Page 141 - 2019_08-Haematologica-web

Non-Hodgkin Lymphoma
The novel CD19-targeting antibody-drug conjugate huB4-DGN462 shows improved anti-tumor activity compared to SAR3419 in CD19-positive lymphoma and leukemia models
Stuart W. Hicks,1* Chiara Tarantelli,2* Alan Wilhem,1 Eugenio Gaudio,2 Min Li,1 Alberto J. Arribas,2 Filippo Spriano,2 Roberta Bordone,3 Luciano Cascione,2,4 Katharine C. Lai,1 Qifeng Qiu,1 Monica Taborelli,5 Davide Rossi,2,3 Georg Stussi,3 Emanuele Zucca,3 Anastasios Stathis,3 Callum M. Sloss1 and Francesco Bertoni2
1ImmunoGen Inc., Waltham, MA, USA; 2Università della Svizzera italiana, Institute of Oncology Research, Bellinzona, Switzerland; 3Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; 4Swiss Institute of Bioinformatics, Lausanne, Switzerland and 5Cytogenetics Laboratory, Ente Ospedaliero Cantonale, Bellinzona, Switzerland
ABSTRACT
Antibody-drug conjugates (ADC) are a novel way to deliver potent cytotoxic compounds to cells expressing a specific antigen. Four ADC targeting CD19, including SAR3419 (coltuximab ravtansine), have entered clinical development. Here, we present huB4-DGN462, a novel ADC based on the SAR3419 anti-CD19 antibody linked via sulfo- SPDB to the potent DNA-alkylating agent DGN462. huB4-DGN462 had improved in vitro anti-proliferative and cytotoxic activity compared to SAR3419 across multiple B-cell lymphoma and human acute lymphoblastic leukemia cell lines. In vivo experiments using lymphoma xenografts models confirmed the in vitro data. The response of B-cell lymphoma lines to huB4- DGN462 was not correlated with CD19 expression, the presence of BCL2 or MYC translocations, TP53 inactivation or lymphoma histology. In con- clusion, huB4-DGN462 is an attractive candidate for clinical investigation in patients with B-cell malignancies.
Introduction
Lymphomas are among the most common cancers and causes of cancer-related cell deaths in both adults and children.1 In western countries, B-cell lymphomas, and diffuse large B-cell lymphoma (DLBCL) in particular, represent the vast majority of cases. Despite treatment improvements, a proportion of B-cell lymphoma patients still succumb because of chemorefractory disease, requiring the need to find novel therapeutic modalities to extend patients’ lives.2,3 These neoplastic B cells express many proteins on their cell surface that are potential therapeutic targets.4 The clinical success of the anti-CD20 monoclonal antibody, rituximab, demon- strates the potential of targeting B-cell specific surface proteins.5 Antibody-drug con- jugates (ADC) are an innovative way to deliver potent cytotoxic compounds to cells expressing a specific antigen, as shown by brentuximab vedotin in patients with CD30-positive lymphomas and for ado-trastuzumab emtansine in patients with HER2-positive breast cancer.4 Another plasma membrane target, CD19, is almost exclusively expressed on B cells, appearing at the pre-B-cell stage and remaining expressed until their terminal differentiation into plasma cells6 and unlike CD20, CD19 is rapidly internalized, which makes it better suited for ADC development.6- 8 Four ADC targeting CD19, SAR3419 (coltuximab ravtansine, huB4-DM4),9-13 SGN- CD19A (denintuzumab mafodotin),14,15 ADCT-402 (loncastuximab tesirine),16-18 and SGN-CD19B19 have entered clinical development. SAR3419 is composed of the maytansinoid payload DM4 attached to the anti-CD19 humanized monoclonal
Ferrata Storti Foundation
Haematologica 2019 Volume 104(8):1633-1639
*These authors contributed equally to this work.
Correspondence:
FRANCESCO BERTONI/CALLUM SLOSS
frbertoni@mac.com/ callum.sloss@immunogen.com
Received: November 3, 2018. Accepted: February 7, 2019. Pre-published: February 7, 2019.
doi:10.3324/haematol.2018.211011
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/8/1633
©2019 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
haematologica | 2019; 104(8)
1633
ARTICLE