EP4329792A1

EP4329792A1 - Compound for treating covid-19 infections

Info

Publication number: EP4329792A1
Application number: EP22726694.7A
Authority: EP
Inventors: Horst Kessler; Ute REUNING; Susanne KOSSATZ; Kairbaan HODIVALA-DILKE; Beatrice Stefanie LUDWIG
Original assignee: Technische Universitaet Muenchen
Current assignee: Technische Universitaet Muenchen
Priority date: 2021-04-30
Filing date: 2022-04-29
Publication date: 2024-03-06
Also published as: WO2022229459A1

Abstract

The present invention provides agents, pharmaceutical compositions, and therapeutic methods for the treatment or prevention of Covid-19 infection relying on a αvβ3 integrin ligand, pharmaceutically acceptable salt, ester, polymorph, solvate or hydrate thereof, that is administered in a low dosage.

Description

Compound for treating Covid-19 Infections Technical Field The present invention relates to the field of medicine. More specifically, the present invention provides medical therapies for the treatment of patients suffering from Covid 19 infection. Background of the Invention The high mortality of SARS-Cov-2-infected patients suffering von Covid 19 and the challenges due to the so-called „Long Covid“ symptoms as high clinical complications are so far without any curative treatment and represent an immense burden on the health care system [1]. Especially dysfunctional vascular endothelial cells represent crucial players in SARS-CoV-2 infections leading to chronic inflammation and disease processes like thrombosis, atherosclerosis, lung injury, and fibrosis [2-5]. Immune dysregulation and hyper- inflammatory states in the vascular endothelium are considered to play a relevant role in the development of the severe forms of Covid 19 infection [2]. Angiotensin II-mediated pro- inflammatory signals and associated oxidative stress may play a vital role in the development of such hyperinflammatory states [2]. Recent studies have unraveled that vascular stabilization can be achieved with αvβ3 targeting and/or VEGF-targeted drugs [11]. Low-dose treatment [12, 13] with the integrin ligands cilengitide [7, 8] or 29 [9] or its prodrug 29P [9] may also lead to vascular stabilization [10] and exert pro-angiogenic effects by stabilizing endothelial cell anchoring on the base and allowing increased vessel dilation and blood flow [13]. Low dose administration of cilengitide has been established to enhance VEGFR2 expression [12]. VEGFR2 is known to cooperate with integrin αvβ5 to thereby lead to SRC-dependent phosphorylation of Raf Tyr340 and Tyr341, which may in turn lead to resistance to extrinsic apoptosis that is induced by inflammatory mediators such as tumour necrosis factor (TNF) [14]. Cilengitide [7, 8] is a highly selective integrin αvβ3/αvβ5-directed RGD-based ligand, designed as anti-cancer drug due to proposed anti-angiogenic effects [8,14,15]. During exploration of its clinical efficacy, e.g. in the CENTRIC Phase III clinical study with glioma patients by Merck [15], where Cilengitide was intravenously administered twice a week at a dose of 2.5 g, it was unexpectedly found that the drug enhanced pro-angiogenic effects in tumors and promoted vessel stabilization [8]. The reasons for these unexpected effects are largely unknown. The half-life of Cilengitide in man is only 4 h [16], hence, after 2 days, its plasma concentration ranges around a very low level corresponding to an administered dose of approximately 1 µg/kg. The associated low-dose effects were then shown to be mediated by increased signaling downstream of integrin αvβ3, involving integrin crosstalk with the vascular endothelial growth factor receptor-2 (VEGFR2) [12,13] Summary of the Invention There is an urgent and unmet need to provide effective therapies for the treatment or prophylaxis of Covid 19 infections. The present invention thus has the objective of providing effective therapies for the treatment or prophylaxis of Covid 19 infections. In one aspect, the present invention has the objective of providing effective therapies for the treatment or prophylaxis of Covid 19 infections, wherein vascular stabilization is accomplished while vascular symptoms and complications such as endothelial injury, thrombosis, embolies, Long Covid symptoms and the like are prevented, cured or at least reduced. In another aspect, the present invention has the objective of providing effective therapies for the treatment or prophylaxis of Covid 19 infections, wherein Long Covid symptoms are prevented or at least ameliorated. To accomplish these objectives, the present invention provides integrin αvβ3-directed ligands [6], such as Cilengitide [7,8] or 29P [9], which are to be administered at a low dosage. The treatments provided by the present invention allow to avoid or reduce the Covid 19- related devastating effects on the vascular system of the lungs and other affected organs and protect against these life-threatening effects after SARS-Cov-2 infection. Description of Figures Fig.1 depicts schematic activation of integrins and possible intervention. Right: The antagonistic effect to inhibit multivalent integrin binding to extracellular matrix (ECM) requires high doses of ligands. Left and centre: On the other hand an outside-in activation needs low concentration of binding ligands (more details are given in [6]). Outside-in activation gives rise to integrin clustering and cluster maturation and eventually formation of focal adhesions. One of the consequences of the formation of focal adhesions is a strong interaction between cell and ECM. In case of endothelial cells of blood vessels, such strong interactions are likely to contribute to vascular stabilization. Fig. 2 shows results of determination of qPCR SARS-CoV-2 RdRp gene levels in test animals after the treatments of Experiment 1 (A) and Experiment 2 (B) described in Example 1. Fig.3 shows results of determination of virus titers in the lungs of the test animals after the treatments of Experiment 1 (A) and Experiment 2 (B) described in Example 1. Fig.4 shows the total score of the histology assessments of the test animals as described in Example 1. Detailed description of the invention Definitions The following definitions are provided to assist the reader. Unless otherwise defined, all terms of art, notations, and other scientific or medical terms or terminology used herein are intended to have the meanings commonly understood by those of skill in the chemical and medical arts. In some cases, terms with commonly understood meanings are defined herein for clarity and/or for ready reference, and the inclusion of such definitions herein should not be construed as representing a substantial difference over the definition of the term as generally understood in the art. All cited documents are incorporated herein by reference in their entirety. References to internet pages are meant to be references to the specified pages in the version as accessible on April 30, 2021. The content of these pages may be assessed via the revision history function in case of Wikipedia pages and otherwise via internet archives such as the wayback machine (accessible under https://archive.org/web/ ) or the like. The articles “a”, “an” and “the” are used herein to refer to one or to more than one (i.e. to at least one) of the grammatical object of the article unless otherwise clearly indicated by contrast. By way of example, “an element” means one element or more than one element. The term “or” is used herein to mean, and is used interchangeably with, the term “and/or,” unless context clearly indicates otherwise. The term “comprising” includes, as one embodiment, the meaning “consisting of”. In some embodiments, the term “about” refers to a deviation of ± 10 % from the recited value. When the word “about” is used herein in reference to a number, it should be understood that still another embodiment of the invention includes that number not modified by the presence of the word “about”. In the absence of the term “about” and unless the context dictates otherwise, generally accepted rounding rules apply to the specified values. Binding of ligands to integrins, binding affinities and their specificities to other integrin subtypes is tested in an ELISA-based test system, described in detail in [T. G. Kapp, F. Rechenmacher, S. Neubauer, O. V. Maltsev, A. E. Cavalcanti-Adam, R. Zarka, U. Reuning, J. Notni, H.