Therapeutic afucosylated monoclonal antibody and bispecific T-cell engagers for T-cell acute lymphoblastic leukemia
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Journal articleDate
2021-02-17Author
Caracciolo, DanieleRiillo, Caterina
Ballerini, Andrea
Gaipa, Giuseppe
Lhermitte, Ludovic
Rossi, Marco
Botta, Cirino
Duroyon, Eugénie
Grillone, Katia
Cantafio, Maria Eugenia Gallo
Buracchi, Chiara
Alampi, Greta
Gulino, Alessandro
Belmonte, Beatrice
Conforti, Francesco
Golino, Gaetanina
Juli, Giada
Altomare, Emanuela
Polerà, Nicoletta
Scionti, Francesca
Arbitrio, Mariamena
Iannone, Michelangelo
Martino, Massimo
Correale, Pierpaolo
Talarico, Gabriella
Luserna di Rorà, Andrea Ghelli
Ferrari, Anna
Concolino, Daniela
Sestito, Simona
Pensabene, Licia
Giordano, Antonio

Hildinger, Markus
Di Martino, Maria Teresa
Martinelli, Giovanni
Tripodo, Claudio
Asnafi, Vahid
Biondi, Andrea
Tagliaferri, Pierosandro
Tassone, Pierfrancesco
Group
Sbarro Institute for Cancer Research and Molecular Medicine (Temple University)Department
BiologyPermanent link to this record
http://hdl.handle.net/20.500.12613/7045
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https://doi.org/10.1136/jitc-2020-002026Abstract
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) CD3ε 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.Citation
Caracciolo D, Riillo C, Ballerini A, et al. Therapeutic afucosylated monoclonal antibody and bispecific T-cell engagers for T-cell acute lymphoblastic leukemia. Journal for ImmunoTherapy of Cancer 2021;9:e002026. doi: 10.1136/jitc-2020-002026Citation to related work
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http://dx.doi.org/10.34944/dspace/7026
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