PRECISION MEDICINE THERANOSTICS AND DIAGNOSTICS A COMBINATION THEREOF

Abstract

The component drug new molecule for combining metals into complexes through a ring structure (DOTA) or linear structure, and a radionuclidic component, and chelating agent wherein embodiments may include a companion diagnostic, and in which embodiments further include anti-integrin precision medicines for cancers expressing v3 and v5 integrins, second component for combining metals into complexes through a ring or linear structure, and one or more radionuclidic components, a chelating agent for diagnosis and/or therapy (theranostic) in which the embodiments further include a anti-integrin peptidomimetic for precision medicine for cancers expressing v3 and v5 integrins.

Claims

1. A therapeutic and diagnostic pharmaceutical composition for targeting and treating human epidermal growth factor receptor 2-Positive, hereinafter referred to as HER2+, or other cancer that overexpresses integrin receptors, the composition comprising an v3/v5 anti-integrin antagonist peptidomimetic that includes an integrin whose molecular structure includes a tetrahydropyridimidinyl-aminoethyloxybenzoyl group on a sulfonylamino--alanine nucleus, exhibiting selective, high binding affinity for 53; at least one radionuclide; a spacer sequence, wherein said integrin is covalently linked by a spacer sequence; a chelator selected from the group consisting of NODAGA, DOTAGA, DOTATATE, and CHX-A; and a pharmaceutically acceptable excipient.

2. The therapeutic and diagnostic composition of claim 1, wherein said spacer sequence is a linear artificial sequence.

3. The therapeutic and diagnostic composition of claim 1, wherein the radionuclide is selected from the group consisting of Lutetium-177, Actinium-225, Bismuth-213, Thorium-227, Lead-212, Astatine-211, Yttrium-90, Gallium-68, Zirconium-69 and Iodine-131.

4. The therapeutic composition of claim 1, wherein the radionuclide is selected from the group consisting of Lutetium-177.

5. The therapeutic composition of claim 3, wherein the radionuclide is selected from the group consisting of Actinium-225.

6. The therapeutic composition of claim 1, wherein said radionuclide is Lu-177, and wherein said chelator is DOTAGA, the active moiety consisting of: [177Lu] DOTAGA IAC.

7. The therapeutic composition of claim 1, wherein said spacer sequence is provided between said chelator and said tetrahydropyridimidinyl-aminoethyloxybenzoyl group on the sulfonylamino--alanine nucleus, exhibiting selective, high binding affinity for 53.

8. The therapeutic and diagnostic composition of claim 1, wherein said chelator is DOTAGA.

9. The therapeutic and diagnostic composition of claim 1, wherein said chelator is NODAGA.

10. The therapeutic and diagnostic composition of claim 1, wherein said chelator is DOTATATE.

11. The therapeutic and diagnostic composition of claim 1, wherein said chelator is CHX-A.

12. The therapeutic and diagnostic composition of claim 1, wherein said chelator also includes IAC.

13. A composition for tumor targeted radionuclide therapy (TRNT) for targeting and treating human epidermal growth factor receptor 2-Positive (HER2+) or other cancer that overexpresses integrin receptors, the composition comprising: (1) a ligand containing the active moiety, said ligand comprising an v3 integrin antagonist peptidomimetic, and (i) 4-[2-(3,4,5,6-tetrahydropyrimidine-2-ylamino) ethyloxy]benzoyl-2-[N-(3-aminoneopenta-1-carbamyl)]-aminoethylsulfonyl-amino--alanine (IAC), and (ii) at least one of the following: (a) 1-(1-carboxy-3-carbotertbutoxymethyl)-1,4,7,10-tetraazacyclododecane (DOTAGA) (tBu).sub.4; or (b) 4-[4,7-Bis-(carboxymethyl)-[1,4,7]triazonan-1-yl]-4-carboxy-butyryl (NODAGA); or (c) DOTATATE; (d) C26H34N4O10S (CHX-A); and (2) a radionuclide selected from the group consisting of Lutetium-177, Actinium-225, Bismuth-213, Thorium-227, Lead-212, Astatine-211, Yttrium-90, Iodine-131, Gallium-68, Zirconium-68, or a combination of radionuclides.

