WO1993021963A2 - Carboxamide modified polyamine chelators and radioactive complexes and conjugation - Google Patents
Carboxamide modified polyamine chelators and radioactive complexes and conjugation Download PDFInfo
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- WO1993021963A2 WO1993021963A2 PCT/US1993/003844 US9303844W WO9321963A2 WO 1993021963 A2 WO1993021963 A2 WO 1993021963A2 US 9303844 W US9303844 W US 9303844W WO 9321963 A2 WO9321963 A2 WO 9321963A2
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- 0 CC*C(*CC1)C2C1=*2 Chemical compound CC*C(*CC1)C2C1=*2 0.000 description 3
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
- A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
- A61K51/1093—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody conjugates with carriers being antibodies
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
- A61K51/0478—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group complexes from non-cyclic ligands, e.g. EDTA, MAG3
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
- A61K51/0482—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group chelates from cyclic ligands, e.g. DOTA
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2123/00—Preparations for testing in vivo
Definitions
- the present invention relates to novel charge-modified chelators useful to attach radioactive metal ions to tumor selective antibodies.
- Radionuclide complexes of such antibody/chelant conjugates are useful in diagnostic and/or therapeutic applications as a means of conveying the radionuclide to a cancer or tumor cell. See, for example, Meares et aI., Anal. Biochem., 124, 68-78 ( 1984); and Krejcarek et al., Biochem and Biophys. Res. Comr., 77, 581-585 (1977).
- Attachment of the metal ion to a protein such as an antibody has been achieved by compiexation by an acyclic chelate such as carboxymethylated amine derivatives of ethylenediaminetetraacetic acid (EDTA) (U.S. Patent 4,662,420) ordiethylenetriamine-pentaacetic acid (DTPA) (U.S. Patents 4,479,930 and 4,454,106), covalently linked to the antibody.
- EDTA ethylenediaminetetraacetic acid
- DTPA diethylenetriamine-pentaacetic acid
- Such acyclic complexes tend to be unstable in vivo either as a result of acid-catalyzed decomplexation or competitive chelate binding by calcium or zinc in serum.
- the lack of stability can result in uncomplexed metal atoms in the body which have a cytotoxic effect on healthy tissue (e.g., bone marrow).
- Tetraazamacrocycles which can act as bifunctional chelating agents for use in diagnosis and therapy are described in published European PatentApplicat ⁇ on 0 382 582, on August 16, 1990. At least one of the side arms emanating from an amine of the ring being a phosphinate ester The linker group being attached to a ring carbon of the
- U.S. Patent 4,994,560 discloses rhodium complexed to bifunctionai chelators containing a poiyamine, wnerein the polyamine chelating agent can be a polyazamacrocycle, where the linker group is covalentiy attached to any one of the carbon or nitrogen atoms of the polyamine.
- Such polya mines form outstandingly inert complexes with rhodium (III), but are inappropriate for the radiochelation of lanthanide (III) metal ions.
- Carboxymethylated tetraazamacrocycles have been described which are capable of forming inert complexes with copper and lanthanide metal ions and can be conjugated to antibodies [WO 87/05030, WO 89/01476 and Moi et al., J. Am Chem. Soc, 110, 6266 (1988)].
- Published PCT Application WO 89/02788 describes bifunctional chelators wherein a number of the secondary amine groups are carboxymethylated.
- the present invention provides carboxymethylated tetrazamacrocycles, wherein one or two of the carboxylates are replaced with carboxamides.
- These chelating agents are antibody conjugatable and form complexes with lanthanides and other substitutionally labile metal ions which are kinetically inert. Upon metabolism of the antibody conjugate, these chelates exhibit rapid whole body clearance, and in certain cases have unexpectedly lower propensity for uptake in bone. Lower bone uptake would be expected to result in a less toxic radiopharmaceutical.
- the chelates also rapidly form chelate-protein conjugates.
- the present invention is directed to novel bifunctional chelating agents that form complexes with metal ions, especially "radioactive" metal ions having rare earth-type chemistry.
- the complexes so formed can be covalently attached to an antibody or antibody fragment to form conjugates and used for therapeutic and/or diagnostic purposes.
- the complexes and/or conjugates can be formulated for in vivo or in vitro uses.
- a preferred use of the formulated conjugates is the treatment of cancer in animals, especially humans.