-J. Wester, C. Mas-Moruno, J. P. Spatz, B. Geiger, H. Kessler; A Comprehensive Evaluation of the Activity and Selectivity Profile of Ligands for RGD-binding Integrins, Scientific Reports 2017 7:39805 | DOI: 10.1038/srep39805]. The term “combination product” can refer to (i) a product comprised of two or more regulated components that are physically, chemically, or otherwise combined or mixed and produced as a single entity; (ii) two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products; (iii) a drug, device, or biological product packaged separately that according to its investigational plan or proposed labeling is intended for use only with an approved individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect and where upon approval of the proposed product the labeling of the approved product would need to be changed, e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose; or (iv) any investigational drug, device, or biological product packaged separately that according to its proposed labeling is for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication, or effect. "Combination therapy", “combination treatment”, “in combination with”, “together with” or “in conjunction with” as used herein denotes any form of concurrent, parallel, simultaneous, sequential or intermittent treatment with at least two distinct treatment modalities (i.e., compounds, components, targeted agents or therapeutic agents). As such, the terms refer to administration of one treatment modality before, during, or after administration of the other treatment modality to the subject. The modalities in combination can be administered in any order. The therapeutically active modalities are administered together (e.g., simultaneously in the same or separate compositions, formulations or unit dosage forms) or separately (e.g., on the same day or on different days and in any order as according to an appropriate dosing protocol for the separate compositions, formulations or unit dosage forms) in a manner and dosing regimen prescribed by a medical care taker or according to a regulatory agency. In general, each treatment modality will be administered at a dose and/or on a time schedule determined for that treatment modality. Optionally, three or more modalities may be used in a combination therapy. Additionally, the combination therapies provided herein may be used in conjunction with other types of treatment. The disclosure below sometimes relies on expressions such as the “combination therapy of the present invention” or the like. Unless the context dictates otherwise, these indications should be understood as references not only to the described combination therapy but also as disclosures of the respective features in the context of the materials to be used for this purpose, i.e. the respective compounds for use in the specified manner, the resulting drug combinations for the specified use, including kits and combination products for the specified use. Of course, descriptions of the “combination therapy of the present invention” are also to be understood as descriptions of methods of treating Covid 19 patients in need thereof. In the context of the present invention, “Covid 19 infection” refers to a condition, in which a patient is infected by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The terms “individual”, “patient” or “subject” are used interchangeably in the present application and are not meant to be limiting in any way. The “individual”, “patient” or “subject” can be of any age, sex and physical condition. Preferably, the methods of treatment and combination products of the present invention are for use in a human patient. In other words, the individual, patient or subject is preferably human. "Infusion" or "infusing" refers to the introduction of a drug-containing solution into the body through a blood vessel for therapeutic purposes. Generally, this is achieved via an intravenous bag. “Integrins” are adhesion receptors involved in a number of essential physiological processes including embryogenesis, angiogenesis, homeostasis, hemostasis, and wound healing [Hynes RO. Integrins: versatility, modulation, and signaling in cell adhesion. Cell.1992;69(1):11-25. A subclass of integrins recognize the tripeptide sequence RGD [Ruoslahti E, Pierschbacher MD. New perspectives in cell adhesion: RGD and integrins. Science. 1987;238(4826):491]. Their biological function and interaction with subtype selective ligands was recently reviewed [B. S. Ludwig, H. Kessler, S. Kossatz, U. Reuning, RGD-binding Integrins Revisited: How Recently Discovered Functions and Novel Synthetic Ligands (Re-)Shape an Ever-Evolving Field, Cancers 2021, 13, 1711] The present invention refers to a substance as a “ligand” if the substance shows high affinity binding to the target receptor. For instance, a substance may be considered a “αvβ3 integrin ligand” if it shows the binding affinities specified in the next section. As used herein, a “pharmaceutically acceptable” component is one that is suitable for use with humans without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio. As used herein, "pharmaceutically acceptable carrier", “pharmaceutically acceptable diluent”, “pharmaceutically acceptable excipient” or “pharmaceutically acceptable stabilizer” means any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed and, without limiting the scope of the present invention, include: additional buffering agents; preservatives; co-solvents; antioxidants, including ascorbic acid and methionine; chelating agents such as EDTA; metal complexes (e.g., Zn-protein complexes); biodegradable polymers, such as polyesters; salt-forming counterions, such as sodium, polyhydric sugar alcohols; amino acids, such as alanine, glycine, glutamine, asparagine, histidine, arginine, lysine, ornithine, leucine, 2-phenylalanine, glutamic acid, and threonine; organic sugars or sugar alcohols, such as lactitol, stachyose, mannose, sorbose, xylose, ribose, ribitol, myoinisitose, myoinisitol, galactose, galactitol, glycerol, cyclitols (e.g., inositol), polyethylene glycol; sulfur containing reducing agents, such as urea, glutathione, thioctic acid, sodium thioglycolate, thioglycerol, [alpha]- monothioglycerol, and sodium thio sulfate; low molecular weight proteins, such as human serum albumin, bovine serum albumin, gelatin, or other immunoglobulins; and hydrophilic polymers, such as polyvinylpyrrolidone. Other pharmaceutically acceptable carriers, excipients, or stabilizers, such as those described in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980) may also be included in a pharmaceutical composition described herein, provided that they do not adversely affect the desired characteristics of the pharmaceutical composition. Pharmaceutical