Key Points

  • Humanized, non–FcγR-binding anti-CD3 mAbs offer a novel therapeutic strategy in T-ALL.

  • Antileukemic properties of anti-CD3 mAbs are largely independent of FcγR pathways in T-ALL PDXs.

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy that accounts for ∼20% of ALL cases. Intensive chemotherapy regimens result in cure rates >85% in children and <50% in adults, warranting a search of novel therapeutic strategies. Although immune-based therapies have tremendously improved the treatment of B-ALL and other B-cell malignancies, they are not yet available for T-ALL. We report here that humanized, non–Fcγ receptor (FcγR)–binding monoclonal antibodies (mAbs) to CD3 have antileukemic properties in xenograft (PDX) models of CD3+ T-ALL, resulting in prolonged host survival. We also report that these antibodies cooperate with chemotherapy to enhance antileukemic effects and host survival. Because these antibodies show only minor, manageable adverse effects in humans, they offer a new therapeutic option for the treatment of T-ALL. Our results also show that the antileukemic properties of anti-CD3 mAbs are largely independent of FcγR-mediated pathways in T-ALL PDXs.

REFERENCES

REFERENCES
1.
Pui
C-H
,
Yang
JJ
,
Hunger
SP
, et al
.
Childhood acute lymphoblastic leukemia: Progress through collaboration
.
J Clin Oncol
.
2015
;
33
(
27
):
2938
-
2948
.
2.
Litzow
MR
,
Ferrando
AA
.
How I treat T-cell acute lymphoblastic leukemia in adults
.
Blood
.
2015
;
126
(
7
):
833
-
841
.
3.
Belver
L
,
Ferrando
A
.
The genetics and mechanisms of T cell acute lymphoblastic leukaemia
.
Nat Rev Cancer
.
2016
;
16
(
8
):
494
-
507
.
4.
Liu
Y
,
Easton
J
,
Shao
Y
, et al
.
The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia
.
Nat Genet
.
2017
;
49
(
8
):
1211
-
1218
.
5.
Rafei
H
,
Kantarjian
HM
,
Jabbour
EJ
.
Recent advances in the treatment of acute lymphoblastic leukemia
.
Leuk Lymphoma
.
2019
;
60
(
11
):
2606
-
2621
.
6.
Trinquand
A
,
Dos Santos
NR
,
Tran Quang
C
, et al
.
Triggering the TCR developmental checkpoint activates a therapeutically targetable tumor suppressive pathway in T-cell leukemia
.
Cancer Discov
.
2016
;
6
(
9
):
972
-
985
.
7.
Kuhn
C
,
Weiner
HL
.
Therapeutic anti-CD3 monoclonal antibodies: from bench to bedside
.
Immunotherapy
.
2016
;
8
(
8
):
889
-
906
.
8.
Xu
D
,
Alegre
ML
,
Varga
SS
, et al
.
In vitro characterization of five humanized OKT3 effector function variant antibodies
.
Cell Immunol
.
2000
;
200
(
1
):
16
-
26
.
9.
Alegre
ML
,
Peterson
LJ
,
Xu
D
, et al
.
A non-activating “humanized” anti-CD3 monoclonal antibody retains immunosuppressive properties in vivo
.
Transplantation
.
1994
;
57
(
11
):
1537
-
1543
.
10.
Schlothauer
T
,
Herter
S
,
Koller
CF
, et al
.
Novel human IgG1 and IgG4 Fc-engineered antibodies with completely abolished immune effector functions
.
Protein Eng Des Sel
.
2016
;
29
(
10
):
457
-
466
.
11.
Lo
M
,
Kim
HS
,
Tong
RK
, et al
.