- the present invention is directed to a compound of the formula:
- each Q is independently hydrogen, (CHR 5 ) P CO 2 R; or (CHR 5 ) P C(O)N(R 6 ) 2 with the proviso that at least one Q is (CHR 5 ) p C(O)N(R 6 ) 2 ;
- R at each occurrence is independently hydrogen, benzyl or C 1 -C 4 alkyl; each R 5 independently is hydrogen, C 1 -C 4 alkyl or -(C 1 -C 2 alkyl)phenyl;
- each R 6 independently is hydrogen, C 1 -C 9 alkyl, or -(C 1 -C 2 alkyl)phenyl;
- X and Y are each independently hydrogen or may be taken with an adjacent X and Y to form an additional carbon-carbon bond to produce an alkene or alkyne;
- n 0 or 1 ;
- n is an integer from 0 to 10 inclusive
- n is only 1 when X and/or Y form an additional carbon-carbon bond, and the sum of r and w is 0 or 1 ;
- R 2 and R 4 are independently hydrogen, amino, isothiocyanato, semicarbazido, thiosemicarbazido, maleimido, bromoacetamido or carboxyl;
- R 3 is C 1 -C 4 alkoxy, -OCH 2 CO 2 H, hydroxy or hydrogen;
- R 2 and R 4 cannot both be hydrogen but one of R 2 and R 4 must be hydrogen
- alkyl means a linear or branched alkyl.
- the present invention is also directed to rare-earth type metal ion complexes, especially radioactive neutral or charged rare-earth type metal ion complexes, and to conjugates formed with the aforementioned complexes and antibody or antibody fragments.
- radioactive means a metal ion that emits particles and/or electromagnetic radiation from the nucleus.
- the use of the amide-modified side arms offers advantages over chelating agents known in the prior art which contain carboxylated side arms in that the chelating agents containing the amide-modified side arms can be conjugated to proteins, such as antibodies, under more mild conditions. The rapid formation of the conjugate is of importance in production of a radiochemical compound for therapeutic and/or diagnostic purposes
- the chelating agents of the present invention which contain one amide-modified side arm, have a lower propensity for uptake in the bone than do chelating agents known in the prior art such as 1 ,4,7,10-tetraazacyclododecane-1 ,4,7,10-tetraacetic acid and bifunctional derivatives thereof.
- the present invention also includes formulations having the conjugates of the invention and a pharmaceutically acceptable carrier, especially formulations where the pharmaceutically acceptable carrier is a liquid.
- the invention also includes a method for the diagnosis or treatment of a disease state, especially cancer, in a mammal which comprises administering to the mammal an effective amount of the formulation.
- mammal includes especially humans.
- chelating agent means a compound capable of chelating or sequestering a metal ion.
- chelate means a chelating agent which has chelated or sequestered a metal ion.
- bifunctional chelating agent means a compound that has a moiety capable of chelating a metal ion and a linker/spacer moiety covalently bonded to the chelating moiety that is capable of being activated or functionalized to serve as a means to covalently attach to a biological molecule.
- biological molecule refers to any protein, antibody, antibody fragment, hormone, antigen or hapten which functions to recognize a specific biological target site.
- a biological molecule when attached to a functionalized chelate, serves to carry the attached metal ion to specific targeted tissues.
- the biological material is an antibody or antibody fragment.
- antibody refers to any polyclonal, monoclonal, chimeric antibody or heteroantibody. preferably a monoclonal antibody.
- antibody fragment includes Fab fragments and F(ab') 2 fragments and any portion of an antibody having specificity toward a desired epitope orepitopes.
- conjugate refers to a complex of a biological material attached to a bifunctional chelating agent or bifunctional chelate.
- antibody/chelate conjugate refersto an antibody which is covalently attached to a bifunctional chelate (i.e., the bifunctional chelating agent having a chelated metal ion).
- Metals which can form complexes with the bifunctional chelating agents of the present invention include La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Y and Sc.
- Preferred radioactive rare earth-type metal ions include 153 Sm, 166 Ho, 90 Y, 149 Pm, 159 Gd, 140 La, 177 Lu, 175 Yb , 47 Sc, and 142 Pr.
- radioactive metal ions which may be of interest are 47 Sc, 99m Tc, 186 Re, 188 Re, 97 Ru, 105 Rh, 109 Pd, 197 Pt, 67 Cu, 198 Au, 199 Au, 67 Ga, 68 Ga, 111 ln, 113m In,
- radioactive refers to one or more isotopes of the rare-earth type elements that emit particles and/or photons, such as 153 Sm, 166 Ho, 90 Y, 149 Pm, 159 Gd, 140 La, 177 Lu, 175 Yb, 47 Sc, and
- salts means any salt of a compound of Formula (I) which is sufficiently non-toxic to be useful in therapy or diagnosis of mammals.
- the salts are useful in accordance with this invention.
- Representative of those salts, which are formed by standard reactions, from both organic and inorganic sources include, for example, sulfuric, hydrochloric, phosphoric, acetic, succinic, citric, lactic, maleic, fumaric, palmitic, cholic, palmoic, mucic, glutamrc, d-camphoric, glutaric, glycolic, phthaiic, tartatric, formic, laur ⁇ c, steric, alicylic, methanesulfonic, benzenesulfonic, sorbic, picric, benzoic, cinnamic acids and other suitable acids.