compositions comprising a compounds may comprise Starch 1500 (reference to quality standard: Ph. Eur. 01/2010:1267) as a pharmaceutically acceptable excipient. The term “pharmaceutically acceptable salts” refers to the relatively non-toxic, inorganic and organic acid addition salts, or inorganic or organic base addition salts of compounds, including, for example, those contained in compositions of the present invention, and including those present in other approved drugs (wherein approval may be by any competent authority in the EU, USA, CA, JP, CN or KR). Pharmaceutically acceptable salts are meant to be encompassed by the present invention. Hence, all references to compounds of the invention are to be understood as references not only to the compounds as such, but also to pharmaceutically acceptable salts of the respective compounds. According to one aspect, the pharmaceutically acceptable salts may be selected from the salts acknowledged as pharmaceutically acceptable in the literature at the filing date, and in particular as described in G.S. Paulekuhn et al. in J. Med. Chem.2007, 50, 6665-6672 and references cited therein. The term “pharmaceutically acceptable salts” is intended to include salts of the active compounds which are prepared with acids or bases, depending on the particular substituents found on the compounds described herein. All references to αvβ3 integrin ligands in the present description are to be understood also as references to pharmaceutically acceptable salts of the respective specified active substances. Likewise, unless the context dictates otherwise, all references to αvβ3 integrin ligands in the present description are to be understood also as references to pharmaceutically acceptable prodrugs, polymorphs, solvates or hydrates of the respective specified active substances. The term “pharmaceutical composition” refers to any composition comprising at least one active agent, which is suitable for use in therapy, possibly after reconstitution. This includes unit dosage forms such as tablets or capsules but also infusion liquids, compositions for inhalation or any other administration form. Such pharmaceutical compositions may comprise one or more pharmaceutically acceptable excipients as described herein. The terms “treatment” and “therapy”, as used in the present application, refer to any hygienic, pharmacological, surgical and/or physical means used with the intent to cure and/or alleviate Covid-19 infection and/or symptoms thereof with the goal of remediating the health problem. The terms “treatment” and “therapy” include preventive and curative methods, since both are directed to the maintenance and/or reestablishment of the health of an individual. "Unit dosage form" as used herein refers to a physically discrete unit of therapeutic formulation appropriate for the subject to be treated. Unless the context dictates otherwise, ranges provided herein are to be understood to be shorthand disclosure of all of the values, combinations of numbers, or sub-ranges within the specified ranges. For example, a range of 1 to 50 is to be understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50. Unless the context dictates otherwise, any specific features of compositions or methods provided herein can be combined with one or more of any other feature of the compositions and methods provided herein including, but not limited to, combinations of dosing rates, dosing times, dosing amounts, treatment methods, and use of agents other than the αvβ3 integrin ligand. αvβ3 Integrin Ligand The αvβ3 integrin ligand is a compound that is capable of binding to the αvβ3 integrin with high affinity. Preferably, the αvβ3 integrin ligand shows a binding affinity towards the αvβ3 integrin with an IC₅₀ value of about 10 nM or less, such as 6 nM or less, preferably 4 nM or less, more preferably 2 nM or less and most preferably 1 nM or less. There is no restriction of the lower limit for this value although, in practice, binding affinities are typically at 0.1 nM or higher. A possible binding of the compound to other integrin subtypes is not necessarily harmful for the present invention as long as the compound binds with sufficiently high affinity to the αvβ3 integrin, in accordance with the preceding paragraph. Hence, in one embodiment, the compound is a pan-RGD ligand, i.e. a compound that binds to all integrins recognizing the RGD-recognition motif. A suitable example for this class of compounds is MK-0429 (L-000845704), which has the following structure: It is an orally active, potent and nonpeptide pan-integrin antagonist with IC₅₀ values of 1.6 nM, 2.8 nM, 0.1 nM, 0.7 nM, 0.5 nM and 12.2 nM for αvβ1, αvβ3, αvβ5, αvβ6, αvβ8 and α5β1, respectively. [Murphy MG, Cerchio K, Stoch SA, Gottesdiener K, Wu M, Recker R. Effect of L-000845704, an alphaVbeta3 integrin antagonist, on markers of bone turnover and bone mineral density in postmenopausal osteoporotic women. J Clin Endocrinol Metab.2005;90(4):2022-8. 328. Hutchinson JH, Halczenko W, Brashear KM, Breslin MJ, Coleman PJ, Duong LT, et al. Nonpeptide alphavbeta3 antagonists. 8. In vitro and in vivo evaluation of a potent alphavbeta3 antagonist for the prevention and treatment of osteoporosis. J Med Chem.2003;46(22):4790-8] In another embodiment, the compound is a compound binding specifically to the αvβ3 integrin and αvβ5 integrin. In another embodiment, the compound is a compound binding specifically to the αvβ3 integrin and αvβ6 integrin. In yet another embodiment, the compound is a compound binding specifically to the αvβ3 integrin and α5β1 integrin. In other preferred embodiments, the αvβ3 integrin ligand shows high specificity in the binding to αvβ3 integrin in relation to the binding to one or more other integrin subtypes. Preferably, the ratio of IC₅₀(αvβ3):IC₅₀(other integrin subtype) is 1:10 or lower for any other integrin subtype, more preferably lower than 1:30, 1:50 or lower, or even lower than 1:100. The compound may be a peptide, a modified peptide, a protein, or any other molecule having the binding properties specified above. The best studied integrin αvβ3 integrin ligand is cilengitide [7,8]. Hence, a preferred αvβ3 integrin ligand is cilengitide. This is a cyclic peptide having the following structure: cyclo-(Asp-D-Phe-NMeVal-Arg-Gly). [a) M. A. Dechantsreiter, E. Planker, B. Mathä, E. Lohof, G. Hölzemann, A. Jonczyk, S. L. Goodman, H. Kessler; N-Methylated Cyclic RGD Peptides as Highly Active and Selective α_vß₃ Integrin Antagonists; J. Med. Chem.1999, 42, 3033-3040. b) Mas-Moruno C, Rechenmacher F, Kessler H. Cilengitide: the first anti- angiogenic small molecule drug candidate design, synthesis and clinical evaluation. Anticancer Agents Med Chem.2010;10(10):753-68]. In another embodiment, a derivative of cilengitide may be used, in which the phenyl group of cilengitide is further substituted by a para-hydroxy group or, in other words, wherein the D-Phe residue is replaced by a D-Tyr residue. All further indications concerning cilengitide are equally applicable to this cilengitide derivative. Another preferred αvβ3 integrin ligand is the peptide “29” with the structure cyclo-(D- NMeVal-Arg-Gly-Asp-Ala-NMeAla). The compound, its manufacture and its integrin binding characteristics are described in [9] and in the associated supplementary information. Also other αvβ3 integrin ligands, such as peptidic compounds or non-peptidic compounds or peptidomimetics, may be used. Suitable further αvβ3 integrin ligands are the compounds described for instance in Figure 7 of [6], such as iRGD with the following structure:

