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WO2008124467A1 - Ligands d'acide hydroxamique bifonctionnels et procede de synthese associe - Google Patents

Ligands d'acide hydroxamique bifonctionnels et procede de synthese associe Download PDF

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Publication number
WO2008124467A1
WO2008124467A1 PCT/US2008/059213 US2008059213W WO2008124467A1 WO 2008124467 A1 WO2008124467 A1 WO 2008124467A1 US 2008059213 W US2008059213 W US 2008059213W WO 2008124467 A1 WO2008124467 A1 WO 2008124467A1
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WIPO (PCT)
Prior art keywords
hydroxamic acid
acid ligand
bifunctional
group
targeting vector
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PCT/US2008/059213
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English (en)
Inventor
Paul Jurek
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Macrocyclics
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Publication of WO2008124467A1 publication Critical patent/WO2008124467A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C335/04—Derivatives of thiourea
    • C07C335/16—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • 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

Definitions

  • the present invention is directed to bifunctional hydroxamic acid ligands and processes for synthesizing the bifunctional hydroxamic acid ligands and for prepared radiological contrast agent using the bifunctional hydroxamic acid ligands.
  • Positron Emission Tomography (PET) imaging has become an important diagnostic tool for accurate and sensitive detection of small tumors as well as a means of assessing metabolic function.
  • PET Positron Emission Tomography
  • FDG farnesote-di(ti /2 ) is one of the most utilized PET imaging agent approved by the U.S. Federal Drug Administration for human use. Nevertheless, the production and availably of useful positron emitting isotopes for PET has been a limiting factor in the growth of this imaging modality. For instance, the very short half life (ti /2 ) of the F-18 isotope (110 minutes) requires high-yield and rapid processes to synthesis FDG, and close proximity to a cyclotron facility. Consequently, there is a long-felt need to refine techniques for the isolation and purification of longer lived isotopes.
  • One embodiment of the present disclosure is a process for synthesizing a bifunctional hydroxamic acid ligand.
  • the process includes providing a hydroxamic acid ligand, and reacting the hydroxamic acid ligand with a reactive linking moiety.
  • the reactive linking moiety includes at least one isothiocyanato group.
  • Another embodiment of the present disclosure is a process for preparing a radiological contrast agent .
  • the process comprises forming a bifunctional hydroxamic acid ligand- targeting vector conjugate. Forming the conjugate includes providing a bifunctional hydroxamic acid ligand and providing a targeting vector.
  • the bifunctional hydroxamic acid ligand includes at least two hydroxamic acid groups and at least one isothiocyanato group.
  • the targeting vector includes one or more terminal amine functional groups. Forming the conjugate also includes mixing the bifunctional hydroxamic acid ligand and the targeting vector such that the bifunctional hydroxamic acid ligand is conjugated to the one or more terminal amine functional groups by a thiourea group.
  • the bifunctional hydroxamic acid ligand comprises first functional groups that include hydroxamic acid groups configured to complex to a metal ion and second functional groups that include an isothiocyanato group.
  • the contrast agent comprises a bifunctional hydroxamic acid ligand having the above- described first and second functional groups, a target vector covalently bonded to the isothiocyanato group and a metal ion complexed to the hydroxamic acid groups.
  • FIG. 1 presents a flow diagram showing selected steps in an example synthesis of a bifunctional hydroxamic acid ligand of the present disclosure
  • FIG. 2 presents a flow diagram showing selected steps in an example preparation of a radiological contrast agent of the present disclosure
  • FIG. 3 illustrates selected steps in an example synthesis of a bifunctional hydroxamic acid ligand, and an example synthesis of a radiological contrast agent.
  • the present invention benefits from recognizing certain problems with van Dongen's process to synthesize a Zr-89 Immuno PET agent.
  • van Dongen performed a complicated 6 -step synthesis to prepare a Zr-89 Immuno PET agent in which a modified desferrioxamine ligand is conjugated to a monoclonal antibody for targeted imaging.
