Gpcr inhibitors and uses thereof

Abstract

This invention relates to methods and compositions directed to mobilizing a cell in a subject by blocking CXCR4, a beta-adrenergic receptor, a GPCR, or any combination thereof. In some embodiments, the cell is a hematopoietic stem cell. In some embodiments, the method further comprises administration of G-CSF. This invention also relates to methods of treatment, methods for qualifying a subject for treatment, and methods for preparing a subject for treatment, by blocking CXCR4, a beta-adrenergic receptor, a GPCR, or any combination thereof. In some embodiments, the cell is a hematopoietic stem cell. In some embodiments, the treatment is for cancer. In some embodiments, the CXCR4 is GPC-100. In some embodiments, the method further comprises administration of G-CSF.

Description

GPCR INHIBITORS AND USES THEREOFTECHNICAL FIELD

[0001] The present technology generally relates to GPCR inhibitors and their use in treating diseases.BACKGROUND

[0002] Multiple myeloma (MM) is a leading hematological malignancy with an estimated 34,920 cases in the United States and approximately 588,161 cases worldwide each year [1], Autologous Stem Cell Transplant (ASCT) is integral to the overall management of eligible MM patients and has improved the anti-cancer response and survival compared to conventional chemotherapy [2-5], The success of ASCT relies on harvesting a sufficient number of hematopoietic stem cells (HSC), which are predominantly obtained by mobilizing the HSCs from the bone marrow (BM) into the peripheral blood (PB) [6, 7], In humans, HSCs are phenotypically characterized by the expression of CD34. A minimum of 2X106CD34+cells / kg are essential for the HSC harvest, whereas the optimal number for improved engraftment and survival is >5-6*106CD34+cells / kg [8, 9], Granulocyte-colony stimulating factor (G-CSF) is a clinical standard of care for HSC mobilization

[0010] , However, G-CSF fails to mobilize optimal number of HSC in at least 40-50% MM patients [10, 11], Some patients are treated with the combination of G-CSF and a small molecule CXCR4 antagonist AMD3100 (Plerixafor, or Mozobil)

[0010] , Despite this combination treatment, 15-35% MM patients do not mobilize a sufficient number of cells [10, 12], In a recent phase 3 clinical study, the combination of G-CSF and BL8040 (motixafortide), a peptide inhibitor of CXCR4, mobilized significantly greater CD34+cells compared to G-CSF plus placebo

[0013] , While this is promising, this study did not include patients on daratumumab

[0014] , which was recently approved and accumulating data suggests can negatively impact HSC mobilization, even more so than the traditional therapeutic lenalidomide

[0015] , Mobilization failure can lead to potential loss of ASCT as a treatment option and significant toxicity from repeated mobilization attempts. Moreover, G-CSF is contraindicated in conditions like sickle cell disease for stem cell collection

[0016] and exacerbates autoimmune diseases

[0017] , Therefore, there is need for identification of novel strategies that not only addresspoor mobilization in MM patients, but also provide non-GCS-F options for adequate mobilization in MM as well as other disease indications [18, 19],BRIEF DESCRIPTION OF THE DRAWINGS

[0003] FIGs. 1A-1B show molecular level comparisons of the CXCR4 inhibitors GPC-100 and AMD3100. (FIG. 1A) Chemical structures of AMD3100 and GPC-100. (FIG. 1B) Overlay of the proposed binding modes for GPC-100 and AMD3100 obtained from molecular docking with the template of an inactive structure of CXCR4 and induced-fit algorithm from Schrodinger. CXCR4 transmembrane helices are shown and annotated as gray ribbons. The 2D ligand interaction diagram represents its amino acid residues as colored triangular picks. Picks that are pointing away represent the backbone of residue facing towards the respective ligand. Picks facing towards the respective ligand represent the side chain of residue facing the ligand.

[0004] FIG. 2 shows dose response curves showing competitive inhibition of CXCL12 binding to CXCR4 by GPC-100 and AMD3100. Ki for the respective compounds were determined by plotting the normalized HTRF ratio (% CXCL12 bound) versus the compound concentrations and using non-linear regression competitive binding “one site - fit Ki equation”. Data expressed as mean ± SEM.

[0005] FIGs. 3A-3D show pharmacological inhibition of the CXCR4 / CXCL12 axis by GPC-100 and AMD3100. (FIG. 3A) Inhibition of CXCL12 (20 nM)-induced calcium flux by GPC-100 and AMD3100 in MDA-MB-231 cells transduced with CXCR4.(FIG. 3B) Inhibition of CXCL12 induced p-arrestin recruitment to CXCR4 by GPC- 100 and AMD3100 using Presto-Tango assay in HTLA cells overexpressing CXCR4- tango and 2AR. (FIGs. 3C-3D) Inhibition of CXCL12 induced migration of human cells by GPC-100 and AMD3100. (FIG. 3C) Inhibition profile in U937 cells. (FIG. 3D) Inhibition profile in MM.1S cells. Data expressed as mean ± SEM.

[0006] FIG. 4 shows expression of CXCR4 in LI937 cells. LI937 cells were pretreated with Fc receptor binding inhibitor polyclonal antibody and surface expression of CXCR4 was detected by flow cytometry with isotype control or anti-CXCR4 antibody (Ulocuplumab) followed by Alexa Fluor 568-conjugated goat anti-human IgG antibody.

[0007] FIGs. 5A-5B show CXCL12 induced migration. Cells were suspended in serum-free media containing 0.5% BSA at 5x106cells / ml and 100 pl of cellsuspension was added to the transwell insert wherein the transwell contains increasing concentrations of CXCL12. (FIG. 5A) Migration profile in MM.1S cells. (FIG. 5B) Migration profile in U937 cells.

[0008] FIGs. 6A-6B show expression of CXCR4 and P2AR in Namalwa cells. Flow cytometry was used to detect the surface expression of endogenous CXCR4 and P2AR in Namalwa cells after staining with anti-CXCR4 or anti-p2AR antibodies. (FIG. 6A) Endogenous CXCR4 profiles visualized using PE-conjugated anti-human CXCR4 antibodies (1 D9). (FIG. 6B) Endogenous P2AR visualized using Alexa-Fluor 488-conjugated anti-human P2AR (R11 E1) antibodies.

[0009] FIGs. 7A-7B show CXCR4 and P2AR co-localization in cancer cells. PLA showing proximity between CXCR4 and P2AR in Namalwa cells. (FIG. 7A) Colocalization profile in Namalwa parental and Namalwa CXCR4 knock-out cells. (FIG. 7B) Co-localization profile in MDA-MB-231 parental and MDA-MB-231 ADRB2 knock-out cells. Data expressed as mean ± SEM with statistical significance.

[0010] FIGs. 8A-8D show validation of Namalwa-CXCR4 knockout and MDA-MB- 231 -ADRB2 knockout cells. Cell surface expression of CXCR4 in Namalwa cells treated control and knock-out agent was detected by flow cytometry with isotype control or PE-conjugated anti-human CXCR4 antibodies (1 D9), or Alexa-Fluor 488- conjugated anti-human P2AR (R11 E1) antibodies. (FIG. 8A) Flow cytometry profile of with CRISPR / Cas9-sgControl control treatment. (FIG. 8B) Flow cytometry profile of with CRISPR / Cas9-sgCXCR4 control treatment. (FIG. 8C) Flow cytometry showing cell surface expression of P2AR in parental, control cells. (FIG. 8D) Flow cytometry showing cell surface expression of P2AR in MDA-MB-231 cells treated with CRISPR / Cas9-sgADRB2.

[0011] FIGs. 9A-9C show CXCR4 and p2AR co-activation causes synergistic increase in p-arrestin recruitment to CXCR4. HTLA cells overexpressing CXCR4- tango and P2AR were treated in two separate experiments. (FIG. 9A) p-arrestin recruitment profile in the presence of a constant 1 pM epinephrine and a varying 0- 200 nM CXCL12.(FIG. 9B) p-arrestin recruitment profile in the presence of a constant 100 nM CXCL12 and a varying 0-10 pM epinephrine. Co-treatment with epinephrine and CXCL12 led to synergistic increase in p-arrestin recruitment. (FIG. 9C) Fold-change in p-arrestin recruitment to CXCR4 by 100 nM CXCL12, 400 nMepinephrine, agonist co-treatment, 10 pM GPC-100, 10 pM propranolol or antagonist co-treatment. Data expressed as mean ± SEM. Pro: Propranolol.

[0012] FIGs. 10A-10B show expression of CXCR4 and p?AR in MDA-MB-231 cells. Flow cytometry was used to detect the surface expression of endogenous CXCR4 and P2AR in MDA-MB-231 cells after staining with anti-human CXCR4 (Ulocuplumab) followed by Alexa Fluor 568-conjugated goat anti-human IgG antibody (FIG. 10A) and Alexa-Fluor 488-conjugated anti-human P2AR antibody (R11 E1) (FIG. 10B).

[0013] FIGs. 11A-11B show effect of co-treatment with GPC-100 and propranolol on CXCL12 and epinephrine-induced crosstalk. (FIG. 11 A) Calcium flux in MDA-MB- 231 cells endogenously expressing CXCR4 and P2AR incubated with vehicle, 200 nM CXCL12, 10 pM epinephrine or CXCL12 and epinephrine. Data indicate foldincrease compared to vehicle. (FIG. 11B) Inhibition of synergistic calcium increase by 10 pM GPC-100, 10 pM AMD3100, 10 pM propranolol or their co-treatment in MDA-MB-231 cells treated with CXCL12 and epinephrine. Percent calcium flux was normalized to CXCL12. Data expressed as mean ± SEM with statistical significance. Pro: Propranolol.

[0014] FIGs. 12A-12B show in vivo mobilization by GPC-100 or AMD3100 (FIG.12A) WBC mobilization to peripheral blood (PB) following a single injection of GPC- 100 (30 mg / kg, IV) or AMD3100 (5 mg / kg, SC). PB was collected 1 -hour post-drug. (FIG. 12B) Time course of mobilization by GPC-100 or AMD3100. PB was collected at various time points post-drug. Each mouse was bled twice. The bleeding at 0.5h, 1 h and 2h was non-terminal, whereas at 3h, 4h, 5h it was terminal. FIG. 12A and FIG. 12B refer to two independent studies. Data expressed as mean ± SEM.

[0015] FIG. 13 shows propranolol dose response for GPC-100 mobilization. Propranolol (0 to 40 mg / kg, IP) was administered for 7 days, and GPC-100 was coadministered on day 7. Data expressed as mean ± SEM. Statistical significance *p<0.05, **p<0.01 . Pro: Propranolol.

[0016] FIGs. 14A-14D show in vivo mobilization by GPC-100 and propranolol. (FIG. 14A) Dosing regimen indicating propranolol (20 mg / kg, IP) pretreatment for 7 days, followed by GPC-100 (30 mg / kg, IV) co-administration on day 7. AMD3100 (5 mg / kg, SC) was similarly co-administered on day 7 with propranolol. (FIG. 14B) WBC mobilization by GPC-100 and propranolol, and AMD3100 and propranololcombinations. (FIG. 14C) Representative LSK frequency analysis in PB. (FIG. 14D) Number of mobilized LSK cells in mice treated with PBS, GPC-100 alone or in combination with propranolol. Data from two separate experiments. Pro: Propranolol. Data expressed as mean ± SEM.

[0017] FIGs. 15A-15D show Lymphocyte and neutrophil mobilization by GPC-100 and AMD3100 alone and in combination with propranolol. Propranolol (20 mg / kg, IP) was administered for 7 days and GPC-100 or AMD3100 were co-administered on day 7. Cell mobilization was measured after GPC-100 treatment with or without propranolol. (FIG. 15A) Lymphocyte mobilization profile. (FIG. 15B) Neutrophil mobilization profile. Cell mobilization was measured after AM D3100 treatment with or without propranolol. (FIG. 15C) Lymphocyte mobilization profile. (FIG. 15D) Neutrophil mobilization profile. Data expressed as mean ± SEM. Statistical significance *p<0.05, **p<0.01

[0018] FIGs. 16A-16H show in vivo mobilization by the triple combination of GPC- 100, propranolol, and G-CSF. (FIG. 16A) Dosing regimen. G-CSF (0.1 mg / kg, SC) was administered 5 days two-times a day (BID) from day 2 to day 6, propranolol (20 mg / kg, IP) was administered for 7 days. GPC-100 (30 mg / kg, IV) was coadministered with propranolol on day 7. Mice in the triple combination group received all three treatments. For comparison with standards of care, G-CSF was administered alone or with AMD3100 (5 mg / kg SC) administered on day 7, 12 h post G-CSF. (FIG. 16B) WBC mobilization. (FIG. 16C) Mobilization of LSK cells (Lin- Sca1+ckit+). (FIG. 16D) colony forming units. (FIG. 16E) Mobilization of LSK cells (CD34-). (FIG. 16F) Mobilization of LSK cells (CD150+) evaluated by flow cytometry G: G-CSF. Propranolol administration improves GPC-100 induced mobilization of primitive cells characterized as Lin=Sca-1+cKit+(LSK) cells devoid of CD34 expression. Propranolol was administered for 7, 14 or 21 days. Duration of propranolol pretreatment does not drive improvement of GPC-100 mobilization.(FIG. 16G) Mobilization profile of CD34-LSK cells. (FIG. 16H) Mobilization profile of LSK cells. Pro: Propranolol. Data expressed as mean ± SEM.

[0019] FIG. 17 shows in vivo LT-LSK cell mobilization. Mice were treated with propranolol (20 mg / kg, IP) or PBS (IP) for 7 days, G-CSF (0.1 mg / kg, SC) twice daily from days 2-6 and GPC-100 (30 mg / kg, IV) co-administered with propranolol on day 7. Blood was collected 2 hours later. Sca-1+and cKit+cells were gated from lineagenegative cells (LSK cells). CD150+and CD48+cells were then selected with LSK CD34- as the parent gate. The long-tern HSC population was defined as CD34- CD150+CD48+LSK cells.

[0020] FIGs. 18A-18C shows functional capacity of cells mobilized by the triple combination. (FIG. 18A) Number of total CFU, (FIG. 18B) CD150+LSK cells and (FIG. 18C) CD34' LSK cells in mobilized PB of mice. Total number of mobilized cells was normalized based on the WBC count following the treatments. Flow cytometry and CFU assay was performed on different cohorts of age- and weight- matched mice. Each mouse is assayed individually. Pro: Propranolol, G: G-CSF. Data expressed as mean ± SEM.

[0021] FIGs. 19A-19C show time-course of WBC subset mobilization by GPC-100 (Burixafor, or TG-0054), AMD3100 (Plerixafor, or Mozobil) and BL8040 (Motixafortide) in mice.

[0022] FIGs. 20A-20C show the superiority of GPC-100 over BL8040 was enhanced specifically in balb / c mouse strain.

[0023] FIG. 21 shows myeloid cell (non-lymphocyte, C11 b+ or F4 / 80+ cells) mobilization by GPC-100 is further improved by addition of 7-day propranolol pretreatment.

[0024] FIGs. 22A-22B shows greater mobilization in tumor bearing mice (CT26-colon cancer) compared to naive mice, especially for Cd11 b+ myeloid cells.

[0025] FIGs. 23A-23B show the mobilization kinetics of CD34+ in PB of MM patients following administration of GPC-100. FIG. 23A shows the average mobilization at each timepoint for all patients. FIG. 23B shows relative change in CD34+ cells for each patient at each timepoint, with the percent peak relative change for all nine patients being in the range of 45 minutes ± 15 minutes (or from about 30 minutes to about 60 minutes).

[0026] FIG. 24 shows that the primary endpoint of +2*106CD34+ cells / kg is met by all MM patients treated with a combination treatment of GPC-100, propranolol, and G-CSF.DETAILED DESCRIPTION

[0027] CXCR4 is a member of the chemokine G protein-coupled receptor (GPCR) family [20, 21] and is expressed on HSCs [20, 22], CXCR4 signaling, mediated byits natural ligand CXCL12, plays a pivotal role in cellular chemotaxis, as well as retention and survival of HSCs in the BM

[0022] , GPC-100, also known as Burixafor or TG-0054, is a novel small molecule antagonist with a high binding affinity to CXCR4. In a phase 1 trial with healthy volunteers, GPC-100 was well-tolerated and induced a 3- to 12-fold increase in circulating CD34+HSCs compared to baseline following a single intravenous injection

[0023] , GPC-100, in combination with G-CSF, has been tested clinically in MM patients as an HSC mobilizer (NCT02104427)

[0024] , and was shown to elicit a significant increase in HSCs with >5.0x106CD34+cells / kg in 1-2 leukapheresis sessions

[0025] , This result was comparable with the historical results from G-CSF plus AMD3100 treatment.