, Table 1 of [7] and Table 3 of [8], such as the compounds cyclo(RGDfV) and cyclo(-N(Me)R- GDfV), Tables 1 and 2 of [9], such as cyclo(NMeA-RGDA-NMeA-), cyclo(D-NMeF-RGDA- NMeA-), cyclo(D-NMeR-GDA-NMe-A-V), cyclo(D-NMeR-GDA-NMeA-F), cyclo(D-NMeA-RGDA- NMeA-), S 36578 ((5-(S)-7-{[4-(pyridin-2-ylamino)-butyryl amino]-methyl}-6,9-dihydro-5H- benzocyclohepten-5-yl) acetic acid or salt thereof) as mentioned with further literature in [12] as well as compounds 2, 3 and 6 of Scheme 1 and Table 1 of [17] having the following structures: wherein the variable groups have the following meanings: Compound 2: R₁ = OiPr; R₂ = OH and Y = CO Compound 3: R₁ = Me; R₂ = OH and Y = SO₂ Compound 6: R₁ = F; R₂ = OH and Y = CO. The above-mentioned compounds are all suitable for use in the present invention on condition that they show binding affinity to the αvβ3 integrin in accordance with the above criteria. Prodrugs of αvβ3 Integrin Ligand The αvβ3 integrin ligand may be provided in prodrug form. This may be advantageous for improving oral bioavailability and/or for improving other performance characteristics. This concept and the relevant literature is described generally in [Rautio J et al.; Prodrugs: design and clinical applications, Nature Reviews 2008, 7, 255-270, doi:10.1038/nrd2468] and specifically with respect to integrin-binding peptides in Schumacher-Klinger A et al.; Enhancing Oral Bioavailability of Cyclic RGD Hexa-peptides by the Lipophilic Prodrug Charge Masking Approach: Redirection of Peptide Intestinal Permeability from a Paracellular to Transcellular Pathway, Mol. Pharmaceutics 2018, 15, 3468-3477, DOI: 10.1021/acs.molpharmaceut.8b00466]. The prodrugs for use in the invention are compounds that are hydrolysed under physiological conditions to yield an αvβ3 integrin ligand in accordance with at least the high affinity αvβ3 integrin binding criterion specified in the preceding section. Prodrugs suitable for use in the present invention may contain one or more of the following modifications: (i) a carboxyl group in an amino acid sidechain (e.g. sidechain of aspartic acid or glutamic acid) is converted to an ester (e.g., *-C(O)-O-R with R being a C_1-6 alkyl group, preferably a C_1-3 alkyl group, more preferably a methyl or ethyl group and most preferably a methyl group, wherein the asterisk characterizes the point of attachment of the remainder of the molecule); (ii) a carboxyl group in an amino acid sidechain (e.g. sidechain of aspartic acid or glutamic acid) is converted to an amide (e.g., *-C(O)-NH-R with R being a C_1-6 alkyl group, preferably a C_1-3 alkyl group, more preferably a methyl or ethyl group and most preferably a methyl group, wherein the asterisk characterizes the point of attachment of the remainder of the molecule); (iii) the terminal nitrogen atoms of a guanidine group in an amino acid sidechain (e.g. sidechain of arginine) are converted to yield alkyloxycarbonyl groups (e.g., *-NH- C(NH-C(O)-O-R)(=N-C(O)-O-R)) wherein the alkyl groups R may be a C_1-10 alkyl group, preferably a C_4-8 alkyl group, more preferably a pentyl, hexyl or heptyl group and most preferably a hexyl group and wherein the asterisk characterizes the point of attachment of the remainder of the molecule). (iv) a hydroxyl group in an amino acid sidechain (e.g. sidechain of tyrosine, serine or threonine) is converted to an ether group (e.g., having the structure *-O-CH(R1)- C(O)-R2, wherein R1 is hydrogen or methyl and R2 is C_1-6 alkyl and preferably C_3-6 alkyl, more preferably butyl such as tert-butyl and wherein the asterisk characterizes the point of attachment of the remainder of the molecule); (v) a hydroxyl group in an amino acid sidechain (e.g. sidechain of tyrosine, serine or threonine) is converted to a carbonate group (e.g., having the structure *-O-C(O)- O-R, wherein R is C_1-6 alkyl, preferably C2-6 alkyl, more preferably butyl and most preferably tert-butyl and wherein the asterisk characterizes the point of attachment of the remainder of the molecule); and/or (vi) a hydroxyl group in an amino acid sidechain (e.g. sidechain of tyrosine, serine or threonine) is converted to an ester group (e.g., having the structure *-O-C(O)-R, wherein R is C_1-6 alkyl, preferably C2-6 alkyl, more preferably butyl and most preferably tert-butyl and wherein the asterisk characterizes the point of attachment of the remainder of the molecule). One or more of the modifications listed above may be incorporated into any αvβ3 integrin ligand that is suitable for use in the present invention, including especially the specific compounds described hereinabove. Of course, it is also possible to modify the above- mentioned functional groups if they form part of a non-peptidic compound such as MK-0429 (L-000845704) or compounds 2, 3 and 6 of [17]. More preferably, the modifications under items (i) and (iii) are combined in the sidechains of the Asp and Arg amino acids, respectively. These amino acids are present in most αvβ3 integrin ligands since they form part of the RGD-recognition motif. This concept has been implemented in the prodrug “29P” which is derived from peptide 29 mentioned above. Compared to compound 29, the prodrug 29P additionally contains a methyl ester group at the Asp sidechain and two hexyloxycarbonyl (“Hoc”) groups at the guanidino group of the Arg residue, so that this compound has the structure cyclo-(D-NMe-Val-Arg(Hoc)₂-Gly- Asp(OMe)-Ala-NMe-Ala). The prodrug 29P is a modified cyclic peptide, which also acts as an integrin αvβ3 ligand after cleavage. It has the advantage of being orally available in low concentrations [9] and the prodrug modification groups are rapidly cleaved-off in the serum to yield the binding ligand for integrin αvβ3. It shows improved lipophilicity and, after cleavage in vivo to form 29, very high affinity (0.6 nM, identical to Cilengitide) and specificity towards integrin αvβ3 compared to other RGD-recognizing integrins, such as α5β1, αvβ6, and αvβ8. Further details on 29P are described in [9] and the associated supplementary information. The structures of 29 and 29P are shown below: Patient The patient to be treated is a human patient infected with Covid 19 or at risk of being infected with Covid 19. This can be an infection with any mutant form of Covid-19, including for instance the mutants B.1.1.1.7, P.1, B.1.351, B.1.427, B.1.429, B.1.525, B.1.526, B.1.617 or any other mutant form. The patient may be a patient at risk of getting infected by Covid 19, a patient freshly infected by Covid 19 (infection less than 5 days ago), or a patient infected for a longer time of 5 or more days. Administration form The αvβ3 integrin ligand may be administered via any administration route that is feasible for the αvβ3 integrin ligand, including but not limited to intravenous, oral, nasal inhalation or mouth inhalation. Cilengitide, for instance, should be administered via a parenteral route and preferably by intravenous infusion or injection. By contrast, 29P may be administered orally although other administration types may also be used. Dosage and timing It is important to administer the αvβ3 integrin ligand at a low dosage. This means that the dosage must be such that it can exercise the above-mentioned agonistic binding and vascular stabilization effect. Typically, the daily dosage is in the range of 0.01 µg/kg to 1000 µg/kg, preferably 0.05 µg/kg to 500 µg/kg, more preferably 0.1 µg/kg to 100 µg/kg and even more preferably 0.2 µg/kg to 50 µg/kg, such as especially 0.5 µg/kg to 30 µg/kg or 0.25 µg/kg to 20 µg/kg. If the αvβ3 integrin ligand is administered orally, the daily dosage is preferably in the range of 0.02 µg/kg to 1000 µg/kg, more preferably 0.1 µg/kg to 400 µg/kg and even more preferably 0.2 µg/kg to 200 µg/kg. For instance, when using orally administered 29P, the daily dosage is most preferably in the range of 0.5 µg/kg to 50 µg/kg. In further embodiments, the dose may be selected from one of the following ranges: 1.3 – 130 µg/kg, 1.0 – 140 µg/kg, 1.5 – 120 µg/kg, 1.5 – 210 µg/kg, 0.5 – 70 µg/kg, 2.3 – 180 µg/kg, 0.8 – 60 µg/kg, 5.2 – 104 µg/kg, 5 – 100 µg/kg, 6 – 110 µg/kg, 8 – 150 µg/kg, 3.0 – 50 µg/kg, 9 – 170 µg/kg, 3 – 55 µg/kg, 20 – 130 µg/kg, 20 – 140 µg/kg, 20 – 120 µg/kg, 20 – 210 µg/kg, 20 – 70 µg/kg, 20 – 180 µg/kg, 20 – 60 µg/kg, 20 – 104 µg/kg, 20 – 100 µg/kg, 20 – 110 µg/kg, 20 – 150 µg/kg, 20 – 50 µg/kg, 20 – 170 µg/kg, 20 – 55 µg/kg, 33 – 130 µg/kg, 33 – 140 µg/kg, 33 – 120 µg/kg, 33 – 210 µg/kg, 33 – 70 µg/kg, 33 – 180 µg/kg, 33 – 60 µg/kg, 33 – 104 µg/kg, 33 – 100 µg/kg, 33 – 110 µg/kg, 33 – 150 µg/kg, 33 – 50 µg/kg, 33 – 170 µg/kg, 33 – 55 µg/kg 33 – 330 µg/kg, and 33 – 260 µg/kg. Suitable