1800 mg subcutaneously or 16 mg/kg intravenously) weekly during cycles 1 and 2, every 2 weeks during cycles 3-6, and every 4 weeks thereafter until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, NCT03180736. FINDINGS: Between June 22, 2017, and June 13, 2019, 304 patients (median age 67 years [IQR 60-72]; 161 [53%] men and 143 [47%] women) were randomly assigned to the daratumumab plus pomalidomide and dexamethasone group (n=151) or the pomalidomide and dexamethasone group (n=153). At a median follow-up of 16·9 months (IQR 14·4-20·6), the daratumumab plus pomalidomide and dexamethasone group showed improved progression-free survival compared with the pomalidomide and dexamethasone group (median 12·4 months [95% CI 8·3-19·3] vs 6·9 months [5·5-9·3]; hazard ratio 0·63 [95% CI 0·47-0·85], two-sided p=0·0018). The most common grade 3 or 4 adverse events were neutropenia (101 [68%] of 149 patients in the daratumumab plus pomalidomide and dexamethasone group vs 76 [51%] of 150 patients in the pomalidomide and dexamethasone group), anaemia (25 [17%] vs 32 [21%]), and thrombocytopenia (26 [17%] vs 27 [18%]). Serious adverse events occurred in 75 (50%) of 149 patients in the daratumumab plus pomalidomide and dexamethasone group versus 59 (39%) of 150 patients in the pomalidomide and dexamethasone group; pneumonia (23 [15%] vs 12 [8%] patients) and lower respiratory tract infection (18 [12%] vs 14 [9%]) were most common. Treatment-emergent deaths were reported in 11 (7%) patients in the daratumumab plus pomalidomide and dexamethasone group versus 11 (7%) patients in the pomalidomide and dexamethasone group. INTERPRETATION: Among patients with relapsed or refractory multiple myeloma, daratumumab plus pomalidomide and dexamethasone reduced the risk of disease progression or death versus pomalidomide and dexamethasone alone and could be considered a new treatment option in this setting. FUNDING: European Myeloma Network and Janssen Research and Development.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Dexametasona/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Talidomida/análogos & derivados , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Neutropenia/induzido quimicamente , Neutropenia/patologia , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Talidomida/administração & dosagem , Talidomida/efeitos adversos
12.
Dokl Biochem Biophys ; 498(1): 199-202, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34189650

RESUMO

Two monoclonal antibodies recognizing non-overlapping epitopes of the PRAME protein were injected into immunocompetent mice to study their influence on the growth of subcutaneous tumor nodes. The B16F10 murine melanoma line, either expressing human PRAME protein or bearing only a vector without PRAME gene, were used as transplants. Each of the antibodies showed the ability to suppress tumor growth of a PRAME-expressing tumour, but not a tumor without PRAME.


Assuntos
Anticorpos Monoclonais/farmacologia , Antígenos de Neoplasias/imunologia , Epitopos/imunologia , Melanoma Experimental/prevenção & controle , Animais , Anticorpos Monoclonais/administração & dosagem , Feminino , Melanoma Experimental/etiologia , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL
13.
Nat Commun ; 12(1): 2904, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-34006855

RESUMO

Enterovirus D68 (EV-D68) is an emerging pathogen associated with respiratory diseases and/or acute flaccid myelitis. Here, two MAbs, 2H12 and 8F12, raised against EV-D68 virus-like particle (VLP), show distinct preference in binding VLP and virion and in neutralizing different EV-D68 strains. A combination of 2H12 and 8F12 exhibits balanced and potent neutralization effects and confers broader protection in mice than single MAbs when given at onset of symptoms. Cryo-EM structures of EV-D68 virion complexed with 2H12 or 8F12 show that both antibodies bind to the canyon region of the virion, creating steric hindrance for sialic acid receptor binding. Additionally, 2H12 binding can impair virion integrity and trigger premature viral uncoating. We also capture an uncoating intermediate induced by 2H12 binding, not previously described for picornaviruses. Our study elucidates the structural basis and neutralizing mechanisms of the 2H12 and 8F12 MAbs and supports further development of the 2H12/8F12 cocktail as a broad-spectrum therapeutic agent against EV-D68 infections in humans.


