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1.
J Immunother ; 45(3): 167-179, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35034046

RESUMO

Budigalimab, a novel anti-PD-1 monoclonal antibody, demonstrated efficacy and biomarker pharmacodynamics in patients with head and neck squamous cell carcinoma (HNSCC) or non-small cell lung cancer (NSCLC) consistent with those reported by other PD-1 inhibitors. Herein are presented additional outcomes of biomarker analyses from the phase 1 study of budigalimab monotherapy in patients with HNSCC and NSCLC (NCT03000257). PD-1 inhibitor naive patients with advanced HNSCC (n=41) or NSCLC (n=40) received budigalimab intravenously at 250 mg every 2 weeks (Q2W) or 500 mg Q4W until progression. Archival tumor specimens were evaluated by immunohistochemistry for CD8 and tumor PD-1 ligand 1 (PD-L1) expression, RNA, and whole-exome sequencing. Serum and whole blood samples were acquired at baseline and at select on-treatment time points. As of October 2019, best overall response of 15% in HNSCC and 18% in NSCLC was observed in all treated patients; both cohorts reported responses in PD-L1+ and PD-L1- tumors. Treatment with budigalimab was associated with increases in multiple soluble biomarkers including interferon gamma-induced chemokines. Expanded overall T-cell counts, total CD8 T-cell counts, and percentages of CD8+CD45RA-CD62L- effector memory T cells were observed at cycle 1, day 15 in responders. Univariate analysis demonstrated an association between prolonged progression-free survival and higher tumor mutational burden/neoantigen load, smaller tumor size, lower platelet-lymphocyte ratios, lower CCL23, lower colony-stimulating factor 1, and lower interleukin-6 levels at baseline. The biomarker analysis presented herein identified additional early pharmacodynamic biomarkers associated with anti-PD-1 activity and improved clinical responses to budigalimab in patients with advanced HNSCC and NSCLC.


Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias de Cabeça e Pescoço , Neoplasias Pulmonares , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Antineoplásicos/uso terapêutico , Antígeno B7-H1 , Biomarcadores , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico
2.
Cancer Immunol Res ; 7(11): 1864-1875, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31462409

RESUMO

Agonistic CD40 monoclonal antibodies (mAb) have demonstrated some clinical activity, but with dose-limiting toxicity. To reduce systemic toxicity, we developed a bispecific molecule that was maximally active in the presence of a tumor antigen and had limited activity in the absence of the tumor antigen. LB-1 is a bispecific molecule containing single-chain Fv domains targeting mouse CD40 and the tumor antigen mesothelin. LB-1 exhibited enhanced activity upon binding to cell-surface mesothelin but was less potent in the absence of mesothelin binding. In a mouse model implanted with syngeneic 4T1 tumors expressing cell-surface mesothelin, LB-1 demonstrated comparable antitumor activity as an agonistic CD40 mAb but did not cause elevation of serum cytokines and liver enzymes, as was observed in anti-CD40-treated mice. The results from our study of LB-1 were used to develop a human cross-reactive bispecific molecule (ABBV-428) that targeted human CD40 and mesothelin. ABBV-428 demonstrated enhanced activation of antigen-presenting cells and T cells upon binding to cell-surface mesothelin, and inhibition of cultured or implanted PC3 tumor cell growth after immune activation. Although expression of cell-surface mesothelin is necessary, the bispecific molecules induced immune-mediated antitumor activity against both mesothelin+ and mesothelin- tumor cells. ABBV-428 represents a class of bispecific molecules with conditional activity dependent on the binding of a tumor-specific antigen, and such activity could potentially maximize antitumor potency while limiting systemic toxicity in clinical studies.


Assuntos
Anticorpos Biespecíficos/imunologia , Antígenos de Neoplasias/imunologia , Antineoplásicos Imunológicos/imunologia , Antígenos CD40/imunologia , Proteínas Ligadas por GPI/imunologia , Animais , Anticorpos Biespecíficos/química , Anticorpos Biespecíficos/farmacologia , Anticorpos Biespecíficos/uso terapêutico , Células Apresentadoras de Antígenos/efeitos dos fármacos , Células Apresentadoras de Antígenos/imunologia , Antígenos de Neoplasias/metabolismo , Antineoplásicos Imunológicos/química , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Antígenos CD40/agonistas , Linhagem Celular Tumoral , Proteínas Ligadas por GPI/metabolismo , Humanos , Ativação Linfocitária/efeitos dos fármacos , Mesotelina , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Mutantes , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
3.
Ann Rheum Dis ; 78(3): 413-420, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30552176

RESUMO

OBJECTIVE: To assess the efficacy, safety, pharmacokinetics and pharmacodynamics of the anti-interleukin (IL)-1α/ß dual variable domain immunoglobulin lutikizumab (ABT-981) in erosive hand osteoarthritis (HOA). METHODS: Patients with ≥1 erosive and ≥3 tender and/or swollen hand joints were randomised to placebo or lutikizumab 200 mg subcutaneously every 2 weeks for 24 weeks. The primary endpoint was change in Australian/Canadian Osteoarthritis Hand Index (AUSCAN) pain subdomain score from baseline to 16 weeks. At baseline and week 26, subjects had bilateral hand radiographs and MRI of the hand with the greatest number of baseline tender and/or swollen joints. Continuous endpoints were assessed using analysis of covariance models, with treatment and country as main factors and baseline measurements as covariates. RESULTS: Of 132 randomised subjects, 1 received no study drug and 110 completed the study (placebo, 61/67 (91%); lutikizumab, 49/64 (77%)). AUSCAN pain was not different among subjects treated with lutikizumab versus placebo at week 16 (least squares mean difference, 1.5 (95% CI -1.9 to 5.0)). Other clinical and imaging endpoints were not different between lutikizumab and placebo. Lutikizumab significantly decreased serum high-sensitivity C reactive protein levels, IL-1α and IL-1ß levels, and blood neutrophils. Lutikizumab pharmacokinetics were consistent with phase I studies and not affected by antidrug antibodies. Injection site reactions and neutropaenia were more common in the lutikizumab group; discontinuations because of adverse events occurred more frequently with lutikizumab (4/64) versus placebo (1/67). CONCLUSION: Despite adequate blockade of IL-1, lutikizumab did not improve pain or imaging outcomes in erosive HOA compared with placebo.


