Therapeutic afucosylated monoclonal antibody and bispecific T-cell engagers for T-cell acute lymphoblastic leukemia.
Animals
Antibodies, Bispecific
/ pharmacology
Antibodies, Monoclonal, Humanized
/ pharmacology
Antibody Specificity
Antineoplastic Agents, Immunological
/ pharmacology
Cell Proliferation
/ drug effects
Cytotoxicity, Immunologic
/ drug effects
Epitopes
Female
Humans
Jurkat Cells
Leukosialin
/ agonists
Lymphocyte Activation
/ drug effects
Mice, Inbred NOD
Mice, SCID
Phagocytosis
/ drug effects
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
/ drug therapy
T-Lymphocytes
/ drug effects
Tumor Microenvironment
Xenograft Model Antitumor Assays
T-ALL
T-cell engagers
antibodies
antigens
hematologic neoplasms
immunotherapy
neoplasm
translational medical research
translational research
hematological malignancies
Journal
Journal for immunotherapy of cancer
ISSN: 2051-1426
Titre abrégé: J Immunother Cancer
Pays: England
ID NLM: 101620585
Informations de publication
Date de publication:
02 2021
02 2021
Historique:
accepted:
17
01
2021
entrez:
18
2
2021
pubmed:
19
2
2021
medline:
5
1
2022
Statut:
ppublish
Résumé
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. 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) 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. 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.
Sections du résumé
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)
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.
Identifiants
pubmed: 33597219
pii: jitc-2020-002026
doi: 10.1136/jitc-2020-002026
pmc: PMC7893666
pii:
doi:
Substances chimiques
Antibodies, Bispecific
0
Antibodies, Monoclonal, Humanized
0
Antineoplastic Agents, Immunological
0
Epitopes
0
Leukosialin
0
SPN protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: None declared.
Références
Blood. 2007 Jun 1;109(11):4655-62
pubmed: 17311990
J Biol Chem. 2008 Aug 29;283(35):23627-35
pubmed: 18586676
Blood Adv. 2017 Aug 18;1(19):1551-1564
pubmed: 29296797
Leukemia. 1995 Oct;9(10):1783-6
pubmed: 7564526
J Exp Med. 1989 Jul 1;170(1):259-67
pubmed: 2787380
Infect Immun. 2006 Jul;74(7):4310-21
pubmed: 16790805
J Clin Invest. 2012 Oct;122(10):3398-406
pubmed: 23023710
Blood. 2011 Aug 25;118(8):2077-84
pubmed: 21719599
Immunology. 2016 Nov;149(3):280-296
pubmed: 27392084
Leukemia. 2018 Nov;32(11):2307-2315
pubmed: 30315238
Cancer Immunol Immunother. 2011 Dec;60(12):1697-706
pubmed: 21710258
Tissue Antigens. 1998 May;51(5):528-35
pubmed: 9672151
Exp Hematol. 1998 Dec;26(13):1209-14
pubmed: 9845376
J Clin Oncol. 2018 Oct 10;36(29):2926-2934
pubmed: 30138085
Biomed Res Int. 2014;2014:742831
pubmed: 24689054
Blood. 2018 Apr 5;131(14):1522-1531
pubmed: 29358182
Clin Lymphoma Myeloma. 2009;9 Suppl 3:S214-21
pubmed: 19778844
Blood. 2007 Jun 15;109(12):5136-42
pubmed: 17344466
MAbs. 2018 May/Jun;10(4):539-546
pubmed: 29485921
Eur J Immunol. 1995 Apr;25(4):1051-5
pubmed: 7537669
Blood. 2002 Feb 1;99(3):863-71
pubmed: 11806988
Immune Netw. 2014 Jun;14(3):164-70
pubmed: 24999313
Biol Blood Marrow Transplant. 2012 Dec;18(12):1897-904
pubmed: 22824185
J Immunol. 2020 Mar 15;204(6):1674-1688
pubmed: 32060138
Mol Cell Proteomics. 2011 May;10(5):M111.007898
pubmed: 21372249
Cancer Res. 2019 Jul 1;79(13):3372-3382
pubmed: 31064847
J Clin Invest. 1999 Mar 15;103(6):921
pubmed: 10079114
Leukemia. 2017 Oct;31(10):2037-2047
pubmed: 28074072
Nat Rev Cancer. 2019 Jul;19(7):369
pubmed: 31201391
Bone Marrow Transplant. 2017 Jan;52(1):20-27
pubmed: 27618682
Blood. 2003 Feb 1;101(3):949-54
pubmed: 12393572
Tissue Antigens. 1994 Aug;44(2):73-82
pubmed: 7817381
Cancer Res. 2003 Oct 1;63(19):6453-7
pubmed: 14559836
J Immunol. 2019 Feb 15;202(4):1137-1144
pubmed: 30651344
Oncotarget. 2017 Oct 23;8(63):106753-106763
pubmed: 29290986