[0028] Previous studies have demonstrated that CXCR4 physically interacts with the beta-2-adrenergic receptor or P2AR (gene ADRB2) in cell systems that overexpress both receptors [26-28], Findings from Nakai et al suggest that P2AR selectively forms heteromeric complexes with CXCR4, and the stimulation of P2AR enhances CXCR4 signaling, potentially leading to increased lymphocyte retention in lymph nodes and decreased mobilization to PB

[0026] , P2AR is also expressed on HSCs [29, 30] and the adrenergic signaling plays a key role in regulating the HSC niche in BM [31 , 32], Epinephrine and norepinephrine, the natural ligands of P2AR, were shown to influence the turnover and trafficking

[0033] , as well as reduce the proliferative and differentiation capacity of the HSCs

[0034] , When human HSCs were co-stimulated with G-CSF and P2AR agonists, the expression of CXCR4 on HSCs increased, suggesting that the interactions between P2AR agonists and G-CSF in BM niche promote HSC retention by CXCR4 and impair mobilization by G-CSF

[0030] ,

[0029] Studies have noted the link between beta adrenergic inhibitor (beta blocker) usage and positive survival outcome in several cancer types, including MM [35, 36], The MM microenvironment is known to cause dysregulation of HSC function leading to changes in gene expression and altered hematopoietic differentiation [37, 38], Effects of beta-adrenergic blockade on HSC differentiation in MM have been evaluated using propranolol, the FDA-approved non-selective beta blocker with a safe side effect profile

[0039] , A Phase II biomarker-driven randomized study showed that in MM patients undergoing ASCT, propranolol shifted cell differentiation away from the myeloid-lineage bias and toward the CD34+HSC-like profile, which leads to enhanced engraftment

[0038] , In this study, activation of the sympathetic nervoussystem induced a shift in the basal gene expression profile towards a more inflammatory pattern termed as Conserved Transcriptional Response to Adversity (CTRA), which is associated with poor outcomes in ASCT

[0038] , Propranolol was shown to reduce the CTRA gene signature. In another study, BM samples from MM patients showed that propranolol can augment differentiation of HSCs into megakaryocyte-erythrocyte progenitors and reduce the number of granulocytemonocyte progenitor cells, which are known to contribute to a pro-tumorigenic niche

[0040] , Together these studies indicate that propranolol can block the negative effects of adrenergic signaling on HSC biology, induce HSC proliferation and differentiation, as well as synergize with a CXCR4 inhibitor considering the possible crosstalk between P2AR and CXCR4 in BM. Therefore, the co-inhibition of CXCR4 and P2AR pathways may improve HSC mobilization.

[0030] The present technology presents in vitro characterization and in vivo mobilization efficacy of GPC-100 in comparison with AMD3100, and provides evidence for the first time that in cancer cells endogenously expressing CXCR4 and P2AR, the two receptors co-localize and exhibit functional synergy. Furthermore, the present technology demonstrates enhanced mobilization by GPC-100 in combination with propranolol and demonstrates a new strategy for clinical application in stem cell mobilization.

[0031] As used herein, the term “progenitor cells” refers to cells that, in response to certain stimuli, can form differentiated hematopoietic or myeloid cells. The presence of progenitor cells can be assessed by the ability of the cells in a sample to form colony-forming units of various types, including, for example, CFU-GM (colonyforming units, granulocyte-macrophage); CFU-GEMM (colony-forming units, multipotential); BFU-E (burst-forming units, erythroid); HPP-CFC (high proliferative potential colony-forming cells); or other types of differentiated colonies which can be obtained in culture using known protocols.

[0032] As used herein, “stem” cells are less differentiated forms of progenitor cells. Typically, such cells are often positive for CD34. Some stem cells do not contain this marker, however. These CD34+cells can be assayed using fluorescence activated cell sorting (FACS) and thus their presence can be assessed in a sample using this technique. In general, CD34+cells are present only in low levels in the blood, but are present in large numbers in bone marrow. While other types of cells such asendothelial cells and mast cells also may exhibit this marker, CD34 is considered an index of stem cell presence.

[0033] The term “CXCR4” as used herein refers to C-X-C Motif Chemokine Receptor 4, also identified by unique database identifiers (IDs) and alternate names as shown in Table 1 (Chatterjee et al., 2014; Debnath et al., 2013; Domanska et al., 2013; Guo et al., 2016; Peled et al., 2012; Roccaro et al., 2014; Walenkamp et al., 2017).Table 1 : CXCR4, GPCRx, and their alternative names*GCID: Genecards identificationHGNC: HUGO Gene Nomenclature Committee

[0034] The terms “GPCRx” as used herein refers to GPCRs that were used in this study to investigate if these GPCRs interact with CXCR4 and show properties distinct from those of individual protomers. Examples of GPCRx, their alternate names, and unique database identifiers (IDs) are shown in Table 1 , and they include, ADCYAP Receptor Type I (ADCYAP1 R1), Adenosine A2b Receptor (ADORA2B), Adenosine A3 Receptor (ADORA3), Adrenoceptor Beta 2 (ADRB2), Apelin Receptor (APLNR), Complement C5a Receptor 1 (C5AR1), Calcitonin Receptor (CALCR),(Chemokine (C-C Motif) Receptor 5) (CCR5), Receptor 5 C-C Motif), Cholinergic Receptor Muscarinic 1 (CHRM1 ), Galanin Receptor 1 (GALR1 ), Endothelin Receptor Type B (EDNRB), Histamine Receptor H1 (HRH1 ), Motilin Receptor (MLNR), Neurotensin Receptor 1 (NTSR1 ), Prostaglandin E Receptor 2 (PTGER2), Prostaglandin E Receptor s (PTGER3), Somatostatin Receptor 2 (SSTR2), and Tachykinin Receptor s (TACR3).

[0035] Table 1 also provides both the nomenclature of CXCR4 as well as the nomenclature of GPCRx that form heteromers with CXCR4 to synergistically enhance Ca2+response upon co-stimulation with both agonists.

[0036] The term “GPC-100” (also known as Burixafor, TG-0054), as used herein refers to the chemical compound 2-[4-[6-amino-2-[[4-[[3- (cyclohexylamino)propylamino]methyl]cyclohexyl]methylamino]pyrimidin-4- yl]piperazin-1-yl]ethylphosphonic acid, having the chemical formula C27H51N8O3P. A representation of the chemical structure is shown at FIG. 1A. An exemplar form of GPC-100 as used herein is GPC-100 hydrobromide.

[0037] The term “AMD3100” (also known as Plerixafor, or Mozobil), as used herein refers to the chemical compound 1-[[4-(1 ,4,8,11-tetrazacyclotetradec-1- ylmethyl)phenyl]methyl]-1 ,4,8,11 -tetrazacyclotetradecane, having the chemical formula C28H54N8. An exemplar form of AMD3100 as used herein is Plerixafor octahydrochloride.

[0038] The term “beta-adrenergic receptor inhibitor” as used herein refers to a compound or a pharmaceutical composition that effectively blocks the activation of a beta-adrenergic receptor. A beta-adrenergic receptor as used herein refers to one of three types of beta-adrenergic receptor: Adrenergic Beta-1 Receptor, Adrenergic Beta-2 Receptor, and Adrenergic Beta-3 Receptor. An exemplar beta-adrenergic receptor inhibitor as used herein is propranolol.

[0039] The term “ADRB2 inhibitor” as used herein refers to a compound or a pharmaceutical composition that effectively blocks the activation of a Adrenergic Beta-2 Receptor (ADRB2). An exemplar ADRB2 inhibitor as used herein is propranolol.

[0040] The term “Propranolol” (also known as Anaprilin, Anapriline, Avlocardyl, AY 20694, AY-20694, AY20694, Betadren, Dexpropranolol, Dociton, Hydrochloride, Propranolol, Inderal, Obsidan, Obzidan, Propanolol, Propranolol, PropranololHydrochloride, Rexigen, among others), as used herein refers to the chemical compound 1-naphthalen-1-yloxy-3-(propan-2-ylamino)propan-2-ol, having the chemical formula C16H21NO2. An exemplar form of propranolol as used herein is propranolol hydrochloride.

[0041] The term “G-CSF” (also known as GCSF, or CSF 3) as used herein refers to the glycoprotein, granulocyte colony-stimulating factor, known to function as a cytokine and a hormone. The term G-CSF as used herein includes all variants, forms, structural analogs, functional analogs, derivatives, biosimilars, and the likes, of the natural glycoprotein. The term G-CSF also includes any recombinant forms of G-CSF. Analogs of G-CSF can include filgrastim and lenograstim.

[0042] The term “Lenalidomide” (also known as Revlimid) as used herein refers to the chemical compound 3-(7-amino-3-oxo-1 H-isoindol-2-yl)piperidine-2, 6-dione, having a chemical formula C13H13N3O3. Lenalidomide can be administered to treat multiple myeloma.

[0043] The term “Daratumumab” (also known as Darzalex) as used herein refers to the monocolonal antibody that binds to CD38. The term Daratumumab as used herein includes all variants, forms, structural analogs, functional analogs, derivatives, biosimilars, and the likes, of the monoclonal antibody that is approved by the relevant regulatory agency for treating cancer.

[0044] The term “apheresis” as used herein is a medical procedure in which the blood of a subject is passed through an apparatus that separates out one particular constituent within the blood and returns the remainder of the blood back to the subject. Apheresis .and a specific type of apheresis. In leukapheresis, the white blood cells are separated from a sample of blood. Exemplar apheresis techniques include: (1) plasma exchange, (2) LDL apheresis, (3) photopheresis, (4) immunoadsorption with Staphylococcal protein A-agarose column, (5) leukocytapheresis, (6) erythrocytapheresis, (7) thrombocytapheresisand, and (8) leukapheresis. Apheresis is a difficult procedure, inconvenient, and expensive.

[0045] The term “leukapheresis” as used herein is a medical procedure and a specific type of apheresis. In leukapheresis, the white blood cells are separated from a sample of blood.

[0046] The term “inhibitor” as used herein refers to molecule that inhibits or suppresses the enhanced function of a biological molecule. For example, thebiological molecule can be: a CXCR4, a beta-adrenergic receptor, a GPCR, a heteromer of CXCR4 and a beta-adrenergic receptor, a CXCR4-GPCRx heteromer, a CXCR4 homodimer, and / or a beta-adrenergic receptor homodimer. Non-limiting examples of the inhibitor of the invention that can be used for mobilization of cells include, GPCRx antagonist, GPCRx inverse agonist, GPCRx positive and negative allosteric modulator, CXCR4-GPCRx heteromer-specific antibody or its antigen biding portions including single-domain antibody-like scaffolds, bivalent ligands which have a pharmacophore selective for CXCR4 joined by a spacer arm to a pharmacophore selective for GPCRx, bispecific antibody against CXCR4 and GPCRx, radiolabeled CXCR4 ligand linked with GPCRx ligand, and small molecule ligands that inhibit heteromer-selective signaling. Certain examples of inhibitors against GPCRx that form heteromers with CXCR4 and enhance Ca2+response upon co-stimulation with both agonists are listed in Table 2. A non-limiting example of an inhibitor can be natural or man-made, and can include a small molecule inhibitor; a peptide inhibitor; an antibody, a fragment thereof, or the likes; a aptamer. An inhibitor can be an antagonist.

[0047] The term “antagonist” as used herein refers to a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor, also called blockers. Antagonists have affinity but no efficacy for their cognate receptors, and their binding disrupts the interaction and inhibit the function of an agonist or inverse agonist at the cognate receptors. Certain examples of antagonists against GPCRx that form heteromers with CXCR4 and enhance Ca2+response upon co-stimulation with both agonists are listed in Table 2.Table 2. Examples of inhibitors against CXCR4 and ADRB2

[0048] The term “heteromer” as used herein refers to macromolecular complex composed of different macromolecules or variations of a macromolecule that bind together to have one or more functions as a single unit. The different macromolecules or the variation of the macromolecule can have distinct structure(s) and function(s). In contrast, a “homomer” is a macromolecular complex composed of one or more of the same macromolecule. Like heteromer, the macromolecules of a homomer binds together to have one or more functions as a single unit. When referring to GPCR, the two GPCR units [protomers] have biochemical properties that are demonstrably different from those of its individual components.Heteromerization and homomerization can be evaluated by, colocalization assays based on immunochemistry, microscopy, and the likes; DNA / RNA analysis; resonance energy transfer assays based on fluorescence, bioluminescence, and the likes; chromatography; crystallography; mass spectrometry, nuclear magneticresonance spectroscopy, among others. Exemplar methods to evaluate heteromerization and homomerization can include, in situ hybridization, immunohistochemistry, RNAseq, Reverse transcription-quantitative PCR (RT-qPCR, realtime PCR), microarray, proximity ligation assay (PLA), time-resolved FRET (TR- FRET), whole-body Single-photon emission computed tomography (SPECT) or Positron Emission Tomography / Computed Tomography (PET / CT), cryo-electron microscopy (cryo-EM), Brightness / Number analysis, Fluorescence Correlation Spectroscopy (FCS), Fluorescence Cross Correlation Spectroscopy (FCCS), and / or similar technology.

[0049] The phrase “effective amount” as used herein refers to an amount sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications or dosages. Such delivery is dependent on a number of variables including the time period for which the individual dosage unit is to be used, the bioavailability of the agent, the route of administration, etc.

[0050] The phrase “therapeutically effective amount” as used herein refers to the amount of a therapeutic agent (e.g., an inhibitor, an antagonist, or any other therapeutic agent provided herein) which is sufficient to reduce, ameliorate, and / or prevent the severity and / or duration of a cancer and / or a symptom related thereto. A therapeutically effective amount of a therapeutic agent can be an amount necessary for the reduction, amelioration, or prevention of the advancement or progression of a cancer, reduction, amelioration, or prevention of the recurrence, development or onset of a cancer, and / or to improve or enhance the prophylactic or therapeutic effect of another therapy (e.g., a therapy other than the administration of an inhibitor, an antagonist, or any other therapeutic agent provided herein).

[0051] The phrase “therapeutic agent” refers to any agent that can be used in the treatment, amelioration, prevention, or management of a cancer and / or a symptom related thereto. In some embodiments, a therapeutic agent refers to an inhibitor of CXCR4-GPCRx heteromer of the invention. A therapeutic agent can be an agent which is well known to be useful for, or has been or is currently being used for the treatment, amelioration, prevention, or management of a cancer and / or a symptom related thereto.

[0052] The phrase “intracellular Ca2+assay,” “calcium mobilization assay,” or their variants as used herein refer to a cell-based assay to measure the calcium fluxassociated with GPCR activation or inhibition. The method utilizes a calcium sensitive fluorescent dye that is taken up into the cytoplasm of most cells. The dye binds the calcium released from intracellular store and its fluorescence increases. The change in the fluorescence Intensity is directly correlated to the amount of intracellular calcium that is released into cytoplasm in response to ligand activation of the receptor of interest.

[0053] The phrase “proximity-based assay” as used herein refers to biophysical and biochemical techniques that are able to monitor proximity and / or binding of two protein molecules in vitro (in cell lysates) and in live cells, including bioluminescence resonance energy transfer (BRET), fluorescence resonance energy transfer (FRET), bimolecular fluorescence complementation (BiFC), Proximity ligation assay (PLA), cysteine crosslinking, co-immunoprecipitation (Ferre et al., 2009; Gomes et al., 2016), Fluorescence Correlation Spectroscopy (FCS), Fluorescence Cross Correlation Spectroscopy (FCCS), Proximity-Dependent Biotin Identification, Proximity Extension Assay, Split-Luciferase Assay, Proximity-Dependent Tethered Biotinylation, and the likes.

[0054] As used herein, the following terms shall have the specified meaning.The term “about” takes on its plain and ordinary meaning of “approximately” as a person of skill in the art would understand. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” or “approximately” is used herein to modify a numerical value above and below the stated value by a variance of 20%.The term “comprise,” “comprising,” “contain,” “containing,”1include,” “including,” “include but not limited to,” or “characterized by” is inclusive or open- ended and does not exclude additional, unrecited elements.The term “administer,” “administering,” “administered,” “administration of” and the likes, as used herein refers to administering a substance to a subject in need thereof via any pharmacologically appropriate routes. Common routes for administering a substance to a subject includes oral, intravenous, intramuscular, subcutaneous, topical, transdermal, inhalation, sublingual, buccal, rectal, intranasal, intraocular, intrathecal, epidural, vaginal, intra-articular, intradermally, Intratumoral, and combinations thereof.

