WO2019169241A1 - Procédés de traitement et d'imagerie de fourbure des ongulés - Google Patents

Procédés de traitement et d'imagerie de fourbure des ongulés Download PDF

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Publication number
WO2019169241A1
WO2019169241A1 PCT/US2019/020244 US2019020244W WO2019169241A1 WO 2019169241 A1 WO2019169241 A1 WO 2019169241A1 US 2019020244 W US2019020244 W US 2019020244W WO 2019169241 A1 WO2019169241 A1 WO 2019169241A1
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WO
WIPO (PCT)
Prior art keywords
tin
laminitis
radionuclide
subject
annexin
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Application number
PCT/US2019/020244
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English (en)
Inventor
Gilbert R. Gonzales
Nigel R. Stevenson
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Serene, Llc
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Publication date
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Publication of WO2019169241A1 publication Critical patent/WO2019169241A1/fr

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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
    • 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
    • A61K51/087—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins the peptide being an annexin, e.g. annexin V

Definitions

  • Embodiments of the invention are directed to methods of treating, imaging, or both treating and imaging inflammatory conditions in hooved animals ("ungulates"), and more particularly, compositions and method of treating, imaging, or both treating and imaging laminitis in an ungulate.
  • ungulates hooved animals
  • Laminitis is the most serious disease of the equine foot, causing pathological changes in anatomy that lead to long lasting, crippling changes in function. It is the second biggest killer of horses, with 30% of US non-race horses with this condition dying or being euthanized.
  • laminitis There are three general types of laminitis including: (1) Systemic
  • inflammatory/enzymatic pathway-most common and typically related to a systemic infection, retained placenta etc. (2) Insulin/hormonal pathway-related to conditions causing increased insulin such as Cushing's Disease, Equine Metabolic Syndrome, and ingestion of carbohydrate -rich grass, and (3) Supporting limb injury pathway-related to an uninjured leg bearing all of the animals weight due to the injured limb being held up.
  • the first two pathways appear to have different mechanisms than the last pathway which appears to be purely mechanical.
  • Laminitis also occurs in distinct phases: developmental, acute, and chronic, each of which exhibits unique histopathology and inflammatory cell (macrophage) expression.
  • laminitis results in disintegration of the membrane connecting the structures (papillae) which interdigitate between the skeleton and the hoof.
  • the skeleton of the foot shears away from the hoof causing intense pain and structural changes from which the horse may not recover.
  • the developmental phase includes vasodilatation
  • the acute phase includes vasoconstriction
  • increase in CD 163 macrophages in the secondary dermal laminae and an increase in matrix metalloproteinases 2, 9 and 13 which can destroy key components of the lamellar attachment apparatus in the laminae.
  • matrix metalloproteinases 2, 9 and 13 which can destroy key components of the lamellar attachment apparatus in the laminae.
  • Tin- 117m is an isotope that emits both conversion electrons for therapy, and gamma energy for imaging. Tin- 117m offers several distinct advantages over traditional isotopes including (1) the electron energy emitted (-140 KeV) is manifold lower than that of traditional radiation therapy, (2) the conversion electrons deposit their energy in a very short, uniformly predictable fashion up to -300 pm, (3) an ideal two-week half-life, (4) imaged with standard equipment due to the 159 KeV photon being similar to technetium-99m, and (5) inexpensively manufactured on demand.
  • the electron energy emitted is manifold lower than that of traditional radiation therapy
  • the conversion electrons deposit their energy in a very short, uniformly predictable fashion up to -300 pm
  • an ideal two-week half-life (4) imaged with standard equipment due to the 159 KeV photon being similar to technetium-99m, and (5) inexpensively manufactured on demand.
  • Described herein are methods of treating, imaging, or both treating and imaging laminitis in hooved subjects.
  • Embodiments of the methods include administering to the subject a radionuclide conjugated to a targeting molecule in an amount effective to treat, image, or both treat and image laminitis in a subject.
  • the radionuclide is Tin-l l7m, and preferably is Tin- H7m with a specific activity that has at least a medium specific activity, i.e., an activity of at least 100 Ci/g.
  • the Tin-l l7m has a specific activity that is at least a high specific activity, i.e., an activity of at least 1,000 Ci/g.
  • the Tin-ll7m has a specific activity that is a very high specific activity, i.e., a specific activity of at least 10,000 Ci/g.
  • the radionuclide is a beta emitting isotope such as P 32 , Y 90 , Re 188 , Er 169 , Lu 177 , Sm 153 or combinations thereof.
  • the targeting molecule is annexin-V.
  • the targeting molecule is annexin-Al, which is also known as lipocortin 1.
  • the targeting molecule is T-DPA (tyrosine-containing DPA [docosapentaenoie acid] derivative).
  • the radionuclide is conjugated to the targeting molecule with a chelating molecule, such as aminobenzyl DOTA (ABD) or diethylene tri amine pentaacetic acid (DTPA). Other chelants may apply.
  • the radionuclide conjugate or a Sn-l l7m colloid is administered to the subject via injection to the subject.
  • the radionuclide conjugate is injected intra arterially into the subject.
  • the radionuclide conjugate is injected into the Palmar Distal Artery.
  • the radionuclide conjugate is injected intravenously using a Bier block technique.