14. The composition of claim 13, having a binding region with binding affinity for 53, and including a tetrahydropyridimidinyl-aminoethyloxybenzoyl group on a sulfonylamino--alanine nucleus.

15. The composition of claim 13, including a spacer sequence covalently linking said v3 integrin antagonist peptidomimetic to said at least one of (ii)(a), or (ii)(b), or (ii)(c), or (iii)(d).

16. The composition of claim 14, wherein said composition comprises [177Lu] DOTAGA IAC.

17. A composition for tumor targeted radionuclide therapy (TRNT) for targeting and treating human epidermal growth factor receptor 2-Positive (HER2+) or other cancer that overexpresses integrin receptors, the composition comprising: a) an v3 integrin antagonist peptidomimetic; and b) a radionuclide; c) wherein said radionuclide is covalently bound to a spacer, chelator, directly to the peptidomimetic, to a nanoparticle or to more than one amino acid unit of the peptidomimetic; and d) wherein said composition comprises one or more of the following to which said radionuclide is chelated: (i) 4-[2-(3,4,5,6-tetrahydropyrimidine-2-ylamino) ethyloxy]benzoyl-2-[N-(3-aminoneopenta-1-carbamyl)]-aminoethylsulfonyl-amino--alanine (IAC), and (ii) at least one of the following: (iii) 1-(1-carboxy-3-carbotertbutoxymethyl)-1,4,7,10-tetraazacyclododecane (DOTAGA) (tBu).sub.4; or (iv) 4-[4,7-Bis-(carboxymethyl)-[1,4,7]triazonan-1-yl]-4-carboxy-butyryl (NODAGA); or (v) DOTATATE; or (vi) C26H34N4O10S (CHX-A).

18. The therapeutic composition of claim 1, wherein said integrin antagonist is a peptide mimetic chelated to a radionuclide.

19. The therapeutic composition of claim 1, containing the active moiety 4-[2-(3,4,5,6-tetrahydropyrimidine-2-ylamino) ethyloxy]benzoyl-2-[N-(3-aminoneopenta-1-carbamyl)]-aminoethylsulfonyl-amino--alanine (IAC).

20. The therapeutic composition of claim 1, containing the active moiety acetylsulfanyl-ethoxy}-ethoxy)ethox-y]ethoxy}-propionylamino)-propoxy]-benzyl}-ureido]-thiazole-4-carbonyl)-amino}-acetylamino]-phenyl-3-yl-propionic acid.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0028] Unless otherwise indicated, the following specific terms and phrases used in the description and claims are defined as follows:

[0029] The term moiety refers to an atom or group of chemically bonded atoms that is attached to another atom or molecule by one or more chemical bonds thereby forming part of a molecule.

[0030] The term conjugated moiety refers to moiety which is a therapeutic or useful compound, peptidomimetic, peptide, polymer, small molecule, fluorescent moiety, oligonucleotide or nucleic acid. Examples include drugs, diagnostic peptidomimetics, therapeutic peptidomimetics, therapeutic peptides, antisense oligonucleotides, siRNA, and fluorescein isothiocyanate (FITC).

[0031] The term alkyl denotes a monovalent linear or branched saturated hydrocarbon group of 1 to 12 carbon atoms. In particular embodiments, alkyl has 1 to 7 carbon atoms, and in more particular embodiments 1 to 4 carbon atoms. Examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, or tert-butyl.