[0055] The term “treatment” or “treating,” and the likes, as used herein means a specific method, process, composition (such as a drug, device, or chemical, biochemical, or biological substance), or combinations thereof, to manage, cure, alleviate, or prevent a particular disease, condition, or symptom in a subject. The term encompasses therapeutic, prophylactic, and palliative interventions aimed at improving the health or quality of life of individuals or populations. A treatment can include combination treatments, multistep treatments, and multiphase treatments.

[0056] The phrase “qualify for treatment” or “qualifying for treatment” or “qualify... for treatment” or “qualifying... for treatment,” and the likes, as used herein means a specific method, process, composition (such as a drug, device, or chemical, biochemical, or biological substance), or combinations thereof, to qualify a subject for a treatment, or to satisfy the prerequisite conditions for a treatment. The subject may ultimately proceed with the treatment, or the subject may ultimately not be treated.

[0057] The phrase “prepare for treatment” or “preparing for treatment” or “prepare... for treatment” or “preparing... for treatment, and the likes, as used herein means a specific method, process, composition (such as a drug, device, or chemical, biochemical, or biological substance), or combinations thereof, to qualify a subject for a treatment that the subject ultimately undergoes.

[0058] As used in this specification and the appended claims, the following general rules apply.Singular forms “a,” “an” and “the” include plural references unless the content clearly indicates otherwise.As used herein, the recitation of a numerical range for a variable is intended to convey that the invention may be practiced with the variable equal to any of the values within that range. Thus, for a variable which is inherently discrete, the variable can be equal to any integer value of the numerical range, including the endpoints of the range. Similarly, for a variable which is inherently continuous, the variable can be equal to any real value of the numerical range, including the endpoints of the range. As an example, a variable which is described as having values between 0 and 10, can be 0, or 1 , or 2, or 3... , or 10 for variables which are inherently discrete, and can be 0.0, 0.1 , 0.01 , 0.001 , or any other real value for variables which are inherently continuous.

[0059] Unless otherwise indicated, this description employs conventional chemical, biochemical, molecular biology, immunology, cancer biology, and pharmacology methods and terms that have their ordinary meaning to persons of skill in this field. All publications, references, patents, and patent applications cited herein are hereby incorporated by reference in their entireties.

[0060] Disclosed herein are methods and compositions directed to mobilizing a cell in a subject by blocking CXCR4, a beta-adrenergic receptor, a GPCR, or any combination thereof. In some embodiments, the cell is a stem cell. In some embodiments, the cell is an immune cell. In some embodiments, the mobilization of a cell in a subject comprises blocking CXCR4. In some embodiments, the mobilization of a cell in a subject comprises blocking a beta-adrenergic receptor. In some embodiments, the mobilization of a cell in a subject comprises blocking a GPCR. In some embodiments, the mobilization of a cell in a subject comprises blocking CXCR4 and a beta-adrenergic receptor. In some embodiments, the mobilization of a cell in a subject comprises blocking CXCR4 and a GPCR. In some embodiments, the mobilization of a cell in a subject comprises blocking a CXCR4- GPCR heteromer.

[0061] Disclosed herein are methods of mobilizing a cell in a subject, the method comprising: blocking CXCR4 signaling and beta-adrenergic receptor signaling in the subject. Also disclosed herein are methods of inducing cell mobilization in a subject, the method comprising: blocking CXCR4 signaling and beta-adrenergic receptor signaling in the subject. In some embodiments, the blocking beta-adrenergic receptor signaling is performed before the blocking CXCR4 signaling. In some embodiments, the blockade of the beta-adrenergic receptor signaling is performed at a first specific time interval before blockade of the CXCR4 signaling. In some embodiments, the first specific time interval is between 5 minutes to 10 minutes, 10 minutes to 20 minutes, 20 minutes to 30 minutes, 30 minutes to 40 minutes, 40 minutes to 50 minutes, 50 minutes to 1 hour, 1 hour to 2 hours, 2 hours to 3 hours, 3 hours to 4 hours, 4 hours to 5 hours, 5 hours to 6 hours, 6 hours to 12 hours, 12 hours to 24 hours, 1 day to 2 days, 2 days to 3 days, 3 days to 4 days, 4 days to 5 days, 5 days to 6 days, 6 days to 7 days, 7 days to 8 days, 8 days to 9 days, 9 days to 10 days, 10 days to 11 days, 11 days to 12 days, 12 days to 13 days, 13 days to 14 days, or 14 days or more. In some embodiments, the blockade of the beta-adrenergic receptor signaling continues after the blockade of the CXCR4 signaling is terminated. In some embodiments, the blockade of the beta-adrenergic receptor signaling continues for a second specific time interval after the blockade CXCR4 signaling is terminated. In some embodiments, the second specific time interval is between 5 minutes to 10 minutes, 10 minutes to 20 minutes, 20 minutes to 30 minutes, 30 minutes to 40 minutes, 40 minutes to 50 minutes, 50 minutes to 1 hour, 1 hour to 2 hours, 2 hours to 3 hours, 3 hours to 4 hours, 4 hours to 5 hours, 5 hours to 6 hours, 6 hours to 12 hours, 12 hours to 24 hours, 1 day to 2 days, 2 days to 3 days, 3 days to 4 days, 4 days to 5 days, 5 days to 6 days, 6 days to 7 days, 7 days to 8 days, 8 days to 9 days, 9 days to 10 days, 10 days to 11 days, 11 days to 12 days, 12 days to 13 days, 13 days to 14 days, or 14 days or more.

[0062] In some embodiments, the blockade of the CXCR4 signaling comprises administration of a CXCR4 inhibitor to the subject.

[0063] In some embodiments, the blockade of the beta-adrenergic receptor signaling comprises administration of a beta-adrenergic receptor inhibitor to the subject. In some embodiments, the blockade of the CXCR4 signaling comprises administration of a CXCR4 inhibitor to the subject and the blockade of the beta-adrenergic receptor signaling comprises administration of a beta-adrenergic receptor inhibitor to the subject. In some embodiments, the cell is a stem cell. In some embodiments, the cell is an immune cell.

[0064] Disclosed herein are methods of mobilizing a stem cell in a subject, the method comprising: administration of a beta-adrenergic receptor inhibitor and a CXCR4 inhibitor to the subject. Also disclosed herein are methods of inducing stem cell mobilization in a subject, the method comprising: administration of a beta- adrenergic receptor inhibitor and a CXCR4 inhibitor to the subject. In some embodiments, the administration of the beta-adrenergic receptor inhibitor is performed before the administration of the CXCR4 inhibitor. In some embodiments, the administration of the beta-adrenergic receptor inhibitor is performed at a first specific time interval before the administration of the CXCR4 inhibitor. In some embodiments, the first specific time interval is between 5 minutes to 10 minutes, 10 minutes to 20 minutes, 20 minutes to 30 minutes, 30 minutes to 40 minutes, 40 minutes to 50 minutes, 50 minutes to 1 hour, 1 hour to 2 hours, 2 hours to 3 hours, 3 hours to 4 hours, 4 hours to 5 hours, 5 hours to 6 hours, 6 hours to 12 hours, 12hours to 24 hours, 1 day to 2 days, 2 days to 3 days, 3 days to 4 days, 4 days to 5 days, 5 days to 6 days, 6 days to 7 days, 7 days to 8 days, 8 days to 9 days, 9 days to 10 days, 10 days to 11 days, 11 days to 12 days, 12 days to 13 days, 13 days to 14 days, or 14 days or more. In some embodiments, the administration of the beta- adrenergic receptor inhibitor continues after the administration of the CXCR4 inhibitor is terminated. In some embodiments, the administration of the beta- adrenergic receptor inhibitor continues for a second specific time interval after the administration of the CXCR4 Inhibitor is terminated. In some embodiments, the second specific time interval is between 5 minutes to 10 minutes, 10 minutes to 20 minutes, 20 minutes to 30 minutes, 30 minutes to 40 minutes, 40 minutes to 50 minutes, 50 minutes to 1 hour, 1 hour to 2 hours, 2 hours to 3 hours, 3 hours to 4 hours, 4 hours to 5 hours, 5 hours to 6 hours, 6 hours to 12 hours, 12 hours to 24 hours, 1 day to 2 days, 2 days to 3 days, 3 days to 4 days, 4 days to 5 days, 5 days to 6 days, 6 days to 7 days, 7 days to 8 days, 8 days to 9 days, 9 days to 10 days, 10 days to 11 days, 11 days to 12 days, 12 days to 13 days, 13 days to 14 days, or 14 days or more.

[0065] In some embodiments, the beta-adrenergic receptor inhibitor is an ADRB2 inhibitor. In some embodiments, the beta-adrenergic receptor inhibitor is selected from the group consisting of alprenolol, atenolol, betaxolol, bupranolol, butoxamine, carazolol, carvedilol, CGP 12177, cicloprolol, ICI 118551 , ICYP, labetalol, levobetaxolol, levobunolol, LK 204-545, metoprolol, nadolol, NIHP, NIP, propafenone, propranolol, sotalol, SR59230A, and timolol. In some embodiments, the beta-adrenergic receptor inhibitor is selected from the group consisting of propranolol, nadolol, and ICI 118551. In some embodiments, the beta-adrenergic receptor inhibitor is propranolol.

[0066] In some embodiments, the CXCR4 inhibitor is selected from the group consisting of ALX40-4C, AMD070 (AMD11070, X4P-001), AMD3100 (Plerixafor, or Mozobil), AMD3465, ATI 2341 , BKT140 (BL-8040; TF14016; 4F-Benzoyl-TN 14003), CTCE-9908, CX549, D-[Lys3] GHRP-6, FC122, FC131 , GMI-1359, GSK812397, GST-NT21 MP, isothiourea-1 a, isothiourea-11 (IT1t), KRH-1636, KRH-3955, LY2510924, MSX-122, N-[11C]Methyl-AMD3465, POL6326, SDF-1 1-9[P2G] dimer, SDF1 P2G, T134, T140, T22, TC 14012, GPC-100 (Burixafor, or TG-0054), USL311 , viral macrophage inflammatory protein-ll (vMIP-ll), WZ811 , [64Cu]-AMD3100,[64Cu]-AMD3465, [68Ga]pentixafor, [90Y]pentixather, [99mTc]02-AMD3100, [177Lu]pentixather, Ulocuplumab (MDX1338 / BMS-936564), AD-214, LY2624587, PF-06747143, POL6326, MB1707, and 508MCI (Compound 26). GPC-100 is also referred to as Burixafor or TG-0054. AMD3100 is also referred to as Plerixafor or Mozobil. In some embodiments, the CXCR4 inhibitor is selected from the group consisting of AD-214, AMD070 (AMD11070, X4P-001), AMD3100 (Plerixafor, or Mozobil), BKT140 (BL-8040; TF14016; 4F-Benzoyl-TN 14003), CTCE-9908, LY2510924, LY2624587, T140, GPC-100 (Burixafor, or TG-0054), PF-06747143, POL6326, and ulocuplumab (MDX1338 / BMS-936564). In some embodiments, the CXCR4 inhibitor is GPC-100 (Burixafor, or TG-0054). In some embodiments, the CXCR4 inhibitor is AMD3100 (Plerixafor, or Mozobil). In some embodiments, the CXCR4 inhibitor is ulocuplumab (MDX1338 / BMS-936564).

[0067] In some embodiments, the administration of the CXCR4 inhibitor to the subject comprises administration of GPC-100 (Burixafor, or TG-0054) and propranolol. In some embodiments, the administration of the CXCR4 inhibitor to the subject comprises administration AMD3100 (Plerixafor, or Mozobil) and propranolol. In some embodiments, the administration of the CXCR4 inhibitor to the subject comprises administration ulocuplumab (MDX1338 / BMS-936564) and propranolol.

[0068] In some embodiments, the method further comprises administration of G-CSF to the subject. In some embodiments, the administration of the beta-adrenergic receptor inhibitor and the CXCR4 inhibitor to the subject is performed in the absence of G-CSF. Disclosed herein are methods of mobilizing a stem cell in a subject, the method comprising: administration of a CXCR4 inhibitor and G-CSF to the subject, in the absence of a beta-adrenergic receptor inhibitor. Also disclosed herein are methods of inducing stem cell mobilization in a subject, the method comprising: administration of a CXCR4 inhibitor and G-CSF to the subject, in the absence of a beta-adrenergic receptor inhibitor. In some embodiments, the administration of the CXCR4 inhibitor to the subject comprises administration of GPC-100 (Burixafor, or TG-0054) and G-CSF. In some embodiments, the administration of the CXCR4 inhibitor to the subject comprises administration of AMD3100 (Plerixafor, or Mozobil) and G-CSF. In some embodiments, the administration of the CXCR4 inhibitor to the subject comprises administration of ulocuplumab (MDX1338 / BMS-936564) and G- CSF.

[0069] Also disclosed herein are methods of inducing stem cell mobilization in a subject, the method comprising: administration of a CXCR4 inhibitor, G-CSF, and a beta-adrenergic receptor inhibitor. In some embodiments, the administration of the CXCR4 inhibitor to the subject comprises administration of GPC-100 (Burixafor, or TG-0054), G-CSF, and propranolol. In some embodiments, the administration of the CXCR4 inhibitor to the subject comprises administration of AMD3100 (Plerixafor, or Mozobil), G-CSF, and propranolol. In some embodiments, the administration of the CXCR4 inhibitor to the subject comprises administration of ulocuplumab (MDX1338 / BMS-936564), G-CSF, and propranolol.

[0070] In some embodiments, the administration of a combination of the CXCR4 inhibitor and the G-CSF induces an enhanced amount of cell mobilization relative to the amount of cell mobilization induced by the CXCR4 inhibitor only. In some embodiments, the administration of a combination of the CXCR4 inhibitor and the G- CSF mobilizes a cell by an amount enhanced relative to the amount of cell mobilization induced by the CXCR4 inhibitor only. In some embodiments, the enhanced amount of cell mobilization relative to the amount of cell mobilization induced by the CXCR4 inhibitor only is between 1 .1 -fold to 1 .2-fold, 1 .2-fold to 1 .3- fold, 1.3-fold to 1.4-fold, 1.4-fold to 1.5-fold, 1.5-fold to 1.6-fold, 1.6-fold to 1.7-fold, 1.7-fold to 1.8-fold, 1.8-fold to 1.9-fold, 1.9-fold to 2-fold, 2-fold to 2.5-fold, 2.5-fold to 3-fold, 3-fold to 4-fold, 4-fold to 5-fold, 5-fold to 10-fold, or 10-fold or more. In some embodiments, the enhanced amount of cell mobilization relative to the amount of cell mobilization induced by the CXCR4 inhibitor only is between 5%-10% more, 10%- 20% more, 20%-30% more, 30%-40% more, 40%-50% more, 50%-60% more, 60%- 70% more, 70%-80% more, 80%-90% more, 90%-100% more, 100%-120% more, 120%-140% more, 140%-160% more, 160%-180% more, 180%-200% more, 200%- 250% more, 250%-300% more, 300%-400% more, 400%-500% more, 500%-750% more, 750%-1000% more, or 1000% or more.

[0071] In some embodiments, the administration of a combination of the CXCR4 inhibitor and the beta-adrenergic receptor inhibitor induces an enhanced amount of cell mobilization relative to the amount of cell mobilization induced by the CXCR4 inhibitor only. In some embodiments, the administration of a combination of the CXCR4 inhibitor and the beta-adrenergic receptor inhibitor mobilizes a cell by an amount enhanced relative to the amount of cell mobilization induced by the CXCR4inhibitor only. In some embodiments, the enhanced amount of cell mobilization relative to the amount of cell mobilization induced by the CXCR4 inhibitor only is between 1.1-fold to 1.2-fold, 1.2-fold to 1.3-fold, 1.3-fold to 1.4-fold, 1.4-fold to 1.5- fold, 1.5-fold to 1.6-fold, 1.6-fold to 1.7-fold, 1.7-fold to 1.8-fold, 1.8-fold to 1.9-fold, 1.9-fold to 2-fold, 2-fold to 2.5-fold, 2.5-fold to 3-fold, 3-fold to 4-fold, 4-fold to 5-fold, 5-fold to 10-fold, or 10-fold or more. In some embodiments, the enhanced amount of cell mobilization relative to the amount of cell mobilization induced by the CXCR4 inhibitor only is between 5%-10% more, 10%-20% more, 20%-30% more, 30%-40% more, 40%-50% more, 50%-60% more, 60%-70% more, 70%-80% more, 80%-90% more, 90%-100% more, 100%-120% more, 120%-140% more, 140%-160% more, 160%-180% more, 180%-200% more, 200%-250% more, 250%-300% more, 300%- 400% more, 400%-500% more, 500%-750% more, 750%-1000% more, or 1000% or more.