  • the terminal amine of desferrioxamine was functionalized to introduce a carboxylic acid moiety, a key functional group for monoclonal antibody (Mab) attachment.
  • Step 2 Due to the reactive nature of the hydroxamic acid groups, before antibody attachment, Fe +3 was introduced (step 2) to coordinate to the oxygen atoms of the hydroxyl amines .
  • the complexing iron serves as a protecting group, to thereby prevent undesirable side reactions in the following step.
  • Step 3 introduced an activated tetrafluorophenyl ester (TFP) functionality which is highly reactive with the amine groups (e.g., -NH 2 residues of lysine) present in the MAb.
  • TFP tetrafluorophenyl ester
  • the present disclosure presents novel bifunctional hydroxamic acid ligands and radiological contrast agents that include the bifunctional hydroxamic acid ligand, and, novel processes for the synthesis of such bifunctional hydroxamic acid ligands and preparation of the contrast agent .
  • bifunctional hydroxamic acid ligand refers to an organic molecule having at least two different types of functional groups: a first type for complexation to a metal ion and a second type for conjugation to a targeting vector.
  • one of the isothiocyanato groups can be covalently bonded to the hydroxamic acid ligand.
  • one of the isothiocyanato groups can be covalently bonded to a nitrogen atom of one of the hydroxamic acid groups.
  • the synthesis of the bifunctional hydroxamic acid ligands includes the use of a reactive linking moiety to facilitate the direct conjugation, via covalent bonding, to the terminal amine functionality (e.g., a lysine residue) of a targeting vector (e.g., peptides, proteins or Mabs) .
  • the reactive linking moiety can be introduced early in the synthesis of a radiological contrast agent (e.g., in the first of a three reaction step embodiment of a process to prepare an Immuno PET contrast agent) . Additionally, several synthetic transformations are eliminated compared to van Dongen ' s process, thereby shortening the time to prepare the bifunctional hydroxamic acid ligands.
  • the processes for preparing radiological contrast agents provide a more efficient synthetic transformation under milder reactions conditions than van Dongen's process.
  • a reactive linking moiety that includes an isothiocyanato group can be used for direct conjugation to a targeting vector (e.g., the terminal amine groups of the Mab) .
  • a targeting vector e.g., the terminal amine groups of the Mab
  • an activated bifunctional isothiocyante can be synthesized in a single step, and then directly conjugated to the targeting vector without the need for hydroxamic acid group protection and deprotection steps. Therefore, unlike van Dongen's process, the introduction of iron as a protecting group is not required.
  • FIG. 1 presents a flow diagram of an example process 100 for synthesizing the bifunctional hydroxamic acid ligand.
  • the process comprises a step 110 of providing a hydroxamic acid ligand.
  • hydroxamic acid ligand refers to chemical having general molecular formula of:
  • CO is a carbonyl group
  • NH-OH is a hydroxylamine
  • R is an linear or macrocylic organic group having a molecular weight of about 1000 gm/mol or less
  • n is between 1 and 4.
  • the hydroxamic acid ligand provided in step 110 can be obtained from commercial sources, or, can be synthesized using processes well known to those skilled in the art.
  • the hydroxamic acid ligand can be an acyclic or macrocyclic molecule.
  • One preferred hydroxamic acid ligand is desferrioxamine :
  • Desferrioxamine is a preferred hydroxamic acid ligand because this molecule is readily available commercially, is known to chelate Fe, Zr-89, Ga-68 and similar metals with high affinity, and its use and side-effects in humans and other animals have been studied. Desferrioxamine advantageously forms highly stable complexes with zirconium that are compatible with in vivo use.
  • hydroxamic acid ligands include piperazine derivatives that have one or more hydroxamic acid groups covalently attached as pendant arms to the piperazine ring (e.g., H2L 1 or H2L 2 ) :
  • hydroxamic acid ligands include macrocyclic tetraaza and triaza structures that have one or more hydroxamic acid groups covalently attached as pendant arms to the ring (e.g., TETMAHA, DOCYDMAHA, DOTRMAHA), or, linear ethylenediameine derivative (CDTMAHA) :
  • the process 100 for synthesizing the bifunctional hydroxamic acid ligand also includes a step 120 of reacting the hydroxamic acid ligand provided in step 110, with a reactive linking moiety to produce the bifunctional hydroxamic acid ligand.
