MEN1309/OBT076, a First-In-Class Antibody-Drug Conjugate Targeting CD205 in Solid Tumors
Giuseppe Merlino1, Alessio Fiascarelli2, Mario Bigioni2
1Department of Experimental and Translational Oncology, Menarini Ricerche SpA, Pomezia, Rome, Italy. gmerlino@menarini-ricerche.it.
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.
Insights
A novel antibody-drug conjugate, MEN1309/OBT076, targets CD205, showing potent activity against pancreatic, bladder, and triple-negative breast cancers (TNBC). This CD205-targeting therapy demonstrates significant anti-tumor effects in preclinical models, supporting its clinical development.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- CD205, a C-type lectin receptor, is highly expressed in various solid tumors, including pancreatic, bladder, and triple-negative breast cancer (TNBC).
- Rapid internalization of CD205 upon binding suggests its potential as a target for drug delivery.
Purpose of the Study:
- To evaluate the preclinical efficacy and characteristics of MEN1309/OBT076, a novel antibody-drug conjugate (ADC) targeting CD205.
- To assess the anti-tumor activity of MEN1309/OBT076 in various solid malignancy models.
Main Methods:
- Mass spectrometry and immunohistochemistry (IHC) were used to confirm CD205 expression in cancer tissues.
- In vitro characterization included target binding, mechanism of action, and cytotoxicity assays.
- In vivo studies utilized xenograft models derived from cell lines and patients.
- Pharmacokinetic and pharmacodynamic analyses were performed in tumor-bearing mice.
Main Results:
- MEN1309/OBT076 demonstrated potent and selective cytotoxic effects against CD205-expressing cancer cell lines.
- Significant anti-tumor activity, including durable responses and complete regressions, was observed in TNBC, pancreatic, and bladder cancer xenograft models.
- The ADC's serum levels correlated with its anti-tumor efficacy.
Conclusions:
- MEN1309/OBT076 is a novel, selective ADC with potent activity against CD205-positive solid tumors.
- Preclinical data support the ongoing clinical development of MEN1309/OBT076 in the SHUTTLE trial.
More Related Videos
Related Concept Videos
01:25Antibody Structure and Classes
The basic structure of an antibody consists of four protein chains: two identical heavy chains and two identical light chains. These chains are held together by disulfide bonds and other non-covalent interactions, forming a Y-shaped structure.
01:25Drug Classes and Categories
01:15Antihypertensive Drugs: Thiazide-Class Diuretics
02:50Conjugated Proteins
Nucleoproteins are protein complexes that contain nucleic acids, categorized as deoxyribonucleoproteins (DNPs) or ribonucleoproteins (RNPs) respectively. The nucleosome is a typical example of a DNP where nuclear DNA is associated with histone proteins. The major antigen for the Covid-19 virus SARS-CoV is an RNP that is critical...
01:22Antiarrhythmic Drugs: Class I Agents as Sodium Channel Blockers
Class 1A Antiarrhythmic Drugs: These drugs work by moderately blocking sodium channels,...
01:24Antiarrhythmic Drugs: Class II Agents as β-Adrenergic Blockers