MÉTODOS DE MOBILIZAÇÃO DE CÉLULAS PRECURSORAS HEMATOPOIÉTICAS

Abstract

A method of mobilizing hematopoietic precursor cells from the bone marrow to the peripheral blood of a subject is provided. The method comprising (a) administering to the subject an effective amount of natalizumab; and (b) administering to the subject an effective amount of a CXCR4 inhibitor, wherein step (b) is effected at least 48 hours following step (a). Also provided are uses of such mobilization procedures in cell collection and in treatment.

Description

1 / 42 Methods of mobilizing hematopoietic precursor cells RELATED ORDERS

[001] This application claims the benefit of priority under U.S. Provisional Application No. 63 / 454,684, filed March 26, 2023, the content of which is incorporated herein by reference in its entirety. SEQUENCE LISTING STATEMENT

[002] The XML file entitled 99455.xml, created on March 25, 2024, comprising 215,618 bytes, submitted concurrently with the filing of this application, is incorporated into the present invention by reference. FIELD AND BACKGROUND OF THE INVENTION

[003] The present invention, in some embodiments thereof, relates to methods of mobilizing hematopoietic precursor cells.

[004] Hematopoietic stem cell transplantation is an important and often life-saving treatment for many malignant hematological diseases and solid tumors as a means of reconstituting blood cells after high-dose chemotherapy. The gold standard for mobilization typically includes the use of peripheral blood stem cells (PBSCs) mobilized with granulocyte colony-stimulating factor (G-CSF), which have largely replaced bone marrow (BM) as a source of stem cells for autologous and allogeneic stem cell transplantation. Despite the increased number of CD34+ stem cells obtained after G-CSF mobilization compared to BM harvests, a minimum number of CD34 / kg (~ >2 x 106) is still required to ensure successful and consistent multilineage grafting and sustained hematopoietic recovery. On the other hand, the SDF-1 / CXCR4 interaction plays a key role in HSC quiescence and retention in the bone marrow.Plerixafor (Mozobil, AMD3100) is a bicyclamen molecule that reversibly inhibits the binding of SDF-1 to CXCR4. Petition 870250085447, dated 09 / 22 / 2025, pages 102 / 148 2 / 42 promoting HSC mobilization. Plerixafor has been approved for use in combination with G-CSF for stem cell mobilization in patients with myeloma and lymphoma.

[005] Motixafortide (4F-benzoyl-TN 14003; Biokine Therapeutics, Rehovit, Israel) (T-140), also known as BKT 140, is a highly selective CXCR4 antagonist, originally developed to inhibit the binding of human immunodeficiency virus (HIV) to CXCR4. In mice, this agent induced up to a 10-fold increase in PB progenitor cells, which peaked 1-2 hours after dose administration. BKT 140 acted synergistically with G-CSF, leading to a 78-fold increase in PB progenitor cells compared to controls, greater than that observed with a combination of Plerixafor and G-CSF (Abraham et al. Stem Cells. 2007; 25:215866). In a phase I / IIA dose-escalation trial in myeloma patients, BTK 140 was well tolerated and resulted in a dose-dependent increase in the absolute mean of CD34+ PB cells.The highest dose tested (900 pg / kg) resulted in a mean CD34+ PB count of 20.6 χ 106 / kg, reducing the number of apheresis sessions required from 2.25 with lower doses to 1 (Nagler et al. ASH Annual Meeting Abstracts; 2010. ρ. 2260).

[006] Integrins are a structurally and functionally diverse family of transmembrane glycoproteins that mediate cell-cell and cell-matrix interactions in a wide range of biological contexts. There are eighteen different α subunits and eight different α subunits in vertebrates, giving rise to 24 non-covalently linked αβ heterodimers, which are capable of binding to a wide variety of ligands. One such heterodimer expressed in hematopoietic stem cells, α4βι, termed very late antigen 4 (VLA-4), mediates HSC adhesion to vascular cell adhesion molecule-1 (VCAM-1) within the bone marrow stroma. In pre-studies Petition 870250085447, dated 09 / 22 / 2025, pp. 103 / 148 In 3 / 42 clinical trials, administration of anti-VLA-4 antibodies resulted in the mobilization of HSC progenitors into the bloodstream (Vermeulen et al. Blood. 1998;92:894-900).

[007] Natalizumab, a recombinant humanized monoclonal antibody against the VLA-4 subunit, approved for the treatment of multiple sclerosis (MS) and Crohn's disease, has been shown to increase peripheral blood CD34+ cells in patients with relapsing-remitting MS. Zohren et al. showed a gradual increase in circulating CD34+ cells in MS patients, with a peak concentration of 10.4 CD34+ cells / pL 72 hours after Natalizumab administration (Zohren et al. Blood. 2008;111:3893-5). Jing et al. demonstrated a 7-fold increase in CD34+ PB cells and a dose-dependent 7-fold increase in CD34+ BM cells in MS patients treated with Natalizumab, with a peak absolute count reached on day 4 after treatment (Jing et al. 2010; 45:1489-96). Furthermore, simultaneous blockade of VLA-4 and CXCR4 has been shown to have a greater than additive effect on stem cell mobilization in primates, when compared to either agent alone (Bonig et al.Stem Cells. 2009;27:836-7). Unfortunately, the natalizumab-induced elevation in CD34+ PB cells persists for at least 1 month after drug administration, which limits its use in healthy donors (Zohren supra and Bonig supra).

[008] Despite many advances, there is still a need for new therapeutic modalities that lead to more effective and efficient stem cell mobilization strategies, especially in patients at risk of mobilization failure.

[009] Additional technical background includes: US Patent Nos. 28,455,450 WO 2018 / 085574 Petition 870250085447, dated 09 / 22 / 2025, pp. 104 / 148 4 / 42 PMID: 24476957 SUMMARY OF THE INVENTION

[010] According to one aspect of some embodiments of the present invention, a method is provided for mobilizing hematopoietic precursor cells from the bone marrow into the peripheral blood of an individual, comprising: (a) administering an effective amount of natalizumab to the individual; and (b) administering an effective amount of a CXCR4 inhibitor to the individual, wherein step (b) is performed at least 48 hours following step (a).

[011] According to one aspect of some embodiments of the present invention, a method is provided for obtaining a therapeutically effective quantity of hematopoietic precursor cells from an individual, comprising: (a) administer an effective dose of natalizumab to the individual; (b) administering an effective amount of a CXCR4 inhibitor to the individual, wherein step (b) is performed at least 48 hours following step (a); and (c) collecting hematopoietic precursor cells by apheresis.

[012] According to one aspect of some embodiments of the present invention, an effective amount of a combination of natalizumab and a CXCR4 inhibitor is provided for use in mobilizing hematopoietic precursor cells in an individual, wherein the CXCR4 inhibitor is administered to the individual at least 48 hours after the administration of natalizumab.

[013] According to one aspect of some embodiments of the present invention, an effective amount of a combination of natalizumab and a CXCR4 inhibitor is provided for use in a collection method of Petition 870250085447, dated 09 / 22 / 2025, pp. 105 / 148 5 / 42 hematopoietic precursor cells by apheresis, comprising the mobilization of hematopoietic precursor cells, wherein the hematopoietic precursor cells are subsequently collected by apheresis, wherein the CXCR4 inhibitor is administered to the individual at least 48 hours after the administration of natalizumab.

[014] According to some embodiments of the invention, the individual is a human individual.

[015] According to some embodiments of the invention, the individual is a donor of hematopoietic precursor cells.

[016] According to some embodiments of the invention, the individual is diagnosed with cancer.

[017] According to some embodiments of the invention, the hematopoietic precursor cells are for autologous transplantation.

[018] According to some embodiments of the invention, hematopoietic precursor cells are for allogeneic transplantation.

[019] According to some embodiments of the invention, the effective amount comprises repeated cycles of administration of natalizumab and the CXCR4 inhibitor.

[020] According to some embodiments of the invention, the minimum of 48 hours comprises up to 96 hours.

[021] According to some embodiments of the invention, the minimum of 48 hours comprises up to 72 hours.

[022] According to some embodiments of the invention, the CXCR4 inhibitor is a peptide, a small molecule, an antibody, a nucleic acid, or a combination thereof.

[023] According to some embodiments of the invention, the CXCR4 inhibitor is a peptide as set forth in SEQ ID NO: 1. Petition 870250085447, dated 09 / 22 / 2025, pp. 106 / 148 6 / 42

[024] According to some embodiments of the invention, the CXCR4 inhibitor is a small molecule.

[025] According to some embodiments of the invention, the CXCR4 inhibitor is AMD3100.

[026] Unless otherwise defined, all technical and / or scientific terms used in the present invention have the same meaning as commonly understood by a person skilled in the art to which the invention pertains. Although methods and materials similar or equivalent to those described in the present invention may be used in the practice or testing of embodiments of the invention, exemplary methods and / or materials are described below. In case of conflict, the descriptive report of the patent, including definitions, shall prevail. Furthermore, the materials, methods, and examples are for illustrative purposes only and are not intended to be necessarily limiting. DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION

[027] The present invention, in some embodiments thereof, relates to methods of mobilizing hematopoietic precursor cells.

[028] Before explaining at least one embodiment of the invention in detail, it should be understood that the invention is not necessarily limited in its application to the details presented in the following description or exemplified by the Examples. The invention is capable of other embodiments or of being practiced or carried out in various ways.

[029] The present inventor has unexpectedly discovered that scheduling the administration of the CXCR4 inhibitor for at least 48 hours after the administration of natalizumab allows obtaining substantially high quantities of hematopoietic precursor cells.

[030] Thus, according to one aspect of the invention, a method is provided for mobilizing hematopoietic precursor cells from the Petition 870250085447, dated 09 / 22 / 2025, pp. 107 / 148 7 / 42 bone marrow into the peripheral blood of an individual, comprising: (a) administering an effective amount of natalizumab to the individual; and (b) administering an effective amount of a CXCR4 inhibitor to the individual, wherein step (b) is performed at least 48 hours following step (a). [03 1] According to an additional or alternative aspect, a method is provided for obtaining a therapeutically effective quantity of hematopoietic precursor cells from an individual, comprising: (a) administer an effective dose of natalizumab to the individual; (b) administering an effective amount of a CXCR4 inhibitor to the individual, wherein step (b) is performed at least 48 hours following step (a); and (c) collecting hematopoietic precursor cells by apheresis.

