development and preclinical evaluation of therapeutic radiopharmaceuticals based on lu-177 and y-90...
Post on 16-Oct-2015
17 Views
Preview:
DESCRIPTION
TRANSCRIPT
-
5/26/2018 Development and Preclinical Evaluation of Therapeutic Radiopharmaceuticals Based on Lu-177 and Y-90 Labeled Monoclonal Antibodies And
1/39
Development and preclinical evaluation of theradiopharmaceuticals based on Lu 177 and Y 90 labeantibodies
IAEAs Coordinated
Research Project (CRP)
Establishment and standardization of a technology for rea
production of cold kit formulation of DOTA-Rituximab and p
radiopharmaceuticals for labeling with Lu-177 and Y-90
Emilija Jan
Goce Delce
Repub;ic o
-
5/26/2018 Development and Preclinical Evaluation of Therapeutic Radiopharmaceuticals Based on Lu-177 and Y-90 Labeled Monoclonal Antibodies And
2/39
PET-S+
- Auger-e-
SPECT
Camera
The Nuclear Medicine Alphabet
DIAGNOSTIC
THERAPY
-
5/26/2018 Development and Preclinical Evaluation of Therapeutic Radiopharmaceuticals Based on Lu-177 and Y-90 Labeled Monoclonal Antibodies And
3/39
Koopmans KP, Glaudem
EJNMMMI 2012,39, S4
Tumour
1 Peptides (receptors)
2Antibodies (Antigen)
3 Other molecules (metabolic processes)
Targeted diagnosis and therapy in nuclear medicineInfection
Seite 3
-
5/26/2018 Development and Preclinical Evaluation of Therapeutic Radiopharmaceuticals Based on Lu-177 and Y-90 Labeled Monoclonal Antibodies And
4/39
low-dose SPECT prior to therapy
Mller et al. 2013, Nucl Med Biol, in press: doi:10.1016/j.nucmedbio.2013.11.002
-
5/26/2018 Development and Preclinical Evaluation of Therapeutic Radiopharmaceuticals Based on Lu-177 and Y-90 Labeled Monoclonal Antibodies And
5/39
ISOTOPES in Therapy =surgery with radiation
Tissuesurgery Cellsurgery Molesur
ISOTOPE
131I, 90Y, 153Sm,166Ho,177Lu
Others
E 1 3 MeV
212, 213 Bi, 211At,149Tb,
223, 224Ra
E 48 MeV
1
16
Ee fe
Range about 1 cm 30 80 m 1
-Knife -Knife AuKn
-
5/26/2018 Development and Preclinical Evaluation of Therapeutic Radiopharmaceuticals Based on Lu-177 and Y-90 Labeled Monoclonal Antibodies And
6/39
Questions to be answered:
Realtionship between radiation dose delivered to a lesion andthe therapeutic response (in addition toxicity)
In vivo dosimetry by quantitative PET imaging
need for +-emitting metallic radionuclides
Relationship between beta energy and therapeutic responseVariation of radionuclides with different -energy
need for metallic - -emitters with very different
energy
-
5/26/2018 Development and Preclinical Evaluation of Therapeutic Radiopharmaceuticals Based on Lu-177 and Y-90 Labeled Monoclonal Antibodies And
7/39
- emitter for therapy
Sorted along the beta energy(starting from very soft radiation 169Er) to very hard beta energy (90Most of them are produced with reactors. However, some of them neproduced with a cyclotron (67Cu).Others can be produced with a cyclotron in much better quality (186R
-
5/26/2018 Development and Preclinical Evaluation of Therapeutic Radiopharmaceuticals Based on Lu-177 and Y-90 Labeled Monoclonal Antibodies And
8/39
PeptideAbs
Chelator
M
Receptor
