Download Ekaterina Dadachova, Ph.D.

Novel approaches to therapy
of infectious diseases
Ekaterina Dadachova, Ph.D.
Sylvia and Robert Olnick Faculty Scholar in Cancer Research
Associate Professor
Departments of Nuclear Medicine and Microbiology and Immunology
Albert Einstein College of Medicine, Bronx, NY
Production of radionuclides
Preparation of 225Ac
generators in a glovebox at
the Institute for
Transuranium Elements, EC
(source ITU website)
Higher levels of radioactivity are handled in
“hot cells”. Hot cell (operator side with
manipulators for
remote-controlled work is shown on this
photo.
(source European Nuclear Society website)
Radioactive substances really glow in the dark
– a vial with 50 milliCurie of 225-Actinium
which we use in our research
Courtesy of Dr. J. Harvey, Northstar Nuclear
Medicine
What is ionizing radiation?
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The following kinds of ionizing radiation are used in nuclear medicine:
electrons, positrons, alpha particles, gamma rays.
Electron (beta-particle) has a mass of nearly 1/2000 of the mass of a
proton or neutron. Depending on its energy, an electron can traverse
different distances in water-less than 1 mm for 3H to ~1 cm for 32P.
Positron is an antiparticle of an ordinary electron. It loses its kinetic
energy the same way as an electron and has the same range in water.
It then combines with an electron in annihilation reaction, in which its
mass and that of electron are converted into the energy of two 511
keV annihilation photons emitted in exact opposite directions (180o
apart).
An alpha particle is a nucleus of 4He. Because of its large mass and
positive charge, an alpha particle can usually pass only 20-100 m in
water.
A gamma ray is an electromagnetic wave, a gamma ray is similar to
ordinary visible light but differs in energy and wavelength. Gammas
penetrate several cm into the body.
Mechanisms by which RIT is effective against microbes
Casadevall A, Dadachova E, Pirofski L. Nature Rev. Microbiol., 2: 695-703 (2004)
A.
C. neoformans
RADIOLABELED
ANTIBODY BOUND
TO SHED POLYSACCHARIDE
KILLS NEARBY C. neoformans
INFECTED
MACROPHAGE
KILLED BY
‘CROSS-FIRE’ EFFECT
B.
RADIOLABELED
ANTIBODY
INFECTED
CELL
KILLED BY
‘CROSS-FIRE’
EFFECT
ANTIBODY
BOUND TO MICROBIAL
ANTIGEN EXPRESSED ON
SURFACE KILLS CELL WITH
RADIATION
Radioimmunotherapy of
experimental fungal
infection
Survival of A/JCr mice infected IV with 105
C. neoformans fungal cells
24 h prior to treatment with 213Bi- or 188Re-labeled
antibodies
a)
100
188
% survival
80
60
Re-18B7, 50 Ci
188
Re-18B7, 100 Ci
188
Re-18B7, 200 Ci
PBS
40
"cold" 18B7, 50 g
188
20
Re-MOPC21, 100 Ci
0
0
10
20
30
40
50
60
70
80
b)
Days post-treatment
100
213
213
Dadachova E. et al.
Proc. Natl. Acad. Sci. USA
100:10942, 2003.
% survival
80
Bi-18B7, 50 Ci
Bi-18B7, 100 Ci
213
60
Bi-18B7, 200 Ci
PBS
"cold" 18B7, 50 g
40
213
Bi-MOPC21,100
Ci
20
0
0
10
20
30
40
50
60
Days post-treatment
70
80
RIT for treatment of fungal biofilms
Percentage of Metabolic
Activity (492 nm)
120
B3501 Biofilms
100
B3501 Planktonic
p<0.05
*
80
60
40
*
20
Percentage of Metabolic
Activity (492 nm)
The use of indwelling medical
devices — pacemakers,
prosthetic joints, catheters —
is rapidly growing and is often
complicated by infections with
biofilm-forming microbes that
are resistant to antimicrobial
agents and host defense
mechanisms.
B3501 Planktonic
100
80
15
30
MAb 18B7-Bismuth-213 (µCi)
p<0.05
*
60
40
*
20
0
0
B3501 biofilm
120
200
400
MAb 18B7-Rhenium-188 (Ci)
L.R. Martinez et al Antimicrob. Agents Chemother., 50(6):2132-2136 (2006)
Radioimmunotherapy of
experimental bacterial
infections
RIT of S.pneumoniae infection with 213Bi-labeled
antibodies in C57BL/6 mice
100
a)
5 ug "cold" D11
Survival, %
80
5 ug 213Bi-D11
untreated
60
40
20
0
0
2
4
6
8
10
12
14
Days post-treatment
100
5 g "cold" D11
b)
213
Bi-IgM
Survival, %
80
213
Bi-D11
untreated
60
40
20
0
0
2
4
6
8
10
12
14
Days post-treatment
Dadachova E. et al Antimicrob. Agents Chemother., 48, 1624 (2004 )
Radioimmunotherapy of HIV
RIT EFFECTIVE IN MICE HARBORING
HIV-INFECTED HUMAN CELLS
MODEL: SCID mice injected intrasplenically with HIV-1 infected hPBMCs
188-Re-246-D before
infection
188-Re-246-D after
infection
213-Bi-246-D after
infection
188-Re-1418 irrel. mAb
213-Bi-1418 irrel. mAb
"cold" 246-D mAb
Untreated controls
1
10
100
6
TCID 50/10 splenocytes
1000
10000
THINKING BEYOND RIT OF HIV

NEW OPTIONS FOR THE TREATMENT OF VIRAL
DISEASES SUCH AS Hepatitis C virus, Epstein Barr virus,
human papilloma virus etc.
(A. Casadevall, H. Goldstein, and E. Dadachova Expert Opinion Biol.
Therapy, 7:595-597, 2007)

RIT POTENTIALLY APPLICABLE TO TREATMENT AND
PREVENTION OF CANCERS CAUSED BY ONCOGENIC
VIRUSES SUCH AS HEPATOCELLULAR CARCINOMA,
CERVICAL CANCER, AND CERTAIN LEUKEMIAS AND
LYMPHOMAS
(E. Dadachova, X.-G. Wang, and A. Casadevall Cancer Biother.
Radiopharm., 22: 303-308, 2007)
RIT of cervical tumors in nude mice with
188Re-anti-E6 antibody
Treated mouse
Untreated mouse
315 uCi 188Re-C1P5 anti-E-6
mAb (hot)
or 30 ug unlabeled C1P5 antiE-6 mAb (cold)
RIT of hepatocellular carcinoam in nude
mice with
188Re-4H9 antibody
X-G. Wang, et. al. PLOS One 2(10): e1114 (2007).