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

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 cyto-toxic 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 patientderived 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-inhuman SHUTTLE clinical trial.

Precision medicine for human cancers with Notch signaling dysregulation (Review)

“…LGR5 Adc Anti-LGR5-mc-vc-PAB-MMAE Preclinical study (rodent) tumor necrosis factor receptor superfamily member 17 (193) are also in phase III clinical trials. An anti-cd205 Adc that targets mesenchymal tumor cells and cAFs (194) and…”

A CD205-directed antibody drug conjugate – lymphoma precision oncology or sophisticated chemotherapy?

“…In an in vitro screen, MEN1309/OBT076 efficacy did not depend on B-cell lymphoma subtype. Together with previous preclinical results in CD205-positive triplenegative breast, pancreatic and bladder cancer cell lines and xenografts, 7 this creates a virtual preclinical basket trial which now awaits clinical validation.…”

“…Expression of the antigen is also important to predict toxicities in human trials. Even though previous work has not identified relevant toxicities in cynomolgus monkeys, 7 potential risks to humans will also depend on disease characteristics and are still to be determined in ongoing clinical trials.…”

NRXN1 as a novel potential target of antibody-drug conjugates for small cell lung cancer

“…Five ADCs have been approved by the Food and Drug Administration: brentuximab vedotin for Hodgkin lymphoma [15], ado-trastuzumab emtansine for HER2positive metastatic breast cancer [16,17], inotuzumab ozogamicin for acute lymphoblastic leukemia [18], gemtuzumab ozogamicin for CD33-positive acute myeloid leukemia [19], and trastuzumab deruxtecan for unresectable or metastatic HER2-positive breast cancer patients who have received two or more prior anti-HER2based regimens in a metastatic setting [20]. To date, ADCs targeting solid tumors other than metastatic breast cancer have not exhibited distinct clinical benefits [21][22][23][24][25][26][27][28][29]. In SCLC, DLL3, a cell surface Notch ligand that appear to be a direct downstream target of ASCL1 [30,31], has been identified as a novel target for ADCs [32].…”