Assuntos
Anticorpos Monoclonais/imunologia , Enterovirus Humano D/imunologia , Infecções por Enterovirus/imunologia , Vírion/imunologia , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/metabolismo , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/metabolismo , Linhagem Celular Tumoral , Microscopia Crioeletrônica , Enterovirus Humano D/efeitos dos fármacos , Enterovirus Humano D/fisiologia , Infecções por Enterovirus/tratamento farmacológico , Infecções por Enterovirus/virologia , Feminino , Humanos , Camundongos Endogâmicos BALB C , Ligação Proteica/efeitos dos fármacos , Receptores de Superfície Celular/imunologia , Receptores de Superfície Celular/metabolismo , Tempo para o Tratamento , Resultado do Tratamento , Vírion/efeitos dos fármacos , Vírion/metabolismo , Vírion/ultraestrutura , Desenvelopamento do Vírus/efeitos dos fármacos
15.
Nat Rev Clin Oncol ; 18(9): 558-576, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34006998

RESUMO

Immune-checkpoint inhibitors and chimeric antigen receptor (CAR) T cells are revolutionizing oncology and haematology practice. With these and other immunotherapies, however, systemic biodistribution raises safety issues, potentially requiring the use of suboptimal doses or even precluding their clinical development. Delivering or attracting immune cells or immunomodulatory factors directly to the tumour and/or draining lymph nodes might overcome these problems. Hence, intratumoural delivery and tumour tissue-targeted compounds are attractive options to increase the in situ bioavailability and, thus, the efficacy of immunotherapies. In mouse models, intratumoural administration of immunostimulatory monoclonal antibodies, pattern recognition receptor agonists, genetically engineered viruses, bacteria, cytokines or immune cells can exert powerful effects not only against the injected tumours but also often against uninjected lesions (abscopal or anenestic effects). Alternatively, or additionally, biotechnology strategies are being used to achieve higher functional concentrations of immune mediators in tumour tissues, either by targeting locally overexpressed moieties or engineering 'unmaskable' agents to be activated by elements enriched within tumour tissues. Clinical trials evaluating these strategies are ongoing, but their development faces issues relating to the administration methodology, pharmacokinetic parameters, pharmacodynamic end points, and immunobiological and clinical response assessments. Herein, we discuss these approaches in the context of their historical development and describe the current landscape of intratumoural or tumour tissue-targeted immunotherapies.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Imunoterapia/métodos , Neoplasias/tratamento farmacológico , Animais , Anticorpos Monoclonais/administração & dosagem , Citocinas/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Humanos , Fatores Imunológicos/administração & dosagem , Imunoterapia/tendências , Injeções Intralesionais , Camundongos , Terapia de Alvo Molecular/métodos , Neoplasias/patologia , Neoplasias/terapia , Terapia Viral Oncolítica/métodos , Distribuição Tecidual , Microambiente Tumoral/imunologia
16.
Mayo Clin Proc ; 96(5): 1250-1261, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33958056

RESUMO

The administration of spike monoclonal antibody treatment to patients with mild to moderate COVID-19 is very challenging. This article summarizes essential components and processes in establishing an effective spike monoclonal antibody infusion program. Rapid identification of a dedicated physical infrastructure was essential to circumvent the logistical challenges of caring for infectious patients while maintaining compliance with regulations and ensuring the safety of our personnel and other patients. Our partnerships and collaborations among multiple different specialties and disciplines enabled contributions from personnel with specific expertise in medicine, nursing, pharmacy, infection prevention and control, electronic health record (EHR) informatics, compliance, legal, medical ethics, engineering, administration, and other critical areas. Clear communication and a culture in which all roles are welcomed at the planning and operational tables are critical to the rapid development and refinement needed to adapt and thrive in providing this time-sensitive beneficial therapy. Our partnerships with leaders and providers outside our institutions, including those who care for underserved populations, have promoted equity in the access of monoclonal antibodies in our regions. Strong support from institutional leadership facilitated expedited action when needed, from a physical, personnel, and system infrastructure standpoint. Our ongoing real-time assessment and monitoring of our clinical program allowed us to improve and optimize our processes to ensure that the needs of our patients with COVID-19 in the outpatient setting are met.