[0072] In some embodiments, the administration of a combination of the CXCR4 inhibitor, the beta-adrenergic receptor inhibitor, and the G-CSF induces an enhanced amount of cell mobilization relative to the amount of cell mobilization induced by the CXCR4 inhibitor and the beta-adrenergic receptor inhibitor only. In some embodiments, the administration of a combination of the CXCR4 inhibitor, the beta- adrenergic receptor inhibitor, and the G-CSF mobilizes a cell by an amount enhanced relative to the amount of cell mobilization induced by the CXCR4 inhibitor and the beta-adrenergic receptor inhibitor only. In some embodiments, the administration of a combination of AMD3100 (Plerixafor, or Mozobil) and the G-CSF induces an enhanced amount of cell mobilization relative to the amount of cell mobilization induced by AMD3100 (Plerixafor, or Mozobil) and the G-CSF. In some embodiments, the administration of a combination of the AMD3100 (Plerixafor, or Mozobil) and the G-CSF mobilizes a cell by an amount enhanced relative to the amount of cell mobilization induced by the AMD3100 (Plerixafor, or Mozobil) and the G-CSF. In some embodiments, the enhanced amount of cell mobilization relative to the amount of cell mobilization induced by the CXCR4 inhibitor only is between 1.1- fold to 1.2-fold, 1.2-fold to 1.3-fold, 1.3-fold to 1.4-fold, 1.4-fold to 1.5-fold, 1.5-fold to 1.6-fold, 1.6-fold to 1.7-fold, 1.7-fold to 1.8-fold, 1.8-fold to 1.9-fold, 1.9-fold to 2-fold, 2-fold to 2.5-fold, 2.5-fold to 3-fold, 3-fold to 4-fold, 4-fold to 5-fold, 5-fold to 10-fold, or 10-fold or more. In some embodiments, the enhanced amount of cell mobilizationrelative to the amount of cell mobilization induced by the CXCR4 inhibitor only is between 5%-10% more, 10%-20% more, 20%-30% more, 30%-40% more, 40%- 50% more, 50%-60% more, 60%-70% more, 70%-80% more, 80%-90% more, 90%- 100% more, 100%-120% more, 120%-140% more, 140%-160% more, 160%-180% more, 180%-200% more, 200%-250% more, 250%-300% more, 300%-400% more, 400%-500% more, 500%-750% more, 750%-1000% more, or 1000% or more. In some embodiments, an enhanced amount of cell mobilization or apheresis is measured by a method selected from the group consisting of complete blood count (CBC) analysis, flow cytometry, and colony forming unit (CPU) assay. In some embodiments, the enhanced amount of cell mobilization or apheresis is measured by flow cytometry. In some embodiments, the flow cytometry is performed on (Lin- Sca1+c-Kit+) LSK cells. In some embodiments, the flow cytometry is performed on CD34- LSK cells. In some embodiments, the flow cytometry is performed on CD150+LSK cells. In some embodiments, the flow cytometry is performed on CD48+cells. In some embodiments, the enhanced amount of cell mobilization or apheresis is measured by colony forming unit (CPU) assay.

[0073] In some embodiments, the administration of a combination of the CXCR4 inhibitor, the beta-adrenergic receptor inhibitor, and the G-CSF induces an enhanced amount of cell mobilization relative to the amount of cell mobilization induced by the CXCR4 inhibitor and G-CSF only. In some embodiments, the administration of a combination of the CXCR4 inhibitor, the beta-adrenergic receptor inhibitor, and the G-CSF mobilizes a cell by an amount enhanced relative to the amount of cell mobilization induced by the CXCR4 inhibitor and G-CSF only. In some embodiments, the administration of a combination of GPC-100 (Burixafor, orTG- 0054), G-CSF, and a beta-adrenergic receptor inhibitor induces an enhanced amount of cell mobilization relative to the amount of cell mobilization induced by AMD3100 (Plerixafor, or Mozobil) and the G-CSF. In some embodiments, the administration of a combination of the GPC-100 (Burixafor, or TG-0054), the G-CSF, and the beta-adrenergic receptor inhibitor mobilizes a cell by an amount enhanced relative to the amount of cell mobilization induced by the AMD3100 (Plerixafor, or Mozobil) and the G-CSF. In some embodiments, the enhanced amount of cell mobilization relative to the amount of cell mobilization induced by the CXCR4 inhibitor only is between 1.1 -fold to 1.2-fold, 1.2-fold to 1.3-fold, 1.3-fold to 1.4-fold,1.4-fold to 1.5-fold, 1.5-fold to 1.6-fold, 1.6-fold to 1.7-fold, 1.7-fold to 1.8-fold, 1.8- fold to 1 .9-fold, 1 .9-fold to 2-fold, 2-fold to 2.5-fold, 2.5-fold to 3-fold, 3-fold to 4-fold, 4-fold to 5-fold, 5-fold to 10-fold, or 10-fold or more. In some embodiments, the enhanced amount of cell mobilization relative to the amount of cell mobilization induced by the CXCR4 inhibitor only is between 5%-10% more, 10%-20% more, 20%-30% more, 30%-40% more, 40%-50% more, 50%-60% more, 60%-70% more, 70%-80% more, 80%-90% more, 90%-100% more, 100%-120% more, 120%-140% more, 140%-160% more, 160%-180% more, 180%-200% more, 200%-250% more, 250%-300% more, 300%-400% more, 400%-500% more, 500%-750% more, 750%- 1000% more, or 1000% or more. In some embodiments, an enhanced amount of cell mobilization or apheresis is measured by a method selected from the group consisting of complete blood count (CBC) analysis, flow cytometry, and colony forming unit (CPU) assay. In some embodiments, the enhanced amount of cell mobilization or apheresis is measured by flow cytometry. In some embodiments, the flow cytometry is performed on (Lin Sca1+c-Kit+) LSK cells. In some embodiments, the flow cytometry is performed on CD34’ LSK cells. In some embodiments, the flow cytometry is performed on CD150+LSK cells. In some embodiments, the flow cytometry is performed on CD48+LSK cells. In some embodiments, the enhanced amount of cell mobilization or apheresis Is measured by colony forming unit (CFU) assay.

[0074] In some embodiments, the administration of a combination of the CXCR4 inhibitor, the beta-adrenergic receptor inhibitor, and the G-CSF induces an enhanced amount of long-term repopulating hematopoietic stem cell (LT-HSC) mobilization relative to the amount of long-term repopulating HSC mobilization induced by the CXCR4 inhibitor and G-CSF only. As used herein a LT-HSC includes CD150+, CD34; or CD48+LSK cells. In some embodiments, the administration of a combination of the CXCR4 inhibitor, the beta-adrenergic receptor inhibitor, and the G-CSF mobilizes a LT-HSC by an amount enhanced relative to the amount of LT- HSC mobilization induced by the CXCR4 inhibitor and G-CSF only. In some embodiments, the administration of a combination of GPC-100 (Burixafor, orTG- 0054), G-CSF, and a beta-adrenergic receptor inhibitor induces an enhanced amount of LT-HSC mobilization relative to the amount of LT-HSC mobilization induced by AMD3100 (Plerixafor, or Mozobil) and the G-CSF. In someembodiments, the administration of a combination of the GPC-100 (Burixafor, or TG- 0054), the G-CSF, and the beta-adrenergic receptor inhibitor mobilizes a LT-HSC by an amount enhanced relative to the amount of LT-HSC mobilization induced by the AMD3100 (Plerixafor, or Mozobil) and the G-CSF. In some embodiments, the enhanced amount of LT-HSC mobilization relative to the amount of LT-HSC mobilization induced by the CXCR4 inhibitor only is between 1 .1 -fold to 1 .2-fold, 1 .2- fold to 1.3-fold, 1.3-fold to 1.4-fold, 1.4-fold to 1.5-fold, 1.5-fold to 1.6-fold, 1.6-fold to 1.7-fold, 1.7-fold to 1.8-fold, 1.8-fold to 1.9-fold, 1.9-fold to 2-fold, 2-fold to 2.5-fold, 2.5-fold to 3-fold, 3-fold to 4-fold, 4-fold to 5-fold, 5-fold to 10-fold, or 10-fold or more.

[0075] In some embodiments, the subject has a CXCR4 protomer in the cell. In some embodiments, the subject has an ADRB2 protomer in the cell. In some embodiments, the subject has a CXCR4 protomer and an ADRB2 protomer in the cell. In some embodiments, the subject has a CXCR4-ADRB2 heteromer in the cell. In some embodiments, i) the CXCR4-ADRB2 heteromer has an enhanced amount of downstream calcium mobilization relative to downstream calcium mobilization from a CXCR4 protomer or ADRB2 protomer; and ii) the administered combination of inhibitors suppresses the enhanced downstream calcium mobilization from said CXCR4-ADRB2 heteromer in the stem cell.

[0076] In some embodiments, the cell is a stem cell. In some embodiments, the stem cell is selected from the group consisting of a hematopoietic stem cell (HSC), a hematopoietic progenitor cell (HPC), a mesenchymal stem cell, an endothelial progenitor cell, a neural stem cell, an epithelial stem cell, a skin stem cell, and a cancer stem cell. In some embodiments, the stem cell is a HSC or a HPC. In some embodiments, the HSC or the HPC is mobilized from bone marrow to PB. In some embodiments, the mobilized HSC or HPC is collected for transplantation to a patient having cancer. In some embodiments, the cancer is selected from the group consisting of lymphoma, leukemia, and myeloma. In some embodiments, the cancer is non-Hodgkin’s lymphoma (NHL), Hodgkin’s Disease (HD) or Hodgkin’s Lymphoma (HL), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), multiple myeloma (MM), or Burkitt’s Lymphoma. In some embodiments, the stem cell is a mesenchymal stem cell. In some embodiments, the mesenchymal stem cell is mobilized from bone marrow to PB. In some embodiments, the mesenchymal stem cell is mobilized for treatment of a condition selected from the group consisting ofneurological disorder, cardiac ischemia, myocardial infarction, diabetes, tissue repair, bone and cartilage disease, autoimmune disease, graft versus host disease, Crohn’s disease, multiple sclerosis, systemic lupus erythematosus, and systemic sclerosis. In some embodiments, the stem cell is a cancer stem cell. In some embodiments, the cancer stem cell is mobilized into blood. In some embodiments, the cancer stem cell is mobilized for treatment of a cancer.

[0077] In some embodiments, the cell is an immune cell. In some embodiments, the immune cell is a white blood cell (WBC). In some embodiments, the WBC is a lymphocyte. In some embodiments, the lymphocyte is selected from the group consisting of a T cell, a B cell, and a natural killer (NK) cell. In some embodiments, the lymphocyte is a T cell. In some embodiments, the lymphocyte is a natural killer (NK) cell. In some embodiments, the WBC is a granulocyte. In some embodiments, the granulocyte is selected from the group consisting of a neutrophile, an eosinophile, and a basophile. In some embodiments, the granulocyte is a neutrophile. In some embodiments, the WBC is a monocyte. In some embodiments, the immune cell is mobilized from bone marrow to PB. In some embodiments, the immune cell is mobilized from lymph node to PB. In some embodiments, the mobilized immune cell is used for adoptive cell therapy (ACT). In some embodiments, the adoptive cell therapy (ACT) is chimeric antigen receptor (CAR) T cell therapy. In some embodiments, the adoptive cell therapy (ACT) is natural killer (NK) cell therapy. In some embodiments, the adoptive cell therapy (ACT) is engineered T-cell receptor (TCR) therapy. In some embodiments, the adoptive cell therapy (ACT) is tumor-infiltrating lymphocyte (TIL) therapy.

[0078] In some embodiments of the present invention, the mobilization of a cell in a subject comprises blocking CXCR4. Many antiviral agents that inhibit HIV replication via inhibition of CXCR4, the co-receptor required for fusion and entry of T-tropic HIV strains, also inhibit the binding and signaling induced by the natural ligand, the chemokine CXCL12 (also known as SDF-1). While not wishing to be bound by any theory, the agents which inhibit the binding of CXCL12 to CXCR4 can effect an increase in mobilization of stem and / or progenitor cells to the periphery by virtue of such inhibition. Enhancing mobilization of the stem and / or progenitor cells to PB is helpful in treatments to alleviate the effects of protocols that adversely affect the bone marrow, such as those that result in leukopenia, which are known side effectsof chemotherapy and radiotherapy. The agents inhibiting the binding of CXCL12 to CXCR4 also enhance the success of bone marrow transplantation, enhance wound healing and bum treatment, and aid in restoration of damaged organ tissue. They also combat bacterial infections that are prevalent in leukemia. They are used to mobilize and harvest CD34+cells via apheresis with and without combinations with other mobilizing factors. The harvested cells are used in treatments requiring stem cell transplantations.

[0079] In some embodiments of the present invention, mobilizing a stem cell in a subject comprises blocking a CXCR4-GPCR heteromer. Various CXCR4-GPCR heteromers with distinct physiological and pharmacological properties have been reported, but their roles in stem cell mobilization or possibilities for developing stem cell mobilization therapeutics targeting CXCR4-GPCR heteromers have not been clearly understood or appreciated.

[0080] In some embodiments, the CXCR4-GPCR heteromer is blocked on a cell that expresses CXCR4 and 2AR receptors in close proximity. As used herein, “close proximity” include a proximity that is close enough to be detected using a PLA assay. In some embodiments, the cancer is a blood cancer. In some embodiments, a cancer cell expresses endogenous CXCR4 and 02AR receptors in close proximity. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is Burkitt’s Lymphoma.

[0081] In the art, GPCRs were believed to function as monomers that interact with hetero-trimeric G proteins upon ligand binding, and drugs were developed based on monomeric or homomeric GPCRs

[0041] , Recently, this view changed drastically based on discoveries that GPCRs can form heteromers, and that heteromerization is obligatory for some GPCRs. GPCR heteromerization is known to alter GPCR maturation and cell surface delivery, ligand binding affinity, signaling intensity and pathways, as well as receptor desensitization and recycling [42-46], Different GPCR heteromers display distinct functional and pharmacological properties, and GPCR heteromerization can vary depending on cell types, tissues, and diseases or pathological conditions [42-46], GPCR heteromerization is currently regarded as a general phenomenon, and deciphering GPCR heteromerization opens new avenues for understanding receptor function, physiology, roles in diseases and pathological conditions. Accordingly, identification of GPCR heteromers and their functionalproperties offers new opportunity for developing new pharmaceuticals or finding new use of old drugs with fewer side effects, higher efficacy, and increased tissue selectivity [42, 43, 45],

[0082] Apheresis is a standard practice to obtain a larger number of immune cells as starting material for Adoptive Cell Therapy (ACT), which is a treatment based on transferring cells into a patient. Apheresis may involve passing the blood of a patient through an apparatus that separates out one particular constituent and returns the remainder to the blood circulation of the patient. Apheresis is thus an extracorporeal therapy. Depending on the substance being removed, different processes are employed in apheresis. If separation by density is required, centrifugation is the most common method. Other methods involve absorption onto beads coated with an absorbent material and filtration. The centrifugation method can be divided into two basic categories: continuous flow centrifugation (CFC) and intermittent flow centrifugation.

[0083] The various apheresis techniques may be used whenever the removed constituent is causing severe symptoms of disease in a patient. Generally, apheresis has to be performed fairly often and is an invasive procedure. It is therefore generally employed if other means to control a particular disease have failed, or if the symptoms are of such a nature that waiting for medication to become effective would cause suffering or risk of complications. Apheresis techniques include: (1) plasma exchange - removal of the liquid portion of blood to remove harmful substances, where the plasma is replaced with a replacement so”ution; (2) LDL apheresis - removal of low density lipoprotein in patients with familial hypercholesterolemia; (3) photopheresis - used to treat graft-versus-host disease, cutaneous T-cell lymphoma, and rejection in heart transplantation; (4) immunoadsorption with Staphylococcal protein A-agarose column - removal of allo- and autoantibodies (in autoimmune diseases, transplant rejection, hemophilia) by directing plasma through protein A-agarose columns (Protein A is a cell wall component produced by several strains of Staphylococcus aureus which binds to the Fc region of IgG); (5) leukocytapheresis - removal of malignant WBC in people with leukemia and very high WBC counts causing symptoms; (6) erythrocytapheresis - removal of erythrocytes (red blood cells) in people with iron overload as a result of Hereditary haemochromatosis or transfusional iron overload; (7)thrombocytapheresis - removal of platelets in people with symptoms from extreme elevations in platelet count such as those with essential thrombocythemia or polycythemia vera; and (8) leukapheresis - separates out excess WBC of leukemia patients while recycling the remainder of their blood.

[0084] Apheresis is a difficult procedure, inconvenient and expensive. With the rapid growth of ACTs including CAR-T, CAR-NK, Tumor-Infiltrating Lymphocyte (TIL), and engineered T-cell receptor (TCR), the need for apheresis technology for the routine production of pure immune cells is increasing. The industry that supplies GMP- grade starting materials for ACTs is also growing rapidly. Thus, stem cell mobilization technologies that can control types of immune cells and improve the yield of apheresis have become important.

