Group needs corporate support for further workRadiopharmaceutical firms are not the only ones using monoclonalantibodies to develop site-specific contrast agents. A team ofphysicians and scientists representing The Jewish Hospital andthe Laboratory
Radiopharmaceutical firms are not the only ones using monoclonalantibodies to develop site-specific contrast agents. A team ofphysicians and scientists representing The Jewish Hospital andthe Laboratory for Ultrasonics of the Department of Physics atWashington University in St. Louis is developing a targetableultrasound contrast agent using monoclonal antibody technology.Dr. Gregory Lanza, a cardiology fellow affiliated with the hospital,described the novel contrast agent and discussed the results ofhis group's experiments at the American Heart Association meetingin Anaheim, CA, last November.
Clinicians have been investigating ultrasound contrast agentsfor about 25 years. Their primary goal has been to develop blood-poolcontrast agents that highlight cardiovascular anatomy and perfusionpatterns. Targeted agents represent the next step in ultrasoundcontrast technology. Sonus Pharmaceuticals of Bothell, WA, forexample, is exploring targeted agents that home in on specifictissue sites.
Lanza's group has developed an intravenous contrast agent capableof attaching itself to specific tissues, such as thrombi, tumorsand regions of atherosclerosis, and enhancing the acoustic reflectivityof those tissues. The agent is a non-gaseous, lipid-encapsulatedperfluorocarbon-based microemulsion that has a small particlesize. Its acoustic reflectivity is low in the blood stream butdramatically higher when clustered on a tissue surface, Lanzasaid.
"Our site-targeted ultrasonic contrast agent can targetand identify tissues bearing specific molecular surface markers,"Lanza said. "It is acoustically invisible in circulationyet brilliant when bound and clustered on a targeted surface.This property provides a high signal-to-noise ratio and minimizesfalse-positive diagnoses."
The group's technology is based on a three-step process. Inthe first step, a monoclonal antibody labeled with biotin, a vitamin,is injected into a patient. Several hours later, avidin, a proteinthat binds to biotin, is injected, and finally the contrast material,labeled with another layer of biotin that binds to the avidin,is administered.
The biotin-avidin-biotin combination creates a sort of sandwichthat allows the contrast material to be linked to the monoclonalantibody, which is attached to the target tissue. The group developedthe technique to avoid problems created by the fast clearanceof ultrasound contrast materials. If a single injection were used,the contrast material would clear from the body before the monoclonalantibody had a chance to collect at the target site, Lanza said.
Targeting an agent. In validating its agent, the group setout to demonstrate that the site-targeted product would in factwork with ultrasound and that it could enhance the acoustic reflectivityof a membrane surface. They reasoned that the ideal propertiesof site-targeted acoustic contrast agents would include smallparticle size, and at 250 nanometers their agent is less thanone micron in diameter. It has a long half-life as well, becauseperfluorocarbon-based agents have half-lives of several hours.The group also believed that the bound particle should providea high signal-to-noise ratio.
"The bottom line is that instead of enhancing the bloodpool and knowing where the blood goes, we wanted to be able tospecifically target a given tissue and diagnose thrombus or tumor,and perhaps things that are less obvious, such as early atherosclerosis,"Lanza said.
The researchers chose to investigate thrombus imaging becausethrombi contribute significantly to mortality and morbidity acrossa broad spectrum of clinical conditions. They reasoned that increasedsensitivity in detecting thrombus in patients with stroke, pulmonaryembolism or myocardial infarction could be beneficial.
After completing a series of in vitro experiments using clotssuspended and imaged in dialysis tubing, they used a 7.5-MHz linear-arraytransducer to image nonocclusive thrombi that had been electricallyinduced in canine femoral arteries before and after the administrationof control and site-targeted contrasts. They found that the basicreflectivity of thrombi was low without contrast, but reflectivityincreased substantially in those parts of the clot exposed tothe experimental agent.
Because the site-targeted contrast agent is a particle withunique binding capabilities, it may be possible to deposit otheragents on its surface, such as a drug or gene for therapy applications,according to Kirk Wallace, a doctoral fellow at the Laboratoryfor Ultrasonics. Gadolinium could also be attached, possibly facilitatingthe product's use for MRI as well as for ultrasound.
Formerly a research manager with Monsanto, Lanza recognizesthat commercializing the new product will take the financial strengthand clinical expertise of an industry partner that has experiencein bringing new drugs from development to Food and Drug Administrationapproval. For example, the group would probably need some kindof corporate support to begin clinical studies on humans. At present,the team does not have a company sponsor.
"To design and execute safety studies, or even all thepharmacology and optimization studies, is beyond the scope ofan academic environment," Lanza said. "We're going tohave to have someone pick this up and help us carry it forward."