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Mol Cancer Ther. 2019 Sep;18(9):1533-1543. doi: 10.1158/1535-7163.MCT-18-0624. Epub 2019 Jun 21.

MEN1309/OBT076, a First-In-Class Antibody-Drug Conjugate Targeting CD205 in Solid Tumors.

Author information

1
Department of Experimental and Translational Oncology, Menarini Ricerche SpA, Pomezia, Rome, Italy. gmerlino@menarini-ricerche.it.
2
Department of Experimental and Translational Oncology, Menarini Ricerche SpA, Pomezia, Rome, Italy.
3
Department of Pharmacokinetics and Metabolism, Menarini Ricerche, Pomezia, Rome, Italy.
4
Research Toxicology Center, Pomezia, Rome, Italy.
5
Preclinical Research Program, Vall D'Hebron, Institute of Oncology and Centro de Investigación Biomédica en Red en Oncologia (CIBERONC), Barcelona, Spain.
6
Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UAB, Bellaterra, Spain.
7
Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
8
Oxford BioTherapeutics, Ltd., Abingdon, United Kingdom.
9
Menarini Ricerche S.p.A - Menarini Group, Florence, Italy.
#
Contributed equally

Abstract

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.

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