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Mol Cancer Ther ; 18(9): 1533-1543, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31227646

RESUMO

CD205 is a type I transmembrane glycoprotein and is a member of the C-type lectin receptor family. Analysis by mass spectrometry revealed that CD205 was robustly expressed and highly prevalent in a variety of solid malignancies from different histotypes. IHC confirmed the increased expression of CD205 in pancreatic, bladder, and triple-negative breast cancer (TNBC) compared with that in the corresponding normal tissues. Using immunofluorescence microscopy, rapid internalization of the CD205 antigen was observed. These results supported the development of MEN1309/OBT076, a fully humanized CD205-targeting mAb conjugated to DM4, a potent maytansinoid derivate, via a cleavable N-succinimidyl-4-(2-pyridyldithio) butanoate linker. MEN1309/OBT076 was characterized in vitro for target binding affinity, mechanism of action, and cytotoxic activity against a panel of cancer cell lines. MEN1309/OBT076 displayed selective and potent cytotoxic effects against tumor cells exhibiting strong and low to moderate CD205 expression. In vivo, MEN1309/OBT076 showed potent antitumor activity resulting in durable responses and complete tumor regressions in many TNBC, pancreatic, and bladder cancer cell line-derived and patient-derived xenograft models, independent of antigen expression levels. Finally, the pharmacokinetics and pharmacodynamic profile of MEN1309/OBT076 was characterized in pancreatic tumor-bearing mice, demonstrating that the serum level of antibody-drug conjugate (ADC) achieved through dosing was consistent with the kinetics of its antitumor activity. Overall, our data demonstrate that MEN1309/OBT076 is a novel and selective ADC with potent activity against CD205-positive tumors. These data supported the clinical development of MEN1309/OBT076, and further evaluation of this ADC is currently ongoing in the first-in-human SHUTTLE clinical trial.


Assuntos
Imunoconjugados/farmacologia , Lectinas Tipo C/antagonistas & inibidores , Terapia de Alvo Molecular/métodos , Neoplasias/tratamento farmacológico , Receptores de Superfície Celular/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/farmacologia , Antígenos CD/imunologia , Antígenos CD/metabolismo , Células CHO , Linhagem Celular Tumoral , Cricetulus , Feminino , Células HEK293 , Células HT29 , Humanos , Imunoconjugados/química , Lectinas Tipo C/imunologia , Lectinas Tipo C/metabolismo , Células MCF-7 , Maitansina/química , Maitansina/farmacologia , Camundongos , Camundongos Nus , Camundongos SCID , Antígenos de Histocompatibilidade Menor/imunologia , Antígenos de Histocompatibilidade Menor/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Receptores de Superfície Celular/imunologia , Receptores de Superfície Celular/metabolismo
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