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.
Subject(s)
Immunoconjugates/pharmacology , Lectins, C-Type/antagonists & inhibitors , Molecular Targeted Therapy/methods , Neoplasms/drug therapy , Receptors, Cell Surface/antagonists & inhibitors , Xenograft Model Antitumor Assays/methods , Animals , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/pharmacology , Antigens, CD/immunology , Antigens, CD/metabolism , CHO Cells , Cell Line, Tumor , Cricetulus , Female , HEK293 Cells , HT29 Cells , Humans , Immunoconjugates/chemistry , Lectins, C-Type/immunology , Lectins, C-Type/metabolism , MCF-7 Cells , Maytansine/chemistry , Maytansine/pharmacology , Mice , Mice, Nude , Mice, SCID , Minor Histocompatibility Antigens/immunology , Minor Histocompatibility Antigens/metabolism , Neoplasms/metabolism , Neoplasms/pathology , Receptors, Cell Surface/immunology , Receptors, Cell Surface/metabolismABSTRACT
OBJECTIVES: In the present work, a method to induce experimental allergic encephalomyelitis (EAE) in female SJL/J mice was developed and validated in our laboratory. Although the latter is a popular animal model to mimic human multiple sclerosis, it remains to be clarified if: (1) the measurement of circulating antibodies against myelin antigens can be used as an index to predict the development of clinical EAE, as well as the severity of disease, and (2) the genetic susceptibility of this strain is associated with altered hypothalamo-pituitary-adrenal (HPA) function. METHODS AND RESULTS: We observed that SJL/J mice display a strong humoral response to immunization with myelin basic protein (MBP), as assessed by the titration of circulating anti-MBP antibodies. However, there was no apparent correlation between the presence and amount of circulating antibodies and the occurrence or severity of disease. Concerning the responsiveness of the HPA axis, we observed that circulating corticosterone levels are not modified at all during the induction of EAE, whereas an increase is observed at a later stage of the disease. CONCLUSIONS: The above profile is strongly reminiscent of the HPA axis response to the induction of EAE in Lewis rats, suggesting that the susceptibility of SJL/J mice to EAE may similarly be caused, at least in part, by blunted HPA reactivity to immune challenges.