Antigen
Radiometals for diagnostic imaging and therapy
Photon or positron emitters 99mTc, 68Ga, for imaging
Particle emitters 90Y, 177Lu, for radionuclide therapy
applicable only
with high specific activity and chemical purity
-
5/26/2018 Development and Preclinical Evaluation of Therapeutic Radiopharmaceuticals Based on Lu-177 and Y-90 Labeled Monoclonal Antibodies And
9/39
90 Y
177 Lu
131I, ..153S
Nature, behavior,
RADIOPHARMACEUTICALS
THERAPY -
-
5/26/2018 Development and Preclinical Evaluation of Therapeutic Radiopharmaceuticals Based on Lu-177 and Y-90 Labeled Monoclonal Antibodies And
10/39
linical application.177Lu-Labeled Targeted Radiotherapeutics for Treatment ofCentral Nervous System Tumors
Nature of problem and rationale for 177Lu disease sites and their constraints
A well-studied clinical application with a new radionuclide: 177Lu-MeO-DOTA-81C6
A well-studied radiotherapeutic in a new application: 177Lu-DOTA-TATE for medulloblastoma
A cocktail glass: DOTA-SIB mixing 177Lu with radiohalogens
-
5/26/2018 Development and Preclinical Evaluation of Therapeutic Radiopharmaceuticals Based on Lu-177 and Y-90 Labeled Monoclonal Antibodies And
11/39
Two approaches for Targeted Radiotherapy of Bra
Direct Injection into SCRC Convection EnhancedDelivery
More than 200 patients with131
I-labeled 81C6 mAb
92%
6%
2%
-
5/26/2018 Development and Preclinical Evaluation of Therapeutic Radiopharmaceuticals Based on Lu-177 and Y-90 Labeled Monoclonal Antibodies And
12/39
Potential Advantages of 177Lu for Brain Tumor Treatm
Property 131I 177Lu
Half-life (days) 8.1 6.7
Ave. -energy (keV) 182 133
Mean range (mm) 0.91 0.67
Max. range (mm) 2.3 1.8
-ray energy (keV) 364, 637 113, 208
-ray intensity (%) 81,7 7, 11
0.01
0.1
1
10
100
1000
10000
2.0 3.0 4.0 5.0
Radial distance (cm)
Absorbed
dose
(Gy)
interface
177Lu
131I
90Y
Assume 2-cm radius cavity (33.5 cm3
-
5/26/2018 Development and Preclinical Evaluation of Therapeutic Radiopharmaceuticals Based on Lu-177 and Y-90 Labeled Monoclonal Antibodies And
13/39
Dose to Brain beyond SCRC Interface
ThresholdDose (Gy)
Brain volume (cm3) > threshold dose
131I 177Lu 90Y
110 2.05 1.02 11.70
50 4.73 1.79 18.12
10 180.3 3.64 31.14
-
5/26/2018 Development and Preclinical Evaluation of Therapeutic Radiopharmaceuticals Based on Lu-177 and Y-90 Labeled Monoclonal Antibodies And
14/39
177Lu-DOTA-TATE vs. 90Y-DOTA-TOC
Property 90Y 177Lu
Half-life (days) 2.7 6.7
Ave. -energy (keV) 935 133
Mean range (mm) 3.9 0.67
Max. range (mm) 10.0 1.8
-ray energy (keV) none 113, 208
-ray intensity (%) none 7, 11
DOTA-TATE has 10x highaffinity vs. DOTA-TOC
Compared with 90Y, 177L
More focal field of th-particles results indamage to normal C
Imaging177
Lu -rays determination of PKpatient-specific dosi
-
5/26/2018 Development and Preclinical Evaluation of Therapeutic Radiopharmaceuticals Based on Lu-177 and Y-90 Labeled Monoclonal Antibodies And
15/39
177Lu-DOTA-TATE: Children
Six children with relapsed or refractory neuroblastoma PET imaging with [68Ga]DOTA-TATE to determine eligibil
200 mCi 2-3 cycles i.v. at 9-wk intervals with