[0085] Enhanced stem cell mobilization (SCM) or cell mobilization methods as disclosed herein, can further augment or facilitate the conventional apheresis procedure. In a specific embodiment, enhanced stem cell mobilization (SCM) or cell mobilization is particularly beneficial for the apheresis technique of leukapheresis. In some embodiments, administration of a CXCR4 antagonist to a subject further enhances apheresis by augmenting SCM or cell mobilization. In some embodiments, administration of a beta-adrenergic receptor antagonist in conjunction with a CXCR4 antagonist to a subject further enhances apheresis by augmenting SCM or cell mobilization, and / or replacing the G-CSF component of the treatment regime with a non-selective beta-blocker, such as propranolol. In some embodiments, the augmentation of SCM in turn benefits HSC transplantation or manufacturing of CAR-T cells for cancer immunotherapy. Currently, CXCR4 inhibitors, such as AMD3100 (Plerixafor, or Mozobil) which have been approved as stem cell mobilizers, are being used together with G-CSF as the standard of care to provide enriched HSC and HPC from healthy donors, marketed as the product “mobilized leukopaks.”

[0086] Disclosed herein are methods of enhancing apheresis in a subject, the method comprising: blocking CXCR4 signaling and beta-adrenergic receptor signaling in the subject. Also disclosed herein are methods of enhancing apheresis by inducing cell mobilization in a subject, the method comprising: blocking CXCR4 signaling and beta-adrenergic receptor signaling in the subject. Further disclosed herein are methods of enhancing apheresis by mobilizing a cell in a subject, themethod comprising: blocking CXCR4 signaling and beta-adrenergic receptor signaling in the subject. In some embodiments, the blocking beta-adrenergic receptor signaling is performed before the blocking CXCR4 signaling. In some embodiments, the blocking beta-adrenergic receptor signaling is performed at a first specific time interval before the blocking CXCR4 signaling. In some embodiments, the first specific time interval is between 5 minutes to 10 minutes, 10 minutes to 20 minutes, 20 minutes to 30 minutes, 30 minutes to 40 minutes, 40 minutes to 50 minutes, 50 minutes to 1 hour, 1 hour to 2 hours, 2 hours to 3 hours, 3 hours to 4 hours, 4 hours to 5 hours, 5 hours to 6 hours, 6 hours to 12 hours, 12 hours to 24 hours, 1 day to 2 days, 2 days to 3 days, 3 days to 4 days, 4 days to 5 days, 5 days to 6 days, 6 days to 7 days, 7 days to 8 days, 8 days to 9 days, 9 days to 10 days, 10 days to 11 days, 11 days to 12 days, 12 days to 13 days, 13 days to 14 days, or 14 days or more. In some embodiments, the blocking beta-adrenergic receptor signaling continues after the blocking CXCR4 signaling is terminated. In some embodiments, the blocking beta-adrenergic receptor signaling continues for a second specific time interval after the blocking CXCR4 signaling is terminated. In some embodiments, the second specific time interval is between 5 minutes to 10 minutes, 10 minutes to 20 minutes, 20 minutes to 30 minutes, 30 minutes to 40 minutes, 40 minutes to 50 minutes, 50 minutes to 1 hour, 1 hour to 2 hours, 2 hours to 3 hours, 3 hours to 4 hours, 4 hours to 5 hours, 5 hours to 6 hours, 6 hours to 12 hours, 12 hours to 24 hours, 1 day to 2 days, 2 days to 3 days, 3 days to 4 days, 4 days to 5 days, 5 days to 6 days, 6 days to 7 days, 7 days to 8 days, 8 days to 9 days, 9 days to 10 days, 10 days to 11 days, 11 days to 12 days, 12 days to 13 days, 13 days to 14 days, or 14 days or more.

[0087] In some embodiments, the blocking CXCR4 signaling comprises administration of a CXCR4 inhibitor to the subject.

[0088] Disclosed herein are methods of enhancing apheresis in a subject, the method comprising: administration of a beta-adrenergic receptor inhibitor and a CXCR4 inhibitor to the subject. Also disclosed herein are methods of enhancing apheresis by inducing cell mobilization in a subject, the method comprising: administration of a beta-adrenergic receptor inhibitor and a CXCR4 inhibitor to the subject. Further disclosed herein are methods of enhancing apheresis by mobilizing a cell in a subject, the method comprising: administration of a beta-adrenergicreceptor inhibitor and a CXCR4 inhibitor to the subject. In some embodiments, the administration of the beta-adrenergic receptor inhibitor is performed at a first specific time interval before the administration of the CXCR4 inhibitor. In some embodiments, the first specific time interval is between 5 minutes to 10 minutes, 10 minutes to 20 minutes, 20 minutes to 30 minutes, 30 minutes to 40 minutes, 40 minutes to 50 minutes, 50 minutes to 1 hour, 1 hour to 2 hours, 2 hours to 3 hours, 3 hours to 4 hours, 4 hours to 5 hours, 5 hours to 6 hours, 6 hours to 12 hours, 12 hours to 24 hours, 1 day to 2 days, 2 days to 3 days, 3 days to 4 days, 4 days to 5 days, 5 days to 6 days, 6 days to 7 days, 7 days to 8 days, 8 days to 9 days, 9 days to 10 days, 10 days to 11 days, 11 days to 12 days, 12 days to 13 days, 13 days to 14 days, or 14 days or more. In some embodiments, the administration of the beta- adrenergic receptor inhibitor continues after the administration of the CXCR4 inhibitor is terminated. In some embodiments, the administration of the beta- adrenergic receptor inhibitor continues for a second specific time interval after the administration of the CXCR4 Inhibitor is terminated. In some embodiments, the second specific time interval is between 5 minutes to 10 minutes, 10 minutes to 20 minutes, 20 minutes to 30 minutes, 30 minutes to 40 minutes, 40 minutes to 50 minutes, 50 minutes to 1 hour, 1 hour to 2 hours, 2 hours to 3 hours, 3 hours to 4 hours, 4 hours to 5 hours, 5 hours to 6 hours, 6 hours to 12 hours, 12 hours to 24 hours, 1 day to 2 days, 2 days to 3 days, 3 days to 4 days, 4 days to 5 days, 5 days to 6 days, 6 days to 7 days, 7 days to 8 days, 8 days to 9 days, 9 days to 10 days, 10 days to 11 days, 11 days to 12 days, 12 days to 13 days, 13 days to 14 days, or 14 days or more.

[0089] In some embodiments, the beta-adrenergic receptor inhibitor is an ADRB2 inhibitor. In some embodiments, the beta-adrenergic receptor inhibitor is selected from the group consisting of alprenolol, atenolol, betaxolol, bupranolol, butoxamine, carazolol, carvedilol, CGP 12177, cicloprolol, ICI 118551 , ICYP, labetalol, levobetaxolol, levobunolol, LK 204-545, metoprolol, nadolol, NIHP, NIP, propafenone, propranolol, sotalol, SR59230A, and timolol. In some embodiments, the beta-adrenergic receptor inhibitor is selected from the group consisting of propranolol, nadolol, and ICI 118551. In some embodiments, the beta-adrenergic receptor inhibitor is propranolol.

[0090] In some embodiments, the CXCR4 inhibitor is selected from the group consisting of ALX40-4C, AMD070 (AMD11070, X4P-001), AMD3100 (Plerixafor, or Mozobil), AMD3465, ATI 2341 , BKT140 (BL-8040; TF14016; 4F-Benzoyl-TN 14003), CTCE-9908, CX549„D-[Lys3] GHRP-6, FC122, FC131 , GMI-1359, GSK812397, GST-NT21 MP, isothiourea-1 a, isothiourea-11 (IT1t), KRH-1636, KRH-3955, LY2510924, MSX-122, N-[11C]Methyl-AMD3465, POL6326, SDF-1 1-9[P2G] dimer, SDF1 P2G, T134, T140, T22, TC 14012, GPC-100 (Burixafor, or TG-0054), USL311 , viral macrophage inflammatory protein-ll (vMIP-ll), WZ811 , [64Cu]-AMD3100, [64Cu]-AMD3465, [68Ga]pentixafor, [90Y]pentixather, [99mTc]02-AMD3100, [177Lu]pentixather, Ulocuplumab (MDX1338 / BMS-936564), AD-214, LY2624587, PF-06747143, POL6326, MB1707, and 508MCI (Compound 26). In some embodiments, the CXCR4 inhibitor is selected from the group consisting of AD-214, AMD070 (AMD11070, or X4P-001), AMD3100 (Plerixafor, or Mozobil), BKT140 (BL- 8040, TF14016, or 4F-Benzoyl-TN 14003), CTCE-9908, LY2510924, LY2624587, T140, GPC-100 (Burixafor, or TG-0054), PF-06747143, POL6326, and ulocuplumab (MDX1338 / BMS-936564). In some embodiments, the CXCR4 inhibitor is GPC-100 (Burixafor, or TG-0054). In some embodiments, the CXCR4 inhibitor is AMD3100 (Plerixafor, or Mozobil). In some embodiments, the CXCR4 inhibitor is ulocuplumab (MDX1338 / BMS-936564).

[0091] In some embodiments, the CXCR4 inhibitor forms an ionic interaction with Arg188 on CXCR4. In some embodiments, the CXCR4 inhibitor forms a hydrogen bond with Gln200 on CXCR4. In some embodiments, the CXCR4 inhibitor forms an ionic interaction with Arg188 on CXCR4 and a hydrogen bond with Gln200 on CXCR4.

[0092] In some embodiments, the CXCR4 inhibitor has a higher binding affinity to CXCL12 than AMD3100. In some embodiments, the CXCR4 inhibitor has a lower inhibitory constant (Ki) than AMD3100. In some embodiments, the CXCR4 inhibitor has at least a 2-fold, 5-fold, 10-fold, or 20-fold lower inhibitory constant than AMD3100. In some embodiments, the CXCR4 inhibitor inhibits CXCL12-induced calcium flux at an equal or greater level as AMD3100. In some embodiments, the CXCR4 inhibitor inhibits CXCL12-induced p-arrestin recruitment at an equal or greater level as AMD3100. In some embodiments, the CXCR4 inhibitor inhibits CXCL12-induced migration of cancer cells at an equal or greater level as AMD3100.In some embodiments, the CXCR4 inhibitor inhibits CXCL12-induced migration of U937 and MM.1S cells at an equal or greater level as AMD3100. In some embodiments, the CXCR4 inhibitor inhibits calcium flux induced by CXCL12 and epinephrine.

[0093] In some embodiments, the administration of the CXCR4 inhibitor to the subject comprises administration of GPC-100 (Burixafor, or TG-0054) and propranolol. In some embodiments, the administration of the CXCR4 inhibitor to the subject comprises administration of AMD3100 (Plerixafor, or Mozobil) and propranolol. In some embodiments, the administration of the CXCR4 inhibitor to the subject comprises administration of ulocuplumab (MDX1338 / BMS-936564) and propranolol.

[0094] In some embodiments, the method further comprises administration of G-CSF to the subject. In some embodiments, the administration of the beta-adrenergic receptor inhibitor and the CXCR4 inhibitor to the subject is performed in the absence of G-CSF. Disclosed herein are methods of enhancing apheresis in a subject, the method comprising: administration of a CXCR4 inhibitor and G-CSF to the subject, in the absence of a beta-adrenergic receptor inhibitor. Further disclosed herein are methods of enhancing apheresis by inducing cell mobilization in a subject, the method comprising: administration of a CXCR4 inhibitor and G-CSF to the subject, in the absence of a beta-adrenergic receptor inhibitor. Also disclosed herein are methods of enhancing apheresis by mobilizing a cell in a subject, the method comprising: administration of a CXCR4 inhibitor and G-CSF to the subject, in the absence of a beta-adrenergic receptor inhibitor. In some embodiments, the administration of a combination of the CXCR4 inhibitor and the G-CSF induces an enhanced amount of apheresis relative to the amount of apheresis induced by the CXCR4 inhibitor only. In some embodiments, the administration of a combination of the CXCR4 inhibitor and the beta-adrenergic receptor inhibitor induces an enhanced amount of apheresis relative to the amount of apheresis induced by the CXCR4 inhibitor only. In some embodiments, the administration of a combination of the CXCR4 inhibitor and the beta-adrenergic receptor inhibitor, and the G-CSF induces an enhanced amount of apheresis relative to the amount of apheresis induced by the CXCR4 inhibitor and the beta-adrenergic receptor inhibitor only. In some embodiments, the administration of a combination of the GPC-100 (Burixafor, or TG-0054) and the G-CSF induces an enhanced amount of apheresis relative to the amount of apheresis induced by the AMD3100 (Plerixafor, or Mozobil) and the G- CSF. In some embodiments, the enhanced amount of cell mobilization relative to the amount of cell mobilization induced by the CXCR4 inhibitor only is between 1.1- fold to 1 2-fold, 1 .2-fold to 1.3-fold, 1.3 -fold to 1 .4-fold, 1 .4-fold to 1 .5-fold, 1 .5-fold to 1.6-fold, 1.6-fold to 1.7-fold, 1.7-fold to 1.8-fold, 1.8-fold to 1.9-fold, 1.9-fold to 2-fold, 2-fold to 2.5-fold, 2.5-fold to 3-fold, 3-fold to 4-fold, 4-fold to 5-fold, 5-fold to 10-fold, or 10-fold or more. In some embodiments, the enhanced amount of cell mobilization relative to the amount of cell mobilization induced by the CXCR4 inhibitor only is between 5%-10% more, 10%-20% more, 20%-30% more, 30%-40% more, 40%- 50% more, 50%-60% more, 60%-70% more, 70%-80% more, 80%-90% more, 90%- 100% more, 100%-120% more, 120%-140% more, 140%-160% more, 160%-180% more, 180%-200% more, 200%-250% more, 250%-300% more, 300%-400% more, 400%-500% more, 500%-750% more, 750%-1000% more, or 1000% or more. In some embodiments, an enhanced amount of cell mobilization or apheresis is measured by a method selected from the group consisting of complete blood count (CBC) analysis, flow cytometry, and colony forming unit (CFU) assay. In some embodiments, the enhanced amount of cell mobilization or apheresis is measured by flow cytometry. In some embodiments, the flow cytometry is performed on (Lin- Sca1+c-Kit+) LSK cells. In some embodiments, the enhanced amount of cell mobilization or apheresis is measured by colony forming unit (CFU) assay.

[0095] Further information regarding the ADRB2, evaluated herein as forming heteromers with CXCR4, are detailed below:

[0096] ADRB2 - The beta-2 adrenergic receptor (P2 adrenoreceptor), also known as ADRB2, is a cell membrane-spanning beta-adrenergic receptor that interacts with epinephrine, a hormone and neurotransmitter (ligand synonym, adrenaline) whose signaling, via a downstream L-type calcium channel interaction, mediates physiologic responses such as smooth muscle relaxation and bronchodilation (Gregorio et al., 2017). ADRB2 functions in muscular system such as smooth muscle relaxation, motor nerve terminals, glycogenolysis and in circulatory system such as heart muscle contraction, cardiac output increase. In the normal eye, beta-2 stimulation by salbutamol increases intraocular pressure via net. In digestive system, the ADRB2induces glycogenolysis and gluconeogenesis in liver and insulin secretion from pancreas (Fitzpatrick, 2004).

[0097] ADRB2 signaling in the cardiac myocyte is modulated by interactions with CXCR4 (LaRocca et al., 2010). Norepinephrine attenuates CXCR4 expression and the corresponding invasion of MDA-MB-231 breast cancer cells via ADRB2 (Wang et al., 2015a). ADRB2 is expressed in several cancers such as pancreatic, prostate (Braadland et al., 2014; Xu et al., 2017), renal and breast cancer (Choy et al., 2016).

[0098] Alternative methods for detecting heteromer formation include, but are not limited to: immunostaing (Bushlin et al., 2012; Decaillot et al., 2008); immunoelectron microscopy; BRET (Pfleger and Eidne, 2006); Time-resolved FRET assays; In Situ Hybridization; FRET (Lohse et al., 2012); -arrestin recruitment assay using GPCR heteromer identification technology (GPCR-HIT, Dimerix Bioscience) using BRET, FRET, BiFC, Bimolecular Luminescence Complementation, enzyme fragmentation assay, and Tango Tango GPCR assay system (Thermo Fisher Scientific); PRESTO- Tango system (Kroeze et al., 2015); regulated secretion / aggregation technology (ARIAD Pharmaceuticals) (Hansen et al., 2009); Receptor Selection and Amplification Technology (ACADIA Pharmaceuticals) (Hansen et al., 2009);DimerScreen (Cara Therapeutics); Dimer / interacting protein translocation assay (Patobios); Co-immunoprecipitation; GPCR internalization assays using surface enzyme-linked immunosorbent assay (ELISA) (Decaillot et al., 2008) or Flow Cytometry (Law et al., 2005); Whole Cell Phosphorylation Assays (Pfeiffer et al., 2002); and Proximity ligation assay (PLA) (Frederick et al., 2015).

