Therapeutic afucosylated monoclonal antibody and bispecific T-cell engagers for T-cell acute lymphoblastic leukemia

Claudio Tripodo, Alessandro Gulino, Beatrice Belmonte, Ludovic Lhermitte, Simona Sestito, Francesca Scionti, Francesco Conforti, Maria Teresa Di Martino, Cirino Botta, Maria Eugenia Gallo Cantafio, Anna Ferrari, Emanuela Altomare, Marco Rossi, Giovanni Martinelli, Gaetanina Golino, Katia Grillone, Markus Hildinger, Andrea Biondi, Daniele Caracciolo, Caterina RiilloVahid Asnafi, Giada Juli, Andrea Ghelli Luserna Di Rorà, Eugénie Duroyon, Massimo Martino, Greta Alampi, Andrea Ballerini, Nicoletta Polerà, Chiara Buracchi, Giuseppe Gaipa, Mariamena Arbitrio, Daniela Concolino, Licia Pensabene, Pierpaolo Correale, Gabriella Talarico, Pierfrancesco Tassone, Michelangelo Iannone, Pierosandro Tagliaferri, Antonio Giordano

Risultato della ricerca: Articlepeer review

Abstract

Background T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease with a poor cure rate for relapsed/resistant patients. Due to the lack of T-cell restricted targetable antigens, effective immune-therapeutics are not presently available and the treatment of chemo-refractory T-ALL is still an unmet clinical need. To develop novel immune-therapy for T-ALL, we generated an afucosylated monoclonal antibody (mAb) (ahuUMG1) and two different bispecific T-cell engagers (BTCEs) against UMG1, a unique CD43-epitope highly and selectively expressed by T-ALL cells from pediatric and adult patients. Methods UMG1 expression was assessed by immunohistochemistry (IHC) on a wide panel of normal tissue microarrays (TMAs), and by flow cytometry on healthy peripheral blood/bone marrow-derived cells, on 10 different T-ALL cell lines, and on 110 T-ALL primary patient-derived cells. CD43-UMG1 binding site was defined through a peptide microarray scanning. ahuUMG1 was generated by Genetic Glyco-Engineering technology from a novel humanized mAb directed against UMG1 (huUMG1). BTCEs were generated as IgG1-(scFv)(2) constructs with bivalent (2+2) or monovalent (2+1) CD3 epsilon arms. Antibody dependent cellular cytotoxicity (ADCC), antibody dependent cellular phagocytosis (ADCP) and redirected T-cell cytotoxicity assays were analysed by flow cytometry. In vivo antitumor activity of ahUMG1 and UMG1-BTCEs was investigated in NSG mice against subcutaneous and orthotopic xenografts of human T-ALL. Results Among 110 T-ALL patient-derived samples, 53 (48.1%) stained positive (24% of TI/TII, 82% of TIII and 42.8% of TIV). Importantly, no expression of UMG1-epitope was found in normal tissues/cells, excluding cortical thymocytes and a minority (<5%) of peripheral blood T lymphocytes. ahUMG1 induced strong ADCC and ADCP on T-ALL cells in vitro, which translated in antitumor activity in vivo and significantly extended survival of treated mice. Both UMG1-BTCEs demonstrated highly effective killing activity against T-ALL cells in vitro. We demonstrated that this effect was specifically exerted by engaged activated T cells. Moreover, UMG1-BTCEs effectively antagonized tumor growth at concentrations >2 log lower as compared with ahuUMG1, with significant mice survival advantage in different T-ALL models in vivo. Conclusion Altogether our findings, including the safe UMG1-epitope expression profile, provide a framework for the clinical development of these innovative immune-therapeutics for this still orphan disease.
Lingua originaleEnglish
pagine (da-a)e002026-
Numero di pagine14
RivistaJournal for ImmunoTherapy of Cancer
Volume9
Stato di pubblicazionePublished - 2021

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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