Co-infusion of Lys/Arg; no renal toxicity
5 of 6 patients had stabilized disease by RECIST
Gaze et al., 201
-
5/26/2018 Development and Preclinical Evaluation of Therapeutic Radiopharmaceuticals Based on Lu-177 and Y-90 Labeled Monoclonal Antibodies And
16/39
Some results from preclinical studies..Introducing the new approach to have kiformulation for labeling
h h d f i
-
5/26/2018 Development and Preclinical Evaluation of Therapeutic Radiopharmaceuticals Based on Lu-177 and Y-90 Labeled Monoclonal Antibodies And
17/39
The same method of preparation
-
5/26/2018 Development and Preclinical Evaluation of Therapeutic Radiopharmaceuticals Based on Lu-177 and Y-90 Labeled Monoclonal Antibodies And
18/39
HPLC characterization before labelling
90Y-DOTATATE
In vitro stability
(EDTA, serum, etc)
Lab yield 98 %
After purification 99 %
razn molar DOTATATE: Y
Purezaradioqumica
5:1
10:1
15:1
20:1
0
50
100Sep-Pak C18
Whatman
-
5/26/2018 Development and Preclinical Evaluation of Therapeutic Radiopharmaceuticals Based on Lu-177 and Y-90 Labeled Monoclonal Antibodies And
19/39
Animal Biodistribution in athimic mice
Sample of ROIs definition
177Lu-DOTA-hR3
20 mCi, 1,5 mg Ab
81 % RCP 95% after purif
id
d l f l i i i
d
-
5/26/2018 Development and Preclinical Evaluation of Therapeutic Radiopharmaceuticals Based on Lu-177 and Y-90 Labeled Monoclonal Antibodies And
20/39
Two different CCK-2-receptor specific tumour-cell-lines:
AR42J exocrine rat pancreas carcinoma cells (rat CC
A431 human epidermoid carcinoma cells stably trahuman CCK-2-receptor
tota
Inte
1 nM
(BL
med
of 1
111In-DOTA-cyclo-MG1
me
BLBL
A431 AR42J
%
Aktivitt/mgPro
tein
BLBL
A431 AR42J
111In-DOTA-MG11
Peptides . development of novel targeting strategies using Lu-177 and
Cell Uptake
Cyclic minigastrin analogues - diagnosis and therapy of medullary thyroid car
-
5/26/2018 Development and Preclinical Evaluation of Therapeutic Radiopharmaceuticals Based on Lu-177 and Y-90 Labeled Monoclonal Antibodies And
21/39
1 h p.i.
4 h p.i.
4 h p.i. + blockage(1000-fold excess ofunlabelled peptide)
111In-DOTA-cyclo-MG1
111In-DOTA-MGD5 111In-DOTA-PP-F11
111In-DOTA-MG11
Biodistribution in the A431 mouse modelTumour-Xenograft: BALB/c nude mice, A431-CCK2R human epidermoid carcinoma cells
2 x 106 cells/mouse, tumour growth ~10 days, tumour size ~0,2 g0,37 MBq 111In-DOTA-Peptide (
-
5/26/2018 Development and Preclinical Evaluation of Therapeutic Radiopharmaceuticals Based on Lu-177 and Y-90 Labeled Monoclonal Antibodies And
22/39
Preclinical evaluation of newbiomolecules
Radiolabelled DOTA-bombesin
for diagnosis and therapy of prostate and breast cancer
-
5/26/2018 Development and Preclinical Evaluation of Therapeutic Radiopharmaceuticals Based on Lu-177 and Y-90 Labeled Monoclonal Antibodies And
23/39
New bombesin analogue
Peptide delivered by Saudi Arabia
DOTA-Glu-Phe-Glu-Trp-Ala-Val--Ala-His-Phe-Nle-NH2
(DOTA-Glu-BNU)
Molecular weight 1670
spacer Glu-Phe-Glu (negatively charged AA)
< abdominal uptake? > renal excretion?
retained tumour uptake?
clinical potential?
