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Supplementary Table S4 from MEN1309/OBT076, a First-In-Class Antibody–Drug Conjugate Targeting CD205 in Solid Tumors

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posted on 2023-04-03, 15:28 authored by Giuseppe Merlino, Alessio Fiascarelli, Mario Bigioni, Alessandro Bressan, Corrado Carrisi, Daniela Bellarosa, Massimiliano Salerno, Rossana Bugianesi, Rosanna Manno, Cristina Bernadó Morales, Joaquin Arribas, Arnima Bisht, Angelo Kaplan, Robert Boyd, Uyen T. Do, Sudha Swaminathan, Nickolas Attanasio, San Lin Lou, Rachel L. Dusek, James E. Ackroyd, Phuoc Huy Pham, Rahel Awdew, Dee Aud, Michael Trang, Carmel M. Lynch, Jonathan Terrett, Keith E. Wilson, Christian Rohlff, Stefano Manzini, Andrea Pellacani, Monica Binaschi

Supplementary Table S4: Antitumor activity of MEN1309/OBT076 on xenograft and PDX models with different CD205 antigen expression. a) PDX models.b) Score indicate the staining intensity. HE = heterogeneous. HO = homogeneous. c) TVI%, tumor volume inhibition, expressed as a percentage, indicates the ratio % between the mean of the tumor volume of the test article-treated group and the control treated with drug vehicle calculated at the Nadir of tumor growth.

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ARTICLE 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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