- salts formed by standard reactions from both organicand inorganic sources such as ammonium, alkali metal ions, alkaline earth metal ions, and other similar ions.
- Particularly preferred are the salts of the compounds of Formula (I) where the salt is chloride or the salt of an anionic buffer such as acetate, or mixtures thereof.
- Preferred compounds of Formula (I) include those compounds where X and Y are each H and r is 0 as shown by the following formula:
- each Q is independently hydrogen, (CHR 5 ) P CO 2 R; or (CHR 5 ) p C(O)N(R 6 ) 2 ; with the proviso that at least one Q is (CHR 5 ) p C(O)N(R 6 ) 2 ;
- R at each occurrence is independently hydrogen, benzyl or C 1 -C 4 alkyl; m is an integer from 0 to 5 inclusive;
- p 1 or 2;
- w O or 1 ;
- R 2 and R 4 are independently hydrogen, amino, isothiocyanato, semicarbazido, thiosemicarbazido, carboxyl, bromoacetamido or maleimido;
- R 3 is C 1 -C 4 alkoxy, -OCH 2 CO 2 H, hydroxy or hydrogen;
- each R 5 independently is hydrogen or C 1 -C 4 alkyl
- each R 6 independently is hydrogen, C 1 -C 9 alkyl, or -(C 1 -C 2 alkyl)phenyl; with the proviso that R 2 and R 4 cannot both be hydrogen but one of R 2 and R 4 must be hydrogen; or
- Formula (I) or (II)] can be used to chelate or sequester the rare-earth type metal ions, particularly radioactive rare-earth type metal ions, so as to form metal ion chelates (also referred to herein as "complexes").
- the complexes because of the presence of the rare-earth type metal ions, particularly radioactive rare-earth type metal ions, so as to form metal ion chelates (also referred to herein as "complexes").
- the complexes because of the presence of the presence of the
- functionalizing moiety [represented by "R 2 " or “R 4 " in Formula (I) or (II)], can be attached to functionalized supports, such as functionalized polymeric supports, or preferably can be covalently attached to proteins, or more specifically to antibodies or antibody fragments.
- functionalized supports such as functionalized polymeric supports
- the complexes described herein represented by either of Formula I or II complexed with rare-earth type metal ions, particularly radioactive rare-earth type metal ions
- conjuggates may be covalently attached to an antibody or antibody fragment and are referred to herein as "conjugates".
- the antibodies or antibody fragments which may be used in the conjugates described herein can be prepared by techniques well known in the art. Highly specific monoclonal antibodies can be produced by hybridization techniques well known in the art, see, for example, Kohler and Miistein [Nature, 256, 495-497 (1975); and Eur. J. Immunol., 6, 51 1-519 (1976)]. Such antibodies normally have a highly specific reactivity.
- antibodies directed against any desired antigen or hapten may be used.
- the antibodies which are used in the radioactive metal ion conjugates are monoclonal antibodies, or fragments thereof having high specificity for a desired epitope(s).
- Antibodies used in the present invention may be directed against, for example, tumors, bacteria, fungi, viruses, parasites, mycoplasma, differentiation and other cell membrane antigens, pathogen surface antigens, toxins, enzymes, allergens, drugs and any biologically active molecules-
- Some examples of antibodies or antibody fragments are CC-11, CC-46, CC-49, CC-49 F(ab') 2, CC-83, CC-83 F(ab') 2, and B72.3. [See D. Colcher et al., Cancer Res., 48, 4597-4603 (Aug. 15, 1988) for CC-49, CC-83 and B72.3 antibodies.
- the hybridoma cell line B72.3 is deposited in the American Type Culture Collection (ATCC) having the accession number HB 8108.
- ATCC American Type Culture Collection
- the various CC antibodies are disclosed in published PCT Application WO 89/00692, on January 26, 1989 and published PCT Application WO 90/04410, on May 3, 1990.
- the other rnurine monoclonal antibodies bind to epitopes of TAG-72, a tumor associated antigen.
- a more complete list of antigens can be found in U.S. Patent 4,193,983, which is incorporated herein by reference.
- the radioactive metal ion conjugates of the present invention are particularly preferred for the diagnosis and treatment of various cancers.
- the metal ion can be complexed with the chelating agent or bifunctional chelating agent by adding the chelating agent or bifunctional chelating agent to a solution of the radionuclide.
- Chelates form readily upon mixing in an aqueous solution at a pH of 1 to 10.
- the reaction is carried out in a medium having a pH of 5 to 7.
- Ambient temperatures of 20°C to 27°C can be readily employed for metal ion chelation.
- the amount of metal ion employed may be from trace amounts to an amount exceeding equi molar with the chelate.
- the conjugates of the present invention are preferably prepared by first forming the chelate and then binding the antibody or antibody fragment.
