MEN1309/OBT076, a First-In-Class Antibody-Drug Conjugate Targeting CD205 in Solid Tumors.
Giuseppe MerlinoAlessio FiascarelliMario BigioniAlessandro BressanCorrado CarrisiDaniela BellarosaMassimiliano SalernoRossana BugianesiRosanna MannoCristina Bernadó MoralesJoaquín ArribasRachel L DusekJames E AckroydPhuoc Huy PhamRahel AwdewDee AudMichael TrangCarmel M LynchJonathan TerrettKeith E WilsonChristian RohlffStefano ManziniAndrea PellacaniMonica BinaschiPublished in: Molecular cancer therapeutics (2019)
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.
Keyphrases
- middle aged
- clinical trial
- poor prognosis
- mass spectrometry
- nk cells
- cancer therapy
- gene expression
- high resolution
- computed tomography
- magnetic resonance imaging
- spinal cord injury
- endothelial cells
- optical coherence tomography
- anti inflammatory
- drug delivery
- photodynamic therapy
- quantum dots
- diffusion weighted imaging
- deep learning
- open label
- long non coding rna
- capillary electrophoresis
- sensitive detection
- high speed