  • the reactive linking moiety includes at least one isothiocyanato group (SCN) .
  • the bifunctional hydroxamic acid ligand produced is a bifunctional hydroxamic acid isothiocyante .
  • the reactive linking moiety has the general molecular formula: (3) R 3 -SCN m where R 3 is an organic group having a molecular weight of about 1000 gm/mol or less, and m equals 1 or 2.
  • a reactive linking moiety having a SCN group is advantageous because the SCN group can be reacted with the amine group of the targeting vector under conditions that do not affect the targeting properties of the targeting vector.
  • a reactive linking moiety with two SCN groups is desirable because the first SCN group can be covalently bonded to an amine of the hydroxamic acid ligand, while the second SCN group can be covalently bonded to an amine of the targeting vector.
  • An example reactive linking moiety having two SCN groups is 1,4- phenylenediisothiocyanate .
  • Suitable reactive linking moieties include included bis-NHS-esters and NHS-malimidio derivatives such as illustrated below (where n equals 1 to 2) :
  • reacting the hydroxamic acid ligand with a reactive linking moiety in step 120 further includes a step 130 of forming a thiourea group ( -NHCSNH-) that covalently links the hydroxamic acid ligand to the reactive linking moiety.
  • forming the thiorea group include a step 135 of mixing a solution of hydroxamic acid ligand with a solution of an isothiocyanato-containing reactive linking moiety under alkaline conditions (e.g., a pH of greater than about 7) .
  • the mixing step 135 includes providing a mole ratio of hydroxamic acid ligand: isothiocyanato- containing reactive linking moiety equals about 1:2.
  • desferrioxamine can be dissolved in water, alcohol (e.g., isopropanol) , or mixture of water and alcohol to provide an about 0.2 to 0.5 mM solution
  • 1,4- phenylenediisothiocyanate can dissolved in an organic solvent (e.g., chloroform) to provide an about 1 to 2 mM solution.
  • the two solutions can be mixed together with small volume of base (e.g., 50 to 100 ⁇ L of triethylamine) added to make the mixture alkaline.
  • Forming the thiourea group in step 130 can also include a step 140 of incubating the mixture formed in step 135 under alkaline conditions for a period sufficient to permit a complete reaction between the hydroxamic acid ligand and reactive linking moiety. For instance, in some embodiments an about 20 to 40 min reaction period at room temperature (20-22 0 C), to facilitate the formation of an thiourea group between desferrioxamine and 1,4- phenylenediisothiocyanate) . In other embodiments, however, the covalent link between the hydroxamic acid ligand and the reactive linking moiety does not involve a thiourea group. For instance the hydroxamic acid ligand and the reactive linking moiety can be covalently bonded to each other by an NHS ester that forms a covalent amide linkage instead of a thiourea linkage .
  • the process 100 further includes a step 145 of purifying the bifunctional hydroxamic acid ligand produced in step 140.
  • purifying the bifunctional hydroxamic acid ligand in step 145 can include precipitating the bifunctional hydroxamic acid ligand produced in step 140.
  • the reacted mixture can be acidified with a volume of dilute acid (e.g., about 0.1 mM HCl), and vacuum distilled at about 30 to 35°C to remove the organic solvent, resulting in a precipitate corresponding to the bifunctional hydroxamic acid ligand.
  • Purifying the bifunctional hydroxamic acid ligand in step 145 can further include isolating the precipitate from the remaining volume of water and alcohol using conventional procedures such as crystallization, filtration or centrifugation .
  • Purifying the bifunctional hydroxamic acid ligand in step 145 can also include preparative flash chromatography to separate the bifunctional hydroxamic acid ligand product from the reactants (e.g., any un-reacted desferrioxamine and 1,4- phenylenediisothiocyanate) .
