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Ferrata Storti Foundation
Non-Hodgkin Lymphoma
Targeting CD205 with the antibody drug conjugate MEN1309/OBT076 is an active new therapeutic strategy in lymphoma models
Haematologica 2020 Volume 105(11):2584-2591
2667 Anastasios Stathis, Robert S. Boyd, Rachel L. Dusek, Arnima Bisht,
Eugenio Gaudio,1* Chiara Tarantelli,1* Filippo Spriano,1 Francesca Guidetti,1 Giulio Sartori,1 Roberta Bordone,2 Alberto J. Arribas,1 Luciano Cascione,1,3 Mario Bigioni,4 Giuseppe Merlino,4 Alessio Fiascarelli,4 Alessandro Bressan,4 Afua Adjeiwaa Mensah,1 Gaetanina Golino,1 Renzo Lucchini,5
Elena Bernasconi,1 Davide Rossi,1,2 Emanuele Zucca,2 Georg Stussi,2
7784 Nickolas Attanasio, Christian Rohlff, Andrea Pellacani, Monica Binaschi
and Francesco Bertoni1,2
1Università della Svizzera italiana, Istituto Oncologico di Ricerca, Bellinzona, Switzerland; 2Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; 3Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland; 4Menarini Ricerche S.p.A., Pomezia, Italy; 5Laboratorio di Diagnostica Molecolare, Dipartimento di Medicina di Laboratorio EOLAB, Bellinzona, Switzerland; 6Oxford BioTherapeutics Ltd., Abingdon, UK; 7Oxford BioTherapeutics Inc., San Jose, CA, USA and 8Menarini Ricerche S.p.A - Menarini Group, Florence, Italy
*EG and CT contributed equally as co-first authors.
ABSTRACT
Antibody drug conjugates represent an important class of anti-cancer drugs in both solid tumors and hematologic cancers. Here, we report preclinical data on the anti-tumor activity of the first-in-class anti- body drug conjugate MEN1309/OBT076 targeting CD205. The study included preclinical in vitro activity screening on a large panel of cell lines, both as single agent and in combination, and validation experiments on in vivo models. CD205 was first shown frequently expressed in lymphomas, leukemias and multiple myeloma by immunohistochemistry on tissue microarrays. Anti-tumor activity of MEN1309/OBT076 as single agent was then shown across 42 B-cell lymphoma cell lines with a median IC50 of 200 pM and induction of apoptosis in 25 of 42 (59.5%) of the cases. The activity appeared highly correlated with its target expression. After in vivo validation as the single agent, the antibody drug conjugate synergized with the BCL2 inhibitor venetoclax and the anti-CD20 monoclonal antibody rituximab. The first-in-class antibody drug targeting CD205, MEN1309/OBT076, demonstrated strong pre-clinical anti-tumor activity in lymphoma, warrant- ing further investigations as a single agent and in combination.
Introduction
Antibody drug conjugates (ADC) represent a class of anti-cancer agents that can have an important impact on the clinical outcome of cancer patients, as exemplified by brentuximab vedotin for Hodgkin lymphoma patients or ado-trastuzumab- emtansine (T-DM1) for breast cancer patients.1 In lymphomas, different surface pro- teins (CD19, CD37, CD79B, CD25) have provided targets for active ADC.1 CD205, encoded by the LY75 gene (Lymphocyte antigen 75, DEC-205), is a surface multi- lectin receptor with a cytoplasmatic domain containing protein motifs crucial for endocytosis and internalization upon ligation. Although its biologic role has not been fully defined, it is known to act as a surface receptor for apoptotic and necrotic cells,2,3 leading to antigen uptake and processing. CD205 is expressed in hematopoi- etic cells, mainly by antigen presenting cells (APC), but also in other tissues, includ- ing solid tumors.4-8 CD205 presents a rapid internalization rate and a favorable profile in terms of differential expression between neoplastic and healthy tissues, and is a potential new target for ADC.7 MEN1309/OBT076 is a novel humanized IgG1 anti-
Correspondence:
FRANCESCO BERTONI
francesco.bertoni@ior.usi.ch
Received: May 16, 2019. Accepted: January 2, 2020. Pre-published: January9,2020.
doi:10.3324/haematol.2019.227215 ©2020 Ferrata Storti Foundation
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