[032] According to an additional or alternative aspect, an effective amount of a combination of natalizumab and a CXCR4 inhibitor is provided for use in mobilizing hematopoietic precursor cells in an individual, wherein the CXCR4 inhibitor is administered to the individual at least 48 hours after the administration of natalizumab.

[033] According to an additional or alternative aspect, an effective amount of a combination of natalizumab and a CXCR4 inhibitor is provided for use in a method of collecting hematopoietic precursor cells by apheresis, comprising mobilizing hematopoietic precursor cells, wherein the hematopoietic precursor cells are subsequently collected by apheresis, wherein the CXCR4 inhibitor is administered to the individual at least 48 hours after the administration of natalizumab.

[034] As used in the present invention, the term “hematopoietic precursor cells” refers to a fraction of cells that can be Petition 870250085447, dated 09 / 22 / 2025, pp. 108 / 148 8 / 42 found in the bone marrow (BM) niche. These cells are characterized by multipotency, which enables them to self-renew and also produce mature blood cells, such as erythrocytes, leukocytes, platelets, and lymphocytes. These cells typically include hematopoietic stem cells (HSCs) that express CD34 and are called CD34+ cells. CD34 is a marker of human HSCs, and all colony-forming activity of human bone marrow (BM) cells is found in the CD34+ fraction.

[035] Hematopoietic precursor cells in their native or modified form (e.g., differentiated in culture, expanded in culture) after apheresis are typically used in the treatment of a variety of medical conditions.

[036] As used in the present invention, the term mobilization refers to the release of hematopoietic precursor cells (e.g., hematopoietic stem cells) from the bone marrow into the peripheral blood circulation.

[037] As used in the present invention, increased mobilization refers to inducing mobilization of peripheral blood precursor cells, to raise circulating levels of HSCs or to improve or facilitate hematopoietic reconstitution or grafting in an individual in need thereof.

[038] According to one embodiment, the mobilization of hematopoietic stem cells is increased by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 150%, or 200% compared to mobilization in the absence of the agents present (i.e., CXCR4 inhibitor and natalizumab). According to one embodiment, the mobilization of hematopoietic precursor cells is increased by at least about 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold in Petition 870250085447, dated 09 / 22 / 2025, pp. 109 / 148 9 / 42 comparison to mobilization in the absence of the agents present. The measurement of the increase in mobilization of hematopoietic precursor cells is known to a person skilled in the art.

[039] As used in the present invention, the term individual refers to a mammalian individual, for example, a human individual, of any gender or age. The individual may be a healthy individual serving as a donor for hematopoietic precursor cell transplantation (e.g., also called a donor individual). Alternatively, the individual may suffer from a disease or condition (e.g., malignant disease or non-malignant disease, such as an immunodeficiency) and therefore needs stem cell mobilization or stem cell transplantation (i.e., autologous); or from a donor (i.e., non-autologous, i.e., allogeneic). In the latter case, the individual is a recipient who needs a stem cell transplant.

[040] The term “healthy individual,” as used in the present invention, refers to an individual who has not been diagnosed with a disease or disorder treatable by hematopoietic stem cell transplantation. According to a specific embodiment, the healthy individual does not suffer from a hematopoietic disorder or malignancy.

[041] As used in the present invention, the term CXCR4 inhibitor refers to molecules and compositions that interfere with or inhibit the biological activity of the CXCR4 receptor. The biological activity of the CXCR4 receptor may include the mobilization of stem cells into the bloodstream, as well as the entry of the virus into the cell or the replication of the virus in the cell.

[042] CXCR4 inhibitors can encompass numerous classes of chemical molecules, for example, small organic or inorganic molecules, polysaccharides, biological macromolecules, for example, peptides, proteins, Petition 870250085447, dated 09 / 22 / 2025, pp. 110 / 148 10 / 42 peptide analogues and derivatives, peptidomimetics, antibodies, antibody fragments, nucleic acids, nucleic acid analogues and derivatives such as aptamers, an extract made from biological materials such as bacteria, plants, fungi or animal cells or tissues, natural or synthetic compositions.

[043] Without wanting to limit myself to one theory, a CXCR4 inhibitor can act through several different pathways. For example, a CXCR4 inhibitor can bind to a ligand-binding site on the CXCR4 receptor and interfere with ligand binding to the CXCR4 receptor, bind to a non-binding site on the CXCR4 receptor and interfere with ligand binding to the CXCR4 receptor, bind to a CXCR4 receptor ligand and interfere with ligand binding to the CXCR4 receptor, or inhibit the expression of a polynucleotide (e.g., mRNA) that expresses CXCR4.

[044] In some embodiments, a CXCR4 inhibitor inhibits the biological activity of the CXCR4 receptor by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% relative to a control. In some embodiments, a CXCR4 inhibitor completely abolishes the biological activity of the CXCR4 receptor relative to a control. A control may comprise a sample that is not treated with an inhibitor.

[045] In some embodiments, a CXCR4 inhibitor is a nucleic acid. Exemplary CXCR4 nucleic acid inhibitors include, but are not limited to, antisense oligonucleotides, siRNAs, shRNAs, microRNAs, aptamers, ribozymes, and decoy oligonucleotides. A CXCR4 nucleic acid inhibitor can inhibit the expression of a CXCR4 gene.

[046] Examples of anti-CXCR4 siRNAs are described, for example, in U.S. Patent Application Publication No. 2007 / 0238868, No. 2009 / 0253772, Petition 870250085447, dated 09 / 22 / 2025, pp. 111 / 148 11 / 42, the content of which is incorporated into the present invention by reference. Examples of anti-CXCR4 siRNAs are described, for example, in U.S. Patent Application Publication No. 2004 / 0209837, the content of which is incorporated into the present invention by reference.

[047] In some embodiments, the CXCR4 inhibitor binds to CXCR4 or CXCL12 (SDF-1 alpha). In another embodiment, the CXCR4 inhibitor is an antibody or antibody fragment. In some embodiments, the CXCR4 inhibitor is a small molecule, for example, AMD-3100, ALX40-4C, T22, T140, Met-SDF-1 alpha, T134, or AMD-3465.

[048] Exemplary CXCR4 inhibitors include, but are not limited to, 2,2'-bicyclame; 6,6'-bicyclame; the embodiments set forth in U.S. Patent Nos. 5,021,409 and 6,001,826, and in particular 1,r—[1,4-phenylene-bis(methylene)]bis-1,4,8,11tetraazacyclotetradecane, set forth in U.S. Patent No. 5,583,131, and designated AMD310 0 in the present invention. In some embodiments, a CXCR4 inhibitor may be N,-(1-H-benzimidazol-2-yl methyl)-N'(5,6,7,8-tetrahydroquinoline-yl)-butane-1,4-diamine, as described in U.S. Patent Publication No. 2003 / 0220341, CTCF-0214; CTCF-9908; CP1221 (linear peptides, cyclic peptides, natural amino acids, non-natural amino acids and peptidomimetic compounds); 4F-benzoylTN24003; KRH-1120; KRH-1636; KRH-2731; polyphenumidine analog; ALX40-4C; or those described in WO 01 / 85196; WO 99 / 50461; WO 01 / 94420; WO 03 / 090512, each of which is incorporated by reference in the present invention in its entirety.

[049] In some embodiments, CXCR4 inhibitors include the T-140 analogs and antibodies described in U.S. Patent Publication 2010 / 0055088, the cyclic polyamines described in U.S. Patent Publication 2009 / 0221683, and the compounds disclosed in U.S. Patent Publications Nos. 2004 / 0209921, 2005 / 0059702, 2005 / 0043367, 2005 / 0277670, Petition 870250085447, dated 09 / 22 / 2025, pages 112 / 148 12 / 42 2010 / 0178271 and 2003 / 0220341; U.S. Patent Nos. 5,021,409, 6,001,826, 5,583,131 and Patent Publication WO 03 / 011277, each of which is incorporated herein by reference in its entirety.

[050] CXCR4 inhibitors may also include, but are not limited to, polypeptides that bind specifically to CXCR4. Such inhibitors include T140 and T140 derivatives. Exemplary derivatives of T140 include, but are not limited to, TN14003, TC14012, and TE14011, as well as those found in Tamamura, H. et al. Org. Biomol. Chem. 1:3656-3662, 2003, which is incorporated by reference in the present invention in its entirety.

[051] According to specific embodiments, the CXCR4 antagonist peptides of the present invention are, for example, 4F-benzoyl-TN14003 (SEQ ID NO: 1) analogs and derivatives and are structurally and functionally related to the peptides disclosed in patent applications WO 2002 / 020561 and WO 2004 / 020462, also known as “T-140 analogs”, as detailed below in the present invention.

[052] In several particular embodiments, the T-140 analogue or derivative has an amino acid sequence as set out in the following formula (I) or a salt thereof: 2 3 4 5 6 7 8 9 10 11 12 13 14 A1-A2-A3-Cys-Tyr-A4-A5-A6-A7-A8-A9-A10-Cys-A11 (I) where: A1 is a residue of arginine, lysine, ornithine, citrulline, alanine, or glutamic acid, or an N-α substituted derivative of these amino acids, or A1 is absent; A2 represents an arginine or glutamic acid residue if A1 is present, or A2 represents an arginine or glutamic acid residue or an N-α substituted derivative of these amino acids if A1 is absent; Petition 870250085447, dated 09 / 22 / 2025, pp. 113 / 148 13 / 42 A3 represents an aromatic amino acid residue; A4, A5, and A9 each independently represent a residue of arginine, lysine, ornithine, citrulline, alanine, or glutamic acid; Ag represents a residue of proline, glycine, ornithine, lysine, alanine, citrulline, arginine, or glutamic acid; A7 represents a residue of proline, glycine, ornithine, lysine, alanine, citrulline, or arginine; As represents a residue of tyrosine, phenylalanine, alanine, naphthylalanine, citrulline, or glutamic acid; A10 represents a residue of citrulline, glutamic acid, arginine, or lysine; A11 represents an arginine, glutamic acid, lysine, or citrulline residue in which the C-terminal carboxyl group can be derivatized; The cysteine ​​residue at position 4 or position 13 can form a disulfide bond, and the amino acids can be of the L or D form.

