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1.
Nat Cancer ; 1(1): 86-98, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-35121834

RESUMO

Despite the significant therapeutic advances provided by immune-checkpoint blockade and chimeric antigen receptor T cell treatments, many malignancies remain unresponsive to immunotherapy. Bispecific antibodies targeting tumor antigens and activating T cell receptor signaling have shown some clinical efficacy; however, providing co-stimulatory signals may improve T cell responses against tumors. Here, we developed a trispecific antibody that interacts with CD38, CD3 and CD28 to enhance both T cell activation and tumor targeting. The engagement of both CD3 and CD28 affords efficient T cell stimulation, whereas the anti-CD38 domain directs T cells to myeloma cells, as well as to certain lymphomas and leukemias. In vivo administration of this antibody suppressed myeloma growth in a humanized mouse model and also stimulated memory/effector T cell proliferation and reduced regulatory T cells in non-human primates at well-tolerated doses. Collectively, trispecific antibodies represent a promising platform for cancer immunotherapy.


Assuntos
Anticorpos Biespecíficos , Mieloma Múltiplo , Animais , Anticorpos Biespecíficos/uso terapêutico , Antígenos CD28 , Camundongos , Mieloma Múltiplo/tratamento farmacológico , Receptores de Antígenos de Linfócitos T , Linfócitos T
2.
Cancer Chemother Pharmacol ; 78(1): 83-90, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27169794

RESUMO

PURPOSE: Pilaralisib (SAR245408), a pan-class I PI3K inhibitor, has been investigated in Phase I/II trials in several solid tumors and lymphomas in capsule and tablet formulations of polymorph A (capsule-A and tablet-A). This Phase I study was conducted to determine the recommended Phase II dose (RP2D) of a more thermodynamically stable form of pilaralisib (polymorph E), in tablet formulation (tablet-E), in patients with advanced solid tumors or relapsed/refractory lymphoma. METHODS: A modified '3 + 3' dose-escalation design was employed. Patients received pilaralisib once daily (QD; starting dose 400 mg) for two 28-day cycles. Primary endpoints were safety and pharmacokinetics (PK). Exploratory endpoints were pharmacodynamics and efficacy. RESULTS: Eighteen patients were enrolled: Six patients received pilaralisib 400 mg QD and 12 patients received pilaralisib 600 mg QD. Two patients in the 600 mg QD cohort had dose-limiting toxicities (DLTs) (one patient with Grade 3 maculopapular rash and one patient with Grade 3 generalized rash and Grade 4 lipase increased). The most frequently occurring treatment-related, treatment-emergent adverse events were decreased appetite (22 %), dry skin (22 %), nausea (22 %) and vomiting (22 %). In PK analyses, individual exposures observed with 600 mg tablet-E were within the range of data at steady state from previous studies of 400 mg tablet-A and 600 mg capsule-A. Five patients (28 %) had stable disease as best response. CONCLUSIONS: With pilaralisib tablet-E, the RP2D was 600 mg QD, drug exposure was similar to the 400 mg tablet-A and 600 mg capsule-A formulations, and safety was consistent with the known safety profile of pilaralisib.


Assuntos
Antineoplásicos/administração & dosagem , Linfoma/tratamento farmacológico , Neoplasias/tratamento farmacológico , Quinoxalinas/administração & dosagem , Sulfonamidas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Cápsulas , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores de Fosfoinositídeo-3 Quinase , Quinoxalinas/efeitos adversos , Quinoxalinas/farmacocinética , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacocinética , Comprimidos
3.
Mol Cancer Ther ; 14(2): 384-94, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25504634

RESUMO

Activation of the MET/HGF pathway is common in human cancer and is thought to promote tumor initiation, metastasis, angiogenesis, and resistance to diverse therapies. We report here the pharmacologic characterization of the triazolopyridazine derivative SAR125844, a potent and highly selective inhibitor of the MET receptor tyrosine kinase (RTK), for intravenous administration. SAR125844 displayed nanomolar activity against the wild-type kinase (IC50 value of 4.2 nmol/L) and the M1250T and Y1235D mutants. Broad biochemical profiling revealed that SAR125844 was highly selective for MET kinase. SAR125844 inhibits MET autophosphorylation in cell-based assays in the nanomolar range, and promotes low nanomolar proapoptotic and antiproliferative activities selectively in cell lines with MET gene amplification or pathway addiction. In two MET-amplified human gastric tumor xenograft models, SNU-5 and Hs 746T, intravenous treatment with SAR125844 leads to potent, dose- and time-dependent inhibition of the MET kinase and to significant impact on downstream PI3K/AKT and RAS/MAPK pathways. Long duration of MET kinase inhibition up to 7 days was achieved with a nanosuspension formulation of SAR125844. Daily or every-2-days intravenous treatment of SAR125844 promoted a dose-dependent tumor regression in MET-amplified human gastric cancer models at tolerated doses without treatment-related body weight loss. Our data demonstrated that SAR125844 is a potent and selective MET kinase inhibitor with a favorable preclinical toxicity profile, supporting its clinical development in patients with MET-amplified and MET pathway-addicted tumors.


Assuntos
Azóis/farmacologia , Benzotiazóis/farmacologia , Amplificação de Genes/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/patologia , Ureia/análogos & derivados , Trifosfato de Adenosina/farmacologia , Administração Intravenosa , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Azóis/administração & dosagem , Azóis/química , Benzotiazóis/administração & dosagem , Benzotiazóis/química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Células HEK293 , Humanos , Camundongos SCID , Mutação/genética , Fosforilação/efeitos dos fármacos , Ureia/administração & dosagem , Ureia/química , Ureia/farmacologia
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