- the process involves preparing or obtaining the iigand, forming the complex with the metal and then adding the antibody.
- a process for making labeled antibody conjugates can involve first conjugation of the bifunctional chelator to the antibody and its subsequent chelation to yield the radionuclide-BFC labeled antibody. Any suitable process that results in the formation of the conjugates of this invention is within the scope of this invention.
- the chelating agents of the present invention containing the amide-modified side arms have been found to conjugate with antibodies under mild conditions more rapidly than chelating agents containing only carboxylated side arms. The rapid conjugation is advantageous in producing radiochemical conjugates for therapeutic and/or diagnostic purposes in that a shortened conjugation time reduces the amount of radiolysis and reduces formation of by-products, such as antibody aggregates and chelate degradation products.
- the conjugates of this invention may be employed as a formulation.
- the formulation comprises a compound of Formula (I) with the antibody and/or metal ion and a physiologically-acceptable carrier, excipient or vehicle therefor.
- the formulation may consist of a physiologically-acceptable carrier with a complex (metal ion + ligand), conjugate (metal ion + ligand + antibody) or (ligand + antibody).
- the methods for preparing such formulations are well known.
- the formulation may be in the form of a suspension, injectable solution or other suitable pharmaceutical formulation. Physiologically-acceptable suspending media, with or without adjuvants, may be used.
- the formulations of the present invention are in the solid or liquid form containing the active radionuclide complexed with the ligand.
- These formulations may be in kit form such that the two components (i.e., ligand and metal, complex and antibody, or ligand/antibody and metal) are mixed at the appropriate time prior to use. Whether premixed or as a kit, the formulations usually require a pharmaceutically-acceptable carrier.
- compositions of the present invention may be either in suspension or solution form.
- suitable formulations it will be recognized that, in general, the water-solubility of the salt is greater than the acid form.
- the complex (or when desired the separate components) is dissolved in a physiologically-acceptable carrier.
- suitable solvent include, for example, water, aqueous alcohols, glycols, and phosphonate or carbonate esters.
- aqueous solutions contain no more than
- Injectable suspensions are compositions of the present invention that require a liquid suspending medium, with or without adjuvants, as a carrier.
- the suspending medium can be, for example, aqueous polyvinylpyrrolidone, inert oils such as vegetable oils or highly refined mineral oils, or aqueous carboxymethylcellulose.
- Physiologically-acceptable adjuvants if necessary to keep the complex in suspension, may be chosen from among thickeners such as carboxymethylcellulose, polyvinylpyrrolidone, gelatin, and the alginates.
- surfactants are also useful as suspending agents, for example, lecithin, alkylphenol, polyethylene oxide adducts, napthalenesulfonates, alkyl benzenesulfonates, and the polyoxyethylene sorbitan esters.
- suspending agents for example, lecithin, alkylphenol, polyethylene oxide adducts, napthalenesulfonates, alkyl benzenesulfonates, and the polyoxyethylene sorbitan esters.
- Many substances which effect the hydro-philicity, density, and surface tension of the liquid suspension medium can assist in making injectable suspensions in individual cases.
- silicone antifoams, sorbitol, and sugars are all useful suspending agents.
- an "effective amount" of the formulation is used for therapy.
- the dose will vary depending on the disease being treated.
- in vitro diagnostics can be performed with the formulations of this invention, in vivo diagnostics are also contemplated.
- the conjugates and formulations of this invention can also be used in radioimmuno-guided surgery (RIGS); however, other metals which could be used forthis purpose also include 99mTc, 1 11 ln, 1 13 mIn, 67 Ga and 68 Ga.
- chelants of the present invention may include magnetic resonance imaging, e.g., the complexes of Formula l, especially complexes of Formula VI, with Gd +3, attachment to polymeric supports for various purposes, e.g., as diagnostic agents, and removal of lanthanide metal or pseudo-lanthanide metal ion by selective extraction.
- the process involves reacting a polyazamacrocycle with between about one to three equivalents of an appropriate electroph ⁇ le (e.g., any appropriately substituted ⁇ -halocarboxylicac ⁇ d ester) in a solvent which will notpromote a proton transfer to produce a mono-N-functional polyazamacrocycle, as disclosed in U.S. Patent 5,064,956, the disclosure of which is hereby incorporated by reference.
- an appropriate electroph ⁇ le e.g., any appropriately substituted ⁇ -halocarboxylicac ⁇ d ester
- substituted ⁇ -haioacid esters used as starting materials, is well known in the art.
- One approach involves brominat ⁇ on or chiorination of the acid halide generated insitu, e.g., D.N. Harpp et al., J. Org. Chem., 40, 3420-27 (1975).
- This approach allows for exclusive alpha-halogenation of alkanoic acids which may contain reactive benzylic groups.