[053] Exemplary peptides according to formula (I) are peptides that have an amino acid sequence as set out in any of the SEQ ID NOS:1-72, as set out in Table 1 below. Table 1 - T-140 and T-140 analogues currently preferred Analog SEQ ID NO: Amino acid sequence 4F-benzoylTN14003 1 4F-benzoyl-Arg-Arg-Nal-Cys-Tyr-Cit-Lys-DLys-Pro-TyrArg-Cit-Cys-Arg-NH2 AcTC14003 2 Ac-Arg-Arg-Nal-Cys-Tyr-Cit-Lys-DLys-Pro-Tyr-Arg-CitCys-Arg-OH AcTC14005 3 Ac-Arg-Arg-Nal-Cys-Tyr-Arg-Lys-DCit-Pro-Tyr-Arg-CitCys-Arg-OH-OH Ac1401 Ac-Arg-Arg-Nal-Cys-Tyr-Cit-Lys-DCit-Pro-Tyr-Arg-CitCys-Arg-OH AcTC14013 5 Ac-Arg-Arg-Nal-Cys-Tyr-Cit-Lys-DLys-Pro-Tyr-Cit-CitCys-Arg-OH Petition 870250085447, of 22 / 09 / 2025, p. 114 / 148 14 / 42 Analog SEQ ID NO: Amino acid sequence AcTC14015 6 Ac-Cit-Arg-Nal-Cys-Tyr-Cit-Lys-DLys-Pro-Tyr-Arg-CitCys-Arg-OH AcTC14017 7 Ac-Cit-Arg-Nal-Cys-Tyr-Arg-Lys-DCit-Pro-Tyr-Arg-CitCys-Arg-OH AcTC14019 8 Ac-Arg-Arg-Nal-Cys-Tyr-Arg-Lys-DCit-Pro-Tyr-Cit-CitCys-Arg-OH-OH AcTC1402 Ac-Cit-Arg-Nal-Cys-Tyr-Arg-Lys-DLys-Pro-Tyr-Cit-CitCys-Arg-OH AcTC14012 10 Ac-Arg-Arg-Nal-Cys-Tyr-Cit-Lys-DCit-Pro-Tyr-Arg-CitCit-Arg-Ac-NH 11402 Ac-Arg-Arg-Nal-Cys-Tyr-Cit-Lys-DLys-Pro-Tyr-Cit-CitCys-Arg-NH2 AcTC14016 12 Ac-Cit-Arg-Nal-Cys-Tyr-Cit-Lys-DLys-Pro-Tyr-Arg-CitCys-Arg-NH-13818 Ac-Cit-Arg-Nal-Cys-Tyr-Arg-Lys-DCit-Pro-Tyr-Arg-CitCys-Arg-NH2 AcTC14020 14 Ac-Arg-Arg-Nal-Cys-Tyr-Arg-Lys-DCit-Pro-Tyr-Cit-CitCys-Arg-NH21502 Ac-Cit-Arg-Nal-Cys-Tyr-Arg-Lys-DLys-Pro-Tyr-Cit-CitCys-Arg-NH2 TE14001 16 H-DGlu-Arg-Nal-Cys-Tyr-Arg-Lys-DLys-Pro-Tyr-Arg-Cit-OHCys-Arg-TE140202 H-Arg-Glu-Nal-Cys-Tyr-Arg-Lys-DLys-Pro-Tyr-Arg-CitCys-Arg-OH TE14003 18H-Arg-Arg-Nal-Cys-Tyr-Glu-Lys-DLys-Pro-Tyr-Arg-CitCys-Arg-OH TE14004 19 H-Arg-Arg-Nal-Cys-Tyr-Arg-Glu-DLys-Pro-Tyr-Arg-CitCys-Arg-OH TE1405 H-Arg-Arg-Nal-Cys-Tyr-Arg-Lys-DGlu-Pro-Tyr-Arg-CitCys-Arg-OH TE14006 21 H-Arg-Arg-Nal-Cys-Tyr-Arg-Lys-DLys-Pro-Tyr-Glu-CitCys-Arg-OH TE12400 H-Arg-Arg-Nal-Cys-Tyr-Arg-Lys-DLys-Pro-Tyr-Arg-CitCys-Glu-OH TE14011 23 H-Arg-Arg-Nal-Cys-Tyr-Cit-Lys-DGlu-Pro-Tyr-Arg-CitCys-Arg-NH-TE14012 24012 H-Arg-Arg-Nal-Cys-Tyr-DGlu-Lys-DCit-Pro-Tyr-Arg-CitCys-Arg-NH2 Petition 870250085447, of 22 / 09 / 2025, p. 115 / 148 15 / 42 Analog SEQ ID NO: Amino acid sequence TE14013 25 H-Arg-Arg-Nal-Cys-Tyr-DGlu-Lys-DGlu-Pro-Tyr-ArgCit-Cys-Arg-NH2 TE14014 26 H-DGlu-Arg-Nal-Cys-Tyr-Cit-Lys-DGlu-Pro-Tyr-Arg-CitCys-Arg-NH2 TE14015 27 H-Arg-Arg-Nal-Cys-Tyr-Cit-Lys-DGlu-Pro-DGlu-Arg-CitCys-NH-201818 H-Arg-Arg-Nal-Cys-Tyr-Cit-Lys-DGlu-Pro-Tyr-ArgDGlu-Cys-Arg-NH2 AcTE14014 29 Ac-DGlu-Arg-Nal-Cys-Tyr-Cit-Lys-DGlu-Pro-Tyr-ArgCit-Cys-Ac-304040 Ac-Arg-Arg-Nal-Cys-Tyr-Cit-Lys-DGlu-Pro-DGlu-ArgCit-Cys-Arg-NH2 AcTE14016 31 Ac-Arg-Arg-Nal-Cys-Tyr-Cit-Lys-DGlu-Pro-Tyr-ArgDGlu-Cit-NH2:TF: AcTE14011 32 Ac-Arg-Arg-Nal-Cys-Tyr-Cit-Lys-DGlu-Pro-Tyr-Arg-CitCys-Arg-NH2 TF2: guanylTE14011 33 guanyl-Arg-Arg-Nal-Cys-Tyr-Cit-Lys-DGlu-Pro-Tyr-ArgCit-Cys-Arg-NH2 TF3: TMguanylTE14011 34 TMguanyl-Arg-Arg-Nal-Cys-Tyr-Cit-Lys-DGlu-Tyr-Arg-Cys-NH2 TF4: TMguanylTE14011 (2-14) 35 TMguanyl-Arg-Nal-Cys-Tyr-Cit-Lys-DGlu-Pro-Tyr-ArgCit-Cys-Arg-NH2 TF5: 4F-benzoylTE14011 364F-benzoil-Arg-Arg-Nal-Cys-Tyr-Cit-Lys-DGlu-Pro-TyrArg-Cit-Cys-Arg-NH2 TF6: 2F-benzoilTE14011 37 2F-benzoil-Arg-Arg-Nal-Cys-Tyr-Cit-Lys-DGlu-Pro-TyrArg-Cit-Cys-Arg-NH2 TF7: APATE14011 (2-14) 38 APA-Arg-Nal-Cys-Tyr-Cit-Lys-DGlu-Pro-Tyr-Arg-CitCys-Arg-NH2 TF8: desaminoR-TE14011 (214) 39 desamino-R-Arg-Nal-Cys-Tyr-Cit-Lys-DGlu-Pro-TyrArg-Cit-Cys-Arg-NH2 TF9: guanilTE14011 (2-14) 40 Guanil-Arg-Nal-Cys-Tyr-Cit-Lys-DGlu-Pro-Tyr-Arg-CitCys-Arg-NH2 TF10: succinil- TE14011 (2-14) 41 succinil-Arg-Nal-Cys-Tyr-Cit-Lys-DGlu-Pro-Tyr-Arg-CitCys-Arg-NH2 TF11: glutarilTE14011 (2-14) 42 glutaril-Arg-Nal-Cys-Tyr-Cit-Lys-DGlu-Pro-Tyr-Arg-CitCys-Arg-NH2 TF12: 43 deaminoTMG-APA-Arg-Nal-Cys-Tyr-Cit-Lys-DGlu-Pro- Petição 870250085447, de 22 / 09 / 2025, pág. 116 / 148 16 / 42 Analogue SEQ ID NO: Deamino amino acid sequence™GAPA-TE14011 (2-14) Tyr-Arg-Cit-Cys-Arg-NH2 TF15: H-ArgCH2NH- RTE14011(2- 14) 44 R-CH2-Arg-Nal-Cys-Tyr-Cit-Lys-DGlu-Pro-Tyr-Arg-CitCys-Arg-NH2 TF17:TE14011 (2-14) 45 H-Arg-Nal-Cys-Tyr-Cit-Lys-DGlu-Pro-Tyr-Cit-Arg-NH18: TMguanylTC14012 46 TMguanyl-Arg-Arg-Nal-Cys-Tyr-Cit-Lys-DCit-Pro-TyrArg-Cit-Cys-Arg-NH2 TF19: ACATC14012 47 ACA-Arg-Arg-Nal-Cys-Tyr-Cit-Lys-DCit-Pro-Tyr-Arg-CitCys-Arg-NH2 TF20: ACA-T140 48 ACA-Arg-Arg-Nal-Cys-Tyr-Arg-Lys-DLys-Pro-Tyr-ArgCit-OH-1400 H-Arg-Arg-Nal-Cys-Tyr-Cit-Arg-DLys-Pro-Tyr-Arg-CitCys-Arg-NH2 AcTZ14011 50 Ac-Arg-Arg-Nal-Cys-Tyr-Cit-Arg-DLys-Pro-Tyr-Arg-CitCys-Arg-DLys-Pro-Tyr-Arg-CitCys-Arg-NH-NH Ac-Arg-Arg-Nal-Cys-Tyr-Cit-Lys-DLys-Pro-Tyr-Arg-CitCys-Arg-NH2 AcTN14005 52 Ac-Arg-Arg-Nal-Cys-Tyr-Arg-Lys-DCit-Pro-Tyr-Arg-Cit-Cit-NH2 4F-benzoylTN14011-Me 53 4F-benzoyl-Arg-Arg-Nal-Cys-Tyr-Cit-Lys-DGlu-Pro-TyrArg-Cit-Cys-Arg-NHMe 4F-benzoyl- TN14011-Et 544F-benzoyl-Arg-Arg-Nal-Cys-Tyr-Cit-Lys-DGlu-Pro-TyrArg-Cit-Cys-Arg-N HEt 4F-benzoylTN14011-iPr 55 4F-benzoyl-Arg-Arg-Nal-Cys-Tyr-Cit-Lys-DGlu-Pro-TyrArg-Cit-Cys-Arg-N HiPr 4F-benzoyl- TN14011tyramine 56 4F-benzoyl-Arg-Arg-Nal-Cys-Tyr-Cit-Lys-DGlu-Pro-TyrArg-Cit-Cys-Arg-tyramine TA14001 57 H-Ala-Arg-Nal-Cys-Tyr-Arg-Lys-DLys-Pro-Tyr-Arg-Cit-Arg-OH TA14055 H-Arg-Arg-Nal-Cys-Tyr-Ala-Lys-DLys-Pro-Tyr-Arg-CitCys-Arg-OH TA14006 59 H-Arg-Arg-Nal-Cys-Tyr-Arg-Ala-DLys-Pro-Tyr-Arg-CitCys-Arg-OH Petition 870250085447, of 22 / 09 / 2025, p. 117 / 148 17 / 42 Analog SEQ ID NO: Amino Acid Sequence TA14007 60 H-Arg-Arg-Nal-Cys-Tyr-Arg-Lys-DAla-Pro-Tyr-Arg-CitCys-Arg-OH TA14008 61 H-Arg-Arg-Nal-Cys-Tyr-Arg-Lys-DLys-Ala-Tyr-Arg-CitCys-Arg-OH TA14009 62 H-Arg-Arg-Nal-Cys-Tyr-Arg-Lys-DLys-Pro-Cy-Ala-CA0-Arg 6 H-Arg-Arg-Nal-Cys-Tyr-Arg-Lys-DLys-Pro-Tyr-Ala-CitCys-Arg-OH TC14001 64 H-Cit-Arg-Nal-Cys-Tyr-Arg-Lys-DLys-Pro-Tyr-OH3-TC15Cit H-Arg-Arg-Nal-Cys-Tyr-Cit-Lys-DLys-Pro-Tyr-Arg-CitCys-Arg-OH TN14003 66 H-Arg-Arg-Nal-Cys-Tyr-Cit-Lys-DLys-Pro-Tyr-70-NH0-Arg61-Cit H-Arg-Arg-Nal-Cys-Tyr-Arg-Cit-DLys-Pro-Tyr-Arg-CitCys-Arg-OH TC14012 68 H-Arg-Arg-Nal-Cys-Tyr-Cit-Lys-DCit-Pro-Tyr-CH0-Arg-6 Trg-Cit H-Arg-Arg-Nal-Cys-Tyr-Arg-Lys-DLys-Pro-Tyr-Arg-CitCys-Arg-OH TC14011 70 H-Arg-Arg-Nal-Cys-Tyr-Cit-Lys-DCit-Pro-Tyr-COHys TCA14Cit H-Arg-Arg-Nal-Cys-Tyr-Arg-Lys-DCit-Pro-Tyr-Arg-CitCys-Arg-OH TC14018 72 H-Cit-Arg-Nal-Cys-Tyr-Arg-Lys-DCit-Pro-Tyr-CAH2-Cit