  • FIG. 2 presents a flow diagram of an example process 200 for preparing a radiological contrast agent of the present disclosure.
  • the process 200 comprises a step 205 of forming a bifunctional hydroxamic acid ligand-targeting vector conjugate.
  • Forming the conjugate (step 205) includes a step 210 of providing a bifunctional hydroxamic acid ligand.
  • the bifunctional hydroxamic acid ligand includes two or more hydroxamic acid groups and at least one isothiocyanato group.
  • the bifunctional hydroxamic acid ligand can be synthesized in accordance with the process 100 described in the context of FIG. 1.
  • Forming the conjugate (step 205) also includes a step 220 of providing a targeting vector.
  • the target vector is a Mab .
  • One skilled in the art would be familiar with the procedures to produce and isolate a Mab that is targeted to bind with high affinity to particular cell types in an animal (e.g., tumor cells) or to a portion of fluid or tissue withdrawn from the animal .
  • the targeting vector includes one or more terminal amine functional groups (e.g., one or more lysine residues) . Having a terminal amine functional group is advantageous because this facilitates the covalent coupling to the bifunctional hydroxamic acid ligand (e.g., a bifunctional hydroxamic acid isothiocyante, such as a desferrioxamine isothiocyante) .
  • Forming the conjugate (step 205) also includes a step 230 of mixing solutions of the bifunctional hydroxamic acid ligand and a solution of the targeting vector together under conditions to facilitate conjugation between the bifunctional hydroxamic acid ligand and the targeting vector.
  • the bifunctional hydroxamic acid ligand is dissolved in an organic solvent (e.g., methyl cyanide, dimethyl suloxide) and a protein targeting vector is dissolved in an alkaline aqueous solution (e.g., pH about 9 to 10) .
  • the two solutions are combined to provide a mole ratio of about 1:1 (e.g., about 50 to 100 nmol of both the bifunctional hydroxamic acid ligand and targeting vector) .
  • step 240 the mixture is incubated under alkaline conditions (e.g., pH of greater than about 7, and more preferably, about 9 to 10) and at room temperature for a period (e.g., about 10 to 60 min) sufficient to permit the conjugation reaction to reach substantial completion.
  • alkaline conditions e.g., pH of greater than about 7, and more preferably, about 9 to 10.
  • the mixture can be substantially iron-free because the hydroxamic acid groups of the bifunctional hydroxamic acid ligand do not need to be protected, via iron chelation, during the conjugation.
  • an acid buffer is added to the mixture. For instance, in some embodiments, 2 , 5-dihydroxybenzoic acid and sulfuric acid or similar acid are added to adjust the mixture to a pH about 4 to 5.
  • the end-product is a bifunctional hydroxamic acid ligand-targeting vector conjugate.
  • the bifunctional hydroxamic acid ligand includes an isothiocyante group available for the conjugation reaction
  • the bifunctional hydroxamic acid ligand is conjugated to the targeting vector by a thiourea group. That is, a nitrogen atom of an amine group of the targeting vector (e.g., a lysine residue in a protein targeting vector) and the isothiocyanato group of the bifunctional hydroxamic acid ligand both participate in forming the thiourea group.
  • the bifunctional hydroxamic acid ligand-targeting vector conjugate includes two thiourea groups.
  • the reactive linking moiety includes two isothiocyante groups
  • hydroxamic acid ligand includes or is desferrioxamine and the reactive linking moiety includes or is 1,4- phenylenediisothiocyanate
  • a first thiourea group covalently links the desferrioxamine to the 1,4- phenylenediisothiocyanate
  • a second thiourea group links the 1 , 4-phenylenediisothiocyanate to an amine of the targeting vector.
  • the process 200 also includes a step 250 of forming a metal -bifunctional hydroxamic acid ligand-targeting vector complex.
  • the metal ion is preferably a transition metal having a radionuclide half-life of at least about 60 minutes. More preferably the metal is a PET isotope such as Zr-89 or Ga-68. In other embodiments, however, the metal ion can be a non radioactive transition metal such as iron, or a lanthanide.
