Mari Manchester
Lab Overview
The ability to specifically target chemotherapies to the site of disease
such as a developing tumor, while avoiding healthy tissue, is an important
therapeutic goal. We use viruses as novel materials to enhance the potency
of drugs and to target therapies and imaging agents directly to the site of
disease. Because multivalency often allows increased potency and efficacy of
a therapy compared to the monomeric components, we also study the ability of
viruses to act as molecular platforms for multivalent display of peptides and
small molecules.
Highlight
The recent use of Bacillus anthracis (anthrax) as a bioweapon has stimulated
the search for novel antitoxins and vaccines that act rapidly and with minimal
adverse effects. B. anthracis produces an AB-type toxin, which is composed
of the receptor-binding moiety protective antigen (PA) and the enzymatic moieties
edema factor and lethal factor. PA enters cells via high-affinity interaction
with a cellular receptor ANTXR2, and in particular its integrin-like I domain.
As both the main antigen and virulence factor for B. anthracis, PA is a key
target of vaccine development, however recombinant PA is difficult to produce
and poorly immunogenic. We reasoned that multivalent display of PA might enhance
its immunogenicity. We used an icosahedral virus as a platform to display 180
copies of the ANTXR2 I-domain per virus particle. The chimeric virus-like particles
(VLPs) correctly displayed the receptor I- domain on their surface, and inhibited
lethal toxin action both in vitro and during lethal toxin challenge of rats.
VLPs complexed with multiple copies of PA elicited a potent toxin-neutralizing
antibody response that protected rats from anthrax lethal toxin challenge after
a single immunization and without adjuvant. In contrast, animals immunized
with monomeric PA showed no protection and no neutralizing antibodies. Thus
this recombinant virus-based platform represents a novel and highly effective
vaccine for anthrax. In addition, the virus-I-domain platform itself acts as
a potent antitoxin, thus yielding an agent with dual therapeutic utility.
2006 Publications
1) Lewis J.D., Destito G., Zjilstra A., Quigley J., Manchester M., Stuhlmann
H. (2006) Viral nanoparticles (VNPs) as tools for in vivo vascular imaging.
Nature Medicine,12(3):354-60.
2) Hsu, C., Singh, P., Ochoa, W., Manayani, D.,, Manchester, M., Schneemann,
A., Reddy, V. (2006) Characterization of polymorphism displayed by the coat
protein mutants of tomato bushy stunt virus. Virology. 2006 May 25;349(1):222-9
3) Singh, P., Destito, G., Schneemann, A., Manchester, M. (2006) Canine parvovirus:
a novel nanomaterial for tumor targeting. J. Nanobiotechnology,4:2.
4) Scobie, H.M., Wiglesworth, D.J., Thomas, D., Marlett J.M., Manchester, M.,
Collier, R.J., Young, J.A.T. (2006) A form of anthrax toxic protective antigen
that specifically binds anthrax toxin receptor 2 supports lethal toxin killing
in vivo. PLoS Pathogens, 2(10):e111.
5) Manchester M, Singh P. (2006) Virus-based nanoparticles (VNPs): platform
technologies for diagnostic imaging. Adv Drug Deliv Rev. 2006 Dec 1;58(14):1505-22.
6) Manchester M. (2006) Targeted therapy using virus-based nanoparticles (VNPs).
Nanomedicine. 2006 Dec;2(4):294.
7) Koudelka, K., Rae, C., Gonzalez, M.J., Manchester M. (2007) Interaction
between a 54kD mammalian cell protein and cowpea mosaic virus (CPMV). (2007)
J. Virol. 81:1632.