  • the radionuclide conjugate is administered in an amount effective to treat the laminitis.
  • the amount administered is effective to treat laminitis in the subject.
  • the amount effective to treat laminitis is an amount that delivers a sufficient dose of the radionuclide conjugate to the inflamed tissue to result in a hormetic response in the tissue.
  • the hormetic response may include inducing apoptosis in inflammatory cells of the inflamed tissue, such as apoptosis in macrophages in the lamina of the hoof of the hooved subject, without inducing wider spread necrosis of the targeted tissue.
  • the amount administered is effective to image laminitis in the subject. In further embodiments, the amount administered is effective to both treat and image laminitis in the subject.
  • imaging can be conducted with a gamma camera or with single-photon emission computerized tomography ("SPECT").
  • SPECT single-photon emission computerized tomography
  • the amount administered can vary depending on the severity of inflammation, the size of the animal, and the route of administration ⁇ In an embodiment, the amount administered is sufficient to deliver a dose in a range from 1 mCi to 10 mCi.
  • the amount administered is sufficient to deliver a dose in a range from 1 mCi to 100 mCi, or a dose in a range from 5 mCi to 100 mCi, or a dose in a range from 5 mCi, to 50 mCi.
  • Lower doses, such as from 1 mCi to 10 mCi, may be administered via direct injection into the Palmar Distal Artery.
  • administration techniques such as the intravenous delivery using a Bier block technique, may require administration of higher dosages, such a dose in a range from 1 mCi to 100 mCi, or a dose in a range from 5 mCi to 100 mCi, or a dose in a range from 5 mCi, to 50 mCi.
  • radionuclide When the radionuclide is conjugated to a targeting molecule that localizes to the outer cell membrane of inflammatory cells, this results in the induction of inflammatory cell apoptosis. Inflammation is considered a significant contributor to laminitis, especially at its onset.
  • a radionuclide such as Tin-ll7m attached to a localizing, inflammation targeting agent has been studied in several animal models. Imaging of human pathologic inflammatory cell collections in vivo as well as animal therapeutic trials in inflammatory states indicates that the presently described radionuclide targeting conjugate may be used as a laminitis therapeutic agent.
  • the radionuclide is selected from Tin-l l7m, which emits gamma energy as well as the conversion electron, and beta emitting isotopes with a half-life of 14 days or less.
  • Exemplary other beta emitting isotopes include Y 90 , P 32 , Re 188 , Er- 169 , Lu 177 , Sm 153 or combinations thereof.
  • Embodiments of the invention utilize at least medium specific activity Tin- 117m, as defined below.
  • Other embodiments utilize at least high specific activity Sn-l 17, as defined below.
  • Other embodiments utilize very high specific activity Tin-l l7m, as defined below.
  • High Specific Activity Tin-ll7m 1,000- 10,000 Ci/g; such as manufactured with proton accelerators (but higher Sn-l 13 so limited use); primarily
  • Tin- 117m in chemical targeting, conjugated form is capable of delivering a therapeutic dosage with additional capabilities of hormesis responses by inducing localized inflammatory cell apoptosis in sub-necrotizing doses common to other radiation therapies, such as those used in oncology therapy.
  • Intraarterial embolization of a LSA Sn-ll7m colloid is also feasible.
  • Embodiments of the radionuclide target in the therapeutic agents described herein is the unique conversion electron energy emitted from the isotope Tin-l l7m.
  • the Tin-l l7m has successfully been chemically linked to an inflammatory cell targeting a large molecule (i.e., annexin V) with statistically significant induction of macrophage apoptosis.
  • Unique delivery methods, ultra-low dosages (i.e., hormesis doses) compared to standard nuclear medicine therapeutics, and the use of the presently described unique high specific activity material exemplifies the benefits and importance of the present method.
  • the methods described herein provide a new therapeutic approach to stabilizing laminitis.
  • radionuclide conjugate such as Tin-ll7m attached or linked into a chelating agent and conjugated to a targeting agent for macrophages, such as annexin V, annexin Al, and T-DPA
  • a targeting agent for macrophages such as annexin V, annexin Al, and T-DPA
  • the radionuclide conjugate is infused, such as with a direct arterial injection into the palmar distal artery or other vascular infusion methods, to target infiltrating macrophages that exacerbate the relentless inflammatory process underlying laminitis.
  • Administering the radionuclide conjugate ameliorates the inflammatory cycle and allow the tissue to heal.
  • the radionuclide conjugate may include‘Tin-ll7m-DOTA-annexin V’,‘Tin-l l7m-DOTA-annexin AT,‘Tin- 117m- [T-DPA]’, or mixtures thereof. Infusions of the radionuclide conjugate not only treats the afflicted area but also allows imaging of the laminitis due to the existence of the Tin- 1 l7m gamma photon. Imaging may be performed with a gamma camera or with single photon emission computerized tomography ("SPECT").
  • SPECT single photon emission computerized tomography
  • the targeting molecule is Annexin V.
  • Annexin V is a naturally occurring protein that binds to specific cell membrane chemicals that are expressed in apoptotic inflammatory cells such as macrophages.
  • the targeting molecule is Annexin Al.
  • Annexin Al also known as lipocortin 1, is a naturally occurring protein that targets apoptotic inflammatory cells such as
  • T-DPA is a small molecule that also targets apoptotic inflammatory cells such as macrophages.
  • Tin-l l7m is high specific activity Tin-ll7m, i.e., Tin-l l7m having a specific activity of between 1,000 Ci/g and 10,000 Ci/g.
  • Tin- H7m- Annexin which is Tin-l l7m bound to annexin V or annexin Al (collectively referred to as "annexin”).