-
5/26/2018 Development and Preclinical Evaluation of Therapeutic Radiopharmaceuticals Based on Lu-177 and Y-90 Labeled Monoclonal Antibodies And
24/39
low protein binding Eppendorf tube
10-15 g DOTA-Glu-BNU (20% EtOH 1g/l)
60 l177
LuCl3 (120 MBq)+ 80 l buffer
80C,25 min
1) 1 M ascorbic acid/0.27 M gentisic acidbuffer pH 4.5
RCY =95.2%
2) 0.8 M sodium acetate buffer pH 5
RCY =99.6%
3) 0.4 M Sodium acetate/ 0.24 M gentisic acid
buffer pH 5
RCY =99.7%
4) 0.2 M 2-(N-morpholino) ethanesulfonic acid
(MES) buffer pH 5.5
RCY =5.9%
Radiolabelling with Lu-177
1)
2)
3)
0, 0 1, 3 2, 5 3, 8 5, 0 6, 3 7, 5 8, 8 10, 0 11, 3 12, 5 13, 8 15, 0 16, 3 17, 5 18, 8 20, 0 21, 3 22, 5 23, 8 25, 0 2
-50
0
100
200
300
400 Gastrin #16 [modif ied by radhplc1] 177Lu-BOMB Ask/gen mV
0, 0 1, 3 2, 5 3, 8 5, 0 6, 3 7, 5 8, 8 1 0, 0 1 1, 3 1 2, 5 13, 8 15, 0 16, 3 17, 5 18, 8 20, 0 21, 3 22, 5 23, 8 25, 0 2
-20
25
50
75
100
125
150
180 Gastrin #14 [modif ied by radhplc1] 177Lu-BOMB NaAc mV
0, 0 1, 3 2, 5 3, 8 5, 0 6, 3 7, 5 8, 8 1 0, 0 1 1, 3 1 2, 5 13, 8 15, 0 16, 3 17, 5 18, 8 20, 0 21, 3 22, 5 23, 8 25, 0 2
-50
0
50
100
150
200
250
300
350 Gastrin #15 [modif ied by radhplc1] 177Lu-BOMB NaAc/gen mV
0, 0 1, 3 2, 5 3, 8 5, 0 6, 3 7, 5 8, 8 10, 0 11, 3 12, 5 13, 8 15, 0 16, 3 17, 5 18, 8 20, 0 21, 3 22, 5 23, 8 25, 0 2
-20
0
20
40
60
80
100
120
140 Gastrin #13 [modif ied by radhplc1] 177Lu-BOMB MES mV
4)
DOTA-Glu-BNU
D bl f i N d i
-
5/26/2018 Development and Preclinical Evaluation of Therapeutic Radiopharmaceuticals Based on Lu-177 and Y-90 Labeled Monoclonal Antibodies And
25/39
Double xenografts in Nude micespecific vs non-specific uptake
-
5/26/2018 Development and Preclinical Evaluation of Therapeutic Radiopharmaceuticals Based on Lu-177 and Y-90 Labeled Monoclonal Antibodies And
26/39
FU-parameters, toxicitythe weight
FU-parameters, efficacy
-
5/26/2018 Development and Preclinical Evaluation of Therapeutic Radiopharmaceuticals Based on Lu-177 and Y-90 Labeled Monoclonal Antibodies And
27/39
the tumor growthand survival time !
The double tumors imaged by
-
5/26/2018 Development and Preclinical Evaluation of Therapeutic Radiopharmaceuticals Based on Lu-177 and Y-90 Labeled Monoclonal Antibodies And
28/39
The double tumors imaged bySPECT/CT
The double tumors imaged
-
5/26/2018 Development and Preclinical Evaluation of Therapeutic Radiopharmaceuticals Based on Lu-177 and Y-90 Labeled Monoclonal Antibodies And
29/39
The double tumors imagedPET/MRI
-
5/26/2018 Development and Preclinical Evaluation of Therapeutic Radiopharmaceuticals Based on Lu-177 and Y-90 Labeled Monoclonal Antibodies And
30/39
Transplanted hu tumors in
immunosuppresseed animals
Biologically similar spontaneous tum
S ll
i l
SPECT/CT i SCID
i
-
5/26/2018 Development and Preclinical Evaluation of Therapeutic Radiopharmaceuticals Based on Lu-177 and Y-90 Labeled Monoclonal Antibodies And
31/39
Nano-SPECT/CT
of the 111In-labellel DOTA-peptidesSosabowski J (London, GB)
Small animal SPECT/CT in SCID-mice
with A431-CCK2R-tumour 4 h p.i.