Assuntos
Antivirais/administração & dosagem , COVID-19 , Procedimentos Clínicos , Terapia por Infusões no Domicílio , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Anticorpos Monoclonais/administração & dosagem , COVID-19/epidemiologia , COVID-19/terapia , Protocolos Clínicos , Procedimentos Clínicos/organização & administração , Procedimentos Clínicos/tendências , Eficiência Organizacional , Terapia por Infusões no Domicílio/métodos , Terapia por Infusões no Domicílio/normas , Humanos , Colaboração Intersetorial , Cultura Organizacional , Desenvolvimento de Programas/métodos , SARS-CoV-2/imunologia , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Glicoproteína da Espícula de Coronavírus/imunologia , Estados Unidos/epidemiologia
17.
Cancer Sci ; 112(7): 2845-2854, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33942442

RESUMO

Polatuzumab vedotin (pola) is a CD79b-targeted antibody-drug conjugate delivering a potent antimitotic agent (monomethyl auristatin E) to B cells. This was an open-label, single-arm study of pola 1.8 mg/kg, bendamustine 90 mg/m2 , rituximab 375 mg/m2 (pola + BR) Q3W for up to six cycles in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who received ≥1 prior line of therapy and were ineligible for autologous stem cell transplantation (ASCT) or experienced treatment failure with prior ASCT. Primary endpoint was complete response rate (CRR) at the end of the treatment (EOT) by positron emission tomography-computed tomography (PET-CT) using modified Lugano Response Criteria. Secondary endpoints included efficacy, safety, and pharmacokinetics. Thirty-five patients (median age 71 [range 46-86] years) were enrolled. Twenty-three (66%) patients had refractory disease, and 23 (66%) had ≥2 prior lines of therapy. At a median follow-up of 5.4 (0.7-11.9) months, patients received a median of five treatment cycles. CRR was 34.3% (95% confidence interval [CI] 19.1-52.2) at EOT. Overall response rate was 42.9% at EOT, and median progression-free survival was 5.2 months (95% CI 3.6-not evaluable). Median overall survival was not reached. No fatal adverse events (AEs) were observed. Grade 3-4 AEs were mainly hematological: anemia (37%), neutropenia (31%), white blood cell count decreased (23%), thrombocytopenia/platelet count decreased/neutrophil count decreased (20% each), and febrile neutropenia (11%). Grade 1-2 peripheral neuropathy (PN; sensory and/or motor) was reported in 14% of patients; there were no ≥grade 3 PN events. This study (JapicCTI-184048) demonstrated the efficacy and safety of pola + BR in Japanese patients with R/R DLBCL who were ineligible for ASCT.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Cloridrato de Bendamustina/administração & dosagem , Cloridrato de Bendamustina/farmacocinética , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Imunoconjugados/administração & dosagem , Imunoconjugados/farmacocinética , Japão , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/patologia , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Intervalo Livre de Progressão , Rituximab/administração & dosagem , Rituximab/farmacocinética
18.
Transfusion ; 61(7): 2054-2063, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33960433

RESUMO

BACKGROUND: Daratumumab, a human anti-CD38 monoclonal antibody used to treat multiple myeloma, interferes with pretransfusion testing and can mask alloantibodies. Incidence of alloimmunization in patients on daratumumab has not been well characterized, and optimal transfusion guidelines regarding prophylactic antigen matching, accounting for both patient safety and efficiency, have not been well established for these patients. METHODS: Records of patients who received daratumumab between January 1, 2014 and July 2, 2019 were reviewed. Daratumumab interference with pretransfusion testing was managed by testing with reagent red blood cells (RBCs) treated with 0.2 M dithiothreitol. When daratumumab was present during antibody testing, patients were transfused with RBC units prophylactically matched for D, C, c, E, e, and K antigens per hospital policy. RESULTS: Out of 90 patients identified, 52 received a total of 638 RBC transfusions (average of 12.3 units per patient, SD 17.2, range 1-105, median 5 among those transfused). Alloantibodies existing before daratumumab initiation were identified in seven patients. No new alloantibodies were detected in any patients after starting daratumumab treatment. CONCLUSIONS: The incidence of alloimmunization in patients receiving daratumumab is low. Whether this is due to the effect of daratumumab, underlying pathophysiology, or other factors, is unknown. Because these patients require a large number of RBC transfusions overall and have little observed alloimmunization, phenotype matching (beyond RhD) may be unnecessary. Since the use of dithiothreitol cannot rule out the presence of anti-K, we recommend transfusion of ABO-compatible units, prophylactically matched for the D and K antigens only.


