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MEN1309/OBT076, a First-In-Class Antibody-Drug Conjugate Targeting CD205 in Solid Tumors.
Merlino, Giuseppe; Fiascarelli, Alessio; Bigioni, Mario; Bressan, Alessandro; Carrisi, Corrado; Bellarosa, Daniela; Salerno, Massimiliano; Bugianesi, Rossana; Manno, Rosanna; Bernadó Morales, Cristina; Arribas, Joaquin; Dusek, Rachel L; Ackroyd, James E; Pham, Phuoc Huy; Awdew, Rahel; Aud, Dee; Trang, Michael; Lynch, Carmel M; Terrett, Jonathan; Wilson, Keith E; Rohlff, Christian; Manzini, Stefano; Pellacani, Andrea; Binaschi, Monica.
Afiliação
  • Merlino G; Department of Experimental and Translational Oncology, Menarini Ricerche SpA, Pomezia, Rome, Italy. gmerlino@menarini-ricerche.it.
  • Fiascarelli A; Department of Experimental and Translational Oncology, Menarini Ricerche SpA, Pomezia, Rome, Italy.
  • Bigioni M; Department of Experimental and Translational Oncology, Menarini Ricerche SpA, Pomezia, Rome, Italy.
  • Bressan A; Department of Experimental and Translational Oncology, Menarini Ricerche SpA, Pomezia, Rome, Italy.
  • Carrisi C; Department of Experimental and Translational Oncology, Menarini Ricerche SpA, Pomezia, Rome, Italy.
  • Bellarosa D; Department of Experimental and Translational Oncology, Menarini Ricerche SpA, Pomezia, Rome, Italy.
  • Salerno M; Department of Experimental and Translational Oncology, Menarini Ricerche SpA, Pomezia, Rome, Italy.
  • Bugianesi R; Department of Pharmacokinetics and Metabolism, Menarini Ricerche, Pomezia, Rome, Italy.
  • Manno R; Research Toxicology Center, Pomezia, Rome, Italy.
  • Bernadó Morales C; Preclinical Research Program, Vall D'Hebron, Institute of Oncology and Centro de Investigación Biomédica en Red en Oncologia (CIBERONC), Barcelona, Spain.
  • Arribas J; Preclinical Research Program, Vall D'Hebron, Institute of Oncology and Centro de Investigación Biomédica en Red en Oncologia (CIBERONC), Barcelona, Spain.
  • Dusek RL; Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UAB, Bellaterra, Spain.
  • Ackroyd JE; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
  • Pham PH; Oxford BioTherapeutics, Ltd., Abingdon, United Kingdom.
  • Awdew R; Oxford BioTherapeutics, Ltd., Abingdon, United Kingdom.
  • Aud D; Oxford BioTherapeutics, Ltd., Abingdon, United Kingdom.
  • Trang M; Oxford BioTherapeutics, Ltd., Abingdon, United Kingdom.
  • Lynch CM; Oxford BioTherapeutics, Ltd., Abingdon, United Kingdom.
  • Terrett J; Oxford BioTherapeutics, Ltd., Abingdon, United Kingdom.
  • Wilson KE; Oxford BioTherapeutics, Ltd., Abingdon, United Kingdom.
  • Rohlff C; Oxford BioTherapeutics, Ltd., Abingdon, United Kingdom.
  • Manzini S; Oxford BioTherapeutics, Ltd., Abingdon, United Kingdom.
  • Pellacani A; Oxford BioTherapeutics, Ltd., Abingdon, United Kingdom.
  • Binaschi M; Menarini Ricerche S.p.A - Menarini Group, Florence, Italy.
Mol Cancer Ther ; 18(9): 1533-1543, 2019 09.
Article em En | MEDLINE | ID: mdl-31227646
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

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Receptores de Superfície Celular / Imunoconjugados / Ensaios Antitumorais Modelo de Xenoenxerto / Lectinas Tipo C / Terapia de Alvo Molecular / Neoplasias Idioma: En Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Receptores de Superfície Celular / Imunoconjugados / Ensaios Antitumorais Modelo de Xenoenxerto / Lectinas Tipo C / Terapia de Alvo Molecular / Neoplasias Idioma: En Ano de publicação: 2019 Tipo de documento: Article