[0099] Alternative methods for detecting changes in pharmacological properties, signaling properties, and / or trafficking properties, in cells expressing both CXCR4 and GPCRx include, but are not limited to: Radioligand Binding Assays (Bushlin et al., 2012; Pfeiffer et al., 2002); Cell Surface Biotinylation and Immunoblotting; immunostaing (Bushlin et al., 2012; Decaillot et al., 2008); immunoelectron microscopy; [35S]GTPyS Binding assays (Bushlin et al., 2012); Calcuim imaging or assays using dyes such as Fura 2-aceto methoxy ester (Molecular Probes), Fluo-4 NW calcium dye (Thermo Fisher Scientific), or FLIPR5 dye (Molecular Devices); cAMP assays using radioimmunoassay kit (Amersham Biosciences); AlphaScreen (PerkinElmer Life Sciences); Parameter Cyclic AMP Assay (R&D Systems); femto cAMP kit (Cisbio); cAMP Direct Immunoassay Kit (Calbiochem) or GloSensor cAMPassay (Promega); GTPase assay (Pello et al., 2008); PKA activation (Stefan et al., 2007); ERK1 / 2 and / or Akt / PKB Phosphorylation Assays (Callen et al., 2012); Src and STAT3 phosphorylation assays (Rios et al., 2006); reporter assays such as cAMP response element (CRE); nuclear factor of activated T-cells response element (NFAT-RE); serum response element (SRE); serum response factor response element (SRF-RE); and NF-KB-response element luciferase reporter assays; Secreted alkaline phosphatase Assay (Decaillot et al., 2011 ); Measurement of Inositol 1 -Phosphate Production Using TR-FRET or [3H]myo-lnositol; RT-qPCR for measuring downstream target gene expression; and Adenylyl Cyclase Activity (George et al., 2000); next generation sequencing (NGS); and any other assay that can detect a change in receptor function as a result of receptor heterodimerization.

[0100] The phrase “protein-protein interaction inhibitor,” “PPI inhibitor,” or their variants as used herein refer to any molecules that can interfere with protein-protein interactions. Protein-protein interaction, unlike enzyme-substrate interaction involving well-defined binding pockets, is a transient interaction or association between proteins over relatively large areas and is often driven by electrostatic interactions, hydrophobic interactions, hydrogen bonds, and / or Van der Waals forces. PPI inhibitors may include, but not limited to, membrane-permeable peptides or lipid fused to a peptide sequence that disrupts the GPCR heteromeric interface, for example, transmembrane helix, intracellular loop, or C-terminal tail of GPCRx. The PPI inhibitor of the CXCR4-GPCRx heteromer, for example, may be a membrane-permeable peptide or cell-penetrating peptide (CPP) conjugated with peptide that targets the CXCR4-GPCRx heteromeric interface(s), or may be a cellpenetrating lipidated peptide targeting the CXCR4-GPCRx heteromeric interface(s).

[0101] For example, the membrane-permeable peptide or cell-penetrating peptide includes: HIV-1 TAT peptides, such as TAT48-60 and TAT49-57; Penetratins, such as pAntp(43-58); Polyarginines (Rn such as R5 to R12); Diatos peptide vector 1047 (DPV1047, Vectocell®); MPG (HIV gp41 fused to the nuclear localization signal (NLS) of the SV40 large T antigen); Pep-1 (tryptophan-rich cluster fused to the NLS of SV40 large T antigen); pVEC peptide (vascular endothelial cadherin); p14 alternative reading frame (ARF) protein-based ARF(1-22); N-terminus of the unprocessed bovine prion protein BPrPr(1-28); Model amphipathic peptide (MAP); Transportans; Azurin-derived p28 peptide; amphipathic p-sheet peptides, such asVT5; proline-rich CPPs, such as Bac 7 (Bad -24); hydrophobic CPPs, such as C105Y derived from a1 -Antitrypsin; PFVYLI derived from synthetic C105Y; Pep-7 peptide (CHL8 peptide phage clone); and modified hydrophobic CPPs, such as stapled peptides and prenylated peptides (Guidotti et al., 2017; Kristensen et al., 2016). The membrane-permeable peptide or cell-penetrating peptide can further include, for example, TAT-derived cell-penetrating peptides, signal sequence-based (e.g., NLS) cell-penetrating peptides, hydrophobic membrane translocating sequence (MTS) peptides, and arginine-rich molecular transporters. The cellpenetrating lapidated peptide includes, for example, pepducins, such as ICL1 / 2 / 3, C- tail- short palmitoylated peptides [47, 48],

[0102] The peptide(s) that target the CXCR4-GPCRx heteromeric interface may be, for example, a transmembrane domain of CXCR4, transmembrane domain of GPCRx, intracellular loop of CXCR4, intracellular loop of GPCRx, C-terminal domain of CXCR4, or C-terminal domain of GPCRx., extracellular loop of CXCR4, extracellular loop of GPCRx, N-terminal region of CXCR4, or N-terminal region of GPCRx.

[0103] Described herein is a method of treatment to a subject in need thereof. In some embodiments, the method comprising blocking a CXCR4 in the subject. In some embodiments, the drug is administered blocking a beta-adrenergic receptor in the subject. In some embodiments, the drug is administered blocking the CXCR4 inhibitor and the beta-adrenergic receptor in the subject.

[0104] In some embodiments, the blocking of the CXCR4 is achieved through an ionic interaction with Arg188 on CXCR4. In some embodiments, the blocking of the CXCR4 is achieved through a hydrogen bond with Gln200 on CXCR4. In some embodiments, the blocking of the CXCR4 is achieved through a combination of an ionic interaction with Arg188 on CXCR4 and a hydrogen bond with Gln200 on CXCR4.

[0105] Described herein is a method of preparing a subject for a treatment. In some embodiments, the method comprising administering an effective amount of a CXCR4 inhibitor. In some embodiments, the drug is administered a beta-adrenergic receptor inhibitor. In some embodiments, the drug is administered a combination thereof.

[0106] Described herein is a method to qualify a subject for treatment. In some embodiments, the method comprising administering an effective amount of a CXCR4inhibitor. In some embodiments, the drug is administered a beta-adrenergic receptor inhibitor. In some embodiments, the drug is administered a combination thereof.

[0107] Described herein is a method of treatment to a subject in need thereof. In some embodiments, the method comprising administering an effective amount of a CXCR4 inhibitor. In some embodiments, the drug is administered a beta-adrenergic receptor inhibitor. In some embodiments, the drug is administered a combination thereof.

[0108] In some embodiments, the treatment further comprises administering an effective amount of: a beta-adrenergic receptor inhibitor, or a G-CSF, or a lenalidomide, or a daratumumab, or a velacade, or a dexamethasone, or a cyclophosphamide, or bortezombil, or combinations thereof.

[0109] In some embodiments, the subject is pre-treated with an administration of an effective amount of: a beta-adrenergic receptor inhibitor, or a G-CSF, or a lenalidomide, or a daratumumab, or a velacade, or a dexamethasone, or a cyclophosphamide, or bortezombil, or combinations thereof.

[0110] In some embodiments, the treatment comprises one or more of: an apheresis step; or a leukapheresis step; or a peripheral blood collection step; or a cell transplant step, a CAR-T therapy step; or a combinations thereof. In some embodiments, the cell is optionally a stem cell. In some embodiments, the cell is optionally a hematopoietic progenitor cell (HSC). In some embodiments, the cell is optionally a T cell, or combinations thereof.

[0111] ln some embodiments, the method further comprises administering of an effective amount of G-CSF.

[0112] In some embodiments, the subject present symptoms of or is diagnosed with a cancer, or a neurological disorder, or any combination thereof. In some embodiments, the cancer is selected from the group consisting of lymphoma, leukemia, and myeloma. In some embodiments, the subject present symptoms of or is diagnosed with a hematologic malignancy. In some embodiments, the cancer is selected from the group consisting of non-Hodgkin's lymphoma (NHL), Hodgkin's Disease (HD) or Hodgkin's Lymphoma (HL), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), multiple myeloma (MM), Burkitt's Lymphoma. In some embodiments, the cancer is HD. In some embodiments, the cancer is NHL. In some embodiments, the cancer is AML. In some embodiments, the cancer is ALL.In some embodiments, the cancer is MM. In some embodiments, the neurological disorder is selected from the group consisting of neurological disorder, cardiac ischemia, myocardial infarction, diabetes, tissue repair, bone and cartilage disease, autoimmune disease, graft versus host disease, Crohn’s disease, multiple sclerosis, systemic lupus erythematosus, and systemic sclerosis. In some embodiments, the subject is a human.

[0113] In some embodiments, the subject is in need of Autologous Stem Cell Transplant (ASCT). In some embodiments, the treatment is Autologous Stem Cell Transplant (ASCT).

[0114] In some embodiments, the CXCR4 inhibitor forms an ionic interaction with Arg188 on CXCR4. In some embodiments, the CXCR4 inhibitor forms a hydrogen bond with Gln200 on CXCR4. In some embodiments, the CXCR4 inhibitor forms an ionic interaction with Arg188 on CXCR4 and a hydrogen bond with Gln200 on CXCR4

[0115] , In some embodiments, the CXCR4 inhibitor has a higher binding affinity to CXCL12 than AMD3100. In some embodiments, the CXCR4 inhibitor has a lower inhibitory constant (Ki) than AMD3100 In some embodiments. In some embodiments, the CXCR4 inhibitor has at least a 2-fold lower inhibitory constant than AMD3100.

[0116] In some embodiments, the CXCR4 inhibitor is selected from the group consisting of ALX40-4C, AMD070 (AMD11070, X4P-001), AMD3100 (Plerixafor, or Mozobil), AMD3465, ATI 2341 , BKT140 (BL-8040; TF14016; 4F-Benzoyl-TN 14003), CTCE-9908, CX549, D-[Lys3] GHRP-6, FC122, FC131 , GMI-1359, GSK812397, GSTNT21 MP, isothiourea-1 a, isothiourea-11 (IT1t), KRH-1636, KRH-3955, LY2510924, MSX-122, N-[11C]Methyl-AMD3465, POL6326, SDF-1 l-9[P2G] dimer, SDFI P2G, T134, T140, T22, TC 14012, GPC-100 (Burixafor, or TG-0054), USL311 , viral macrophage inflammatory protein-ll (vMIP-11), WZ811 , [64Cu]-AMD3100, [64Cu]-AMD3465, [68Ga]pentixafor, [90Y]pentixather, [99mTc]02-AMD3100, [177Lu]pentixather, Ulocuplumab (MDX1338 / BMS-936564), AD-214, LY2624587, PF-06747143, POL6326, MB1707, 508MC1 (Compound 26), and the derivatives and similars thereof. In some embodiments, the inhibitor is selected from the group consisting of AD-214, AMD070 (AMD11070, X4P-001), AMD3100 (Plerixafor, or Mozobil), BKT140 (BL-8040; TF14016; 4F-Benzoyl-TN 14003), CTCE-9908,LY2510924, LY2624587, T140, GPC-100 (Burixafor, or TG-0054), PF-06747143, POL6326, and ulocuplumab (MDX1338 / BMS-936564), and the derivatives and similars thereof. In some embodiments, the inhibitor is ulocuplumab (MDX1338 / B MS-936564). In some embodiments, the inhibitor is AMD3100 (Plerixafor, or Mozobil). In some embodiments, the inhibitor is BL8040. In some embodiments, the inhibitor is GPC-100 (Burixafor, or TG-0054).

[0117] In some embodiments, the beta-adrenergic receptor inhibitor is an ADRB2 inhibitor. In some embodiments, the inhibitor is selected from the group consisting of alprenolol, atenolol, betaxolol, bupranolol, butoxamine, carazolol, carvedilol, CGP 12177, cicloprolol, ICI 118551 , ICYP, labetalol, levobetaxolol, levobunolol, LK 204- 545, metoprolol, nadolol, NIHP, NIP, propafenone, propranolol, sotalol, SR59230A, timolol, and the derivatives and similars thereof. In some embodiments, the inhibitor is selected from the group consisting of propranolol, nadolol, and ICI 118551 . In some embodiments, the inhibitor is propranolol.

[0118] In some embodiments, the CXCR4 inhibitor is GPC-100, orAMD3100, or BL8040, preferably GPC-100. In some embodiments, the beta-adrenergic receptor inhibitor is propranolol.

[0119] In some embodiments the effective amount of the CXCR inhibitor is a pharmacologically effective dose with clinically acceptable severe adverse effects.

[0120] In some embodiments the effective amount of the CXCR inhibitor is: from about 30 mg / kg to about 0.01 mg / kg, or from about 30 mg / kg to about 0.07 mg / kg, or from about 25 mg / kg to about 0.07 mg / kg, or from about 20 mg / kg to about 0.07 mg / kg, or from about 15 mg / kg to about 0.07 mg / kg, or from about 10 mg / kg to about 0.07 mg / kg, or from about 9 mg / kg to about 0.07 mg / kg, or from about 8 mg / kg to about 0.07 mg / kg, or from about 7 mg / kg to about 0.07 mg / kg, or from about 6 mg / kg to about 0.07 mg / kg, or from about 5 mg / kg to about 0.07 mg / kg, or from about 4.40 mg / kg to about 0.07 mg / kg, or from about 3.14 mg / kg to about 0.07 mg / kg, orfrom about 2.24 mg / kg to about 0.07 mg / kg, or from about 1.12 mg / kg to about 0.07 mg / kg, or from about 0.56 mg / kg to about 0.07 mg / kg, or from about 0.28 mg / kg to about 0.07 mg / kg, or from about 0.14 mg / kg to about 0.07 mg / kg, or from about 0.10 mg / kg, to about 0.07 mg / kg, or from about 30 mg / kg to about 0.10 mg / kg, or from about 25 mg / kg to about 0.10 mg / kg, or from about 20 mg / kg to about 0.10 mg / kg, or from about 15 mg / kg to about 0.10 mg / kg, or from about 10 mg / kg to about 0.10 mg / kg, or from about 9 mg / kg to about 0.10 mg / kg, or from about 8 mg / kg to about 0.10 mg / kg, or from about 7 mg / kg to about 0.10 mg / kg, or from about 6 mg / kg to about 0.10 mg / kg, or from about 5 mg / kg to about 0.10 mg / kg, or from about 4.40 mg / kg to about 0.10 mg / kg, or from about 3.14 mg / kg to about 0.10 mg / kg, or from about 2.24 mg / kg to about 0.10 mg / kg, or from about 1.12 mg / kg to about 0.10 mg / kg, or from about 0.56 mg / kg to about 0.10 mg / kg, or from about 0.28 mg / kg to about 0.10 mg / kg, or from about 0.14 mg / kg to about 0.10 mg / kg. about 4.40 mg / kg.

[0121] In some embodiments, the effective amount of the CXCR inhibitor is about 3.14 mg / kg. In some embodiments, the effective amount of the CXCR inhibitor is about 2.24 mg / kg. In some embodiments, the effective amount of the CXCR inhibitor is about 1.12 mg / kg. In some embodiments, the effective amount of the CXCR inhibitor is about 0.56 mg / kg. In some embodiments, the effective amount of the CXCR inhibitor is about 0.28 mg / kg. In some embodiments, the effective amount of the CXCR inhibitor is about 0.14 mg / kg. In some embodiments, the effective amount of the CXCR inhibitor is about 0.10 mg / kg. In some embodiments, the effective amount of the CXCR inhibitor is about 0.07 mg / kg.

[0122] In some embodiments, the CXCR4 inhibitor is administered in a pharmacologically acceptable route. In some embodiments, the CXCR4 inhibitor is administered orally, or subcutaneously, or intravenously.

[0123] In some embodiments, the duration of CXCR4 inhibitor administration is from about 1 minute to about 30 minutes, or from about 5 minute to about 20 minutes, or from about 10 minute to about 18 minutes. In some embodiments, the CXCR4 inhibitor is administered at about 15 minutes.

[0124] In some embodiments, the time of CXCR4 inhibitor administration is: in the morning, or from about 7:00 AM to about 7 PM, or from about 7: 30 AM to about 12:30 PM, or from about 7:30 AM to about 9:30 AM.

[0125] In some embodiments, the time of CXCR4 inhibitor administration is at about 8:30 AM.