  • Tin-l l7m may be bound to annexin as follows: Labeling molecules with Tin-l l7m is usually performed using bifunctional chelates such aminobenzyl DOT A (ABD) or diethylene triamine pentaacetic acid (DTP A). For the laminitis Tin-annexin product the Tin-l l7m is first chelated into the ABD and purified. Subsequently this is converted to the isothiocyanato version (IBD) and attached to the desired target molecule (Annexin) as shown.
  • ABC aminobenzyl DOT A
  • DTP A diethylene triamine pentaacetic acid
  • Sn-ABD Sn-IBD Sn-Annexin [0021] A systemic injection of this combination molecule will target inflammatory cells (such as those found in acute laminitis sites) and have a therapeutic effect in laminitis as a result of the induction of apoptosis in the macrophages responsible for the inflammation- induced process.
  • T-DPA is a small molecule (not a biological) that is easy to manufacture at low cost and it exhibits a favorable biodistribution with low body dose.
  • the scheme for producing [Tin-ll7m]-IBD-[T-DPA] is similar to the process described above for Tn-ll7m-DOTA-annexin.
  • Tin-117m linked compounds and Tin-117m colloids Direct peripheral delivery of Tin-117m linked compounds and Tin-117m colloids:
  • the radionuclide conjugate such as Tin- 117m linked to a variety of targeting compounds including annexin V, annexin Al, T-DPA, or combinations thereof, by a chelating agent, such as IBD or DTPA, or the Tin-ll7m colloid can be infused as a direct arterial injection into the palmar distal artery to inject medication into the horse’s foot and will target infiltrating macrophages in the horse’s foot that are exacerbating the relentless inflammatory process underlying the laminitis.
  • a chelating agent such as IBD or DTPA
  • peripheral venous infusion of the Tin-l l7m conjugates with the use of an Esmarch bandage in order to prolong the distal circulation time and prolonged Tin-l l7m conjugate exposure to the inflammatory cells can be used.
  • This will result in the conversions electron from the Tin-ll7m causing apoptosis in macrophages in the horse’s foot, thereby ameliorating the inflammatory cycle and allowing the tissue to heal.
  • Radionuclide conjugate infusion will treat only the afflicted area due to the local delivery of the conjugate to the foot via injection into the palmar distal artery, thereby avoiding systemic dosing.
  • Direct dosing to the foot allows for the use of a much lower dose of radionuclide conjugate than would be required is systemic dosing were used. Lower local dosing helps prevent other potential side effects of higher systemic dosing.
  • An exemplary method of administering the radionuclide conjugate includes the peripheral evacuation of venous blood in the distal limb of the horse, which may be achieved using a well described Bier block technique with infusion of the distal-to-the-block venous infusion of the radionuclide conjugate for binding to distal lamina macrophages.
  • the systemic therapeutic delivery dose may be in the 8 mCi to 50 mCi range, however a dose of 100 mCi or more may be required in some large horses and in severe laminitis cases.
  • Additional dosing may be required after 3 half-lives of the radionuclide, such as 42 days for Tin-ll7m, plus or minus 3 days.
  • Follow-up repeat treatments on a 6 month or yearly basis may also be needed for the recurrent forms of laminitis.
  • An exemplary method of administering the radionuclide conjugate includes arterial delivery of small amount of the radionuclide conjugate or in-H7m colloid embolization using a direct arterial injection into the palmar distal artery (a routine procedure done to inject medications into the horse foot). This will provide the therapeutic radionuclide conjugate to the lamina while avoiding a significant systemic dose.
  • this provides the therapeutic conversion electron, which induces inflammatory cell apoptosis, as well as imaging via gamma photon from Tin-ll7m conjugate targeting the inflammatory cells in the lamina.
  • both the therapeutic and gamma imaging dose may be in the range of 1 mCi to 8 mCi.
  • Embodiments of the method include additional treatments at a later date after the original treatment date.
  • the subject may receive a second administration of radionuclide conjugate after about three half-lives of the radionuclide.
  • the second dose is administered 42 days after the first dose.
  • additional treatments may be required every 6 months or every 12 months.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Optics & Photonics (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne un procédé de fourniture sélective d'une dosimétrie de rayonnement à des équins ou d'autres animaux à sabots (« ongulés ») ayant besoin d'un tel traitement. Le composé émettant un rayonnement est appliqué sur la lamina du sabot par l'intermédiaire d'une infusion périphérique ou par administration systémique avec des électrons de conversion absorbés de façon immédiatement adjacente à des emplacements sélectionnés sans affecter le tissu environnant à l'extérieur de la zone immédiatement adjacente. Dans des modes de réalisation, le composé émettant un rayonnement est un conjugué de radionucléide dans lequel le radionucléide est choisi parmi étain-117m, Y90, P32, Re188, Er-169, Lu177, Sm153 ou des combinaisons de ceux-ci. Un conjugué de radionucléide est administré au sabot d'un ongulé, se liant aux cellules inflammatoires de la lamina et inversant la fourbure destructrice inflammatoire. Dans des modes de réalisation, le conjugué de radionucléide peut comprendre [étain-117m]-DOTA-annexine V, [étain-117m]-DOTA-[T-DPA], [étain-117m]-DOTA-Annexine A1 (lipocortine 1), un colloïde homogène d'étain-117 m ou un colloïde non homogène d'étain-117 m. Dans d'autres modes de réalisation, d'autres agents chélatants, tels que l'acide diéthylènetriaminepentaacétique (DTPA), peuvent être utilisés à la place de DOTA et d'autres radionucléides, tels que Y90, P32, Re188, Er-169, Lu177, Sm153 ou des combinaisons de ceux-ci peuvent être utilisés à la place d'étain-117m.
PCT/US2019/020244 2018-03-02 2019-03-01 Procédés de traitement et d'imagerie de fourbure des ongulés WO2019169241A1 (fr)