[054] According to a specific modality, in each of the SEQ ID NOS:1-72, two cysteine ​​residues are coupled in a disulfide bond.

[055] In another embodiment, the analogue or derivative has an amino acid sequence as set forth in SEQ ID NO:65 (H-Arg-Arg-Nal-Cys-TyrCit-Lys-DLys-Pro-Tyr-Arg-Cit-Cys-Arg-OH; TC14003).

[056] In another embodiment, the peptide used in the compositions and methods of the invention consists essentially of an amino acid sequence as set forth in SEQ ID NO:1. In another embodiment, the Petition 870250085447, dated 09 / 22 / 2025, pages 118 / 148 The peptide used in the compositions and methods of the invention comprises an amino acid sequence as set forth in SEQ ID NO:1. In another embodiment, the peptide is at least 60%, at least 70%, or at least 80% homologous to SEQ ID NO:1. In another embodiment, the peptide is at least 90% homologous to SEQ ID NO:1. In another embodiment, the peptide is at least about 95% homologous to SEQ ID NO:1. Each embodiment represents a separate embodiment of the present invention.

[057] In several other embodiments, the peptide is selected from SEQ ID NOS:1-72, where each possibility represents a separate embodiment of the present invention.

[058] In another embodiment, the peptide has an amino acid sequence as set forth in any of the SEQ ID NOS: 1-4, 10, 46, 47, 51-56, 65, 66, 68, 70 and 71. In another embodiment, the peptide has an amino acid sequence as set forth in any of the SEQ ID NOS: 4, 10, 46, 47, 68 and 70. In another embodiment, the peptide has an amino acid sequence as set forth in any of the SEQ ID NOS: 1, 2, 51, 65 and 66. In another embodiment, the peptide has an amino acid sequence as set forth in any of the SEQ ID NOS: 53-56.

[059] In one embodiment, the peptide has an amino acid sequence as set forth in SEQ ID NO:1. In another embodiment, the peptide has an amino acid sequence as set forth in SEQ ID NO:2. In another embodiment, the peptide has an amino acid sequence as set forth in SEQ ID NO:51. In another embodiment, the peptide has an amino acid sequence as set forth in SEQ ID NO:66.

[060] Other CXCR4 peptide inhibitors (antagonists) include, but are not limited to, LY2510924 (from Lilly Oncology), CTCE-9908 (Huang et al. 2009 Journal of Surgical Research 155:231-236), Fc131 analogs and Petition 870250085447, dated 09 / 22 / 2025, pp. 119 / 148 19 / 42 nanobodies as specified in the citations below (each of which is incorporated into the present invention by reference in its entirety): Tan NC, Yu P, Kwon YU, KodadekT. High-throughput evaluation of relative cell permeability between peptoids and peptides. Bioorg Med Chern. 2008;16:5853–61.

[061] Kwon YU, Kodadek T. Quantitative evaluation of the relative cell permeability of peptoids and peptides. J Am Chern Soc. 2007;129:1508.

[062] Miller S, Simon R, Ng S, Zuckermann R, Kerr J, Moos W. Comparison of the proteolytic susceptibilities of homologous L-amino acid, D-amino acid, and N-substituted glycine peptide andpeptoid oligomers. Drug Dev Res. 1995;35:2032.

[063] Yoshikawa Y, Kobayashi K, Oishi S, Fujii N, Furuya T. Molecular modeling study of cyclic pentapeptide CXCR4 antagonists: new insight into CXCR4-FC131 interactions. Bioorg With Chern Lett. 2012;22:2146–50.

[064] Jaãhnichen S, Blanchetot C, Maussang D, Gonzalez-Pajuelo M, Chow KY, Bosch L, De Vrieze S, Serruys B, Ulrichts H, Vandevelde W. CXCR4 nanobodies (VHH-based simple variable domains) potentially inhibit HIV-1 chemotaxis and replication and mobilize stem cells. Proc Natl Acad Sci USA. 2010;107:20565-70.

[065] According to a specific embodiment, the peptide has an amino acid sequence as set out in SEQ ID NO: 1 under the name Motixafortide.

[066] As mentioned, the VLA-4 inhibitor (VLA4i) is Natalizumab [abbreviated in the present invention as (N)].

[067] In some embodiments, Natalizumab is sold under the brand name Tysabri®.

[068] In some embodiments, Natalizumab is sold under the brand name Antegren ®. Petition 870250085447, dated 09 / 22 / 2025, pp. 120 / 148 20 / 42

[069] According to specific embodiments, the peptide (e.g., BL-8040) of the invention or the pharmaceutical composition comprising it is administered at a dose ranging from 0.1 to 10 mg / kg of body weight, from 0.1 to 2 mg / kg of body weight, from 0.1 to 1 mg / kg of body weight, from 0.3 to 10 mg / kg of body weight, from 0.3 to 2.

[070] According to a specific embodiment, BL-8040 is administered at a dose of 1-2 mg / kg of body weight.

[071] According to a specific embodiment, BL-8040 is administered at a dose of 1.25-1.5 mg / kg of body weight.

[072] According to a specific embodiment, BL-8040 is administered at a dose of 1.25 mg / kg of body weight.

[073] According to a specific modality, BL-8040 is administered subcutaneously (SC).

[074] As mentioned, the CXCR4 inhibitor (e.g., BL-8040) is administered at least 48 hours after the administration of the aforementioned Natalizumab.

[075] According to a specific modality, the minimum 48 hours comprise up to 96 hours (e.g., 48-96 hours).

[076] According to a specific modality, the minimum 48 hours comprise up to 80 hours (e.g., 48-80 hours).

[077] According to a specific modality, the minimum 48 hours comprise up to 72 hours (e.g., 48-72 hours).

[078] According to a specific modality, the minimum 48 hours comprise approximately 48 hours (for example, 48 hours).

[079] According to a specific embodiment, the method involves performing apheresis to recover hematopoietic precursor cells from the individual's peripheral blood after administration of the agents. Petition 870250085447, dated 09 / 22 / 2025, pages 121 / 148 21 / 42

[080] According to some embodiments of the invention, approximately 4 hours and up to approximately 12 hours after administration of the CXCR4 inhibitor, the individual undergoes apheresis.

[081] Peripheral blood collection methods are well known in the state of the art and include, but are not limited to, collection of (e.g., up to 500 mL) whole blood from the individual and collection in a container containing an anticoagulant (e.g., heparin or citrate); and apheresis.

[082] As used in the present invention, the term apheresis refers to a procedure in which peripheral blood from an individual is passed through an apparatus, producing a predominant constituent (e.g., HSCs) and returning the other constituents to the individual's circulation. Apheresis is generally a three-step process comprising: (1) withdrawing blood from the individual, (2) separating the blood components (e.g., based on density), and (3) returning certain blood component(s) to the individual by transfusion. Blood is normally separated into three fractions: red blood cells (about 45% of total blood), white blood cell count (less than 1% of total blood), and plasma (about 55% of total blood). Various types of apheresis procedures can be used depending on the blood component being removed.

