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(12) Patent Application Publication (10) Pub. No.: US 2005/0013775 A1 Kotov (43) Pub US 2005OO13775A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0013775 A1 Kotov (43) Pub. Date: Jan. 20, 2005 (54) BIOCONJUGATES OF NANOPARTICLES AS (60) Provisional application No. 60/208,631, filed on Jun. RADIOPHARMACEUTICALS 1, 2000. (76) Inventor: Nicholas A. Kotov, Superior, MI (US) Publication Classification Correspondence Address: (51) Int. Cl. ................................................. A61K 51/00 FELLERS SNDER BLANKENSHIP (52) U.S. Cl. ............................................................. 424/1.11 BALEY & TIPPENS THE KENNEDY BUILDING (57) ABSTRACT 321 SOUTH BOSTON SUTE 800 Abioconjugate including a nanoparticle covalently linked to TULSA, OK 74103-3318 (US) a biological vector molecule. The nanoparticle is a generally radioactive metal ion and most typically a metal Sulfide or (21) Appl. No.: 10/774,332 metal oxide. The biological vector molecule is typically a monoclonal antibody or fragment of a monoclonal antibody (22) Filed: Feb. 6, 2004 or a peptide having a known affinity to cancer cells. One or more additional, different biological moieties may be covalently linked to the nanoparticle in addition to the Related U.S. Application Data biological vector molecule to enhance its activity. The bioconjugate of the present invention has utility as an (63) Continuation-in-part of application No. 09/871,166, effective radiopharmaceutical to deliver a radiolabel in filed on May 31, 2001, now Pat. No. 6,689,338. tumor treatment. Patent Application Publication Jan. 20, 2005 Sheet 1 of 3 US 2005/0013775 A1 us 5 S s5 '. 9 5 O - G on I Q O (N r O S 2. N \ y 6 - Patent Application Publication Jan. 20, 2005 Sheet 2 of 3 US 2005/0013775 A1 Lys-NH2 Fig. 2 Patent Application Publication Jan. 20, 2005 Sheet 3 of 3 US 2005/0013775 A1 5 Z C) N N 9. US 2005/0013775 A1 Jan. 20, 2005 BIOCONJUGATES OF NANOPARTICLES AS dride (DTPA), (diethylenetriaminetetraacetic acid (DTTA), RADIOPHARMACEUTICALS (1,4,7,10-tetraazacyclododecane-N,N=N=>.N=>=-tetraace tic acid) (DOTA), ethylenediaminetetra(methylene phos CROSS REFERENCE TO RELATED phonate) (EDTMP), 1, 1-hydroxyethylidine diphosphonate APPLICATIONS (HEDP) and derivatives thereof. For preparation of conju gated Structures they are frequently functionalized in one of 0001. This invention is a continuation-in-part of copend the side chains by -CH-NCS or other groups to form a ing U.S. patent application Ser. No. 09/871,166 filed May covalent bond with proteins. 31, 2001, which claims the benefit of U.S. Provisional Application Ser. No. 60/208,631 filed Jun. 1, 2000. 0009 Entrapment of metal ion into a framework of muldidentate poly (amino carboxylates) such as DOTA, STATEMENT REGARDING FEDERALLY DTPA covalently attached to mAbs has been proven to SPONSORED RESEARCH provide thermodynamically stable compounds Suitable for clinical trials. Nevertheless, results obtained for human 0002 The development of the subject matter of this patients and for animal models indicate that the applicability application was partially Supported by a grant from the of these compounds is limited by the high level of radioac National Science Foundation (NSF-EDS-9876265). Accord tivity in blood, bone marrow, kidney and liver. This neces ingly, the U.S. government may have rights in this invention. sitates reduction of in Vivo decomplexation of metal ions and strengthening radiolabel-mAb bond. BACKGROUND OF THE INVENTION 0010. The tumor uptake and overall biodistribution of the 0003) 1. Field of the Invention radiolabeled compound depends on the metabolism of the mAb and the strength of radionuclide-antibody link. 0004. This invention relates generally to the effective Although there is a Substantial room for improving targeting diagnosis and treatment of cancer patients and, more Spe properties of mAbs, all Studies indicate that the thermody cifically, to radiopharmaceuticals for use in connection with namic and kinetic stability of the chelate in vivo of is of radioimmunotherapy and radioimmunodection. primary importance for the design of clinically Successful 0005 2. Background: radiochemicals. 