[0126] In some embodiments, the last dose of CXCR4 inhibitor prior to the apheresis and / or the leukapheresis is administered at: from about 120 hours to about 30 minutes, or from about 72 hours to about 30 minutes, or from about 24 hours to about 30 minutes, or from about 14 hours to about 30 minutes, or from about 13 hours to about 30 minutes, or from about 13 hours to about 30 minutes, or from about 12 hours to about 30 minutes, or from about 11 hours to about 30 minutes, or from about 10 hours to about 30 minutes, or from about 9 hours to about 30 minutes, or from about 8 hours to about 30 minutes, or from about 7 hours to about 30 minutes, or from about 6 hours to about 30 minutes, or from about 5 hours to about 30 minutes, or from about 4 hours to about 30 minutes, or from about 3 hours to about 30 minutes, or from about 2 hours to about 30 minutes, orfrom about 90 minutes to about 30 minutes, or from about 60 minutes to about 30 minutes, or from about 45 minutes to about 30 minutes before the apheresis and / or the leukapheresis treatment begins.

[0127] In some embodiments, the last dose of CXCR4 inhibitor prior to the apheresis and / or the leukapheresis is administered at: about 11 hours, or about 10 hours, or about 9 hours, or about 8 hours, or about 7 hours, or about 6 hours, or about 5 hours, or about 4 hours, or about 3 hours, before the apheresis and / or the leukapheresis treatment begins.

[0128] In some embodiments, the last dose of CXCR4 inhibitor prior to the apheresis and / or the leukapheresis is administered at about 2 hours before the apheresis and / or the leukapheresis treatment begins.

[0129] In some embodiments, the last dose of CXCR4 inhibitor prior to the apheresis and / or the leukapheresis is administered at about 90 minutes before the apheresis and / or the leukapheresis treatment begins.

[0130] In some embodiments, the last dose of CXCR4 inhibitor prior to the apheresis and / or the leukapheresis is administered at about 60 minutes before the apheresis and / or the leukapheresis treatment begins.

[0131] In some embodiments, the last dose of CXCR4 inhibitor prior to the apheresis and / or the leukapheresis is administered at about 45 minutes before the apheresis and / or the leukapheresis treatment begins.

[0132] In some embodiments, the last dose of CXCR4 inhibitor prior to the apheresis and / or the leukapheresis is administered at about 30 minutes before the apheresis and / or the leukapheresis treatment begins.

[0133] In some embodiments, CXCR4 inhibitor is administered once, twice, or three times, four times, or more than four times. In some embodiments, CXCR4 inhibitoris administered no more than once, no more than twice, or no more than three times, or no more than four times, or no more than five times. In some embodiments, CXCR4 inhibitor is administered for one day, two days, or three days, or four days, or more than four days. In some embodiments, CXCR4 inhibitor is administered no more than one day, no more than two days, or no more than three days, or no more than four days, or no more than five days.

[0134] In some embodiments, the apheresis and / or the leukapheresis treatment comprises from about 1 to about 5 sessions, preferably from about 1 to 2 sessions, more preferably 1 session.

[0135] In some embodiments, CXCR4 inhibitor is administered once daily. In some embodiments, CXCR4 inhibitor is administered from about 7 days to about 11 days of the administration of the propranolol.. In some embodiments, CXCR4 inhibitor is administered from about 9 days to about 11 days of the administration of the propranolol. In some embodiments, CXCR4 inhibitor is administered from about 7 days to about 8 days of the administration of the propranolol.

[0136] In some embodiments, CXCR4 inhibitor is administered on day-7 of the administration of the propranolol. In some embodiments, CXCR4 inhibitor is administered from on day-8 of the administration of the propranolol. In some embodiments, a first dose of CXCR4 inhibitor is administered. In some embodiments, CXCR4 inhibitor is administered from about 7 days to about 11 days of the administration of the propranolol. In some embodiments, CXCR4 inhibitor is administered from about 7 days to about 8 days of the administration of the propranolol.

[0137] In some embodiments, CXCR4 inhibitor is administered on day-7 of the administration of the propranolol. In some embodiments, CXCR4 inhibitor is administered on day-8 of the administration of the propranolol. In some embodiments, CXCR4 inhibitor is administered from about 7 days to about 11 days of the administration of the propranolol. In some embodiments, CXCR4 inhibitor is administered from about 9 days to about 11 days of the administration of the propranolol.

[0138] In some embodiments, CXCR4 inhibitor is administered on day-9 of the administration of the propranolol.

[0139] In some embodiments, CXCR4 inhibitor is administered on day-10 of the administration of the propranolol.

[0140] In some embodiments, CXCR4 inhibitor is administered on day-11 of the administration of the propranolol.

[0141] In some embodiments, from about 0.1 mg / kg to about 4.4 mg / kg of CXCR4 inhibitor is administered intravenously once daily, for one day or up to five days, preferably the last dose of CXCR4 inhibitor prior to the apheresis and / or the leukapheresis is administered at from about 30 minutes to about 60 minutes before the apheresis and / or the leukapheresis treatment begins.

[0142] In some embodiments, the effective amount of GPC-100 is: from about 30 mg / kg to about 0.07 mg / kg, or from about 25 mg / kg to about 0.07 mg / kg, or from about 20 mg / kg to about 0.07 mg / kg, or from about 15 mg / kg to about 0.07 mg / kg, or from about 10 mg / kg to about 0.07 mg / kg, or from about 9 mg / kg to about 0.07 mg / kg, or from about 8 mg / kg to about 0.07 mg / kg, or from about 7 mg / kg to about 0.07 mg / kg, or from about 6 mg / kg to about 0.07 mg / kg, or from about 5 mg / kg to about 0.07 mg / kg, or from about 4.40 mg / kg to about 0.07 mg / kg, or from about 3.14 mg / kg to about 0.07 mg / kg, or from about 2.24 mg / kg to about 0.07 mg / kg, or from about 1.12 mg / kg to about 0.07 mg / kg, or from about 0.56 mg / kg to about 0.07 mg / kg, or from about 0.28 mg / kg to about 0.07 mg / kg, or from about 0.14 mg / kg to about 0.07 mg / kg, or from about 0.10 mg / kg, to about 0.07 mg / kg, or from about 30 mg / kg to about 0.10 mg / kg, or from about 25 mg / kg to about 0.10 mg / kg, or from about 20 mg / kg to about 0.10 mg / kg, or from about 15 mg / kg to about 0.10 mg / kg, or from about 10 mg / kg to about 0.10 mg / kg, orfrom about 9 mg / kg to about 0.10 mg / kg, or from about 8 mg / kg to about 0.10 mg / kg, or from about 7 mg / kg to about 0.10 mg / kg, or from about 6 mg / kg to about 0.10 mg / kg, or from about 5 mg / kg to about 0.10 mg / kg, or from about 4.40 mg / kg to about 0.10 mg / kg, or from about 3.14 mg / kg to about 0.10 mg / kg, or from about 2.24 mg / kg to about 0.10 mg / kg, or from about 1.12 mg / kg to about 0.10 mg / kg, or from about 0.56 mg / kg to about 0.10 mg / kg, or from about 0.28 mg / kg to about 0.10 mg / kg, or from about 0.14 mg / kg to about 0.10 mg / kg.

[0143] In some embodiments, the effective amount of GPC-100 is about 4.40 mg / kg. In some embodiments, the effective amount of GPC-100 is about 3.14 mg / kg. In some embodiments, the effective amount of GPC-100 is about 2.24 mg / kg. In some embodiments, the effective amount of GPC-100 is about 1.12 mg / kg. In some embodiments, the effective amount of GPC-100 is about 0.56 mg / kg. In some embodiments, the effective amount of GPC-100 is about 0.28 mg / kg. In some embodiments, the effective amount of GPC-100 is about 0.14 mg / kg. In some embodiments, the effective amount of GPC-100 is about 0.10 mg / kg. In some embodiments, the effective amount of GPC-100 is about 0.07 mg / kg.

[0144] In certain embodiments, GPC-100 is administered in a pharmacologically acceptable route. In certain embodiments, GPC-100 is administered orally. In certain embodiments, GPC-100 is administered subcutaneously. In certain embodiments, GPC-100 is administered intravenously.

[0145] In certain embodiments, the duration of GPC-100 administration is: from about 1 minute to about 30 minutes, or from about 5 minute to about 20 minutes, or from about 10 minute to about 18 minutes, or about 15 minutes.

[0146] In certain embodiments, the time of GPC-100 administration is: in the morning, or from about 7:00 AM to about 7 PM, orfrom about 7: 30 AM to about 12:30 PM, or from about 7:30 AM to about 9:30 AM, or at about 8:30 AM.

[0147] In certain embodiments, the last dose of GPC-100 prior to the apheresis and / or the leukapheresis is administered at: from about 120 hours to about 30 minutes, or from about 72 hours to about 30 minutes, or from about 24 hours to about 30 minutes, or from about 14 hours to about 30 minutes, or from about 13 hours to about 30 minutes, or from about 13 hours to about 30 minutes, or from about 12 hours to about 30 minutes, or from about 11 hours to about 30 minutes, or from about 10 hours to about 30 minutes, or from about 9 hours to about 30 minutes, or from about 8 hours to about 30 minutes, or from about 7 hours to about 30 minutes, or from about 6 hours to about 30 minutes, or from about 5 hours to about 30 minutes, or from about 4 hours to about 30 minutes, or from about 3 hours to about 30 minutes, or from about 2 hours to about 30 minutes, or from about 90 minutes to about 30 minutes, or from about 60 minutes to about 30 minutes, or from about 45 minutes to about 30 minutes.

[0148] In certain embodiments, the last dose of GPC-100 prior to the apheresis and / or the leukapheresis is administered at: about 11 hours, or about 10 hours, or about 9 hours, or about 8 hours, or about 7 hours, or about 6 hours, orabout 5 hours, or about 4 hours, or about 3 hours before the apheresis and / or the leukapheresis treatment begins.

[0149] In certain embodiments, the last dose of GPC-100 prior to the apheresis and / or the leukapheresis is administered at about 2 hours before the apheresis and / or the leukapheresis treatment begins. In certain embodiments, the last dose of GPC-100 prior to the apheresis and / or the leukapheresis is administered at about 90 minutes, before the apheresis and / or the leukapheresis treatment begins In certain embodiments, the last dose of GPC-100 prior to the apheresis and / or the leukapheresis is administered at about 60 minutes, before the apheresis and / or the leukapheresis treatment begins In certain embodiments, the last dose of GPC-100 prior to the apheresis and / or the leukapheresis is administered at about 45 minutes, before the apheresis and / or the leukapheresis treatment begins In certain embodiments, the last dose of GPC-100 prior to the apheresis and / or the leukapheresis is administered at about 30 minutes before the apheresis and / or the leukapheresis treatment begins.

[0150] In certain embodiments, GPC-100 is administered once, twice, or three times, four times, or more than four times. In certain embodiments, GPC-100 is administered no more than once, no more than twice, or no more than three times, or no more than four times, or no more than five times. In certain embodiments, GPC-100 is administered for one day, two days, or three days, or four days, or more than four days. In certain embodiments, GPC-100 is administered no more than one day, no more than two days, or no more than three days, or no more than four days, or no more than five days.

[0151] In certain embodiments, the apheresis and / or the leukapheresis treatment comprises from about 1 to about 5 sessions, preferably from about 1 to 2 sessions, more preferably 1 session.

[0152] In certain embodiments, GPC-100 is administered once daily.

[0153] In certain embodiments, GPC-100 is administered: from about 7 days to about 11 days of the administration of the propranolol, or from about 9 days to about 11 days of the administration of the propranolol, or from about 7 days to about 8 days of the administration of the propranolol; oron day-7 of the administration of the propranolol, or on day-8 of the administration of the propranolol.

[0154] In certain embodiments, a first dose of GPC-100 is administered: from about 7 days to about 11 days of the administration of the propranolol, or from about 7 days to about 8 days of the administration of the propranolol, or on day-7 of the administration of the propranolol, or on day-8 of the administration of the propranolol.

[0155] In certain embodiments, a second dose of GPC-100 is administered: from about 7 days to about 11 days of the administration of the propranolol, or from about 9 days to about 11 days of the administration of the propranolol, or on day-9 of the administration of the propranolol, or on day-10 of the administration of the propranolol, or on day-11 of the administration of the propranolol.

[0156] In some embodiments, from about 0.1 mg / kg to about 4.4 mg / kg of GPC-100 is administered intravenously once daily, for one day or up to five days, preferably the last dose of GPC-100 prior to the apheresis and / or the leukapheresis is administered at from about 30 minutes to about 60 minutes before the apheresis and / or the leukapheresis treatment begins.

[0157] In some embodiments, the effective amount of AMD3100 is: from about 10 pg / kg to about 480 pg / kg, or from about 40 pg / kg to about 480 pg / kg, or from about 80 pg / kg to about 480 pg / kg.

[0158] In some embodiments, the effective amount of AMD3100 is from about 40 pg / kg to about 480 pg / kg and administered subcutaneously. In some embodiments, the effective amount of AMD3100 is from about 80 pg / kg to about 480 pg / kg and administered subcutaneously.

[0159] In some embodiments, the effective amount of AMD3100 is about 40 pg / kg and administered subcutaneously. In some embodiments, the effective amount of AMD3100 is about 80 pg / kg and administered subcutaneously. In some embodiments, the effective amount of AMD3100 is about 480 pg / kg and administered subcutaneously.

[0160] In some embodiments, the effective amount of AMD3100 is from about 10 pg / kg to about 80 pg / kg and administered intravenously. In some embodiments, theeffective amount of AMD3100 is from about 20 pg / kg to about 80 pg / kg and administered intravenously. In some embodiments, the effective amount of AMD3100 is from about 40 pg / kg to about 80 pg / kg and administered intravenously.

[0161] In some embodiments, the effective amount of AMD3100 is about 10 pg / kg and administered intravenously. In some embodiments, the effective amount of AMD3100 is about 20 pg / kg and administered intravenously. In some embodiments, the effective amount of AMD3100 is about 40 pg / kg and administered intravenously. In some embodiments, the effective amount of AMD3100 is about 80 pg / kg and administered intravenously.

[0162] In certain embodiments, AMD3100 is administered in a pharmacologically acceptable route. In certain embodiments, AMD3100 is administered subcutaneously. In certain embodiments, AMD3100 is administered intravenously.

[0163] In certain embodiments, the last dose of the AMD3100 inhibitor prior to the start of apheresis and / or the start of leukapheresis is administered at: from about 120 hours to about 10 hours, or from about 72 hours to about 10 hours, or from about 24 hours to about 10 hours, or from about 14 hours to about 10 hours, or from about 13 hours to about 10 hours, or from about 13 hours to about 10 hours, or from about 12 hours to about 10 hours, or from about 11 hours to about 10 hours, or about 12 hours, or about 11 hours, or about 10 hours, before the apheresis and / or the leukapheresis treatment begins.

[0164] In certain embodiments, AMD3100 is administered once daily. In certain embodiments, AMD3100 is administered once, twice, three times, four times, or more than four times. In certain embodiments, AMD3100 is administered no more than five times, no more than four times, or no more than three times, no more than twice, or no more than once.

[0165] In some embodiments, AMD3100 is administered at from about 10 pg / kg to about 480 pg / kg mg / kg, intravenously or subcutaneously, preferably subcutaneously,once daily, for one day or up to five days, preferably the last dose of AMD3100 prior to the apheresis and / or the leukapheresis is administered at least about 10 hours before the apheresis and / or the leukapheresis treatment begins, or preferably at from about 12 hours to about 10 hours before the apheresis and / or the leukapheresis treatment begins.

[0166] In some embodiments, the effective amount of BL8040 is: from about 0.5 mg / kg to about 2.0 mg / kg, or from about 0.75 mg / kg to about 2.0 mg / kg, or from about 1 .0 mg / kg to about 2.0 mg / kg, or from about 1 .25 mg / kg to about 2.0 mg / kg, or from about 1 .5 mg / kg to about 2.0 mg / kg.

[0167] In some embodiments, the effective amount of BL8040 is about 0.5 mg / kg. In some embodiments, the effective amount of BL8040 is about 0.75 mg / kg. In some embodiments, the effective amount of BL8040 is about 1 mg / kg. In some embodiments, the effective amount of BL8040 is about 1 .5 mg / kg.

[0168] In certain embodiments, BL8040 is administered in a pharmacologically acceptable route. In certain embodiments, BL8040 is administered subcutaneously. In certain embodiments, BL8040 is administered intravenously.