- a general method to substitute acid halides involves reaction of the organic acid with thionyl chloride or sulfuryl chloride, e.g., E. Schwenk et al., J. Amer. Chem Soc, 70, 3626-27 (1944). Both methods utilize the free carboxylic acid which is frequently available from commercial sources.
- Polyazamacrocycles such as 1,4,7,10-tetraazacyclododecane may be prepared by methods known in the art, such as,T.J. Richman et al., Org. Synthesis, 58, 86-98 (1978).
- Carboxyfation of the mono-N-functional macrocycle maybe performed by the method of Desreux using bromoacetic acid derivatives and a suitable base [J.F. Desreux, Inorg. Chem., 19, 1319-24 (1980)].
- Benzyl, or preferentiallyt-butyl ester of bromoacetic acid should be employed since purification of the resulting ester containing product is straightforward using silica gel chromatography. Importantly, removal of the labile ester group after purification is effected by hydrolysis with mineral acid (aqueous hydrochloride at 30° to 40°C) under mild reaction conditions which preserves the amide functional group. Surprisingly, the analogous methyl ester of 5 could not be hydrolyzed without loss of the amide group.
- the addition of the amide side arm to the polyazamacrocycle may be done by reacting an ⁇ -haloamide with the polyazamacrocycle in a suitable organic solvent, such as chloroform.
- a suitable organic solvent such as chloroform.
- the procedures for preparing an ⁇ -haloamide typically involves reacting a primary or secondary amine with an ⁇ -haloacid halide and are well known in the art.
- Radionuclides can be produced in several ways. In a nuclear reactor a nuclide is bombarded with neutrons to obtain a radionuclide, e.g.,
- Another method of obtaining radionuclides is to bombard nuclides with particles in a linear accelerator or a cyclotron. Yet another way is to isolate the radionuclide from a mixture of fission products.
- the method of obtaining the nuclides employed in the present invention is not critical thereto.
- DTPA diethylenetriaminepentaacetic acid
- PA-DODADA 1,4,7,10-tetraaza-1-N-(1-carboxy-3-(4-aminophenyl)propyl)-7-N-(1-carboxymethyl)-bis-4,10-N,N-(carboxamidomethyl)cyclododecane
- PA-DOTA 1-[2-(4-aminophenyl) ethyl]-1 ,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid
- PA-DOTAMA 1,4,7,10-tetraaza-1-N-(carboxy-3-(4-nitrophenyl)propyl)
- PBS phosphate buffered saline (containing 120 mM NaCI, 2.7 mM KCI, and
- Mass spectra were obtained on a VG ZAB-MS high resolution mass spectrometer (Positive Ion Fast Atom Bombardment with Xenon using a matrix of
- R f values are reported using these solvent systems and commercially available Analtech silica plates (250 micron, Analtech Inc.).
- the mixture was filtered to remove dicyclohexylurea and the resulting solution was extracted with 2 ⁇ 150 mL portions of water, 2 X 150 mL portions of 5 percent aqueous acetic acid, and 2 X 150 mL portions of water.
- the organic phase was dried over magnesium sulfate, filtered and the solvent was removed.
- Example B Synthesis of 1 ,4,7,10-Tetraaza-1-N-(1-Carbo-t-Butoxy-3-(4-Nitrophenyl)Propyl)
- Example C Synthesis of 1,4,7,10-Tetraaza-1-N-(1-Carbo-t-Butoxy-3-(4-Nitrophenyl)Propyl)- Bis-4,7,-N,N-(Carbo-t-Butoxymethyl)Cyclododecane, Monohydrobromide Salt (Compound 4)
- the chloroform was evaporated from the chloroform solution of 5 and the remaining light-yellow glassy solid was dissolved in 10 mL of 70 percent ethanol in water.
- Palladium on carbon catalyst 100 mg, 10 percent Pd on carbon from Lancaster Synthesis Ltd.
- the solution was filtered through a short pad of celite and the solvent was evaporated to provide the corresponding amino compound 5b as a white, glassy solid (150 mg crude containing Hunig base) characterized by:
- Example F 1 ,4,7,10-Tetraaza-1-N-(1-Carbo-t-Butoxy-3-(4-Aminophenyl)Propyl)-7-N-(1-Carbo- -t-Butoxymethyl)-Bis-4,10-N,N-(Carboxyamido-Methyl)Cyclododecane (Compound 9)
- the crude amino derivative 5b (130 mg), prepared as described in Example D, was dissolved in 10 mL of concentrated hydrochloric acid and the solvent removed (temperature did not exceed 40°C at 10 mm to 0.1 mm) to give 6 as a white solid.
- the white solid was applied to a column of acid washed, flash silica gel (1 X 12 cm with 10 g of gel, Alltech Inc.) which had been eluted with 3:3:1 chloroform :methanoI concentrated ammonium hydroxide.