Assuntos
Anticorpos Monoclonais/imunologia , Antineoplásicos Imunológicos/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Artefatos , Incompatibilidade de Grupos Sanguíneos/sangue , Tipagem e Reações Cruzadas Sanguíneas , Transfusão de Sangue , Eritrócitos/imunologia , Isoanticorpos/sangue , Mieloma Múltiplo/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Aloenxertos , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/uso terapêutico , Antígenos de Grupos Sanguíneos/imunologia , Incompatibilidade de Grupos Sanguíneos/diagnóstico , Incompatibilidade de Grupos Sanguíneos/epidemiologia , Tipagem e Reações Cruzadas Sanguíneas/métodos , Terapia Combinada , Ditiotreitol/farmacologia , Eritrócitos/efeitos dos fármacos , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Incidência , Isoanticorpos/biossíntese , Isoanticorpos/imunologia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Transplante Autólogo
19.
J Infect Dis ; 223(12): 2020-2028, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34043806

RESUMO

Effective clinical intervention strategies for coronavirus disease 2019 (COVID-19) are urgently needed. Although several clinical trials have evaluated use of convalescent plasma containing virus-neutralizing antibodies, levels of neutralizing antibodies are usually not assessed and the effectiveness has not been proven. We show that hamsters treated prophylactically with a 1:2560 titer of human convalescent plasma or a 1:5260 titer of monoclonal antibody were protected against weight loss, had a significant reduction of virus replication in the lungs, and showed reduced pneumonia. Interestingly, this protective effect was lost with a titer of 1:320 of convalescent plasma. These data highlight the importance of screening plasma donors for high levels of neutralizing antibodies. Our data show that prophylactic administration of high levels of neutralizing antibody, either monoclonal or from convalescent plasma, prevent severe SARS-CoV-2 pneumonia in a hamster model, and could be used as an alternative or complementary to other antiviral treatments for COVID-19.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , COVID-19/terapia , Pulmão/patologia , SARS-CoV-2/imunologia , Replicação Viral/efeitos dos fármacos , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Neutralizantes/administração & dosagem , COVID-19/imunologia , Cricetinae , Modelos Animais de Doenças , Humanos , Imunização Passiva , Pulmão/efeitos dos fármacos , Eliminação de Partículas Virais/efeitos dos fármacos , Perda de Peso/efeitos dos fármacos
20.
Ann Hematol ; 100(8): 2061-2070, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33987683

RESUMO

Venetoclax is a BCL-2 inhibitor currently indicated for use in treating hematologic malignancies with recommended doses ranging from 400 to 600 mg/day. Although currently not FDA-approved to treat multiple myeloma (MM) patients, there is a growing number of reports indicating its efficacy as a salvage therapy for these patients, especially for those with the t(11;14) chromosomal marker. These studies, however, have also indicated that venetoclax given at doses ≥ 400 mg/day can cause serious adverse events (SAEs) especially when administered with bortezomib, commonly related to infections. The purpose of this single-center retrospective study was to determine the efficacy of low dose venetoclax (defined as ≤ 250 mg/day) in combination with low dose bortezomib (defined as 1.0 mg/m2 per dose), daratumumab, and dexamethasone (Dvvd) as a salvage therapy for relapsed/refractory myeloma (RRMM) patients. Twenty-two RRMM patients were given venetoclax orally at doses ranging from 100 to 250 mg daily using this four-drug regimen. While the low doses resulted in reduced venetoclax efficacy among those lacking t(11;14) (overall response rate [ORR] = 31%), those harboring the t(11;14) marker exhibited an ORR of 80%. Notably, this response was without frequent infection-related SAEs as reported in previous studies. Together, the results of this study demonstrate that treatment of t(11;14) positive RRMM patients with Dvvd is both effective and well-tolerated.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bortezomib/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Dexametasona/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Sulfonamidas/uso terapêutico , Idoso , Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bortezomib/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Dexametasona/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Estudos Retrospectivos , Sulfonamidas/administração & dosagem , Resultado do Tratamento
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