0006 Effective treatment of cancer patients by using 0011. The equilibrium constant of chelation for the best radioimmunotherapy (RAIT) and diagnostics of malignant chelates used in RAIT and RAID is comparable to that for tumors by radioimmunodetection (RAID) requires drastic Some proteins present in blood. Therefore, chelates are improvement of tumor-to-background (T/B) distribution of inherently prone to Slow exchange of radioactivity with a radiolabel. T/B ratio is the principal parameter that deter tumor-indifferent proteins. When radiopharmaceuticals are mines tumoricidal action, Sensitivity of tumor detection and, administered intravenously, they encounter endogenous most importantly, Systemic toxicity of the compound. Radio metal-binding proteins Such as albumin in concentrations active isotopes of metals are used very often in various 100-1000-fold greater than that of the radiopharmaceutical. modalities of RAIT and RAID in the form of conjugates LOSS of radiometal to Serum proteins leads to accumulation with monoclonal antibodies (mAbs). of radioactivity in normal tissues, especially liver, Spleen, and kidney, reducing the radioactivity available for tumor 0007 Attachment of the radioisotope to the targeting uptake. Stability of the radioimmunoconjugate is a critically molecule is the most important part of the preparation of the important factor in determining its usefulneSS for in vivo radioconjugate. In Some cases, a direct approach to radio applications. This fact was experimentally established for labeling of antibodies with therapeutic radionuclides can be adopted by reducing internal disulfide bonds within the the majority of radionuclides. antibody and allowing, for example, technetium or rhenium 0012 For complexes of 'In and bleomycin, partial ions to react directly with the resultant Sulfhydryl groups. dissociation of the ion from bleomycin caused Severe bone However, labeling Strategies usually rely on the utilization marrow toxicity and increased the background Y-radiation of a multidentate ligand capable of Selective chelation of the Significantly impairing its therapeutic and imaging capabili desired radionuclide. In order to avoid the release of the ties. The tumor-to-background ratio varied from 1.0 to 2.9. metal ion in the circulation and inevitable radiation injuries Even for one of the most widely used and the strongest 'In to healthy organs, metalions must be strongly complexed by chelate with octadentate ligand DTPA (K=28.5) a high a chelating agent. liver background has been observed. Most researchers agree 0008 Ideally, the chelated nuclide would be rapidly that chelate instability is the primary reason for various excreted via the urinary tract without intracellular retention, immune mechanisms which contribute to accumulation of with intact conjugate accumulating and being retained Selec the radioactivity in non target organs. Recent Study clearly tively at the tumor site. This is however clearly not always indicate the direct dependence between the thermodynamic the case, and in Several instances, persistent and unwanted stability of various chelates (NTA, EGTA, EDTA, DTPA) retention of metallic nuclides has been reported. AS the in bound to the B72.3 antibody and the tissue distribution and Vivo behavior of a given nuclide-chelator complex cannot be accumulated activity in blood and kidney. predicted easily, the choice of potential multidentate ligands 0013) Retention of 'In in normal tissues has been the is guided by conventional chelation chemistry. Macrocyclic major limitation in RAID applications. Improved clearance multidentate ligands which provide the highest thermody of 'In from liver tissue correlated with the strength of a namic Stability of the complex are frequently used for labile linkage between the antibody and the chelator and preparation of immunoconjugates. The typical examples of with the structure of the chelator to provide for higher chelating agents are diethylenetriaminepentaacetic anhy stability under in vivo conditions. US 2005/0013775 A1 Jan. 20, 2005 0.014. The loss of metal ion in circulation greatly limits for "Te and Re without specially designed chelating the utilization of potent radionuclides with convenient agents simplifies the procedure. However, it cannot be energy and half-life characteristics such as 'Pb. The short applied for other metals and may induce conformational decay of Pb time (10.6 hours, B, 0.57 and 0.33 MeV) changes in mab or its fragments. permits rapid clearance from the System. When conjugated to specific mAb 103 A, ''Pb-DOTA chelate was very 0019 Entrapment of a metal ion into a framework of efficacious at eliminating the tumor even in mice with large multidentate complex yields a thermodynamically stable tumor burdens. However, due to lower pH values found in Structure, but quite often, is slow to form. Typically, incor cells in which catabolism occurs, 'Pb escapes the chelator poration of a radioactive ion takes >3 hours. The fast and is taken up in bone and marrow. Bone marrow toxicity forming chelates like those of EDTA, undergo rapid tran in this case was so high that accumulation of 'Pb in bones Schelation to blood proteins. Slow kinetics of metal incor was dose limiting and lethal. LOSS of the Specificity of poration decreases the overall activity of short half-life radiometal deposition was observed for "Sc, Ga, and 'Y radionuclides and necessitates removal of unbound radioac
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