Novel approaches to therapy Novel approaches to therapy of infectious diseasesof infectious diseases

Ekaterina Dadachova, Ph.D. Ekaterina Dadachova, Ph.D. Sylvia and Robert Olnick Faculty Scholar in Cancer ResearchSylvia and Robert Olnick Faculty Scholar in Cancer Research

Associate ProfessorAssociate Professor

Departments of Nuclear Medicine and Microbiology and ImmunologyDepartments of Nuclear Medicine and Microbiology and Immunology

Albert Einstein College of Medicine, Bronx, NYAlbert Einstein College of Medicine, Bronx, NY

Production of radionuclidesProduction 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 forremote-controlled work is shown on this

photo. (source European Nuclear Society website)

Radioactive substances really glow in the dark Radioactive substances really glow in the dark – a vial with 50 milliCurie of 225-Actinium – a vial with 50 milliCurie of 225-Actinium

which we use in our researchwhich we use in our research

Courtesy of Dr. J. Harvey, Northstar Nuclear Medicine

What is ionizing What is ionizing radiationradiation??

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.

INFECTEDMACROPHAGEKILLED BY‘CROSS-FIRE’ EFFECT

RADIOLABELEDANTIBODY BOUNDTO SHED POLYSACCHARIDEKILLS NEARBY C. neoformans

C. neoformans

INFECTEDCELLKILLED BY‘CROSS-FIRE’ EFFECT

RADIOLABELEDANTIBODYA. B.

ANTIBODYBOUND TO MICROBIALANTIGEN EXPRESSED ONSURFACE KILLS CELL WITHRADIATION

Mechanisms by which RIT is effective against microbes

Casadevall A, Dadachova E, Pirofski L. Nature Rev. Microbiol., 2: 695-703 (2004)

Radioimmunotherapy of Radioimmunotherapy of experimental fungal experimental fungal

infectioninfection

Survival of A/JCr mice infected IV with 105 C. neoformans fungal cells24 h prior to treatment with 213Bi- or 188Re-labeled antibodies

a)

0 10 20 30 40 50 60 70 800

20

40

60

80

100

PBS

188Re-18B7, 100 Ci

188Re-MOPC21, 100 Ci

188Re-18B7, 50 Ci

188Re-18B7, 200 Ci

"cold" 18B7, 50 g

Days post-treatment

% s

urv

ival

b)

0 10 20 30 40 50 60 70 800

20

40

60

80

100

PBS

213Bi-18B7, 100 Ci

213Bi-MOPC21,100Ci

213Bi-18B7, 50 Ci

213Bi-18B7, 200 Ci

"cold" 18B7, 50 g

Days post-treatment

% s

urv

ival

Dadachova E. et al.

Proc. Natl. Acad. Sci. USA 100:10942, 2003.

0

20

40

60

80

100

120

15 30MAb 18B7-Bismuth-213 (µCi)

Per

ce

nta

ge

of

Met

ab

oli

c A

ctiv

ity

(492

nm

)

B3501 Biofilms

B3501 Planktonic

*

*

p<0.05

200 4000

20

40

60

80

100

120 B3501 biofilm

B3501 Planktonic

p<0.05*

*

MAb 18B7-Rhenium-188 (Ci)

Per

cen

tag

e o

f M

etab

olic

Act

ivit

y (4

92 n

m)

RIT for treatment of fungal biofilms

L.R. Martinez et al Antimicrob. Agents Chemother., 50(6):2132-2136 (2006)

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.

Radioimmunotherapy of Radioimmunotherapy of experimental bacterial experimental bacterial

infectionsinfections

0 2 4 6 8 10 12 140

20

40

60

80

100

untreated

5 ug "cold" D11

5 ug 213Bi-D11

Days post-treatment

Su

rviv

al,

%

0 2 4 6 8 10 12 140

20

40

60

80

1005 g "cold" D11213Bi-IgM213Bi-D11untreated

Days post-treatment

Su

rviv

al,

%a)

b)

RIT of S.pneumoniae infection with 213Bi-labeled antibodies in C57BL/6 mice

Dadachova E. et al Antimicrob. Agents Chemother., 48, 1624 (2004 )

Radioimmunotherapy of HIVRadioimmunotherapy of HIV

RIT EFFECTIVE IN MICE HARBORING RIT EFFECTIVE IN MICE HARBORING HIV-INFECTED HUMAN CELLSHIV-INFECTED HUMAN CELLS

MODEL: SCID mice injected intrasplenically with HIV-1 infected hPBMCs

1 10 100 1000 10000

Untreated controls

"cold" 246-D mAb

213-Bi-1418 irrel. mAb

188-Re-1418 irrel. mAb

213-Bi-246-D afterinfection

188-Re-246-D afterinfection

188-Re-246-D beforeinfection

TCID50/106 splenocytes

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 RIT of cervical tumors in nude mice with 188188Re-Re-anti-E6 antibodyanti-E6 antibody

Treated mouse Untreated mouse

315 uCi 188Re-C1P5 anti-E-6 mAb (hot)

or 30 ug unlabeled C1P5 anti-E-6 mAb (cold)

RIT of hepatocellular carcinoam in nude RIT of hepatocellular carcinoam in nude mice with mice with

188188Re-4H9 antibodyRe-4H9 antibody

X-G. Wang, et. al. PLOS One 2(10): e1114 (2007).