at1412, a patient-derived antibody in development for the ... · at1412, a patient-derived antibody...
TRANSCRIPT
Greta de Jong1,2,3,4, Sophie E. Levie1, Remko Schotte1, Wouter Pos1, Daniel Go1, E. Yasuda1, Madalina G. Cercel1, Susan E. van Hal-van Veen1, Esmay Frankin1, Anikó Szabó5, Martijn Kedde1, Els Verdegaal6, Julien Villaudy1, Sjoerd van der Burg6, Pauline M. van Helden1, Hans van Eenennaam1, Hergen Spits1,4,Anita W. Rijneveld5, Mette D. Hazenberg2,3,4
Background
‣ AT1412 was isolated using AIMSelect from B cells of a patient who was cured of stage IV metastatic melanoma‣ AT1412 is a fully human patient derived IgG1 antibody that targets CD9.‣ CD9 is overexpressed on many different types of tumor, making it an attractive target for immunotherapy.‣ AT1412 binds CD9-expressing tumor cells including melanoma and gastric, colon- and pancreatic cancer. ‣ AT1412 is able to control human melanoma growth in vitro and in mice (Abstract #1310 Poster #532).
‣ In B-ALL, CD9 is expressed in 60-80% of cases and correlates with an adverse prognosis.‣ Here we explore the efficacy of AT1412 for potential treatment of B-ALL.
Conflict of interest disclosure:
RS, JV, SL, DG, EY, EF, MC, SvH, DvB, CF, MK, YC, PvH, HvE are employees of AIMM Therapeutics.
RS, JV, SL, DG, EY, EF, MC, SvH, DvB, CF, MK, YC, PvH, HS, HvE have equity ownerschip in AIMM Therapeutics.
RS, WP, DG, JV, CF, PvH, HS are inventors on a patent relevant to this subject.
4. AT1412 reduces B-ALL tumor burden in human immune system mice
ConclusionAT1412‣ Is a fully human patient derived IgG1 antibody targeting CD9.‣ Induces ADCC in CD9-expressing B-ALL cells and controls B-ALL growth in human immune system mice.‣ Does not induce thrombocyte aggregation, which is in sharp contrast to previously described CD9 antibodies.‣ Induced transient thrombocytopenia in non-human primates without increased risk of bleeding and bruising.‣ AT1412 does not induce any other signs of toxicity in humanized mice or in non-human primates.‣ AT1412 is currently in preclinical development. First in Human studies are scheduled to start Q1 2021.
1. AT1412 targets CD9 on platelets but does not cause platelet aggregationin contrast to other anti CD9 antibodies
(A) Platelet Rich Plasma was incubated with AT1412. Antibody binding was visualized by secondary anti-human IgG A647 staining and flow cytometry.
(B) Whole blood was incubated with indicated stimuli at 37 °C under stirring conditions. Thrombocyte aggregation assessed by impedance aggregometry.
AT1412, a Patient-Derived Antibody in Development for the Treatment of CD9 positive B-Acute Lymphoblastic Leukemia
A B
1AIMM Therapeutics, Amsterdam, The Netherlands 2Department of Hematology, Amsterdam University Medical Center, location AMC, Amsterdam, The Netherlands3Cancer Center Amsterdam (CCA), Amsterdam, The Netherlands 4Amsterdam Infection and Immunity Institute (AI&II), Amsterdam, The Netherlands5Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands 6 Dept. of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, Netherlands Abstract #1912 Poster #531
no/low AT1412 bindingno ADCC
positive AT1412 bindingdetectable ADCC
10 100 1000 10000 100000
1
10
100
AT1412 binding (DMFI)
AT14
12 in
duce
d cy
toto
xici
ty(%
ADCC
)
(A) AT1412 binding of primary B-ALL samples as detected by flow cytometry. Binding ratio of AT1412 over isotype control of B-ALL versus T-ALL samples ***: p<0.0001 (Mann-Whitney test)
(B) Binding of AT1412 versus AT1412 mediated cytotoxicity on patient B-ALL samples. Binding is represented as MFI of AT1412 subtracted by the MFI of isotype control. The percentage of ADCC is corrected for isotype control cell death ***: p<0.001 (Spearman r)
2. AT1412 binding correlates with level of ADCC of patient-derived B-ALL
0.1
1
10
100
MFI
fold
incr
ease
AT1
412/
isot
ype
cont
rol
T-ALLB-ALL
****
Mice carrying a human immune system xenografted with luciferase expressing human SUP-B15 B-ALL cells,were treated twice per week intravenously with AT1412 or isotype control antibody. Bioluminescence in isolatedorgans was determined after sacrifice. (Kruskall Wallis with Dunn’s multiple comparisons test)
A B101
102
103
104
105
106
cpm
spleen
✱✱✱
✱
mpk15 1.5 5 15isotypecontrol AT1412
101
102
103
104
105
106
cpm
liver
✱✱
✱
mpk15 1.5 5 15isotypecontrol AT1412
101
102
103
104
105
106
cpm
bones
mpk15 1.5 5 15isotypecontrol AT1412
Cynomolgus monkeys were dosed with a single infusion of AT1412 (3, 5, or, 10 mg/kg).Blood was drawn at indicated timepoints to determine (A) platelet counts and (B) coagulation parameters.
A B
0 7 14 21
0
200
400
600
days post AT1412 infusion
plas
ma
conc
.(x10
9 /lite
r) 3 mpk 5 mpk
10 mpk
platelet counts
0 7 14 21
10
15
20
25
coag
ulat
ion
time
(s)
aPTT
PT
0 7 14 21
1.0
1.5
2.0
2.5
3.0
plas
ma
conc
.(g/L
)
3 mpk 5 mpk10 mpk
fibrogen
days post AT1412 infusion
co-aggulation parameters
3. AT1412 does not induce thrombosis, but does induce transient thrombocytopenia in cynomolgus monkeys, without increased the risk of bleeding or other signs of toxicity
PBS TRAP-6 ALB6isotype controlnegative controls positive controls
AT1412
time
units
AT1412dm
AT1412dm = affinity enhanced AT1412,same affinity for CD9 as ALB6