Monoclonal antibody-based imaging agents have long held the insidetrack in the race to develop targeted radiopharmaceuticals fornuclear medicine. That position is being challenged by peptide-basedimaging agents, which are potentially cheaper and easier
Monoclonal antibody-based imaging agents have long held the insidetrack in the race to develop targeted radiopharmaceuticals fornuclear medicine. That position is being challenged by peptide-basedimaging agents, which are potentially cheaper and easier to manufacturethan monoclonals. Some nuclear medicine physicians say peptidescould make monoclonals obsolete before many monoclonal-based agentseven hit the market.
The progress peptides have made in becoming a viable alternativeto monoclonal antibodies was evident at this month's Society ofNuclear Medicine meeting in Toronto. A number of scientific presentationswere made on the use of radiolabeled peptides, and one peptidedeveloper held a media briefing on the topic.
In addition, only weeks before the meeting a Food and DrugAdministration advisory committee recommended for approval a Mallinckrodtproduct that, if approved, would be the first peptide-based imagingagent (SCAN 6/16/93).
Cytogen's OncoScint is the first and only monoclonal antibodyto win FDA approval, granted late last year (SCAN 1/27/93). Becauseof the novelty of monoclonal antibodies, Cytogen struggled toget its product through the agency.
OncoScint's product license application (PLA) was scrutinizedby the FDA, which signed off on OncoScint three years after thePrinceton, NJ-based company filed for approval. Even after OncoScintwon the FDA's imprimatur, the product encountered difficulty witha handful of state radiation control agencies that refused toallow physicians to use the product due to a regulatory technicality(see story, page 2).
Cytogen must also overcome concerns in the nuclear medicinecommunity related to the high price of OncoScint, which adds about$800 to the cost of a nuclear medicine exam. In addition, thecommunity has reservations about human anti-mouse antibodies (HAMA),which are produced by patients who receive monoclonal antibodiescreated in mice. HAMA can reduce the effectiveness of subsequentmonoclonal exams.
Developers of peptide-based imaging agents are hoping to avoidsuch headaches. They aim to undercut monoclonals by offering atargeted imaging agent that they claim is cheaper, easier to useand more effective than monoclonals.
A peptide is the portion of an amino acid molecule that naturallybinds with ligand receptors on cells. Because peptides are muchsmaller than monoclonal antibodies, they have a number of propertiesbeneficial to medical imaging.
For example, peptides clear from the body quicker than monoclonals,thus providing images with better signal-to-noise ratios. Becausethey are not genetically engineered, peptides also avoid contaminationproblems that can occur during the manufacture of monoclonals.Nor is HAMA an issue with peptide imaging.
The small size of peptides initially presented an obstacleto companies seeking to develop them as imaging agents. For sometime it was thought that peptides were too small to carry theweight of a heavy radioisotope such as technetium or indium, accordingto Edward Deutsch, vice president of imaging research and developmentfor Mallinckrodt Medical of St. Louis.
"The mantra in nuclear medicine up until about two orthree years ago was that you needed something big like a monoclonalantibody to put a technetium or indium metal on," Deutschsaid. "The technetium was so big itself that if you triedto (link it) with a small molecule you'd just destroy the biologicalfunction of the small molecule."
But technological breakthroughs at Mallinckrodt and other pharmaceuticalcompanies have resulted in synthesized peptides that are ableto carry heavy radioisotopes yet still perform their biologicalfunction of binding to receptor sites. Like monoclonals, peptidesalso have the potential to be used as therapy agents, carryingpayloads of cancer-killing radioactivity to tumors.
Mallinckrodt's peptide agent is called OctreoScan. OctreoScanis based on a synthetic derivative of the peptide somatostatinproduced by Sandoz of Switzerland. The peptide is linked to theradioisotope indium-111, and when introduced into the body, theentire package binds to receptor sites produced by tumor cells.
An FDA advisory committee recommended OctreoScan for approvallast month for use in the detection and localization of tumorsoriginating from neuroendocrine cells. Mallinckrodt is hopingfor final FDA approval of the agent by the end of this year, accordingto Deutsch.
ANOTHER COMPANY, Diatech of Londonderry, NH, is also moving forwardwith peptide-based imaging agents. Diatech has four products inthe development pipeline, all of which are technetium-99m-labeledagents. The company reported at the SNM meeting that two of itsagents have begun clinical trials--one for imaging thrombi andone for atherosclerosis.
Using technetium rather than higher-priced indium allows Diatechto reduce the cost of peptide-based agents even further, accordingto the company. Diatech's peptide agents will probably cost about$200 a dose, one-fourth the cost of OncoScint.
Diatech's president and CEO, Richard T. Dean, worked with monoclonalantibodies at both Mallinckrodt and Centocor. Centocor recentlywithdrew PLAs for two monoclonal imaging agents, Myoscint andFibriscint, because of deficiencies in the applications discoveredby an independent auditor contracted by the company.
Peptides could give the star-crossed monoclonal antibody imagingindustry its greatest challenge yet, Dean said.
"I think you will see some of the monoclonals in developmentapproved, but by and large peptides will come in as a new waveand take the predominant share of growth in the market,"Dean said.
That sentiment is echoed by Dr. Carol S. Marcus, director ofthe nuclear medicine outpatient clinic at Harbor-UCLA MedicalCenter in Torrance, CA.
"Anything an antibody can do, a peptide can do better,"Marcus said. "It's cheaper to buy, cheaper to make and cheaperto use. It will make antibodies a flash in the pan."
Monoclonal companies, however, are betting that there is roomin nuclear medicine for two types of targeted agents. For itspart, Cytogen is also developing peptide-based agents, accordingto James H. Geddes, group vice president of sales and marketingfor Cytogen.
In any event, OncoScint has the market to itself until a peptidethat can image colorectal and ovarian cancer is approved.
"We have an active peptide program at Cytogen that wesee as having the potential to either complement our monoclonalantibody technology that we have in place, or even replace itin certain circumstances," Geddes said. "But right now,for OncoScint colorectal and ovarian, I don't see peptides asbeing a threat."
Stark's legislation would ban all self-referrals regardlessof the payer, effective Dec. 31, 1994. The budget plan will nowbe sent to a conference committee to iron out differences betweenversions passed by the Senate and House of Representatives. Theself-referral language is identical in both versions of the package,according to an aide to Stark.
The firm's leasing agreement is contingent upon completionof negotiations still under way to restructure payment of itssenior subordinated notes. ASHS operates predominantly high-fieldGE Signa MRI systems.