Compounds for targeting and imaging infection and inflammation

Details Compounds for targeting and imaging infection and inflammation Compounds for targeting and imaging infection and inflammation

2000-04-20

2002-12-10

Hartley, Michael G. (Department: 1616)

Drug, bio-affecting and body treating compositions

Radionuclide or intended radionuclide containing; adjuvant...

Attached to lymphokine, cytokine, or other secreted growth...

C424S001690, C424S009340, C424S001850, C424S001890

Reexamination Certificate

active

06491893

ABSTRACT:

BACKGROUND OF THE INVENTION
Gallium-67 (
67
Ga), which binds in vivo to the plasma protein transferring, was the first true radionuclide infection imaging agent and still is the primary radiopharmaceutical used to detect infection. However, the target-to-background ratio of this agent is relatively low compared to more recently developed agents. In addition, normal physiological accumulation of gallium in the liver, spleen, gastrointestinal tract, and kidneys makes evaluation of the abdomen difficult. There is also significant bone uptake, which can make it difficult to diagnose osteomyelitis. Gallium scans frequently require 24 to 72 hours or more of delayed imaging to make a definite diagnosis. Further,
67
Ga shows uptake in a significant number of tumors, making it less useful in detecting infection in cancer patients and less specific for injection in general.
Although exhibiting higher specificity,
111
In and
99m
Tc labeled leukocytes (granulocytes) are relatively difficult to prepare since, to avoid an immune response, the subject's own neutrophils must be harvested and labeled in vitro, prior to in vivo administration. In addition, relatively high levels of this agent has been found to accumulate in the liver, spleen and bone marrow.
Monoclonal antibodies, both whole and Fab′ fragments, have also been developed. Examples include:
123
I-anti-nonspecific cross-reacting antigen (NCA)-95 immunoglobulin (Ig) G1 antibody (NCA) (Locher JTh et al., (1986) Nucl. Med Comm 7:659-670), a
99m
Tc-anti-NCA-90 Fab′ fragment (Becker, W et al., (1992)
J. Nucl. Med
33: 1817-1825), and
99m
Tc-anti-stage-specific embryonic antigen-1 (SSEA-1) IgM antibody (Thakur, M L (1988)
J. Nucl. Med.
29: 1817-1825). High contrast imaging can be achieved by allowing a nonradiolabeled antibody to localize and clear from the circulation prior to administration of a low molecular weight, radiolabeled moiety with high affinity for the pretargeted moiety. One such method utilizes the high affinity of avidin, a cationic glycoprotein found in egg whites, for biotin, a naturally occurring vitamin. Avidin (or streptavidin) is capable of binding four biotin molecules and forming an avidin-biotin complex with a very high affinity. (Kd=10
−15
M). However, this pretargeting, “two-step” approach, requires that a subject be available to undergo multiple procedures over the course of a few days.
Despite the success of several agents for imaging infection, at least 24 hours is typically required before lesions can be visualized. From a clinical perspective, this is a serious deficiency. Safe and effective agents that rapidly localize at a site of infection or inflammation and produce a clear image are needed.
SUMMARY OF THE INVENTION
In one aspect, the invention features agents comprised of a colony stimulating factor (CSF), which specifically target sites of infection or inflammation in a subject in vivo. Preferred CSFs are selected from the group consisting of: granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte colony stimulating factor (M-CSF or CSF-1) and binding fragments thereof. For use in the invention, a CSF may be: i) purified or recombinant; ii) wildtype (natural) or a variant (mutant); iii) fully, partially or non-glycosylated; iv) a full-length protein, polypeptide or peptide; or v) human or non-human. Particularly preferred agents show a target to non-target ratio of at least about 5:1, are stable in vivo and substantially localize to target within about 18 hours after administration, more preferably within about 10 or 8 hours and optimally within about 4 hours after administration.
In one embodiment, the agent is a pharmaceutical composition comprised of a CSF and a therapeutic agent. Preferred therapeutic agents are capable of preventing the establishment of or treating a site of infection or inflammation. Examples include antimicrobial agents and antiinflammatory agents including non-steroidal and steroidal compounds. In another embodiment, the agent is an imaging agent comprised of a CSF and a label. Preferred labels are radionuclides. Particularly preferred radionuclides are selected from the group consisting of radioisotopes with physical decay characteristics ideal for &ggr;-camera and/or PET camera imaging
123
I,
99m
Tc,
18
F,
68
Ga,
62
Cu,
64
Cu,
55
Co,
111
In. The invention further features kits for use in treating or imaging a site of infection or inflammation in a subject.
In another aspect, the invention features methods for preventing or treating a site of infection or inflammation in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a colony stimulating factor and a therapeutic agent.
In a further aspect, the invention features methods for imaging a site of infection or inflammation in a subject, comprising administering to the subject a diagnostically effective amount of a composition comprising a colony stimulating factor and a therapeutic agent.
The diagnostic agents of the invention rapidly localize at sites of infection or inflammation. In addition, the agents exhibit a relatively high target-to-background ratio and rapid clearance from the background and the target, particularly when administered as a bolus intravenously. Further, clinical pharmacokinetic studies indicate that administration of colony stimulating factors in an amount effective for targeting would be relatively safe.
Other features and advantages of the invention will be apparent from the following detailed description and claims.


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Gough et al.; “Mutagenesis of Murine Granulocyte/Macrophage-Colony-Stimulating Factor Reveals Critical Residue Near the N Terminus”, Euro. J. Biochem. 169: 353-358 (1987).
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