dosage ranges for other orally administered αvβ3 integrin ligands may be adapted to this most preferred range by suitably adjusting the range based on the ratio of αvβ3 integrin binding affinities (i.e. by multiplying with the ratio IC₅₀(other ligand):IC₅₀(29P)) and also by adjusting based on the inverse ratio of oral bioavailabilities (i.e. by multiplying with the ratio AUC_po(29P):AUC_po(other ligand)). Moreover, using pharmaceutically acceptable salts and/or esters also leads to changes in the molecular weight of a compound in comparison with the unmodified free acid or base. Such differences in molecular weight should also be taken into account when adjusting the dosage, namely by multiplying with the ratio of molecular weights M(other ligand):M(29P). In case of intravenous administration the preferred daily dosage is in the range of 0.01 µg/kg to 400 µg/kg, more preferably 0.05 µg/kg to 200 µg/kg and even more preferably 0.1 µg/kg to 50 µg/kg. For instance, if the αvβ3 integrin ligand is i.v. administered cilengitide, the most preferred daily dosage is in the range of 0.2 µg/kg to 20 µg/kg. In further embodiments, the dose may be selected from one of the following ranges: 1.3 – 32.5 µg/kg, 1.0 – 35 µg/kg, 1.5 – 30 µg/kg, 1.5 – 55 µg/kg, 0.5 – 18 µg/kg, 2.3 – 48 µg/kg, 0.8 – 15 µg/kg, 5.2 – 19.5 µg/kg, 5 – 22 µg/kg, 6 – 18 µg/kg, 8 – 33 µg/kg, 3.0 – 11 µg/kg, 9 – 27 µg/kg, 3 – 9 µg/kg, 8.5 – 32.5 µg/kg, 8.5 – 35 µg/kg, 8.5 – 30 µg/kg, 8.5 – 55 µg/kg, 8.5 – 18 µg/kg, 8.5 – 48 µg/kg, 8.5 – 15 µg/kg, 8.5 – 19.5 µg/kg, 8.5 – 22 µg/kg, 8.5 – 18 µg/kg, 8.5 – 33 µg/kg, 8.5 – 11 µg/kg, 8.5 – 27 µg/kg, 11 – 32.5 µg/kg, 11 – 35 µg/kg, 11 – 30 µg/kg, 11 – 55 µg/kg, 11 – 18 µg/kg, 11 – 48 µg/kg, 11 – 15 µg/kg, 11 – 19.5 µg/kg, 11 – 22 µg/kg, 11 – 18 µg/kg, 11 – 33 µg/kg, and 11 – 27 µg/kg. Suitable dosage ranges for other i.v. administered αvβ3 integrin ligands may be adapted to this most preferred range by suitably adjusting the range based on the ratio of αvβ3 integrin binding affinities (i.e. by multiplying with the ratio IC₅₀(other ligand):IC₅₀(cilengitide)) and also by adjusting based on the inverse ratio of i.v. bioavailabilities (i.e. by multiplying with the ratio AUC_iv(cilengitide):AUC_iv(other ligand)). In addition, it needs to be considered that different active agents have different molecular weights. Moreover, similar to the situation described above, differences in molecular weight should also be taken into account when adjusting the dosage, namely by multiplying with the ratio of molecular weights M(other ligand):M(cilengitide). Another way of ascertaining a suitably low dosage is to monitor blood plasma levels of the αvβ3 integrin ligand. Hence, in another embodiment, the blood plasma level should be in the range of 0.01 ng/mL to 1000 ng/mL, preferably 0.05 ng/mL to 500 ng/mL, more preferably 0.1 ng/mL to 200 ng/mL and even more preferably 0.2 ng/mL to 100 ng/mL, such as especially 0.5 ng/mL to 50 ng/mL or 1 ng/mL to 25 ng/mL. It is desirable to adjust administration form, formulation type and administration intervals such that the above target ranges are accomplished for at least 50% of the time, preferably at least 75% of the time, more preferably at least 90% of the time and most preferably for 100% of the time. According to further embodiments, cilengitide may be administered intravenously at a dosage, which corresponds to hamster dosages of one of 10 – 250 µg/kg, 15 – 250 µg/kg, 20 – 250 µg/kg, 30 – 250 µg/kg, 40 – 250 µg/kg, 50 – 250 µg/kg, 65 – 250 µg/kg, 85 – 250 µg/kg, 10 – 150 µg/kg, 15 – 150 µg/kg, 20 – 150 µg/kg, 30 – 150 µg/kg, 40 – 150 µg/kg, 50 – 150 µg/kg, 65 – 150 µg/kg, 85 – 150 µg/kg. In this connection, correspondence means that the dosage administered to the human patient should give rise to a plasma level that is the same (within experimental error) as the hamster plasma levels that can be observed when administering the dosages specified in the beginning of this paragraph. To reduce experimental error, it is preferable to determine plasma levels on at least six hamsters and then calculate the average of the determined values. The plasma level is time dependent. The above assessment of correspondence should be done at a pre-determined point in time which is always the same for all samples, e.g. 1 h after administration or 2 h after administration or 4 h after administration. Hence, suitable dosages for administration to human patients may be derived from one or the above dosage indications by experimentally determining plasma levels of the hamster or hamsters and then determining appropriate human doses resulting in the same plasma levels by means of dose titration/phase I-type trials. The administration frequency of the αvβ3 integrin ligand is not particularly restricted. The αvβ3 integrin ligand may be administered 1, 2, 3 or 4 times per day. Longer administration intervals such as administration every 2, 3, 4, 5, 6, 7, 8, 9, 10 or 14 days are also conceivable. Suitable administration intervals may be determined taking half-life of the αvβ3 integrin ligand into account, as well as administration form and formulation type, such as sustained release formulations typically permitting longer administration intervals. Formulation type and pharmaceutical composition The αvβ3 integrin ligand may be provided as a pharmaceutical composition in any formulation and formulation type that is suitable for the selected administration form. In one embodiment, the present invention provides pharmaceutical compositions that are intended to be administered by infusion or injection may be in the form of a ready-to-use solution containing the αvβ3 integrin ligand together with solvent and optionally further pharmaceutically acceptable components. Such solution type pharmaceutical compositions may be provided as unit dosage forms or in larger quantities containing 2, 3, 4, 5, 6 or more individual doses. The αvβ3 integrin ligands to be administered by infusion or injection may thus be formulated in the form of a solution or suspension in a suitable pharmaceutically acceptable solvent such as water for injection, ethanol, isopropanol, glycerol and/or a fatty oil such as sesame oil. Optionally, the formulation may contain one or more further excipients including stabilizers such as antioxidants and suspension agents, tonicity agents, solubilizers, pH adjusting agents and the like. Alternatively, pharmaceutical compositions of the invention that are intended to be administered by infusion or injection may be in the form of a lyophilized solid or concentrate that needs to be reconstituted with pharmaceutically acceptable solvent before use. Optionally present pharmaceutically acceptable additional components such as pH adjusting agents and/or stabilizers may be present already in the lyophilized solid pharmaceutical composition or in the concentrate pharmaceutical composition. In another embodiment, the present invention provides pharmaceutical compositions for oral administration. The αvβ3 integrin ligand to be orally administered may be formulated in the form of tablets, film-coated tablets, capsules, dragees, powders, granulates, and the like. In the pharmaceutical compositions of this embodiment, the αvβ3 integrin ligand may be admixed with one or more pharmaceutically acceptable excipients selected from binders, fillers, disintegrants, lubricants, glidants, antioxidants, buffering agents, and the like. The pharmaceutical compositions of the present invention and especially the pharmaceutical compositions for infusion or injection are preferably sterilized. This can be done using conventional methods, whereby the selected method must not interfere with the stability of the active agent. Said pharmaceutical compositions may be provided in the form of unit dosage forms such as tablets or capsules packaged in a bottle or blister packaging. Unit dosage forms of the invention may, for instance, contain the αvβ3 integrin ligand in an amount in the range of 0.6 µg to 80 mg, preferably 3 µg to 40 mg, more preferably 6 µg to 8 mg and even more preferably 12 µg to 4 mg, such as especially 30 µg to 2.4 mg or 15 µg to 1.6 mg. If the αvβ3 integrin ligand is administered orally, the unit dosage form may for instance contain the αvβ3 integrin ligand in an amount in the range of preferably 1.2 µg to 80 mg, more preferably 6 µg to 32 mg and even more preferably 12 µg to 16 mg. For instance, when using orally administered 29P, the most preferred unit dosage form contains 29P in the range of 30 µg to 4 mg. If the αvβ3 integrin ligand is administered intravenously, the unit dosage form may for instance be a pre-filled syringe and it may contain