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US62/637,722 2018-03-02

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998048699A1 (fr) * 1997-04-30 1998-11-05 The Board Of Trustees Of The Leland Stanford Junior University Procede d'imagerie de la mort cellulaire in vivo
WO2007038641A2 (fr) * 2005-09-26 2007-04-05 Clear Vascular, Inc. Procedes et therapies pour le traitement de conditions inflammatoires a l'aide de collagene expose
WO2010126544A1 (fr) * 2009-04-29 2010-11-04 Willowcroft Pharm, Llc Stabilisateurs de mastocytes utilisés pour prévenir ou traiter la fourbure
EP3003400A1 (fr) * 2013-06-05 2016-04-13 R-Nav, Llc Traitement d'arthrites auto-immunes, inflammatoires et dégénératives avec l'etain-117m

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998048699A1 (fr) * 1997-04-30 1998-11-05 The Board Of Trustees Of The Leland Stanford Junior University Procede d'imagerie de la mort cellulaire in vivo
WO2007038641A2 (fr) * 2005-09-26 2007-04-05 Clear Vascular, Inc. Procedes et therapies pour le traitement de conditions inflammatoires a l'aide de collagene expose
WO2010126544A1 (fr) * 2009-04-29 2010-11-04 Willowcroft Pharm, Llc Stabilisateurs de mastocytes utilisés pour prévenir ou traiter la fourbure
EP3003400A1 (fr) * 2013-06-05 2016-04-13 R-Nav, Llc Traitement d'arthrites auto-immunes, inflammatoires et dégénératives avec l'etain-117m

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
L. M. KATZ ET AL: "A review of recent advances and current hypotheses on the pathogenesis of acute laminitis : The pathogenesis of equine acute laminitis", EQUINE VETERINARY JOURNAL., vol. 44, no. 6, 1 November 2012 (2012-11-01), GB, pages 752 - 761, XP055596552, ISSN: 0425-1644, DOI: 10.1111/j.2042-3306.2012.00664.x *
TROUT D R ET AL: "Scintigraphic evaluation of digital circulation during the developmental and acute phases of equine laminitis", EQUINE VETERINARY JOURNAL, R & W PUBLICATIONS, SUFFOLK, GB, vol. 22, no. 6, 31 October 1990 (1990-10-31), pages 416 - 421, XP009513852, ISSN: 0425-1644, DOI: 10.1111/J.2042-3306.1990.TB04308.X *

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