The novel CD19-targeting antibody-drug conjugate huB4-DGN462 shows improved anti-tumor activity compared to SAR3419 in CD19-positive lymphoma and leukemia models

  • Haematologica. 2019 Aug;104(8):1633-1639. doi: 10.3324/haematol.2018.211011.
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 Sloss  6 ,  Francesco Bertoni  7
Affiliations
  • 1. ImmunoGen Inc., Waltham, MA, USA.
  • 2. Università della Svizzera italiana, Institute of Oncology Research, Bellinzona, Switzerland.
  • 3. Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
  • 4. Swiss Institute of Bioinformatics, Lausanne, Switzerland and.
  • 5. Cytogenetics Laboratory, Ente Ospedaliero Cantonale, Bellinzona, Switzerland.
  • 6. ImmunoGen Inc., Waltham, MA, USA [email protected] [email protected].
  • 7. Università della Svizzera italiana, Institute of Oncology Research, Bellinzona, Switzerland [email protected] [email protected].
PMID: 30733273 DOI: 10.3324/haematol.2018.211011
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 conclusion, huB4-DGN462 is an attractive candidate for clinical investigation in patients with B-cell malignancies.

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