the αvβ3 integrin ligand in an amount in the range of preferably 0.6 µg to 32 mg, more preferably 3 µg to 16 mg and even more preferably 6 µg to 4 mg. For instance, if the αvβ3 integrin ligand is i.v. administered cilengitide, the most preferred unit dosage form contains cilengitide in the range of 12 µg to 1.6 mg. Methods of treatment The present invention provides therapies and treatments for patients in need thereof. Specifically, the present invention provides methods for treating patients affected by Covid 19 infection. The methods of the invention involve the step of administering the αvβ3 integrin ligand and/or pharmaceutical composition of the present invention to a patient in need thereof. Said administration may be repeated as necessary to accomplish the desired therapeutic effect. Therapeutic effects that may be accomplished with the methods of the present invention are vascular stabilization as well as prevention or reduction of thrombosis events, embolism events, thromboembolic events, microangiopathy, vasoplegia, and endothelial cell dysregulation as well as Long Covid symptoms. Combination therapy and combination products In another embodiment, the present invention provides combination therapies for the treatment or prevention of Covid 19 infection or symptoms thereof. Such combination therapies involve the treatment with the αvβ3 integrin ligand or pharmaceutical composition comprising the same, as described hereinabove, in combination with one or more additional therapies for treating or preventing Covid 19. Such additional therapies may include any established or experimental anti-Covid 19 therapy such as treatment with steroids like dexamethasone or budesonide, antiviral agents like remdesivir or favipiravir, convalescent plasma treatment, antibody treatment like anti-IL6 antibodies such as tocilizumab. In other embodiments of the present invention, an agent for the additional treatment referred to above is combined with the αvβ3 integrin ligand or pharmaceutical composition comprising the same according to the present invention to thereby obtain a combination product of the present invention. This is an attractive option especially if the administration form and frequency of the additional treatment is compatible with administration form and frequency of the treatments of the present invention. For treatments to be administered at different times or frequencies or by means of a different route of admininstration, it is necessary to provide the combination product of the present invention in the form of a kit, in which the different agents are provided as separate dosage forms, typically in separate containers. Examples Example 1 – viral load Ethics statement All experiments in mice were approved by an external committee according to the national guidelines of the animal welfare law in Germany. The protocol used in these experiments has been reviewed by an ethics committee and approved by the ‘Niedersächsisches Landesamt für Verbraucherschutz und Lebensmittelsicherheit, Oldenburg, Germany’. Laboratory Syrian hamster purchased from Janvier, France. All animals were maintained at specific pathogen free conditions at the animal facilities of the Research Center for Emerging Infections and Zoonoses (RIZ). Virus SARS-CoV-2 (BetaCoV/Germany/BavPat1/2020p.1) was propagated in Vero E6 cells (ATCC #CRL-1586) in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 2 % fetal bovine serum, 1 % penicillin-streptomycin and 1 % L-glutamine at 37°C. All infection experiments with SARS-CoV-2 were performed in the biosafety level 3 (BSL-3) laboratory at the Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Germany. Infection of hamsters Hamsters at the age of 8-12 weeks were anesthetized by inhalation of isoflurane. Infection was performed by intranasal application of virus solution in 100 µl sterile phosphate- buffered saline (PBS). For SARS-CoV-2 viruses, we challenge the hamsters with 1x10⁴ TCID₅₀ unit. Mock infected hamster group received 100 µl physiological salt solution intranasally. Subsequently survival, body weight loss, and clinical symptoms were monitored and scored until day 6 p.i. On day 6 p.i., all hamsters were euthanized by applying overdose of intra- peritoneal injection of Ketamin-Medetomidin solution in sterile NaCl (1000 mg/kg Ketamidor®, WDT, Garbsen, Germany; 1.25 mg/kg Domitor®, Orion-Pharma, Ismaning, Germany) with a dose adjusted to the individual body weight. Treatment Experiment 1 The hamsters described above were assigned to treatment groups and received treatments as shown in Table 1 below. The treatment administration scheme was as follows: the test treatments were administered ad days -2, 1, and 4 (with day 0 being the day of virus infection). All treatments as well as the virus infection were administered at 12 am. The hamsters were then euthanized at day 6 at 9 am and subsequently as described hereinbelow. Table 1: treatments of Experiment 1 Treatment Experiment 2 The treatments shown in the Table 2 below were administered according to the same scheme as described above for treatment experiment 1. Table 2: treatments of Experiment 2 Determination of infectious viral particles For determining virus titers in the lung of infected hamster, the right lobe of the lungs were prepared into 500 μl DMEM containing antibiotics (penicillin and streptomycin, Gibco). Tissue was homogenized using the TissueLyser-II (Qiagen), and aliquots were stored at -80 °C, subsequently. Virus titers were determined on Vero cells as median tissue culture infectious dose (TCID₅₀ units). Briefly, Vero cells were seeded in 96-well plates and serial 10- fold dilutions of homogenized lung samples in DMEM containing 5% FBS. After incubation at 37°C, cytopathic effect with cells death were record and calculated as TCID₅₀ unit per gram of hamster lungs by using Reed-Muench method. Real-time RT-PCR for detection of SARS-CoV-2 To determine the viral RNA amount in the lung of infected hamsters, the quantited one-step RT-PCR had performed by using the standard protocol provided by WHO. Two µl of total RNA product were amplified with specific primer/probe set (IP4) to amplify the RdRp gene complex of SARS-CoV-2 as described previously. Quantitative RT-PCR were carried out by using Luna® Universal Probe One-Step RT-qPCR Kit (New England Biolabs) in a CFX96-Touch Real-Time PCR system (Bio-Rad). The Ct value of samples was correlated to standard RNA transcript and the quantity of viral RdRp copynumbers per uL of total RNA was calculated per g lung tissue. Results The results of the above analytical evaluations are shown in Figures 2, 3 and 4. Example 2 – histology Material and Methods: Histology investigations were performed on the same hamsters and in parallel to the experiments described in treatment Experiment 1 of Example 1. In addition, a group of 6 hamsters were treated with orally administered 10 mg/kg methylprednisolone (based on the same administration scheme as described for treatment Experiment 1) as a positive control. Histopathology Formalin-fixed paraffin embedded samples were cut into 2 μm thick serial sections and stained with hematoxylin and eosin (H&E). Sections of the lung were scanned using an Olympus VS200 Digital slide scanner (Olympus Deutschland GmbH, Hamburg, Germany) and evaluated in a blinded manner with a semi-quantitative scoring system with special emphasis on inflammation, degeneration and regeneration as previously described (Bošnjak et al., 2021) with minor modification. Histopathological semi-quantitative evaluations were performed by veterinary pathologists in a blinded fashion. Subsequently, histopathological evaluation and scoring were reviewed confirmed by board certified veterinary pathologists. The scoring was evaluated accorting to a scale from 0 (e.g. no lesions) to maximum of 5 (more than > 75 % of tissue affected with lesions). A separate scoring was done for (1) airway lesions, (2) alveolar lesions, and (3) vascular lesions. Finally, the sum of all three scorings for airways, alevolar and vascular lesions was added together and named as „lung HE total sum“ and compared between all groups. The details are described in the following tables. Reference: Bošnjak, B. et al. Intranasal Delivery of MVA Vector Vaccine Induces Effective Pulmonary Immunity Against SARS-CoV-2 in Rodents. Front Immunol 12, 772240, doi:10.3389/fimmu.2021.772240608 (2021). Histology Assessment and Results The individual assessments of airway lesions, alveolar lesions and vascular lesions were performed on each animal based on the scoring schemes specified in Tables 3, 4 and 5 below. Table 3: Scoring of airway lesions