[083] Any methods, including quantitative and qualitative methods, can be used to identify that hematopoietic stem cells have been mobilized in peripheral blood. The methods typically involve isolating a quantity of blood from the patient and analyzing the number of cells in the blood. Any method can be used to analyze the number of cells, including, but not limited to: ELISA to identify specific cells, FACS analysis, Coulter counters and other blood counting devices, morphological identification, and PCR. The cells can be identified Petition 870250085447, dated 09 / 22 / 2025, pages 122 / 148 22 / 42 by any method known to a person skilled in the art, including, but not limited to, identification of one or more proteins that are specifically expressed by precursor cells, by morphology, by mRNA expression, and by PCR. Cell identification may be performed at any time after administration of the agents (CXCR4 inhibitor administered after natalizumab), including, but not limited to: 5 minutes, 10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 1 day, 2 days.

[084] According to one embodiment, after collection (and optionally separation), hematopoietic stem cells can be stored (e.g., for later use), expanded in culture, or administered to an individual in need of them (as discussed in detail in the present invention below). Therefore, the stem cell mobilization method can be used for mobilizing precursor hematopoietic cells in individuals who will serve as allogeneic or autologous donors of hematopoietic stem cells.

[085] In order to obtain a sufficient number of hematopoietic precursor cells for transplantation, the collected hematopoietic stem cells can be further cultured in vitro in order to increase expansion.

[086] During in vitro culture, hematopoietic precursor cells can alter their cellular phenotype. The presence or absence of an antigen on the cell surface can be analyzed using specific antibodies (e.g., CD34 antibodies) by methods well known to those skilled in the art, such as ELISA or FACS. It can be further analyzed by other methods well known in the state of the art, such as RT-PCR or similar methods. Petition 870250085447, dated 09 / 22 / 2025, pages 123 / 148 23 / 42

[087] Hematopoietic precursor cells can additionally be used for gene therapy. Because pluripotent hematopoietic stem cells are self-renewing and give rise to progenitor blood cells as well as mature blood cells, hematopoietic precursor cells are a suitable target for gene therapy. After collection (and optionally separation), hematopoietic precursor cells can be modified to release genetic products upon reintroduction into the individual. After modification, the cells are reinfused into an individual who needs such treatment.

[088] According to another aspect of the invention, an isolated population of hematopoietic precursor cells obtained by the method of some embodiments of the invention is provided.

[089] The phrase isolated cell population, as used in the present invention, refers to cells that have been isolated from their natural environment (e.g., the human body).

[090] Depending on one embodiment, the population may comprise the inhibitor CXCr4 and / or natalizuman.

[091] Depending on the modality, the cells are grown ex vivo or in vitro.

[092] Each of the agents can be administered to the individual per se or as part of a pharmaceutical composition that also includes a physiologically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate the administration of the active ingredient to an organism.

[093] It will be appreciated that the pharmaceutical composition may additionally comprise other compounds, such as those described in detail above.

[094] As used in the present invention, a “pharmaceutical composition” refers to a preparation of one or more of the ingredients. Petition 870250085447, dated 09 / 22 / 2025, pages 124 / 148 24 / 42 active ingredients described in the present invention with other chemical components, such as physiologically suitable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.

[095] In the present invention, the term active ingredient refers to the agent that affects mobilization.

[096] Hereafter, the expressions physiologically acceptable carrier and pharmaceutically acceptable carrier, which may be used interchangeably, refer to a carrier or diluent that does not cause significant irritation to an organism and does not abolish the biological activity and properties of the administered compound. An adjuvant is included in these phrases.

[097] In the present invention, the term “excipient” refers to an inert substance added to a pharmaceutical composition to further facilitate the administration of an active ingredient. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[098] Techniques for formulating and administering drugs can be found in “Remington's Pharmaceutical Sciences”, Mack Publishing Co., Easton, PA, latest edition, which is incorporated into the present invention by reference.

[099] The amount and dosage interval can be individually adjusted to provide adequate levels of the active ingredient to induce or suppress the biological effect (minimum effective concentration, MEC). The MEC will vary for each preparation but can be estimated from in vitro data. Dosages required to achieve the MEC will depend on individual characteristics and route of administration. Detection assays can be used. Petition 870250085447, dated 09 / 22 / 2025, pp. 125 / 148 25 / 42 to determine plasma concentrations.

[100] Agents of the present invention may, if desired, be presented in a package or dispensing device, such as an FDA-approved kit, which may contain one or more unit dosage forms containing the active ingredient. The package may, for example, comprise foil or plastic, such as a blister pack. The package or dispensing device may be accompanied by instructions for administration. The package or dispenser may also be accommodated by a notice associated with the container in a form prescribed by a government agency that regulates the manufacture, use, or sale of pharmaceutical products, which notice reflects the agency's approval of the form of the compositions or human or veterinary administration. Such notification, for example, may be US Food and Drug Administration-approved labeling for prescription drugs or an approved product insert.Compositions comprising a preparation of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for the treatment of an indicated condition, as further detailed above.

[101] Typical conditions that may be improved or otherwise benefited by enhanced hematopoietic stem cell survival and / or expansion and / or mobilization and / or hematopoietic precursor cell transplantation include, but are not limited to, hematopoietic disorders and malignancies such as aplastic anemia, lymphoma, leukemia, immunodeficiency, severe combined immunodeficiency (SCID), cytopenia (e.g., anemia, leukopenia, neutropenia, thrombocytopenia, granulocytopenia, pancytopenia), drug-induced cytopenia, toxin-induced cytopenia, radiation-induced cytopenia, transplant-associated cytopenia Petition 870250085447, dated 09 / 22 / 2025, pages 126 / 148 26 / 42 conventional bone marrow, hematopoietic deficits associated with cancer treatment, chemotherapy or radiotherapy, anemia or cytopenia of chronic disease (also called anemia or cytopenia of chronic inflammation), osteopetrosis, Gaucher disease, thalassemia and other congenital or genetically determined hematopoietic abnormalities.

[102] According to one embodiment, the methods of the invention are useful for increasing transplant success during and after immunosuppressive treatments, as well as for effecting more efficient wound healing and treatment of bacterial inflammation.

[103] According to one embodiment, the methods of the invention are useful for treating immunocompromised individuals or those whose immune system is otherwise impaired. Typical conditions that are improved or otherwise benefited by the method of the present invention include, but are not limited to, individuals who are infected with a retrovirus and, more specifically, who are infected with the human immunodeficiency virus (HIV).

[104] Consequently, the methods of the invention can be used for the treatment of a wide spectrum of conditions for which raising the levels of hematopoietic precursor cells in an individual would be beneficial or where collecting precursor cells for subsequent stem cell transplantation would be beneficial. The compounds are also administered to regenerate the myocardium by mobilizing precursor cells from the bone marrow.

[105] The methods described in the present invention are also particularly suitable for those individuals who require repeated or high doses of chemotherapy. For some cancer patients, hematopoietic toxicity often limits the opportunity to increase the dose of chemotherapy or to complete the prescribed chemotherapy. Cycles Petition 870250085447, dated 09 / 22 / 2025, pages 127 / 148 Repeated or high-dose chemotherapy treatments (27 / 42) can be responsible for severe depletion of precursor cells, leading to significant long-term hematopoietic sequelae and bone marrow exhaustion. The methods of the present invention provide improved cell survival, blood cell reconstitution, and blood cell count when used in conjunction with chemotherapy.

[106] In one modality, the disease or condition is a malignant disease.

[107] As used in the present invention, the term “malignant disease” or “cancer” refers to any cancerous disease. Cancer cells may be associated with phenotypes such as uncontrolled proliferation, loss of specialized functions, immortality, significant metastatic potential, significant increase in anti-apoptotic activity, rapid growth and proliferation rate, and certain characteristic morphologies and cell markers.

[108] In some circumstances, cancer cells will be in the form of a tumor; such cells may exist locally within an animal (e.g., solid tumor); alternatively, cancer cells may circulate in the bloodstream as independent cells, e.g., leukemic cells (non-solid tumor), or they may be dispersed throughout the body (e.g., metastasis). It will be understood that the term “cancer,” as used in the present invention, encompasses all types of cancer, at any stage and in any form.

[109] Types of malignant diseases that can be diagnosed or treated by the methods of some embodiments of the invention include benign tumors, warts, polyps, pre-cancers and malignant tumors / cancers.

[110] Specific examples of cancerous diseases that can be treated using the methods of the present invention include, but are not limited to Petition 870250085447, dated 09 / 22 / 2025, pages 128 / 148 28 / 42 limited to carcinoma, lymphoma, blastoma, sarcoma and leukemia.More specific examples of such cancers include squamous cell carcinoma, soft tissue sarcoma, Kaposi's sarcoma, melanoma, lung cancer (including small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, and squamous cell lung carcinoma), peritoneal cancer, hepatocellular carcinoma, gastric or stomach cancer (including gastrointestinal cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, rectal cancer, endometrial or uterine carcinoma, carcinoid carcinoma, salivary gland carcinoma, renal or kidney cancer, liver cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatic carcinoma, mesothelioma, multiple myeloma, post-transplant lymphoproliferative disorder (PTLD), and various types of head and neck cancer (e.g., brain tumor).The cancerous conditions treatable by the invention include metastatic cancers.

[111] According to one classification, malignant disease is a hematological malignancy. Exemplary hematological malignancies include, but are not limited to, leukemia [e.g., acute lymphoblastic, acute lymphoblastic, acute lymphoblastic pre-B cell, acute lymphoblastic T cell leukemia, acute megakaryoblastic, monocytic, acute myeloid, acute myeloid, acute myeloid with eosinophilia, B cell, basophilic, chronic myeloid, chronic, B cell, eosinophilic, Friend, granulocytic or myelocytic, hairy cell, lymphocytic, megakaryoblastic, monocytic, monocytic-macrophage, myeloblastic, myeloid, myelomonocytic, plasma cell, pre-B cell, promyelocytic, subacute, T cell, lymphoid neoplasm, myeloid malignancy predisposition, acute non-lymphocytic leukemia, acute lymphocytic T cell leukemia (T-ALL), and chronic lymphocytic B cell leukemia]. (B-CLL)] and lymphoma [e.g., disease Petition 870250085447, dated 09 / 22 / 2025, pages 129 / 148 29 / 42 Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, cutaneous T-cell lymphoma, histiocytic lymphoma, lymphoblastic lymphoma, thymic T-cell lymphoma, B-cell lymphoma, including low-grade / follicular lymphoma; small lymphocytic NHL (SLN); intermediate-grade / follicular NHL; diffuse intermediate-grade NHL; high-grade immunoblastic NHL; high-grade lymphoblastic NHL; high-grade small non-cleaved cell NHL; bulky NHL disease; mantle cell lymphoma; AIDS-related lymphoma; and Waldenstrom's macroglobulinemia.