  • forming the complex includes mixing, in step 255, the solution of the bifunctional hydroxamic acid ligand-targeting vector conjugate prepared in step 205 with a metal ion.
  • metal ions are provided in an aqueous solution as a low molecular weight (e.g., about 1000 gm/mol or less) monocarboxylic acid-metal ion complex at neutral pH (e.g., a pH about 7 to 7.5) and room temperature.
  • the mole-ratio of metal ion to bifunctional hydroxamic acid ligand-targeting vector conjugate in the mixture equals about 1000:1 or greater.
  • about 6 x 10 ⁇ 5 mol of a metal-oxalic acid complex is mixed with 33 nmol of a desferrioxamine-protein conjugate in an aqueous solution buffered with Na 2 CO 3 and 4- (2-hydroxyethyl) -1- piperazineethanesulfonic acid (HEPES) at a pH of about 7.3 at room temperature for a period sufficient to allow complex formation.
  • Forming the complex can further include a step 260 of purifying the complex.
  • the metal -hydroxamic acid ligand-targeting vector complex is separated from the monocarboxylic acid-metal ion complex using size-exclusion chromatography.
  • FIG. 3 illustrates selected steps in an example synthesis of a bifunctional hydroxamic acid ligand using desferrioxamine-B as the hydroxamic acid ligand and 1,4- phenylenediisothiocyanate as the reactive linking moiety.
  • FIG. 3 also illustrates selected steps in an example synthesis of a MAb-N-thiourea-Idesferal- 89 Zr contrast agent.
  • step 1 desferrioxamine-B, and 1,4- phenylenediisothiocyanate are reacted to yield a bifunctional hydroxamic acid isothiocyante intermediate (I) in a single step.
  • desferrioxamine mesylate (0.2g, 0.37 mmol) was dissolved in an isopropanol/water solution (32 mL/4 mL) .
  • a chloroform solution (19 mL) of 1 , 4 -phenylenediisothiocyanate (0.29g, 1.5 mmol) was then added in one portion followed by the immediate addition of triethylamine (80 ⁇ L) .
  • This reaction mixture was then stirred for 30 minutes at room temperature.
  • a 0. IM HCl solution (22.5 ml) was then added to give a 2 -phase system.
  • the organic layer was separated and concentrated under vacuum at 30-35 0 C to remove chloroform.
  • step 2 the bifunctional hydroxamic acid isothiocyante intermediate (I) can be conjugated directly to the targeting vector via e.g., a -NH 2 residues of lysine present in a monoclonal antibody (Mab) to form a desferrioxamine-protein conjugate (II) .
  • conjugation can be accomplished without having to perform additions steps to protect the hydroxamic acid using iron chelation, and then to de-protect the hydroxamic acid by removing the chelated iron.
  • mAb solution 5 mg/rtiL
  • a metal ion e.g., Zr-89, Ga-68, Fe
  • a metal ion can be complexed to the desferrioxamine-protein conjugate (II) to form a metal -desferrioxamine protein conjugate (III) .
  • reaction mixture (6 mL) is divided over 3 PD-10 columns (eluent: 0.9% NaCl/gentisic acid (5 mg/mL), pH 5) .
  • the first 2.5 mL (2-mL sample volume and first 0.5 mL) are discarded, and the metal- desferrioxamine protein conjugate (III) was collected in next 3 mL .

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Abstract

L'invention concerne un procédé de synthèse d'un ligand d'acide hydroxamique bifonctionnel. Ce procédé consiste à obtenir un ligand d'acide hydroxamique et à le mettre en réaction avec une fraction de liaison réactive. Ladite fraction contient au moins un groupe isothiocyanato.