Table 4: Scoring of alveolar lesions

Table 5: Scoring of vascular lesions

Finally, the total HE sum score was calculated for each animal as the sum of the airway lesions score, alveolar lesions score and vascular lesions score. The raw data of these assessments are shown in Table 6 below and the total HE sum score results are shown in Figure 6. Table 6: Raw data of histology assessment

References [1] https://www.health.harvard.edu/diseases-and-conditions/treatments-for-covid-19. [2] H.K. Siddiqi, P. Libby, P.M. Ridker, Trends in Cardiovas. Med.2021,31, 1-5. [3] B. Oronsky, C. Larson, T.C. Hammond, A. Oronsky. S. Kesari, M. Lybeck. T.R. Reid, A Review of Persistent Post-COVID Syndrome (PPCS), Crit. Rev. Allergy & Immunology 2021, available online [4] T.T. Dhawan, L. Howard, A. Vicente, M. Park, K. Manalan, I. Wallner, P. Marshden, S. Dave, H. Branley, G. Russell, N. Dharmarajah, O. M. Kann, Respirattory, Beyond the clot: perfusion imaging of the pulmonary vasculature after COVID-19, Respiratory 2021, 9.107- 116l. [5] [Z. Varga, A. J Flammer, P. Steiger, M. Haberecker, R. Andermatt, A.S. Zinkernagel, M. R Mehra, R.A Schuepbach, F. Ruschitzka, H. Moch, f.Ruschitzka. Lancet.2020, 1417–1418. [6] (a) B. S. Ludwig, H. Kessler, S. Kossatz, U. Reuning, RGD-binding Integrins Revisited: How Recently Discovered Functions and Novel Synthetic Ligands (Re-)Shape an Ever-Evolving Field, Cancers 2021, 13 (7), 1711. DOI: 10.3390/cancers13071711 and (b) M. Nieberler, U. Reuning, F. Reichart, J. Notni, H.-J. Wester, M. Schwaiger, M. Weinmüller, A. Räder, K. Steiger, H. Kessler; Exploring the role of RGD-recognizing integrins in cancer, Cancers 2017, 9(9), 116; doi:10.3390/cancers9090116. [7] M. A. Dechantsreiter, E. Planker, B. Mathä, E. Lohof, G. Hölzemann, A. Jonczyk, S. L. Goodman, H. Kessler; N-Methylated Cyclic RGD Peptides as Highly Active and Selective α_vß₃ Integrin Antagonists; J. Med. Chem.1999, 42, 3033-3040. [8] Mas-Moruno, F. Rechenmacher, H. Kessler; Cilengitide: the first anti-angiogenic small molecule drug candidate. Design, synthesis and clinical evaluation, Anti-Cancer Agents in Medicinal Chemistry 2010, 10, 753-768. [9] M. Weinmüller, F. Rechenmacher, U. Kiran Marelli, F. Reichart, T. G. Kapp, A. F. B. Räder, F. S. Di Leva, L. Marinelli, E. Novellino, J. M. Muñoz-Félix, K. Hodivala-Dilke, A. Schumacher, J. Fanous, C. Gilon, A. Hoffman, H. Kessler, Overcoming the lack of oral availability of cyclic hexapeptides: Design of a new selective and orally available ligand for the integrin αvβ3, Angew. Chem. Int. Ed.2017, 56, 16405-16409. doi10.1002/anie.201709709 [10] E. Bridges and A.L. Harris, Vascular-Promoting Therapy Reduced Tumor Growth and Progression by Improving Chemotherapy Efficacy, Cancer Cell, 2015, 27, 7-9. [11] P. Carmeliet and R.K. Jain, Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases Nat. Rev. Drug Disc.2011, 10, 417-427. [12] A.R. Reynolds, I.R. Hart, A, R. Watson, J. C Welti, R. G Silva, S. D Robinson,G. Da Violante, M. Gourlaouen, M. Salih, M. C Jones, D.T Jones, G. Saunders, V. Kostourou, F. Perron-Sierra, J.C Norman, G.C Tucker & K. M Hodivala-Dilke. Stimulation of tumor growth and angiogenesis by low concentrations of RGD-mimetic integrin inhibitors, Nat. Med.2009, 15, 392-400]. [13] P.-P. Wong, F. Demircioglu, E. Ghazaly, W. Alrawashdeh, M.R.L. Stratford, C. L. Scudamore, B. Cereser, T. Crnogorac-Jurcevic, S. McDonald, G. Elia, T. Hagemann, H. M. Kocher & K. M. Hodivala-Dilke. Dual-Action Combination Therapy Enhances Angiogenesis while Reducing Tumor Growth and Spread, Cancer Cell 2015, 27, 123-137. [14] J.S. Desgrosellier & D.A. Cheresh, Integrins in cancer: biological implications and therapeutic opportunities, Nat. Rev. Cancer, 2010, 10, 9 – 22; see also corrigendum after the references. [15] R. Stupp, et al. Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study):a multicentre, randomised, open-label, phase 3 trial. The Lancet 2014, 15, 1100- 1108. [16] A. Becker, O. von Richter, A. Kovar,H. Scheible, J. J. van Lier, A. Johne, Metabolism and Disposition of the av-Integrin ß3/ß5 Receptor Antagonist Cilengitide, a Cyclic Polypeptide, in Humans, J. Clin. Pharmacol.2015, 55, 815–824 [17] S. Neubauer, F. Rechenmacher, R. Brimioulle, F. Saverio Di Leva, A. Bochen, T. R. Sobahi, M. Schottelius, E. Novellino, C. Mas-Moruno, L. Marinelli, H. Kessler; Pharmacophoric Modifications Lead to Superpotent αvβ3 Integrin Ligands with Suppressed α5β1 Activity; J. Med. Chem.2014, 57, 3410-3417.