[112] According to a specific modality, malignant disease is leukemia, lymphoma, myeloma, melanoma, sarcoma, neuroblastoma, colon cancer, colorectal cancer, breast cancer, ovarian cancer, esophageal cancer, synovial cell cancer, liver cancer and pancreatic cancer.

[113] According to one modality, the individual has a non-malignant disease.

[114] According to one modality, a nonmalignant disease is an organ dysfunction or failure (e.g., renal disease or liver disease that are associated with cytopenia), a nonmalignant hematological disease (e.g., cytopenia, anemia, sickle cell anemia, hemophilia), a graft-related disease (e.g., graft rejection), an immunodeficiency, a severe combined immunodeficiency syndrome (SCID), a genetic disease, a metabolic disorder, an infectious disease, an inflammatory disease (e.g., systemic inflammatory disease, such as that associated with cytopenia), an autoimmune disease, an allergic disease, trauma, and an injury.

[115] Inflammatory diseases - Include, but are not limited to, chronic inflammatory diseases and acute inflammatory diseases. Inflammatory diseases associated with hypersensitivity Petition 870250085447, dated 09 / 22 / 2025, pages 130 / 148 30 / 42

[116] Examples of hypersensitivity include, but are not limited to, Type I hypersensitivity, Type II hypersensitivity, Type III hypersensitivity, Type IV hypersensitivity, immediate hypersensitivity, antibody-mediated hypersensitivity, immune complex-mediated hypersensitivity, T-lymphocyte-mediated hypersensitivity and DTH.

[117] Type I or immediate hypersensitivity, such as asthma.

[118] Type II hypersensitivity includes, but is not limited to, rheumatoid diseases, autoimmune rheumatoid diseases, rheumatoid arthritis (Krenn V. et al., Histol Histopathol 2000 Jul;15 (3):791), spondylitis, ankylosing spondylitis (Jan Voswinkel et al., Arthritis Res 2001; 3 (3): 189), systemic diseases, systemic autoimmune diseases, systemic lupus erythematosus (Erikson J. et al., Immunol Res 1998;17 (1-2):49), sclerosis, systemic sclerosis (Renaudineau Y. et al., Clin Diagn Lab Immunol. 1999 Mar;6(2):156); Chan OT. et al., Immunol Rev 1999 Jun;169:107), glandular diseases, autoimmune glandular diseases, autoimmune pancreatic diseases, diabetes, type I diabetes (Zimmet P. Diabetes Res Clin Pract 1996 Oct;34 Suppl:S125), thyroid diseases, autoimmune thyroid diseases, Graves' disease (Orgiazzi J. Endocrinol Metab Clin North Am 2000 Jun;29 (2):339), thyroiditis, spontaneous autoimmune thyroiditis (Braley-Mullen H.and Yu S, J Immunol 2000 Dec 15; 165 (12): 7262), Hashimoto's thyroiditis (Toyoda N. et al., Nippon Rinsho 1999 Aug; 57 (8): 1810), myxedema, idiopathic myxedema (Mitsuma T. Nippon Rinsho. 1999 Aug; 57 (8): 1759); autoimmune reproductive diseases, ovarian diseases, ovarian autoimmunity (Garza KM. et al., J Reprod Immunol 1998 Feb;37(2):87), autoimmune antisperm infertility (Diekman AB. et al., Am J Reprod Immunol. 2000 Mar;43(3):134), repeated fetal losses (Tincani A. et al., Lupus 1998;7 Suppl 2:S107-9), neurodegenerative diseases, neurological diseases, neurological autoimmune diseases, multiple sclerosis (Cross AH. et al., J. Petition 870250085447, dated 09 / 22 / 2025, pp. 131 / 148 31 / 42 Neuroimmunol 2001 Jan 1;112(1-2):1), Alzheimer's disease (Oron L. et al., J Neural Transm Suppl. 1997;49:77), myasthenia gravis (Infante AJ. and Kraig E, Int Rev Immunol 1999;18(1-2):83), motor neuropathies (Kornberg AJ. J Clin Neurosci. 2000 May;7(3):191), Guillain-Barré syndrome, neuropathies and autoimmune neuropathies (Kusunoki S. Am J Med Sci. 2000 Apr;319(4):234), myasthenic diseases, Lambert-Eaton myasthenic syndrome (Takamori M. Am J Med Sci. 2000 Apr;319(4):204), paraneoplastic neurological diseases, atrophy cerebellar, paraneoplastic cerebellar atrophy, non-paraneoplastic stiff-person syndrome, cerebellar atrophies, progressive cerebellar atrophies, encephalitis, Rasmussen's encephalitis, amyotrophic lateral sclerosis, Sydenham's chorea, Gilles de la Tourette syndrome, polyendocrinopathies, autoimmune polyendocrinopathies (Antoine JC. and Honnorat J. Rev Neurol (Paris) 2000 Jan;156 (1):23); neuropathies, disimmune neuropathies (Nobile-Orazio E. et al., Electroencephalogr Clin Neurophysiol Suppl 1999;50:419); Neuromyotonia, acquired neuromyotonia, congenital multiple arthrogryposis (Vincent A. et al., Ann NY Acad Sci. 1998 May 13;841:482), cardiovascular diseases, autoimmune cardiovascular diseases, atherosclerosis (Matsuura E. et al., Lupus. 1998;7 Suppl 2:S135), myocardial infarction (Vaarala O. Lupus. 1998;7 Suppl 2:S132), thrombosis (Tincani A. et al., Lupus 1998;7 Suppl 2:S107-9), granulomatosis, Wegener's granulomatosis, arteritis, Takayasu's arteritis, and Kawasaki syndrome (Praprotnik S. et al., Wien Klin Wochenschr 2000 Aug 25;112). (15-16):660); anti-factor VIII autoimmune disease (Lacroix-Desmazes S. et al., Semin Thromb Hemost.2000;26 (2):157); vasculitis, necrotizing small vessel vasculitis, microscopic polyangiitis, Churg-Strauss syndrome, glomerulonephritis, pauci-immune focal necrotizing glomerulonephritis, crescentic glomerulonephritis (Noel LH. Ann Med Interne (Paris).2000 May;151 (3):178); antiphospholipid antibody syndrome (Flamholz R. et al., J Clin Apheresis 1999;14 (4):171); heart failure, type. Petition 870250085447, dated 09 / 22 / 2025, pages 132 / 148 32 / 42 agonist β-adrenoceptor antibodies in heart failure (Wallukat G. et al., Am J Cardiol. 1999 Jun 17;83 (12A):75H), thrombocytopenic purpura (Moccia F. Ann Ital Med Int. 1999 Apr-Jun;14 (2):114); hemolytic anemia, autoimmune hemolytic anemia (Efremov DG. et al., Leuk Lymphoma 1998 Jan;28 (34):285), gastrointestinal diseases, autoimmune diseases of the gastrointestinal tract, intestinal diseases, chronic inflammatory bowel disease (Garcia Herola A. et al., Gastroenterol Hepatol. 2000 Jan;23 (1):16), celiac disease (Landau YE. and Shoenfeld Y. Harefuah 2000 Jan 16;138 (2):122), autoimmune diseases of the musculature, myositis, autoimmune myositis, Sjogren's syndrome (Feist E. et al., Int Arch Allergy Immunol 2000 Sep;123 (1):92); autoimmune smooth muscle disease (Zauli D. et al., Biomed Pharmacother 1999 Jun;53 (5-6):234), liver diseases, autoimmune liver diseases, autoimmune hepatitis (Manns MP. J Hepatol 2000 Aug;33 (2):326) and primary biliary cirrhosis (Strassburg CP. et al., Eur J Gastroenterol Hepatol. 1999 Jun;11 (6):595).

[119] Type IV or T-cell mediated hypersensitivity includes, but is not limited to, rheumatoid diseases, rheumatoid arthritis (Tisch R, McDevitt HO. Proc Natl Acad Sci USA 1994 Jan 18;91 (2):437), systemic diseases, systemic autoimmune diseases, systemic lupus erythematosus (Datta SK., Lupus 1998;7 (9):591), glandular diseases, glandular autoimmune diseases, pancreatic diseases, pancreatic autoimmune diseases, type 1 diabetes (Castano L. and Eisenbarth GS. Ann. Rev. Immunol. 8:647); thyroid diseases, autoimmune thyroid diseases, Graves' disease (Sakata S. et al., Mol Cell Endocrinol 1993 Mar;92 (1):77); ovarian diseases (Garza KM. et al., J Reprod Immunol 1998 Feb;37(2):87), prostatitis, autoimmune prostatitis (Alexander RB. et al., Urology 1997 Dec;50(6):893), polyglandular syndrome, autoimmune polyglandular syndrome, autoimmune polyglandular syndrome type I (Hara T. et al., Blood. 1991 Mar 1;77(5):1127), neurological diseases, autoimmune neurological diseases, Petition 870250085447, dated 09 / 22 / 2025, pp. 133 / 148 33 / 42 Multiple sclerosis, neuritis, optic neuritis (Soderstrom M. et al., J Neurol Neurosurg Psychiatry 1994 May;57(5):544), myasthenia gravis (Oshima M. et al., Eur J Immunol 1990 Dec;20(12):2563), stiff-person syndrome (Hiemstra HS. et al., Proc Natl Acad Sci USA 2001 Mar 27;98(7):3988), cardiovascular diseases, cardiac autoimmunity in Chagas disease (Cunha-Neto E. et al., J Clin Invest 1996 Oct 15;98(8):1709), autoimmune thrombocytopenic purpura (Semple JW. et al., Blood 1996 May 15;87(10):4245), anti-lymphocyte autoimmunity T auxin (Caporossi AP. et al., Viral Immunol 1998;11 (1):9), hemolytic anemia (Sallah S. et al., Ann Hematol 1997 Mar;74 (3):139), liver diseases, autoimmune liver diseases, hepatitis, chronic active hepatitis (Franco A. et al., Clin Immunol Immunopathol 1990 Mar;54 (3):382), biliary cirrhosis, primary biliary cirrhosis (Jones DE.Clin Sci (Colch) 1996 Nov;91(5):551), nephritic diseases, autoimmune nephritic diseases, nephritis, interstitial nephritis (Kelly CJ. J Am Soc Nephrol 1990 Aug;1(2):140), connective tissue diseases, ear diseases, autoimmune connective tissue diseases, autoimmune ear disease (Yoo TJ. et al., Cell Immunol 1994 Aug;157(1):249), inner ear disease (Gloddek B. et al., Ann NY Acad Sci 1997 Dec 29;830:266), skin diseases, cutaneous diseases, dermal diseases, bullous skin diseases, pemphigus vulgaris, bullous pemphigoid and pemphigus foliaceus.