- the triacidmonoamide 6 (R f -0.19 in same solvent) was obtained as a non-hygroscopic white solid (52 mg, 0.100 mmol) in 83 percent overall yield from 4.
- the NMR spectra of this material underthe following conditions were consistent with a pair of diastereomeric amides which arise from restricted rotation about the C-N1 bond.
- ammonium citrate at pH 6:acetonitrile to 30:70 in 30 min, 1 mL min -1 at 254 nm using a 100 mm Econosphere C18 column with guard) and indicated the material to be greater than 96 percent area purity:
- PA-H(NH 4 ) 2 DOTAMA in distilled water.
- the free ligand, PA-H(NH 4 ) 2 DOTAMA had a retention time of 1.85 min.
- the starting amide PA-H(NH 4 ) 2 DOTAMA (23 mg) was dissolved in 3 mL of distilled water and thiophosgene (15.8 ⁇ L) was added. The mixture was mixed vigorously in a MixxorTM for approximately 2 minutes. Excess thiophosgene was extracted with three 1 mL portions of chloroform. The aqueous layer was added to 20 mL of acetonitrile and the solvent was removed on a rotary evaporator at room temperature. The solid was dried for 2 hours on a vacuum line at room temperature.
- the product was dissolved in approximately 4 mL of distilled water and stored at -70°C.
- the chelation mixture was loaded onto a PRP-1 cartridge, pretreated with 800 ⁇ l of acetonitrile, 400 ⁇ l of water and 800 ⁇ l of a wash buffer (10 percent acetonitrile in 50 mM carbonate, pH 9.5) after being washed with 800 ⁇ l of the same wash buffer, the SCN-PA-DOTAMA- 177 Lu complex was eluted off in an acetonitrile-carbonate buffer (2: 1) mixture. The first 50 ⁇ l of the eluent was discarded. The bulk of the desired product came off in the next 50 ⁇ l.
- the SCN-PA-DOTAMA- 177 Lu complex was identified by comparison of the retention time on HPLC with that of an authentic sample prepared per Example 5.
- F(ab') 2 CC49 was prepared by enzymatic digestion of IgG CC49 according to the procedure described by Lamoyi and Nisonoff, J. Immunol. Methods, 56, 235-243 (1983), exchanged into a carbonate buffer (50 mM, pH 9.5) and concentrated to approximately 16 mg/ml. To 170 ⁇ l of the antibody solution (25 nmoles) was added 30 ⁇ l of the
- PA-(NH 4 ) 2 DODADA (4 ⁇ l of a 5 mM solution in water) was mixed with 25 ⁇ l of 177 Lu (0.7 mM in 0.05 N hydrochloric acid). To this was added 25 ⁇ l of a HEPES buffer (1.0 M, pH 7). It was vortexed and heated at 90°C in a sand bath for 30 minutes. The yield of chelation was 86 percent based on the 177 Lu activity. The identification was made by comparison with an authentic sample prepared as described in Example 6.
- the 177 Lu chelate was derivatized by the addition of 10 ⁇ l of a thiophosgene solution (1 percent in acetonitrile) at room temperature. After allowing the reaction to continue for 5 to 15 minutes, the 177 Lu-SCN-PA-DOTADA complex was purified on a PRP-1 Mini-CleanTM cartridge as described in the Example 7.
- SCN-PA-DOTAMA- 177 Lu and less than 30 percent for SCN-PA-DOTA- 177 Lu in the carbonate buffer (pH 9.5), at room temperature (22°C) and antibody concentration of about 1.25 ⁇ 10 -4 M.
- the titled compound was prepared according to the procedure described in Examples 8 and 10 except that SCN-PA-DOTA was the starting bifunctional chelant.
- PA-DOTA was prepared as described in PCT Application No. WO 89/02788.
- Example 12 PA-DOTA- 177 Lu, PA-DOTAMA- 177 Lu and PA-DODADA- 177 Lu labeled IgG CC49.
- the whole antibody conjugates were prepared in the similar fashion as described in Examples 8, 10 and 1 1, except that intact monoclonal antibody CC49 (whole IgG) was used. Again, rates of coupling of the SCN-BFC chelates to the antibody are in order of
- SCN-PA-DODADA > SCN-PA-DOTAMA > SCN PA-DOTA.