Tumor Targeted Radionuclide Therapy (TRNT)

[0032] An objective of TRNT is to selectively deliver cytotoxic radiation to cancer cells causing minimal toxicity to surrounding healthy tissues. This is achieved by delivering a radioactive payload into the tumor cells. Examples of this approach are Gallium-68 (68Ga), Yttrium-90 (90Y), Lutetium-177 (177Lu), Iodine-131, (177Lu), Zirconium-68, Actinium-225 (225Ac), Bismuth-213 (213Bi) and Lead-212 (212Pb) as radiolabeled peptides to treat tumors overexpressing specific proteins. In addition, monoclonal antibodies (abs) are also used as vehicles to target tumor-associated antigens providing internal radiotherapy. Regulatory-agency approved radiolabeled agents are 90Y-ibritumomab and 90I, and 177Lu Lutathera for treatment of gastroenteropancreatic tumors. Thus, a therapeutic radiopharmaceutical can consist of two parts: a targeting biomolecule that specifically determines the localization of the radiopharmaceutical and a radionuclide that delivers the mechanism of action through its decay. Radiopharmaceuticals are used as diagnostics for non-invasive imaging by detection of -rays using positron emission tomography (PET) or single-photon emission computerized tomography (SPECT), and/or as therapeutics for TRNT to deliver cancer cell killing radiation to the targeted tumor cells.

[0033] The crucial roles of integrin v3 in tumor angiogenesis have led to a promising strategy to block signaling by antagonists, as this would theoretically inhibit tumor angiogenesis or enhance the efficacy of other tumor therapeutics. In addition, the high expression of integrin v3 on tumor new-blood vessels and some tumor cells makes the anti-integrin v3 suitable marker for cancer-targeted drug delivery. According to a preferred embodiment, the therapeutic compound comprises Ga-68 DOTAGA and Lu-177 DOTAGA: A ligand containing the active moiety, the v3 integrin antagonist peptidomimetic, 4-[2-(3,4,5,6-tetrahydropyrimidine-2-ylamino) ethyloxy]benzoyl-2-[N-(3-aminoneopenta-1-carbamyl)]-aminoethylsulfonyl-amino--alanine (IAC) and 1-(1-carboxy-3-carbon tert butoxymethyl)-1,4,7,10-tetraazacyclododecane (DOTAGA) (tBu)4 to radiolabel Lutetium-177 for peptide receptor Lutetium therapy.

[0034] The preferred molecule used for tumor targeted radiotherapy in the invention consists of an integrin antagonist peptidomimetic isotope preferably [177]Lutetium.

[0035] According to a preferred embodiment, a compound of the invention is comprised of three components. The first component is the integrin antagonist peptidomimetic. This component is the peptidomimetic that targets the HER2+ cells. The second component is a chelator, a compound able to combine radiometals (such as Lu-177) into complexes through a ring-like structure; and the third optional component is the radionuclide to enhance uptake to the tumor and extend biological half life.

[0036] A potent v3 integrin antagonist peptide mimic targeting agent specific for the HER2+ protein was developed, modified for use in humans and radiolabeled with Gallium-68, Fluorine-18 for diagnosis using positron emission tomography, or Lutetium-177 or Actinium-225 for use in humans enabling cancerous tumor detection using positron emission tomography and for tumor targeted radionuclide therapy (TRNT) alone or in combination with standard-of-care; immunotherapy and chemotherapy in the neoadjuvant setting. The radioligands enable non-invasive diagnosis and treatment of a wide range of cancers, while also reducing harmful side effects such as cardiovascular disease, peripheral neuropathy, and improving survival and quality of life.

[0037] The methods and therapeutic compositions of the present invention may be used in connection with a diagnostic. The diagnostic may be administered to the patient to identify areas of tumor or cancer cells or growth, and may be used to determine one or more subsequent treatment parameters for a treatment protocol, such as the treatment dosage and extent (e.g., where the treatment involves administering an a treatment compound according to the invention, such as the preferred composition, Lu-177 DOTAGA IAC. According to some embodiments, a preferred diagnostic composition may comprise Ga-68-NODAGA IAC: A ligand containing the active moiety, the v3 integrin antagonist peptidomimetic 4-[2-(3,4,5,6-tetrahydropyrimidine-2-ylamino)ethyloxy]benzoyl-2-[N-(3-aminoneopenta-1-carbamyl)]-aminoethylsulfonyl-amino--alanine (IAC) and attached (e.g., chelated) to 1-(1-carboxy-3-carbo-t-butoxypropyl)-4,7-(carbo-tert-butoxymethyl)-1,4,7-triazacyclononane.