[120] Examples of delayed-type hypersensitivity include, but are not limited to, contact dermatitis and drug eruption.

[121] Examples of types of T-cell mediated hypersensitivity include, but are not limited to, helper T lymphocytes and cytotoxic T lymphocytes.

[122] Examples of T helper lymphocyte-mediated hypersensitivity include, but are not limited to, Th1 lymphocyte-mediated hypersensitivity and Th12 lymphocyte-mediated hypersensitivity. Petition 870250085447, dated 09 / 22 / 2025, pages 134 / 148 34 / 42 Autoimmune diseases

[123] Includes, but is not limited to, cardiovascular diseases, rheumatoid diseases, glandular diseases, gastrointestinal diseases, skin diseases, liver diseases, neurological diseases, muscle diseases, nephritic diseases, reproductive-related diseases, connective tissue diseases and systemic diseases.

[124] Examples of autoimmune cardiovascular diseases include, but are not limited to, atherosclerosis (Matsuura E. et al., Lupus. 1998;7 Suppl 2:S135), myocardial infarction (Vaarala O. Lupus. 1998;7 Suppl 2:S132), thrombosis (Tincani A. et al., Lupus 1998;7 Suppl 2:S107-9), Wegener's granulomatosis, Takayasu arteritis, Kawasaki syndrome (Praprotnik S. et al., Wien Klin Wochenschr 2000 Aug 25;112 (15-16):660), anti-factor VIII autoimmune disease (Lacroix-Desmazes S. et al., Semin Thromb Hemost.2000;26 (2):157), necrotizing vasculitis of small vessels, microscopic polyangiitis, Churg-Strauss syndrome, focal necrotizing glomerulonephritis and pauci-immune crescent (Noel LH. Ann Med Interne (Paris). 2000 May;151 (3):178), antiphospholipid antibody syndrome (Flamholz R. et al., J Clin Apheresis 1999;14 (4):171), antibody-induced heart failure (Wallukat G. et al., Am J Cardiol. 1999 Jun 17;83 (12A):75H), thrombocytopenic purpura (Moccia F. Ann Ital Med Int.1999 Apr-Jun;14 (2):114; Semple JW. et al., Blood 1996 May 15;87 (10):4245), autoimmune hemolytic anemia (Efremov DG. et al., Leuk Lymphoma 1998 Jan;28 (3-4):285; Sallah S. et al., Ann Hematol 1997 Mar;74 (3):139), cardiac autoimmunity in Chagas disease (Cunha-Neto E. et al., J Clin Invest 1996 Oct 15;98 (8):1709) and anti-T lymphocyte helper autoimmunity (Caporossi AP. et al., Viral Immunology 1998;11 (1):9).

[125] Examples of autoimmune rheumatoid diseases include, but are not limited to, rheumatoid arthritis (Krenn V. et al., Histol Histopathol 2000 Petition 870250085447, dated 09 / 22 / 2025, pp. 135 / 148 35 / 42 Jul;15 (3):791; Tisch R, McDevitt HO. Proc Natl Acad Sci units SA 1994 Jan 18;91 (2):437) and ankylosing spondylitis (Jan Voswinkel et al., Arthritis Res 2001; 3 (3): 189).

[126] Examples of autoimmune glandular diseases include, but are not limited to, pancreatic disease, type I diabetes, thyroid disease, Graves' disease, thyroiditis, spontaneous autoimmune thyroiditis, Hashimoto's thyroiditis, idiopathic myxedema, ovarian autoimmunity, autoimmune antisperm infertility, autoimmune prostatitis, and autoimmune polyglandular syndrome type I. Diseases include, but are not limited to, autoimmune pancreatic diseases, type 1 diabetes (Castano L. and Eisenbarth GS. Ann. Rev. Immunol. 8:647; Zimmet P. Diabetes Res Clin Pract 1996 Oct;34 Suppl:S125), autoimmune thyroid diseases, Graves' disease (Orgiazzi J. Endocrinol Metab Clin North Am 2000 Jun;29 (2):339; Sakata S. et al., Mol Cell Endocrinol 1993 Mar;92(1):77), spontaneous autoimmune thyroiditis (Braley-Mullen H. and Yu S, J Immunol 2000 Dec 15;165(12):7262), Hashimoto's thyroiditis (Toyoda N. et al., Nippon Rinsho 1999 Aug;57(8):1810), idiopathic myxedema (Mitsuma T. Nippon Rinsho.1999 Aug;57 (8):1759), ovarian autoimmunity (Garza KM. et al., J Reprod Immunol 1998 Feb;37 (2):87), autoimmune antisperm infertility (Diekman AB. et al., Am J Reprod Immunol. 2000 Mar;43 (3):134), autoimmune prostatitis (Alexander RB. et al., Urology 1997 Dec;50 (6):893) and autoimmune polyglandular syndrome type I (Hara T. et al., Blood. 1991 Mar 1;77 (5):1127).

[127] Examples of autoimmune gastrointestinal diseases include, but are not limited to, chronic inflammatory bowel diseases (Garcia Herola A. et al., Gastroenterol Hepatol. 2000 Jan;23 (1):16), celiac disease (Landau YE. and Shoenfeld Y. Harefuah 2000 Jan 16;138 (2):122), colitis, ileitis and Crohn's disease.

[128] Examples of autoimmune skin diseases include, but are not limited to Petition 870250085447, dated 09 / 22 / 2025, pages 136 / 148 36 / 42 limited to, autoimmune bullous skin diseases, such as, but not limited to, pemphigus vulgaris, bullous pemphigoid and pemphigus foliaceus.

[129] Examples of autoimmune liver diseases include, but are not limited to, hepatitis, autoimmune chronic active hepatitis (Franco A. et al., Clin Immunol Immunopathol 1990 Mar;54 (3):382), primary biliary cirrhosis (Jones DE. Clin Sci (Colch) 1996 Nov;91 (5):551; Strassburg CP. et al., Eur J Gastroenterol Hepatol. 1999 Jun;11 (6):595) and autoimmune hepatitis (Manns MP. J Hepatol 2000 Aug;33 (2):326).

[130] Examples of autoimmune neurological diseases include, but are not limited to, multiple sclerosis (Cross AH. et al., J Neuroimmunol 2001 Jan 1;112 (1-2):1), Alzheimer's disease (Oron L. et al., J Neural Transm Suppl. 1997;49:77), myasthenia gravis (Infante AJ. and Kraig E, Int Rev Immunol 1999;18 (12):83; Oshima M. et al., Eur J Immunol 1990 Dec;20 (12):2563), neuropathies, motor neuropathies (Kornberg AJ. J Clin Neurosci. 2000 May;7 (3):191); Guillain-Barré syndrome and autoimmune neuropathies (Kusunoki S. Am J Med Sci. 2000 Apr; 319(4): 234), myasthenia, Lambert-Eaton myasthenic syndrome (Takamori M. Am J Med Sci. 2000 Apr; 319(4): 204); paraneoplastic neurological disorders, cerebellar atrophy, paraneoplastic cerebellar atrophy and stiff-person syndrome (Hiemstra HS. et al., Proc Natl Acad Sci units SA 2001 Mar 27;98 (7):3988); non-paraneoplastic stiff-person syndrome, progressive cerebellar atrophies, encephalitis, Rasmussen's encephalitis, amyotrophic lateral sclerosis, Sydenham's chorea, Gilles de la Tourette syndrome and autoimmune polyendocrinopathies (Antoine JC. and Honnorat J. Rev Neurol (Paris) 2000 Jan;156 (1):23); dysimmune neuropathies (Nobile-Orazio E. et al., Electroencephalogr Clin Neurophysiol Suppl 1999;50:419); Acquired neuromyotonia, congenital multiple arthrogryposis (Vincent A. et al., Ann NY Acad Sci. 1998 May 13; 841: 482), neuritis, optic neuritis (Soderstrom M. et al., J Neurol Neurosurg Psychiatry 1994). Petition 870250085447, dated 09 / 22 / 2025, pp. 137 / 148 37 / 42 May;57 (5):544) and neurodegenerative diseases.

[131] Examples of autoimmune muscle diseases include, but are not limited to, myositis, autoimmune myositis and primary Sjogren's syndrome (Feist E. et al., Int Arch Allergy Immunol 2000 Sep;123 (1):92) and autoimmune smooth muscle disease (Zauli D. et al., Biomed Pharmacother 1999 Jun;53 (5-6):234).

[132] Examples of autoimmune nephritic diseases include, but are not limited to, nephritis and autoimmune interstitial nephritis (Kelly CJ. J Am Soc Nephrol 1990 Aug;1 (2):140).

[133] Examples of autoimmune diseases related to reproduction include, but are not limited to, repeated fetal losses (Tincani A. et al., Lupus 1998;7 Suppl 2:S107-9).

[134] Examples of autoimmune connective tissue diseases include, but are not limited to, ear diseases, autoimmune ear diseases (Yoo TJ. et al., Cell Immunol 1994 Aug; 157 (1): 249) and autoimmune inner ear diseases (Gloddek B. et al., Ann NY Acad Sci 1997 Dec 29; 830: 266).

[135] Examples of systemic autoimmune diseases include, but are not limited to, systemic lupus erythematosus (Erikson J. et al., Immunol Res 1998;17 (1-2):49) and systemic sclerosis (Renaudineau Y. et al., Clin Diagn Lab Immunol. 1999 Mar;6(2):156); Chan OT. et al., Immunol Rev 1999 Jun;169:107). Infectious diseases

[136] Examples of infectious diseases include, but are not limited to, chronic infectious diseases, subacute infectious diseases, acute infectious diseases, viral diseases, bacterial diseases, protozoan diseases, parasitic diseases, fungal diseases, mycoplasma diseases and prion diseases.