- Example 13 In Vitro Stability of 177 Lu Pa-DOTAMA and 177 Lu PA-DODADA Antibody
- the experiment was designed to test the stability of the 177 Lu BFC complexes at lysosomal pH 4through 5, or in the presence of other chelators such as
- DTPA diethylenetriaminepentaacetic acid
- mice In vivo localization of the 177 Lu-BFC labeled antibody was determined in Balb/c mice (purchased from Charles River Breeding Laboratories) of approximately 4 weeks of age. Female Balb/c mice were each injected via tail vein with about 10 ⁇ Ci 177 Lu of labeled antibody (7 to 10 ⁇ g) in 50 ⁇ l of PBS. The mice were sacrificed at various time intervals. After exsanguination, the selected organs/tissues were excised, weighed, and radioactivity was measured in a gamma counter. The counts per minute (CPM) of 177 Lu in each tissue was determined and expressed as CPM per gram of tissue per injected dosemultiplied by 100 (percent injected dose/gram). Results forthe chelates PA-DOTA, PA-DOTAMA and PA-DODADA conjugated to CC49 F(ab') 2 are given in Tables II A, B and C.
- PA-DODADA bifunctional chelators with respect to biodistribution when conjugated to F(ab') 2 fragments of CC49.
- the data also show the lower uptake of 177 Lu by bone for PA-DOTAMA F(ab') 2 conjugates as compared to PA-DOTA F(ab') 2 conjugates, especially at longer time points (120 hours).
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Priority Applications (13)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP93912349A EP0637253B1 (en) | 1992-04-24 | 1993-04-23 | Carboxamide modified polyamine chelators and radioactive complexes and conjugates |
JP51940593A JP3850870B2 (en) | 1992-04-24 | 1993-04-23 | Carboxamide-modified polyamine chelating agents and radioactive complexes and conjugates |
CA002134092A CA2134092C (en) | 1992-04-24 | 1993-04-23 | Carboxamide modified polyamine chelators and radioactive complexes thereof for conjugation to antibodies |
DE69317771T DE69317771T2 (en) | 1992-04-24 | 1993-04-23 | CARBOXAMIDE-MODIFIED POLYAMINE CHELATORS, RADIOACTIVE COMPLEXES AND CONJUGATES |
HU9403051A HU222761B1 (en) | 1992-04-24 | 1993-04-23 | Carboxamide modifield polyamine celators and radioactive complexes and conjugates |
ES93912349T ES2114051T3 (en) | 1992-04-24 | 1993-04-23 | CHELANTS BASED ON POLYAMINE MODIFIED BY CARBOXAMIDE AND RADIOACTIVE COMPLEXES AND CONJUGATES. |
DK93912349T DK0637253T3 (en) | 1992-04-24 | 1993-04-23 | Carboxamide modified polyamine chelators as well as radioactive complexes and conjugates |
AU42926/93A AU674853B2 (en) | 1992-04-24 | 1993-04-23 | Carboxamide modified polyamine chelators and radioactive complexes and conjugates |
KR1019940703764A KR100245941B1 (en) | 1992-04-24 | 1993-04-23 | Carboxamide modified polyamine chelators and radioactive complexes and conjugates |
NO944019A NO304552B1 (en) | 1992-04-24 | 1994-10-21 | Complex compounds, conjugates, pharmaceutical preparations containing such and compounds |
FI944973A FI944973A (en) | 1992-04-24 | 1994-10-21 | Carboxamide modified polyaminkelate formers and radioactive complexes and conjugates |
GR980400717T GR3026533T3 (en) | 1992-04-24 | 1998-04-03 | Carboxamide modified polyamine chelators and radioactive complexes and conjugation. |
HK98105598A HK1006632A1 (en) | 1992-04-24 | 1998-06-18 | Carboxamide modified polyamine chelators and radioactive complexes and conjugates |
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US07/874,244 | 1992-04-24 | ||
US07/874,244 US5310535A (en) | 1992-04-24 | 1992-04-24 | Carboxamide modified polyamine chelators and radioactive complexes thereof for conjugation to antibodies |
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WO1993021963A2 true WO1993021963A2 (en) | 1993-11-11 |
WO1993021963A3 WO1993021963A3 (en) | 1993-12-09 |
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PCT/US1993/003844 WO1993021963A2 (en) | 1992-04-24 | 1993-04-23 | Carboxamide modified polyamine chelators and radioactive complexes and conjugation |
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US (2) | US5310535A (en) |
EP (1) | EP0637253B1 (en) |
JP (1) | JP3850870B2 (en) |
KR (1) | KR100245941B1 (en) |
AT (1) | ATE164522T1 (en) |
AU (1) | AU674853B2 (en) |
CA (1) | CA2134092C (en) |
DE (1) | DE69317771T2 (en) |
DK (1) | DK0637253T3 (en) |
ES (1) | ES2114051T3 (en) |
FI (1) | FI944973A (en) |
GR (1) | GR3026533T3 (en) |