Effector-attenuating substitutions that maintain antibody stability and reduce toxicity in mice
.
J Biol Chem
.
2017
;
292
(
9
):
3900
-
3908
.
12.
Herold
KC
,
Bundy
BN
,
Long
SA
, et al;
Type 1 Diabetes TrialNet Study Group
.
An anti-CD3 antibody, teplizumab, in relatives at risk for type 1 diabetes [published correction appears in N Engl J Med. 2020 Feb 6;382(6):586]
.
N Engl J Med
.
2019
;
381
(
7
):
603
-
613
.
13.
Woodle
ES
,
Xu
D
,
Zivin
RA
, et al
.
Phase I trial of a humanized, Fc receptor nonbinding OKT3 antibody, huOKT3gamma1(Ala-Ala) in the treatment of acute renal allograft rejection
.
Transplantation
.
1999
;
68
(
5
):
608
-
616
.
14.
Dean
Y
,
Dépis
F
,
Kosco-Vilbois
M
.
Combination therapies in the context of anti-CD3 antibodies for the treatment of autoimmune diseases
.
Swiss Med Wkly
.
2012
;
142
:
w13711
.
15.
Passaro
D
,
Irigoyen
M
,
Catherinet
C
, et al
.
CXCR4 is required for leukemia-initiating cell activity in T cell acute lymphoblastic leukemia
.
Cancer Cell
.
2015
;
27
(
6
):
769
-
779
.
16.
Laky
K
,
Fleischacker
C
,
Fowlkes
BJ
.
TCR and Notch signaling in CD4 and CD8 T-cell development
.
Immunol Rev
.
2006
;
209
:
274
-
283
.
17.
Shan
X
,
Czar
MJ
,
Bunnell
SC
, et al
.
Deficiency of PTEN in Jurkat T cells causes constitutive localization of Itk to the plasma membrane and hyperresponsiveness to CD3 stimulation
.
Mol Cell Biol
.
2000
;
20
(
18
):
6945
-
6957
.
18.
van der Woude
CJ
,
Stokkers
P
,
van Bodegraven
AA
, et al;
Initiative on Crohn’s and Colitis, The Netherlands
.
Phase I, double-blind, randomized, placebo-controlled, dose-escalation study of NI-0401 (a fully human anti-CD3 monoclonal antibody) in patients with moderate to severe active Crohn’s disease
.
Inflamm Bowel Dis
.
2010
;
16
(
10
):
1708
-
1716
.
19.
Herold
KC
,
Gitelman
S
,
Greenbaum
C
, et al;
Immune Tolerance Network ITN007AI Study Group
.
Treatment of patients with new onset type 1 diabetes with a single course of anti-CD3 mAb teplizumab preserves insulin production for up to 5 years
.
Clin Immunol
.
2009
;
132
(
2
):
166
-
173
.
20.
Hagopian
W
,
Ferry
RJ
Jr.
,
Sherry
N
, et al;
Protégé Trial Investigators
.
Teplizumab preserves C-peptide in recent-onset type 1 diabetes: two-year results from the randomized, placebo-controlled Protégé trial
.
Diabetes
.
2013
;
62
(
11
):
3901
-
3908
.
21.
Marshall
MJE
,
Stopforth
RJ
,
Cragg
MS
.
Therapeutic antibodies: what have we learnt from targeting CD20 and where are we going?
Front Immunol
.
2017
;
8
:
1245
.
22.
Clynes
RA
,
Towers
TL
,
Presta
LG
,
Ravetch
JV
.
Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets
.
Nat Med
.
2000
;
6
(
4
):
443
-
446
.
23.
Schewe
DM
,
Alsadeq
A
,
Sattler
C
, et al
.
An Fc-engineered CD19 antibody eradicates MRD in patient-derived MLL-rearranged acute lymphoblastic leukemia xenografts
.
Blood
.
2017
;
130
(
13
):
1543
-
1552
.
24.
Stevenson
FK
,
Bollard
CM
.
Introduction to a review series on therapeutic antibodies
.
Blood
.
2018
;
131
(
1
):
1
.
You do not currently have access to this content.