National Institutes of Health, Public Health Service, HHS.
The technology describes the composition of several 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and diethylenetriaminepentaacetic acid (DTPA) compounds, their synthesis, metal complexes, conjugates, and their application in diagnostic imaging and radioimmunotherapy.
Monoclonal antibodies (mAbs) have been employed as targeting biomolecules for the delivery of radionuclides into tumor cells in radioimmunotherapy (RIT). Numerous clinical trials have been performed to validate this modality of cancer therapy.
While one critical variable that influences the effectiveness of RIT is the choice of the radionuclide and its Start Printed Page 54275associated emission characteristics, an equally important aspect is the choice of the chemical means by which the radionuclide is bound to the protein. For RIT applications, radioisotopes such as90 Y (Yttium-90) or177 Lu (Lutetium-177) must be linked as a metal complex to a monoclonal antibody (mAb) or immunoprotein via a suitable bifunctional chelating agent, wherein that complex must be thermodynamically and kinetically stable to minimize release of the isotope in order to minimize toxicity in vivo. Compounds that can easily conjugate as metal complexes, and are stable to an extent in vivo are needed for new imaging diagnostics and radiotherapy technologies.
In general, DOTA conjugated to mAbs display relatively slow and inefficient radiolabeling with Y(III) isotopes under mild conditions. This is contrary to the rapid and high-yield radiolabeling (>90%) of mAbs conjugated with bifunctional derivatives of the acyclic chelating agent DTPA.
Since the release of the radiometal from the chelate is a potential source of radiotoxic effects to non-tumor cells and normal tissue, a chelate that forms a kinetically inert complex with the radiometal is critical for successful targeted radiotherapy. Additionally, compounds having complex stability comparable to that of DOTA and complexation kinetics characteristics of DTPA are desirable for effective conjugation and in vivo efficacy.
This technology family describes the synthesis of several DOTA and DTPA based compounds. The technology family consists of three different types of compounds: (1) Backbone-substituted DOTA compounds, metal complexes, and conjugates (2) two protected variants of the 2-(4-isothiocyanatobenzyl)-6-methyldiethylenetriamine pentaacetic acid (1B4M-DTPA), (3) a protected active ester variant of the CHX-A″ DTPA and (4) Substituted 1,4,7-triazacyclononane-N,N′,N″-triacetic acid (NOTA) compounds with a pendant donor amino group, metal complexes, having the properties of both DOTA and DTPA.
More specifically, the NOTA compounds are substituted 1,4,7-triazacyclononane-N,N′,N″-triacetic acid compounds with a pendant donor amino group. These compounds possess the same octadentate coordinating groups as DOTA and DTPA; however, these compounds have a combined macrocyclic and acyclic character. The macrocyclic component chosen is based upon 1,4,7-triazacyclononane-N,N′,N″-triacetic acid (“NOTA”), while the acyclic component is a pendant bis(carboxymethyl)amino donor group that is connected by an alkylene bridge that is optionally substituted with an aralkyl group. The cooperative binding of the pendant donor groups coupled with the pre-organization and macrocyclic effect of the NOTA sub-structure accelerates complexation with metal ions and isotopes (e.g., Y(III), Gd (III)) while maintaining a high level of stability of the complexes.
The 1B4M-DTPA and the CHX-A″ molecules were synthesized for the following uses: (1) Use in the introduction of the chelator to the N-terminus of peptides, aptamers, PNA, wherein deprotection or cleavage from resin or solid phase support of the product is possible and (2) introduction of the chelator to macromolecular structures such as dendrimer wherein this is accomplished in organic solvents eliminating the gross inefficiency of the prior aqueous methods.
The compounds described in the present technology have several applications. All the compounds are useful in the conjugation of nearly all peptides, and antibodies for targeting antigens/peptides associated with cancers. Additionally, the compounds are useful for modification of macromolecules such as dendrimer, carbon tubes, etc., for labeling with radioactive metal ions suitable for imaging and/or therapy and paramagnetics for magnetic resonance imaging (MRI).
Competitive Advantage of Our Technology
It is estimated that the demand for medical imaging products will expand 3.9 percent annually to $15 billion in 2010. The market for contrast media, radiopharmaceuticals, and other consumables and accessories will total $4.6 billion in 2010. Radiopharmaceuticals will provide the best growth opportunities as advances in biotechnology and nanotechnology expand the availability of safe and effective compounds and extend the range of diseases and disorders that can be studied through nuclear medicine. Additionally, the market of the contrast reagents and media used in radiopharmaceuticals will also see a rise in demand.
Our technologies have several advantages over the existing reagents used as contrast agents and in metal complexes. (1) The chemistry is very flexible and provides the basis for an extensive list of conjugation functional groups to be introduced; (2) The elimination of aqueous chemistry steps in synthesizing the 1B4M-DTPA molecules obviates the possibilities of contamination by spurious metals that could compromise subsequent radiolabeling; (3) Furthermore, the elimination of aqueous steps aids in the introduction of paramagnetic ions such as Gd(III) for MRI applications. (4) The DOTA derivatives are very stable in vivo; (5) The NOTA derivatives have improved stability, and faster kinetics of conjugation than either DOTA or DTPA; and (6) The general synthesis process provides a procedure for preparing dendrimer-based MR agents with higher yields and efficiency while enhancing versatility.
This technology consists of the following patents and patent applications:
1. U.S. Patent Application Serial No. 10/525,673 filed April 18, 2005, entitled “Backbone-Substituted Bifunctional Dota Ligands, Complexes And Compositions Thereof, And Methods Of Using Same” [pub.# 20060165600];
2. U.S. Patent Serial No. 7,163,935 issued January 16, 2007 entitled “Scorpionate-Like Pendant Macrocyclic Ligands, Complexes And Compositions Thereof, And Methods Of Using Same”;
3. U.S. Patent Serial No. 7,081,452 issued July 25, 2006 entitled “Scorpionate-Like Pendant Macrocyclic Ligands, Complexes And Compositions Thereof, And Methods Of Using Same”; and
4. U.S. Provisional Patent Application 60/864,503 filed November 06, 2006 entitled “Method Of Preparing Macromolecular Contrast Agents And Uses Thereof”.
5. PCT/US2005/028125 filed August 9, 2005 entitled “Metal Chelators And Methods Of Their Use”.
Next Step: Teleconference
There will be a teleconference where the principal investigator will explain this technology. Licensing and collaborative research opportunities will also be discussed. If you are interested in participating in this teleconference please call or e-mail Mojdeh Bahar; (301) 435-2950; firstname.lastname@example.org. OTT will then e-mail you the date, time and number for the teleconference.Start Signature
Dated: September 14, 2007.
Steven M. Ferguson,
Director, Division of Technology Development and Transfer, Office of Technology Transfer, National Institutes of Health.
[FR Doc. E7-18771 Filed 9-21-07; 8:45 am]
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