PCT/US2008/059213 2007-04-06 2008-04-03 Ligands d'acide hydroxamique bifonctionnels et procede de synthese associe WO2008124467A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10137212B2 (en) * 2013-03-13 2018-11-27 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Tetrahydroxamate chelators of zirconium89 and niobium90 for use in diagnostic applications
US10730944B2 (en) 2017-07-24 2020-08-04 Regeneron Pharmaceuticals, Inc. Anti-CD8 antibodies and uses thereof
US10736976B2 (en) 2016-12-01 2020-08-11 Regeneron Pharmaceuticals, Inc. Radiolabeled anti-PD-L1 antibodies for immuno-PET imaging
US10905784B2 (en) 2017-02-10 2021-02-02 Regeneron Pharmaceuticals, Inc. Radiolabeled anti-LAG3 antibodies for immuno-PET imaging
WO2021020535A1 (fr) 2019-07-31 2021-02-04 アステラス製薬株式会社 Composition pharmaceutique pour administration par voie otique

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4680338A (en) * 1985-10-17 1987-07-14 Immunomedics, Inc. Bifunctional linker
US20030170697A1 (en) * 1989-08-24 2003-09-11 Goldenberg David M. Detection and treatment of infections with immunoconjugates
US20060246005A1 (en) * 2005-04-01 2006-11-02 The Board Of Regents Of The University Of Texas System Poly(peptide) as a chelator: methods of manufacture and uses
US20070037148A1 (en) * 2000-03-31 2007-02-15 Sherman Fong Compositions and methods for the treatmetn of natural killer cell related diseases

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4680338A (en) * 1985-10-17 1987-07-14 Immunomedics, Inc. Bifunctional linker
US20030170697A1 (en) * 1989-08-24 2003-09-11 Goldenberg David M. Detection and treatment of infections with immunoconjugates
US20070037148A1 (en) * 2000-03-31 2007-02-15 Sherman Fong Compositions and methods for the treatmetn of natural killer cell related diseases
US20060246005A1 (en) * 2005-04-01 2006-11-02 The Board Of Regents Of The University Of Texas System Poly(peptide) as a chelator: methods of manufacture and uses

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MEIJS ET AL.: "Zirconium-Labeled Monoclonal Antibodies and Their Distribution in Tumor-Bearing Nude Mice", THE JOURNAL OF NUCLEAR MEDICINE, vol. 38, no. 1, 1997, pages 112 - 118 *
VEREL ET AL.: "89Zr Immuno-PET: Comprehensive Procedures for the Production of 89Zr-Labeled Monoclonal Antibodies", THE JOURNAL OF NUCLEAR MEDICINE, vol. 44, no. 8, 2003, pages 1271 - 1281 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10137212B2 (en) * 2013-03-13 2018-11-27 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Tetrahydroxamate chelators of zirconium89 and niobium90 for use in diagnostic applications
US10736976B2 (en) 2016-12-01 2020-08-11 Regeneron Pharmaceuticals, Inc. Radiolabeled anti-PD-L1 antibodies for immuno-PET imaging
US12053534B2 (en) 2016-12-01 2024-08-06 Regeneron Pharmaceuticals, Inc. Radiolabeled anti-PD-L1 antibodies for immuno-PET imaging
US10905784B2 (en) 2017-02-10 2021-02-02 Regeneron Pharmaceuticals, Inc. Radiolabeled anti-LAG3 antibodies for immuno-PET imaging
US11511001B2 (en) 2017-02-10 2022-11-29 Regeneron Pharmaceuticals, Inc. Radiolabeled anti-LAG3 antibodies for immuno-PET imaging
US10730944B2 (en) 2017-07-24 2020-08-04 Regeneron Pharmaceuticals, Inc. Anti-CD8 antibodies and uses thereof
US11525001B2 (en) 2017-07-24 2022-12-13 Regeneron Pharmaceuticals, Inc. Anti-CD8 antibodies and uses thereof
US12077587B2 (en) 2017-07-24 2024-09-03 Regeneron Pharmaceuticals, Inc. Anti-CD8 antibodies and uses thereof
WO2021020535A1 (fr) 2019-07-31 2021-02-04 アステラス製薬株式会社 Composition pharmaceutique pour administration par voie otique

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