Injected activity
10 MBq111
In-DOTA-Pep(0.3 nmol Pept
10-fold higher
peptide amoun
(comparable w
the therapeutic
application)
MGD5London
cyclo-MGInnsbruck
PP-F11Basel
Seite 31
Rats with SSR positive tumours in liver
-
5/26/2018 Development and Preclinical Evaluation of Therapeutic Radiopharmaceuticals Based on Lu-177 and Y-90 Labeled Monoclonal Antibodies And
32/39
Control
Rats with SSR-positive tumours in liver
model mimics disseminated disease PRRT
177Lu-octreotate
(PRRT = Peptide Receptor Radionuclide Therapy )
Woute
ErasmusThe Netherland
S l ti it i
-
5/26/2018 Development and Preclinical Evaluation of Therapeutic Radiopharmaceuticals Based on Lu-177 and Y-90 Labeled Monoclonal Antibodies And
33/39
-50
-40
-30
-20
-10
0
10
20
30
0 10 20 30 40
Temperature[oC]
Time [h]
Selection criteria:
- physical appearance of the obtained cake of dry product
- clear solution of reconstituted product, after reconstitution in
N t t
-
5/26/2018 Development and Preclinical Evaluation of Therapeutic Radiopharmaceuticals Based on Lu-177 and Y-90 Labeled Monoclonal Antibodies And
34/39
Next step..
2. Freeze-dried product:
Implementation of the lyophilization protocol to thestabile product
Characterization of the lyophilized product (SEM,
DSC, ) Stability of the freeze-dried product
Ne t step
-
5/26/2018 Development and Preclinical Evaluation of Therapeutic Radiopharmaceuticals Based on Lu-177 and Y-90 Labeled Monoclonal Antibodies And
35/39
Next step..
+ emitters for in vivo dosimetry
[111In]DTPA- Scintigraphic abi 5 &
[86Y]DOTA-DPhe1-Tyr3-
t tid
-
5/26/2018 Development and Preclinical Evaluation of Therapeutic Radiopharmaceuticals Based on Lu-177 and Y-90 Labeled Monoclonal Antibodies And
36/39
5 h p.i.
24 h p.i.
[ ]
octreotide
SPECT
images 5 &
affe
carcin
extensive hep
paraaortal met
octreotide
PET
Patients: 3 patients with me
of carcinoid tumo
(histologically co
No therapy with u
somatostatin > 4 w
Age: 46
67 year All were candidat
a possible90Y-DOTATOC th
F.Rsch et.al.
that metallic positr
practical relevance
DOTA-SIB, A TRIFUNCTIONAL PROSTHETIC GROUP
-
5/26/2018 Development and Preclinical Evaluation of Therapeutic Radiopharmaceuticals Based on Lu-177 and Y-90 Labeled Monoclonal Antibodies And
37/39
Long term Objective: Prosthetic moieties to label proteins and
-with two different radionuclides
-augment tumor retention after internalization
Functions:
-Chelating moiety to impart polarity/charge in addition to com
radiometals-Halobenzoyl moiety to carry radiohalogens
-Active ester for mAb/peptide conjugation
,
FOR MULTI-MODAL
LABELING
-
5/26/2018 Development and Preclinical Evaluation of Therapeutic Radiopharmaceuticals Based on Lu-177 and Y-90 Labeled Monoclonal Antibodies And
38/39
DOTA-SIB A TRIFUNCTIONAL PROSTHETIC GROUP FOR MULTI-MOD
Ganesan Vaidyanathan, Benjamin White, Donna Affleck, Xiao-Guang Zhao, Philip Welsh, Marc Hens, and
Duke University, Durham, NC
-
5/26/2018 Development and Preclinical Evaluation of Therapeutic Radiopharmaceuticals Based on Lu-177 and Y-90 Labeled Monoclonal Antibodies And
39/39
165Er3+
1.
2.
4.
5.
6.
7.
p+
Er
165Tm3+
165TmTmEr
165Er3+
SCX
165Tm-DOTA
165Er3+
3.
top related