Patent Number: 052757897
Section: summary

FIELD OF THE INVENTION The present invention relates to the preparation and use of molecules carrying attached thereon radiolabeled species. DESCRIPTION OF THE PRIOR ART The use of radiolabeled therapeutic and diagnostic agents has recently received renewed interest. The development of monoclonal antibodies of high avidity and specificity has encouraged the development of new agents for diagnostic and therapeutic treatment of cancer. These radiolabeled monoclonal antibodies, ligands, unsaturated fatty acids and other compounds are finding clinical applications both in vitro (for example in radioimmunoassay systems) and in vivo (for example in diagnostic imaging, radiotherapy and other novel techniques such as radioimmunoguided surgery). Bifunctional chelates are being utilized to radiolabel the above mentioned biomolecules, e.g., antibodies and other agents with Y.sup.90, In.sup.111 , Re.sup.186, Ga.sup.67 etc., for diagnostic and therapeutic purpose, however, I.sup.125, I.sup.131 and I.sup.123 remain the radioisotopes of choice for use with the method and apparatus of this invention. Several remote or semiautomatic radiolabelling, specifically radioiodination, systems have been described (see for example, Ferens J. M., Krohn K. A., Beaumier P. L. et al., High-level iodination of monoclonal antibody fragments for radiotherapy. J Nucl Med 1984;25:367-70; or James S. F. W., Fairweather D. S. L. , Bradwell A. R., A shielded sterile apparatus for iodinating proteins, Med Lab Sci 1983;40:67-8; or Henville A. Jenkin G., A simple and cheap remotely operated system for the iodination of proteins, Anal Biochem 1973;52:336-41). These systems are dependent on gel filtration columns to separate bound from free isotope and in line pumps to propel reagents from one vessel to another. Such systems are prone to leakage, difficult to shield, and require decontamination after use. Other shieldable, disposable and relatively cheap systems are reported (see for example, Weadock K. S., Anderson L. L. , Kassis A. I., A simple remote system for the high-level radioiodination of monoclonal antibodies; J Nuc Med All Sci 1989;33:37-41, or James Watson S. F., Fairweather D. S. , Bradwell A. R., A shielded, sterile apparatus for iodinating proteins, Med Lab Sci 1983;40:67-68.) but these systems are complex to use requiring manipulation of valves and positioning of needles. These systems are inherently less reliable for iodinating since the result will depend on the mechanics of vial coating and the timing of the iodination and purification reactions. These systems are also more difficult to shield than the present invention because there are multiple vials to shield (apparatus is spread out) and a lead wall is also required. Another technique is the `single vial technique` described in U.S. Pat. No. 4,775,638. This technique, although simple looking, requires manipulations of reagents with a syringe, and the timing of incubations. The mechanics of vial coating with the iodination reagent, manipulation of reagents and timing of the reaction, contribute to reduced consistency of results. Also, it would be difficult to safely shield the user from the radiation field emanating from the syringe utilized in this method, especially when preparing therapeutic doses of I.sup.131 labeled agents. A similar technique to the `single vial technique` described above is the Iodo-Bead.TM. method of Pierce Chemical. This method is essentially identical to the `single vial technique` except that instead of coating the reaction vial with oxidant, one or more Iodo-Beads.TM. are added to the reaction vial. The same concerns for reagent manipulation, timing of incubation and shielding apply to this technique. In addition, the Iodo-Bead.TM. has a polystyrene base which will absorb oxidized iodine from the reaction mixture and thus reduce the percent incorporation of iodine into the agent of interest. Radioiodinated monoclonal antibodies and other radiolabelled compounds may soon serve as standard diagnostic and therapeutic tools in clinical oncology. When preparing these agents, the integrity of the agent must be maintained while minimizing personnel exposure to radioactivity, including direct exposure to radiation and internal exposure to the thyroid. Thyroid uptake of radioiodine can easily result if elemental radioiodine generated in the labeling process is not contained. The ability to prepare these agents in a consistent manner, including specific activity, yield and purity will be useful in evaluating potential therapies. Simplification of the radiolabeling process will allow widespread use of the new therapies as they become available. SUMMARY OF THE INVENTION Many of the disadvantages of the prior art methods and apparatus are alleviated by this invention. According to the invention, a method of labelling materials with a radioisotope comprises the steps of providing a sealed column having an inlet end and an outlet end, the column being packed with sequential stages of (a) beads coated with an oxidizing reagent for coupling the radioisotopes to the biomolecule, (b) an anion exchange resin, and (c) a material for trapping elemental radioisotope, and flowing a mixture of the radioisotope and a solution of the material to be labelled through the column, and collecting the purified product at the effluent side of the device. The radiolabeling reaction (incorporation of radiolabel into the functional material) and the purification reaction (removal of unincorporated radiolabel from the radiolabeled material) occur as the reaction mixture flows through the column. In addition, all unincorporated radiolabel is contained and trapped within the column, thus, reducing the quantity of radioactive waste generated and eliminating the need to handle this waste. In a preferred embodiment of the invention, the mixture is flowed through a device, typically a column, as described. This method is particularly suited for labeling monoclonal and polyclonal antibodies for use in radioimmunoguided surgery, radiotherapy and diagnostic imaging. Consistent radiolabeled antibody yields and purity are obtained when utilizing this method without releasing volatile radioiodine. Higher yields of radiolabeled antibody are obtained when using the device compared to other methods. The apparatus used in the method is easily shielded and can be operated remotely if a pump such as a peristaltic pump is utilized to flow the reaction mixture through the column. Radiolabeling by this method is rapid and easy and does not generate radioactive waste except for that contained within the device itself. The invention also includes an apparatus for labelling materials with a radioisotope comprising a sealed column having an inlet and an outlet, the column being packed with, in the order named, (a) beads coated with an oxidizing reagent for coupling the radioisotope to the material, (b) an anion resin, and (c) a material for trapping elemental radioisotope, whereby when a radioisotope and a buffer solution of the material are passed through the column, the radioisotope becomes reactively coupled to the material. In a preferred embodiment of the invention, the beads of (a) are coated with an iodination reagent. Further the material for trapping elemental radioisotope is chloromethylated styrene resin. Additional material for trapping elemental isotope may be placed at the inlet end of the column. Finally, filters may be placed at the inlet ends and outlet ends of the column between beads (a) and (b). This particular apparatus has many advantages over similar devices of the prior art. For one, the higher surface area of the glass beads coated with an oxidizing agent enhances the reaction kinetics of the operation. The apparatus permits a more efficient conversion of the radiolabel to labelled materials. Virtually all the radioactivity is contained in one vessel and requires no valves or connectors. After use, the ends of the apparatus can be sealed and its entire contents remain self-contained for safe disposal. Exposure of the operator's hands to the radioactivity is not significant. The approaches of the prior art require significant hand manipulation of syringes or bottles thus making the possibility of radiation exposure to the hand a real concern. Finally, the apparatus of the invention permits higher specific activity of the labelled materials.