Assuntos
Artralgia/tratamento farmacológico , Imunoglobulinas/uso terapêutico , Interleucina-1alfa/imunologia , Interleucina-1beta/imunologia , Osteoartrite/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Artralgia/diagnóstico por imagem , Artralgia/imunologia , Proteína C-Reativa/análise , Método Duplo-Cego , Feminino , Articulação da Mão/diagnóstico por imagem , Articulação da Mão/efeitos dos fármacos , Humanos , Imunoglobulinas/imunologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Osteoartrite/diagnóstico por imagem , Osteoartrite/imunologia , Medição da Dor , Resultado do Tratamento
4.
J Immunol Res ; 2017: 5737159, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29075649

RESUMO

Enavatuzumab is a humanized IgG1 anti-TWEAK receptor monoclonal antibody that was evaluated in a phase I clinical study for the treatment of solid malignancies. The current study was to determine whether and how myeloid effector cells were involved in postulated mechanisms for its potent antitumor activity in xenograft models. The initial evidence for a role of effector cells was obtained in a subset of tumor xenograft mouse models whose response to enavatuzumab relied on the binding of Fc of the antibody to Fcγ receptor. The involvement of effector cells was further confirmed by immunohistochemistry, which revealed strong infiltration of CD45+ effector cells into tumor xenografts in responding models, but minimal infiltration in nonresponders. Consistent with the xenograft studies, human effector cells preferentially migrated toward in vivo-responsive tumor cells treated by enavatuzumab in vitro, with the majority of migratory cells being monocytes. Conditioned media from enavatuzumab-treated tumor cells contained elevated levels of chemokines, which might be responsible for enavatuzumab-triggered effector cell migration. These preclinical studies demonstrate that enavatuzumab can exert its potent antitumor activity by actively recruiting and activating myeloid effectors to kill tumor cells. Enavatuzumab-induced chemokines warrant further evaluation in clinical studies as potential biomarkers for such activity.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Imunoterapia/métodos , Linfócitos/imunologia , Monócitos/imunologia , Células Mieloides/imunologia , Neoplasias Experimentais/tratamento farmacológico , Animais , Citotoxicidade Celular Dependente de Anticorpos , Movimento Celular , Citocina TWEAK/imunologia , Citocinas/metabolismo , Células HCT116 , Humanos , Imunidade Inata , Camundongos , Camundongos SCID , Receptores Fc/metabolismo , Carga Tumoral , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
5.
J Exp Ther Oncol ; 5(4): 273-86, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-17024968

RESUMO

Integrin alpha5beta1, the principal fibronectin receptor, is an important survival factor, playing a key role in angiogenesis. Angiogenesis is critical for tumor growth, and anti-angiogenic therapies have met clinical success. To validate the therapeutic potential of an anti-alpha5beta1 strategy, we generated volociximab (M200) a chimeric human IgG4 version of the alpha5beta1 function-blocking murine antibody IIA1; and F200, the Fab derivative. Volociximab, F200 and IIA1 showed similar activity by ELISA (EC50= 0.2nM), Biacore (Kd= 0.1-0.4nM) and inhibition of fibronectin binding (IC50= 2-3nM). The inhibitory potential of alpha5beta1 antibodies was compared to HuMV833, an anti-VEGF antibody. Both volociximab and HuMV833 inhibited HUVEC proliferation (IC50 of volociximab = 0.2-0.5nM; IC50 of HuMV833 = 45nM). However, IIA1, volociximab and F200 were also potent inhibitors of an in vitro model of angiogenesis (HUVEC tube formation assay), unlike HuMV833. Additionally, volociximab inhibited in vitro tube formation induced by VEGF and/or bFGF, suggesting a mechanism of action independent of growth factor stimulus. In fact, inhibition of alpha5beta1 function by volociximab induced apoptosis of actively proliferating, but not resting, endothelial cells. Volociximab does not cross-react with rodent alpha5beta1, therefore in vivo validation of an anti-alpha5beta1 approach was conducted in a cynomolgus model of choroidal revascularization. Volociximab and F200 were potent inhibitors of neovessel formation in this model. These data demonstrate that volociximab has therapeutic potential in diseases in which new vessel formation is a component of the pathology.


Assuntos
Inibidores da Angiogênese/farmacologia , Anticorpos Monoclonais/farmacologia , Anticorpos/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Integrina alfa5beta1/imunologia , Animais , Anticorpos Monoclonais Murinos , Células COS , Chlorocebus aethiops , Matriz Extracelular/metabolismo , Humanos , Concentração Inibidora 50 , Integrina alfa5beta1/química , Cinética , Macaca fascicularis , Degeneração Macular/tratamento farmacológico , Neovascularização Patológica , Rituximab
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