[0038] The diagnostic and the therapeutic compositions preferably are prepared from components of a kit, where the composition is prepared and radiolabeled with the respective radionuclide prior to administering the composition to a patient/subject, which preferably is done intravenously.

PROPOSED EXAMPLES

Proposed Example 1

[0039] Example 1: a preferred compound of the invention, comprising Lu-177 DOTAGA IAC, is administered to a human patient at a fixed dose of 7.4 GBq (every 12 weeks) up to a cumulative dose which is tolerated by the patient (maximum 29.6 GBq). The preferred compound preferably is administered intravenously. Nivolumab is administered twice for each treatment of the preferred Lu-177 DOTAGA IAC compound, at a dose of 3 mg/Kg: one administration seven days before (d7) and the other administration seven days after (dpositive7) administration of the compound of the invention, with the aim of achieving an effective PD-1/PD-L1 blockade, but also in the need not to overlap the anticipated lymphocyte nadir related to the lymphocytopenia-induced effect of the compound of the invention.

[0040] Studies have shown that intravenous administration of amino acids has a renal protective effect. An infusion of amino acids (containing lysine and arginine) could be done 30 to 45 minutes before the administration of 177Lu-DOTATATE IAC and last for 3 to 4 hours.

Proposed Example 2

[0041] Example 2: In a proposed example, the compound of the present invention was administered to a patient suffering from HER2+ breast cancer. The patient was given the compound of the invention (e.g., in an amount of from about 3.7-7.4 GBq) administered intravenously, and representing a dosage. One or more, and preferably a plurality of subsequent treatments of a similar amount are dosed to the patient intravenously, a couple to a few weeks from the first dosage. In this example, an additional therapeutic may be administered on either side of a window based on when the patient receives the inventive compound doses, e.g., such as seven days prior to a dose and seven days after a dose.

Proposed Example 3

[0042] Example 3: The patient was treated as in proposed example 1, above, however, prior to treatment with the Lu-177 DOTAGA IAC, the patient was diagnosed using the preferred diagnostic composition, comprising Ga-68-NODAGA IAC.

Proposed Example 4

[0043] Example 4: The patient was treated as in proposed example 2, above, however, prior to treatment with the Lu-177 DOTAGA IAC, the patient was diagnosed using the preferred diagnostic composition, comprising Ga-68-NODAGA IAC.

Proposed Example 5

[0044] Example 5: The patient was treated as in Example 1, but with the radionuclide consisting of one or more of: Actinium-225, Bismuth-213, Thorium-227, Lead-212, Astatine-211, Yttrium-90, and Iodine-131, Gallium-68, and Zirconium-68.

Proposed Example 6

[0045] Example 6: The patient was treated as in Example 5, but with the chelator comprising one or more of: 4-[2-(3,4,5,6-tetrahydropyrimidine-2-ylamino) ethyloxy]benzoyl-2-[N-(3-aminoneopenta-1-carbamyl)]-aminoethylsulfonyl-amino--alanine (IAC), and (ii) at least one of the following: [0046] (a) 1-(1-carboxy-3-carbotertbutoxymethyl)-1,4,7,10-tetraazacyclododecane (DOTAGA) (tBu).sub.4; or [0047] (b) 4-[4,7-Bis-(carboxymethyl)-[1,4,7]triazonan-1-yl]-4-carboxy-butyryl (NODAGA); or [0048] (c) DOTATATE; or [0049] (d) C26H34N4O10S (CHX-A).