Claims

Claims 1. An αvβ3 integrin ligand, pharmaceutically acceptable salt, prodrug, polymorph, solvate or hydrate thereof, for use in the treatment or prevention of Covid-19 infection, wherein the αvβ3 integrin ligand is administered in a low dosage.

2. The αvβ3 integrin ligand, pharmaceutically acceptable salt, prodrug, polymorph, solvate or hydrate thereof, for use according to claim 1, wherein the αvβ3 integrin ligand is administered daily dosage of 0.01 µg/kg to 1000 µg/kg.

3. The αvβ3 integrin ligand, pharmaceutically acceptable salt, prodrug, polymorph, solvate or hydrate thereof, for use according to claim 1 or 2, wherein the αvβ3 integrin ligand is administered orally in a daily dosage of 0.02 µg/kg to 1000 µg/kg.

4. The αvβ3 integrin ligand, pharmaceutically acceptable salt, prodrug, polymorph, solvate or hydrate thereof, for use according to claim 1 or 2, wherein the αvβ3 integrin ligand is administered intravenously in a daily dosage of 0.01 µg/kg to 400 µg/kg.

5. An αvβ3 integrin ligand, pharmaceutically acceptable salt, prodrug, polymorph, solvate or hydrate thereof, for use in the treatment of Covid-19 infection, wherein the αvβ3 integrin ligand is administered such that the patient’s blood plasma level of the αvβ3 integrin ligand remains in the range from 0.01 ng/mL to 1000 ng/mL.

6. The αvβ3 integrin ligand, pharmaceutically acceptable salt, prodrug, polymorph, solvate or hydrate thereof, for use according to anyone of claims 1 to 5, wherein the αvβ3 integrin ligand binds to αvβ3 integrin with an IC50 of 10 nM or less

7. The αvβ3 integrin ligand, pharmaceutically acceptable salt, prodrug, polymorph, solvate or hydrate thereof, for use according to anyone of claims 1 to 6, wherein the αvβ3 integrin ligand is selected from the group consisting of cilengitide and 29 or the prodrug of the αvβ3 integrin ligand is 29P.

8. The αvβ3 integrin ligand, pharmaceutically acceptable salt, prodrug, polymorph, solvate or hydrate thereof, for use according to claim 7, wherein the αvβ3 integrin ligand is cilengitide, which is administered intravenously at a daily dosage of 0.2 µg/kg to 20 µg/kg or 1 µg/kg to 35 µg/kg or 5 µg/kg to 20 µg/kg.

9. The αvβ3 integrin ligand, pharmaceutically acceptable salt, prodrug, polymorph, solvate or hydrate thereof, for use according to claim 7, wherein the prodrug of the αvβ3 integrin ligand is 29P, which is administered orally at a daily dosage of 0.5 µg/kg to 50 µg/kg or 1 µg/kg to 150 µg/kg or 5 µg/kg to 100 µg/kg.

10. The αvβ3 integrin ligand, pharmaceutically acceptable salt, prodrug, polymorph, solvate or hydrate thereof, for use according to anyone of claims 1 to 9, wherein the treatment involves one or more of vascular stabilization, reduction, treatment or avoidance thrombosis events, embolism events, thromboembolic events, microangiopathy, vasoplegia and/or endothelial cell dysregulation.

11. The αvβ3 integrin ligand, pharmaceutically acceptable salt, prodrug, polymorph, solvate or hydrate thereof, for use according to anyone of claims 1 to 10, wherein the treatment further involves administration of one or more additional anti-Covid 19 treatments.

12. A pharmaceutical composition for use in the treatment or prevention of Covid 19 infection, wherein the pharmaceutical composition comprises the αvβ3 integrin ligand, pharmaceutically acceptable salt, prodrug, polymorph, solvate or hydrate thereof as specified in any of the preceding claims and optionally one or more excipients.

13. The pharmaceutical composition for use according to claim 12, wherein the pharmaceutical composition comprises at least one additional therapeutic agent for the treatment of prevention of Covid 19 infections.

14. A kit for use in the treatment or prevention of Covid 19 infection, which contains the pharmaceutical composition of claim 12 in one container, and at least one additional therapeutic agent and optionally one or more excipients in one or more separate containers.

15. A method of treatment or prevention of Covid 19 infection in a patient in need thereof, wherein the method includes administration of the αvβ3 integrin ligand according to anyone of claims 1 to 11, the pharmaceutical composition according to claims 12 or 13 or the kit according to claim 14 to the patient.

16. The αvβ3 integrin ligand for use according to anyone of claims 1 to 11, the pharmaceutical composition for use according to claims 12 or 13, the kit for use according to claim 14 or the method of claim 15, wherein the medical use is to treat or prevent symptoms of Long Covid.