HK (1) | HK1006632A1 (en) |
HU (1) | HU222761B1 (en) |
NO (1) | NO304552B1 (en) |
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SG (1) | SG49756A1 (en) |
WO (1) | WO1993021963A2 (en) |
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WO2001046202A1 (en) * | 1999-12-22 | 2001-06-28 | L'air Liquide Societe Anonyme A Directoire Et Conseil De Surveillance Pour L'etude Et L'exploitation Des Procedes Georges Claude | Polyazacycloalkanes, organometallic complexes that incorporate them as ligands and the use of said compounds in the extraction of heavy metals |
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US10729669B2 (en) | 2015-07-28 | 2020-08-04 | University Of Iowa Research Foundation | Compositions and methods for treating cancer |
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- 1993-04-23 KR KR1019940703764A patent/KR100245941B1/en not_active IP Right Cessation
- 1993-04-23 ES ES93912349T patent/ES2114051T3/en not_active Expired - Lifetime
- 1993-04-23 SG SG1996004870A patent/SG49756A1/en unknown
- 1993-04-23 AU AU42926/93A patent/AU674853B2/en not_active Ceased
- 1993-04-23 WO PCT/US1993/003844 patent/WO1993021963A2/en active IP Right Grant
- 1993-04-23 DE DE69317771T patent/DE69317771T2/en not_active Expired - Fee Related
- 1993-04-23 DK DK93912349T patent/DK0637253T3/en active
- 1993-04-23 NZ NZ252867A patent/NZ252867A/en unknown
- 1993-04-23 HU HU9403051A patent/HU222761B1/en not_active IP Right Cessation
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Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2001046202A1 (en) * | 1999-12-22 | 2001-06-28 | L'air Liquide Societe Anonyme A Directoire Et Conseil De Surveillance Pour L'etude Et L'exploitation Des Procedes Georges Claude | Polyazacycloalkanes, organometallic complexes that incorporate them as ligands and the use of said compounds in the extraction of heavy metals |
FR2802928A1 (en) * | 1999-12-22 | 2001-06-29 | Air Liquide | Compounds derived from polyazacycloalkane derivatives with at least four cyclic nitrogen atoms used for removing heavy metals from water or hydrogen peroxide |
WO2010000714A2 (en) * | 2008-07-04 | 2010-01-07 | Oslo Universitetssykehus Hf | Radioimmunoconjugate kit |
WO2010000714A3 (en) * | 2008-07-04 | 2010-04-15 | Oslo Universitetssykehus Hf | Radioimmunoconjugate purification |
US10729669B2 (en) | 2015-07-28 | 2020-08-04 | University Of Iowa Research Foundation | Compositions and methods for treating cancer |
US11596613B2 (en) | 2015-07-28 | 2023-03-07 | University Of Iowa Research Foundation | Compositions and methods for treating cancer |
US11179484B2 (en) | 2016-06-24 | 2021-11-23 | University Of Iowa Research Foundation | Compositions and methods of treating melanoma |
US11576987B2 (en) | 2016-06-24 | 2023-02-14 | University Of Iowa Research Foundation | Compositions and methods of treating melanoma |
US20210228749A1 (en) * | 2018-04-27 | 2021-07-29 | University Of Iowa Research Foundation | Compositions for chelating metals at low temperatures |
EP3784294A4 (en) * | 2018-04-27 | 2022-01-05 | University of Iowa Research Foundation | Compositions for chelating metals at low temperatures |
US11529335B2 (en) | 2020-07-31 | 2022-12-20 | University Of Iowa Research Foundation | Compositions and methods for treating cancer |
Also Published As
Publication number | Publication date |
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US5739323A (en) | 1998-04-14 |
FI944973A0 (en) | 1994-10-21 |
US5310535A (en) | 1994-05-10 |
NZ252867A (en) | 1997-03-24 |
ATE164522T1 (en) | 1998-04-15 |
ES2114051T3 (en) | 1998-05-16 |
NO944019L (en) | 1994-12-12 |
HUT70429A (en) | 1995-10-30 |
CA2134092A1 (en) | 1993-11-11 |
SG49756A1 (en) | 1998-06-15 |
DE69317771D1 (en) | 1998-05-07 |
NO304552B1 (en) | 1999-01-11 |
JP3850870B2 (en) | 2006-11-29 |
AU4292693A (en) | 1993-11-29 |
HU222761B1 (en) | 2003-10-28 |
FI944973A (en) | 1994-12-02 |
NO944019D0 (en) | 1994-10-21 |
JPH07506365A (en) | 1995-07-13 |
KR100245941B1 (en) | 2000-04-01 |
DK0637253T3 (en) | 1999-02-01 |
KR950701231A (en) | 1995-03-23 |
GR3026533T3 (en) | 1998-07-31 |
WO1993021963A3 (en) | 1993-12-09 |
AU674853B2 (en) | 1997-01-16 |
DE69317771T2 (en) | 1998-07-30 |
EP0637253A1 (en) | 1995-02-08 |
HK1006632A1 (en) | 1999-03-05 |
EP0637253B1 (en) | 1998-04-01 |
CA2134092C (en) | 2003-07-29 |
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