[137] Specific types of viral pathogens that cause disease Petition 870250085447, dated 09 / 22 / 2025, pages 138 / 148 38 / 42 treatable infectious diseases according to the teachings of the present invention include, but are not limited to, retroviruses, circoviruses, parvoviruses, papovaviruses, adenoviruses, herpesviruses, iridoviruses, poxviruses, hepadnaviruses, picornaviruses, caliciviruses, togaviruses, flaviviruses, reoviruses, orthomyxoviruses, paramyxoviruses, rhabdoviruses, bunyaviruses, coronaviruses, arenaviruses, and filoviruses.

[138] Specific examples of viral infections that can be treated according to the teachings of the present invention include, but are not limited to, those caused by acquired immunodeficiency syndrome (AIDS) induced by human immunodeficiency virus (HIV), influenza, rhinovirus infection, viral meningitis, Epstein-Barr virus (EBV) infection, hepatitis A, B or C virus infection, measles, papillomavirus infection / warts, cytomegalovirus (CMV) infection, herpes simplex virus infection, yellow fever, Ebola virus infection, rabies, adenovirus (Adv), common cold virus, influenza virus, Japanese encephalitis, poliomyelitis, respiratory syncytial virus, rubella, smallpox, varicella zoster, rotavirus, West Nile virus and Zika virus.

[139] Specific examples of bacterial infections that can be treated according to the teachings of the present invention include, but are not limited to, those caused by anthrax; gram-negative bacilli, chlamydia, diphtheria, Haemophilus influenzae, Helicobacter pylori, malaria, Mycobacterium tuberculosis, pertussis toxin, pneumococcus, rickettsiae, staphylococci, streptococci and tetanus.

[140] Specific examples of superbug infections (e.g., multidrug-resistant bacteria) that can be treated according to the teachings of the present invention include, but are not limited to, those caused by Enterococcus faecium, Clostridium difficile, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriaceae (including Escherichia coli, Klebsiella pneumoniae, Enterobacter spp.). Petition 870250085447, dated 09 / 22 / 2025, pp. 139 / 148 39 / 42

[141] Specific examples of fungal infections that can be treated according to the teachings of the present invention include, but are not limited to, those caused by candida, coccidioides, cryptococcus, histoplasma, leishmania, plasmodium, protozoa, parasites, schistosomiasis, tinea, toxoplasma and trypanosoma cruzi. Graft rejection diseases

[142] According to another modality, the disease is associated with the transplantation of a graft. Examples of diseases associated with graft transplantation include, but are not limited to, graft rejection, chronic graft rejection, subacute graft rejection, hyperacute graft rejection, acute graft rejection, allograft rejection, xenograft rejection, and graft-versus-host disease (GVHD). Allergic diseases

[143] Examples of allergic diseases include, but are not limited to, asthma, hives, pollen allergy, dust mite allergy, venom allergy, cosmetic allergy, latex allergy, chemical allergy, drug allergy, insect sting allergy, pet dander allergy, prickly plant allergy, poison ivy allergy and food allergy. Non-malignant hematological disease

[144] Examples of non-malignant hematological diseases include, but are not limited to, cytopenia (e.g., anemia, leukopenia, neutropenia, thrombocytopenia, granulocytopenia, pancytopenia), drug-induced cytopenia, toxin-induced cytopenia, radiation-induced cytopenia or cytopenia associated with conventional bone marrow transplantation, bone marrow disorders, deep vein thrombosis / pulmonary embolism, Diamond-Blackfan anemia, hemochromatosis, hemophilia, immunological hematological disorders, iron metabolism disorders, sickle cell anemia, Petition 870250085447, dated 09 / 22 / 2025, pages 140 / 148 40 / 42 thalassemia, osteopetrosis, von Willebrand disease, and Gaucher disease.

[145] In addition, the hematopoietic stem cell mobilization method can be used for patients who are difficult to mobilize because, for example, they are not sensitive to growth factors.

[146] The hematopoietic stem cells of the present invention can be transplanted into a recipient using any method known in the art for cell transplantation, such as, but not limited to, cell infusion (e.g., IV) or via the intraperitoneal route.

[147] As used in the present invention, the term “about” refers to ± 10%.

[148] The terms “compreende”, “compreendendo”, “inclui”, “incluindo”, “tendo” and their conjugates mean “including, but not limited to”.

[149] The term “consisting of” means “including and limited to”.

[150] The term “essentially consisting of” means that the composition, method or structure may include additional ingredients, steps and / or parts, but only if the additional ingredients, steps and / or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.

[151] As used in the present invention, the singular forms “a”, “an” and “the” include plural references unless the context clearly indicates otherwise. For example, the term “a compound” or “at least one compound” may include a plurality of compounds, including mixtures thereof.

[152] From beginning to end of this application, various embodiments of this invention may be presented in a strip format. It should be understood that the description in strip format is merely for convenience and brevity and should not be interpreted as an inflexible limitation on the scope of the invention. Petition 870250085447, dated 09 / 22 / 2025, pages 141 / 148 41 / 42 Therefore, the description of a range should be considered as having specifically revealed all possible sub-ranges, as well as individual numerical values ​​within that range. For example, the description of a range, such as 1 to 6, should be considered as having specifically revealed sub-ranges, such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the range's width.

[153] Whenever a numerical range is indicated in the present invention, it is intended to include any cited numeral (fractional or integer) included in the indicated range. The expressions “ranging from” a first indicated number and a second indicated number and “ranging from” a first indicated number “to” a second indicated number are used interchangeably in the present invention and are intended to include the first and second indicated numbers and all fractional and integer numerals between them.

[154] As used in the present invention, the term “method” refers to ways, means, techniques and procedures for accomplishing a given task, including, but not limited to, ways, means, techniques and procedures known or readily developed from ways, means, techniques and procedures known to practitioners of chemical, pharmacological, biological, biochemical and medical techniques.

[155] As used in the present invention, the term “treat” includes revoking, substantially inhibiting, delaying or reversing the progression of a condition, substantially improving the clinical or aesthetic symptoms of a condition, or substantially preventing the appearance of clinical or aesthetic symptoms of a condition.

[156] It is appreciated that certain attributes of the invention, which are, for greater clarity, described in the context of separate embodiments, may also be Petition 870250085447, dated 09 / 22 / 2025, pp. 142 / 148 42 / 42 provided in combination in a single embodiment. On the other hand, several attributes of the invention, which are, for short, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or as appropriate in any other described embodiment of the invention. Certain attributes described in the context of several embodiments should not be considered essential attributes of those embodiments unless the embodiment is inoperative without those elements.

[157] Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Therefore, it is intended to cover all such alternatives, modifications and variations that fall within the broad spirit and scope of the appended claims.

[158] It is the Applicant(s)' intention that all publications, patents and patent applications referred to in this descriptive report be incorporated in their entirety by reference in the descriptive report, as if each individual publication, patent or patent application were specifically and individually noted when referenced that it should be incorporated into the present invention by reference. Furthermore, the citation or identification of any reference in this application should not be interpreted as an admission that such reference is available as a prior art to the present invention. To the extent that section headings are used, they should not be interpreted as necessarily limiting. In addition, any priority document(s) of this application is / are incorporated into the present invention by reference in its / their entirety. Petition 870250085447, dated 09 / 22 / 2025, pp. 143 / 148

Claims

1 / 3 CLAIMS 1. A method for mobilizing hematopoietic precursor cells from the bone marrow into the peripheral blood of an individual, characterized in that it comprises: (a) administering to the individual an effective amount of natalizumab; and (b) administering to the individual an effective amount of a CXCR4 inhibitor, wherein step (b) is performed at least 48 hours following step (a).

2. A method for obtaining a therapeutically effective quantity of hematopoietic precursor cells from an individual, characterized in that it comprises: (a) administering to the individual an effective quantity of natalizumab; (b) administering to said individual an effective quantity of a CXCR4 inhibitor, wherein step (b) is performed at least 48 hours following step (a); and (c) collecting said hematopoietic precursor cells by apheresis.

3. An effective amount of a combination of natalizumab and a CXCR4 inhibitor for use in mobilizing hematopoietic precursor cells in an individual, characterized in that said CXCR4 inhibitor is administered to the individual at least 48 hours after the administration of said natalizumab.

4. Effective quantity of a combination of natalizumab and a CXCR4 inhibitor for use in a method of collecting hematopoietic precursor cells by apheresis, characterized in that it comprises mobilizing said hematopoietic precursor cells, wherein said hematopoietic precursor cells are subsequently collected by apheresis, wherein said CXCR4 inhibitor is administered to the individual at least 48 hours after the administration of said natalizumab. Petition 870250085447, dated 09 / 22 / 2025, pp. 144 / 148 2 / 3 5. A method or combination for use, according to any one of claims 1 to 3, characterized in that said individual is a human individual.

6. Method or combination for use, according to any one of claims 1 to 3, characterized in that said individual is a donor of said hematopoietic precursor cells.

7. A method or combination for use, according to any one of claims 1 to 3, characterized in that the individual is diagnosed with cancer.

8. Method or combination for use, according to any one of claims 1 to 3, characterized in that said hematopoietic precursor cells are for autologous transplantation.

9. Method or combination for use, according to any one of claims 1 to 3, characterized in that said hematopoietic precursor cells are for allogeneic transplantation.

10. Method or combination for use, according to any one of claims 1 to 9, characterized in that said effective amount comprises repeated cycles of administration of said natalizumab and said CXCR4 inhibitor.

11. Method or combination for use, according to any one of claims 1 to 10, characterized in that the aforementioned at least 48 hours comprise up to 96 hours.

12. Method or combination for use, according to any one of claims 1 to 10, characterized in that the aforementioned at least 48 hours comprise up to 72 hours.

13. Method or combination for use, according to any of claims 1 to 12, characterized in that the said inhibitor of Petition 870250085447, dated 09 / 22 / 2025, page 145 / 148 3 / 3 CXCR4 is a peptide, a small molecule, an antibody, a nucleic acid or a combination thereof.

14. Method or combination for use, according to any one of claims 1 to 12, characterized in that said CXCR4 inhibitor is a peptide as set forth in SEQ ID NO:

1.

15. Method or combination for use, according to any one of claims 1 to 12, characterized in that said CXCR4 inhibitor is a small molecule.

16. Method or combination for use, according to any one of claims 1 to 12, characterized in that said CXCR4 inhibitor is AMD3100. Petition 870250085447, dated 09 / 22 / 2025, pp. 146 / 148