[0169] In certain embodiments, the last dose of the BL8040 prior to the start of apheresis and / or the start of leukapheresis is administered at: from about 120 hours to about 10 hours, or from about 72 hours to about 10 hours, or from about 24 hours to about 10 hours, or from about 14 hours to about 10 hours, or from about 13 hours to about 10 hours, or from about 13 hours to about 10 hours, or from about 12 hours to about 10 hours, or from about 11 hours to about 10 hours, or about 12 hours, or about 11 hours, or about 10 hours, before the apheresis and / or the leukapheresis treatment begins.

[0170] In certain embodiments, BL8040 is administered once daily. In certain embodiments, BL8040 is administered once, twice, three times, four times, or more than four times. In certain embodiments, BL8040 is administered no more than five times, no more than four times, or no more than three times, no more than twice, or no more than once.

[0171] In certain embodiments, BL8040 is administered at from about 1.5 mg / kg subcutaneously, once daily, for one day or up to five days, preferably the last dose of BL8040 prior to the apheresis and / or the leukapheresis is administered at least 10 hours before the apheresis and / or the leukapheresis treatment begins, preferably at from about 12 hours to about 10 hours before the apheresis and / or the leukapheresis treatment begins.

[0172] In certain embodiments, the effective amount of the beta-adrenergic receptor inhibitor is a pharmacologically effective dose with clinically acceptable severe adverse effects.

[0173] In certain embodiments, the effective amount of the beta-adrenergic receptor inhibitor is: from about 10 mg daily to about 480 mg daily, or from about 20 mg daily to about 480 mg daily, or from about 30 mg daily to about 480 mg daily, or from about 40 mg daily to about 480 mg daily, or from about 50 mg daily to about 480 mg daily, or from about 60 mg daily to about 480 mg daily, or from about 70 mg daily to about 480 mg daily, or from about 80 mg daily to about 480 mg daily, or from about 120 mg daily to about 480 mg daily, or from about 160 mg daily to about 480 mg daily, or from about 200 mg daily to about 480 mg daily, or from about 240 mg daily to about 480 mg daily, or from about 280 mg daily to about 480 mg daily, or from about 320 mg daily to about 480 mg daily, or from about 360 mg daily to about 480 mg daily, or from about 400 mg daily to about 480 mg daily, or from about 440 mg daily to about 480 mg dailyfrom about 10 mg daily to about 480 mg daily, or from about 10 mg daily to about 450 mg daily, or from about 10 mg daily to about 420 mg daily, or from about 10 mg daily to about 390 mg daily, or from about 10 mg daily to about 360 mg daily, or from about 10 mg daily to about 330 mg daily, or from about 10 mg daily to about 300 mg daily, or from about 10 mg daily to about 270 mg daily, or from about 10 mg daily to about 240 mg daily, or from about 10 mg daily to about 210 mg daily, or from about 10 mg daily to about 180 mg daily, or from about 10 mg daily to about 150 mg daily, or from about 10 mg daily to about 120 mg daily, or from about 10 mg daily to about 90 mg daily, or from about 10 mg daily to about 60 mg daily, or from about 10 mg daily to about 30 mg daily, or from about 10 mg daily to about 90 mg daily, or from about 10 mg daily to about 60 mg daily, or from about 10 mg daily to about 30 mg daily, or from about 20 mg daily to about 480 mg daily, or from about 20 mg daily to about 450 mg daily, or from about 20 mg daily to about 440 mg daily, or from about 20 mg daily to about 410 mg daily, or from about 20 mg daily to about 400 mg daily, or from about 20 mg daily to about 370 mg daily, or from about 20 mg daily to about 360 mg daily, or from about 20 mg daily to about 330 mg daily, or from about 20 mg daily to about 320 mg daily, or from about 20 mg daily to about 290 mg daily, or from about 20 mg daily to about 280 mg daily, or from about 20 mg daily to about 250 mg daily, or from about 20 mg daily to about 240 mg daily, or from about 20 mg daily to about 210 mg daily, orfrom about 20 mg daily to about 200 mg daily, or from about 20 mg daily to about 170 mg daily, or from about 20 mg daily to about 160 mg daily, or from about 20 mg daily to about 130 mg daily, or from about 20 mg daily to about 120 mg daily, or from about 20 mg daily to about 90 mg daily, or from about 20 mg daily to about 80 mg daily, or from about 20 mg daily to about 50 mg daily, or from about 20 mg daily to about 40 mg daily, or from about 20 mg daily to about 160 mg daily, or from about 20 mg daily to about 130 mg daily, or from about 20 mg daily to about 120 mg daily, or from about 20 mg daily to about 100 mg daily, or from about 20 mg daily to about 80 mg daily, or from about 20 mg daily to about 70 mg daily, or from about 20 mg daily to about 40 mg daily.

[0174] In some embodiments, the effective amount of BETA-adrenergic receptor inhibitor about 20 mg daily. In some embodiments, the effective amount of BETA- adrenergic receptor inhibitor is about 40 mg daily. In some embodiments, the effective amount of BETA-adrenergic receptor inhibitor is about 60 mg daily. In some embodiments, the effective amount of BETA-adrenergic receptor inhibitor is about 80 mg daily, and / or

[0175] In certain embodiments, BETA-adrenergic receptor inhibitor is administered in a pharmacologically acceptable route. In certain embodiments, BETA-adrenergic receptor inhibitor is administered orally.

[0176] In certain embodiments, BETA-adrenergic receptor inhibitor is administered once daily, or twice daily, or three times daily, or four times daily.

[0177] In certain embodiments, BETA-adrenergic receptor inhibitor is administered: from about 7 hours to about 12 hours apart about 12 hours apart, or about 11 hours apart, or about 10 hours apart, or about 9 hours apart, orabout 8 hours apart, or about 7 hours apart, or about 6 hours apart, or about 5 hours apart, or about 4 hours apart, or about 3 hours apart.

[0178] In certain embodiments, BETA-adrenergic receptor inhibitor is administered at about 30 mg orally, twice daily at from about 7 hours to about 12 hours apart.

[0179] In certain embodiments, the effective amount of the ADRB2 inhibitor is a pharmacologically effective dose with clinically acceptable severe adverse effects.

[0180] In certain embodiments, the effective amount of the ADRB2 inhibitor is: from about 10 mg daily to about 480 mg daily, or from about 20 mg daily to about 480 mg daily, or from about 30 mg daily to about 480 mg daily, or from about 40 mg daily to about 480 mg daily, or from about 50 mg daily to about 480 mg daily, or from about 60 mg daily to about 480 mg daily, or from about 70 mg daily to about 480 mg daily, or from about 80 mg daily to about 480 mg daily, or from about 120 mg daily to about 480 mg daily, or from about 160 mg daily to about 480 mg daily, or from about 200 mg daily to about 480 mg daily, or from about 240 mg daily to about 480 mg daily, or from about 280 mg daily to about 480 mg daily, or from about 320 mg daily to about 480 mg daily, or from about 360 mg daily to about 480 mg daily, or from about 400 mg daily to about 480 mg daily, or from about 440 mg daily to about 480 mg daily, or from about 10 mg daily to about 480 mg daily, or from about 10 mg daily to about 450 mg daily, or from about 10 mg daily to about 420 mg daily, or from about 10 mg daily to about 390 mg daily, or from about 10 mg daily to about 360 mg daily, orfrom about 10 mg daily to about 330 mg daily, or from about 10 mg daily to about 300 mg daily, or from about 10 mg daily to about 270 mg daily, or from about 10 mg daily to about 240 mg daily, or from about 10 mg daily to about 210 mg daily, or from about 10 mg daily to about 180 mg daily, or from about 10 mg daily to about 150 mg daily, or from about 10 mg daily to about 120 mg daily, or from about 10 mg daily to about 90 mg daily, or from about 10 mg daily to about 60 mg daily, or from about 10 mg daily to about 30 mg daily, or from about 10 mg daily to about 90 mg daily, or from about 10 mg daily to about 60 mg daily, or from about 10 mg daily to about 30 mg daily, or from about 20 mg daily to about 480 mg daily, or from about 20 mg daily to about 450 mg daily, or from about 20 mg daily to about 440 mg daily, or from about 20 mg daily to about 410 mg daily, or from about 20 mg daily to about 400 mg daily, or from about 20 mg daily to about 370 mg daily, or from about 20 mg daily to about 360 mg daily, or from about 20 mg daily to about 330 mg daily, or from about 20 mg daily to about 320 mg daily, or from about 20 mg daily to about 290 mg daily, or from about 20 mg daily to about 280 mg daily, or from about 20 mg daily to about 250 mg daily, or from about 20 mg daily to about 240 mg daily, or from about 20 mg daily to about 210 mg daily, or from about 20 mg daily to about 200 mg daily, or from about 20 mg daily to about 170 mg daily, or from about 20 mg daily to about 160 mg daily, or from about 20 mg daily to about 130 mg daily, or from about 20 mg daily to about 120 mg daily, orfrom about 20 mg daily to about 90 mg daily, or from about 20 mg daily to about 80 mg daily, or from about 20 mg daily to about 50 mg daily, or from about 20 mg daily to about 40 mg daily, or from about 20 mg daily to about 160 mg daily, or from about 20 mg daily to about 130 mg daily, or from about 20 mg daily to about 120 mg daily, or from about 20 mg daily to about 100 mg daily, or from about 20 mg daily to about 80 mg daily, or from about 20 mg daily to about 70 mg daily, or from about 20 mg daily to about 40 mg daily, or about 20 mg daily, or about 40 mg daily, or about 60 mg daily, or about 80 mg daily.

[0181] In certain embodiments, ADRB2 inhibitor is administered in a pharmacologically acceptable route. In certain embodiments, In certain embodiments, ADRB2 inhibitor is administered orally.

[0182] In certain embodiments, ADRB2 inhibitor is administered once daily, or twice daily, or three times daily, or four times daily.

[0183] In certain embodiments, ADRB2 inhibitor is administered: from about 7 hours to about 12 hours apart, or about 12 hours apart, or about 11 hours apart, or about 10 hours apart, or about 9 hours apart, or about 8 hours apart, or about 7 hours apart, or about 6 hours apart, or about 5 hours apart, or about 4 hours apart, or about 3 hours apart.

[0184] In certain embodiments, ADRB2 inhibitor is administered at about 30 mg orally, twice daily at from about 7 hours to about 12 hours apart.

[0185] In certain embodiments, the effective amount of propranolol is: from about 10 mg daily to about 480 mg daily, or from about 20 mg daily to about 480 mg daily, or from about 30 mg daily to about 480 mg daily, or from about 40 mg daily to about 480 mg daily, or from about 50 mg daily to about 480 mg daily, or from about 60 mg daily to about 480 mg daily, or from about 70 mg daily to about 480 mg daily, or from about 80 mg daily to about 480 mg daily, or from about 120 mg daily to about 480 mg daily, or from about 160 mg daily to about 480 mg daily, or from about 200 mg daily to about 480 mg daily, or from about 240 mg daily to about 480 mg daily, or from about 280 mg daily to about 480 mg daily, or from about 320 mg daily to about 480 mg daily, or from about 360 mg daily to about 480 mg daily, or from about 400 mg daily to about 480 mg daily, or from about 440 mg daily to about 480 mg daily, or from about 10 mg daily to about 480 mg daily, or from about 10 mg daily to about 450 mg daily, or from about 10 mg daily to about 420 mg daily, or from about 10 mg daily to about 390 mg daily, or from about 10 mg daily to about 360 mg daily, or from about 10 mg daily to about 330 mg daily, or from about 10 mg daily to about 300 mg daily, or from about 10 mg daily to about 270 mg daily, or from about 10 mg daily to about 240 mg daily, or from about 10 mg daily to about 210 mg daily, or from about 10 mg daily to about 180 mg daily, or from about 10 mg daily to about 150 mg daily, or from about 10 mg daily to about 120 mg daily, orfrom about 10 mg daily to about 90 mg daily, or from about 10 mg daily to about 60 mg daily, or from about 10 mg daily to about 30 mg daily, or from about 10 mg daily to about 90 mg daily, or from about 10 mg daily to about 60 mg daily, or from about 10 mg daily to about 30 mg daily, or from about 20 mg daily to about 480 mg daily, or from about 20 mg daily to about 450 mg daily, or from about 20 mg daily to about 440 mg daily, or from about 20 mg daily to about 410 mg daily, or from about 20 mg daily to about 400 mg daily, or from about 20 mg daily to about 370 mg daily, or from about 20 mg daily to about 360 mg daily, or from about 20 mg daily to about 330 mg daily, or from about 20 mg daily to about 320 mg daily, or from about 20 mg daily to about 290 mg daily, or from about 20 mg daily to about 280 mg daily, or from about 20 mg daily to about 250 mg daily, or from about 20 mg daily to about 240 mg daily, or from about 20 mg daily to about 210 mg daily, or from about 20 mg daily to about 200 mg daily, or from about 20 mg daily to about 170 mg daily, or from about 20 mg daily to about 160 mg daily, or from about 20 mg daily to about 130 mg daily, or from about 20 mg daily to about 120 mg daily, or from about 20 mg daily to about 90 mg daily, or from about 20 mg daily to about 80 mg daily, or from about 20 mg daily to about 50 mg daily, or from about 20 mg daily to about 40 mg daily, or from about 20 mg daily to about 160 mg daily, or from about 20 mg daily to about 130 mg daily, or from about 20 mg daily to about 120 mg daily, or from about 20 mg daily to about 100 mg daily, orfrom about 20 mg daily to about 80 mg daily, or from about 20 mg daily to about 70 mg daily, or from about 20 mg daily to about 40 mg daily.

[0186] In certain embodiments, the effective amount of propranolol is about 20 mg daily. In certain embodiments, the effective amount of propranolol is about 40 mg daily. In certain embodiments, the effective amount of propranolol is about 60 mg daily. In certain embodiments, the effective amount of propranolol is about 80 mg daily.

[0187] In certain embodiments, propranolol is administered in a pharmacologically acceptable route.

[0188] In certain embodiments, propranolol is administered orally.

[0189] In certain embodiments, propranolol is administered once daily, or twice daily, or three times daily, or four times daily.

[0190] In certain embodiments, propranolol is administered: from about 7 hours to about 12 hours apart, or about 12 hours apart, or about 11 hours apart, or about 10 hours apart, or about 9 hours apart, or about 8 hours apart, or about 7 hours apart, or about 6 hours apart, or about 5 hours apart, or about 4 hours apart, or about 3 hours apart.

[0191] In certain embodiments, propranolol is administered at about 30 mg orally, twice daily at from about 7 hours to about 12 hours apart.

[0192] In certain embodiments, the effective amount of G-CSF is: from about 1 ug / kg to about 70 ug / kg twice daily by intravenous injection, or from about 1 ug / kg to about 40 ug / kg daily by subcutaneous injection, or from about 3 ug / kg to about 40 ug / kg daily by continuous subcutaneous injection.

[0193] In certain embodiments, the effective amount of G-CSF is from about 10 ug / kg daily to about 40 ug / kg daily. In certain embodiments, the effective amount of G-CSF is about 10 ug / kg daily.

[0194] In certain embodiments, G-CSF is administered in a pharmacologically acceptable route. In certain embodiments, G-CSF is administered intravenously. In certain embodiments, G-CSF is administered subcutaneously. In certain embodiments, G-CSF is administered continuous subcutaneously.

[0195] In certain embodiments, the last dose of the G-CSF inhibitor prior to the start of apheresis and / or the start of leukapheresis is administered at: from about 120 hours to about 10 hours, or from about 72 hours to about 10 hours, or from about 24 hours to about 10 hours, or from about 14 hours to about 10 hours, or from about 13 hours to about 10 hours, or from about 13 hours to about 10 hours, or from about 12 hours to about 10 hours, or from about 11 hours to about 10 hours, or about 12 hours, or about 11 hours, or about 10 hours, before the apheresis and / or the leukapheresis treatment begins.

[0196] In certain embodiments, G-CSF is administered once daily. In certain embodiments, G-CSF is administered once, twice, three times, four times, five times, six times, seven times, eight times, or more than eight times. In certain embodiments, G-CSF is administered no more than eight times, no more than seven times, no more than six times, no more than five times, no more than four times, or no more than three times, no more than twice, or no more than once.

[0197] In certain embodiments, G-CSF is administered at about 10 ug / kg daily by intravenous injection, or subcutaneous injection, or continuous subcutaneous injection, for about four days, preferably at least about 10 hours prior to the apheresis and / or the leukapheresis.

[0198] In some embodiments, the subject is administered a drug that interferes with CD34+cell mobilization. In some embodiments, the drug is a lenalidomide. In someembodiments, the drug is administered in accordance with the drug label. In some embodiments, the drug is administered at a dose of from about 8 mg / kg to about 16 mg / kg, preferably about 16 mg / kg. In some embodiments, the drug is administered in a pharmacologically acceptable route. In some embodiments, the pharmacologically acceptable route is intravenous. In some embodiments, the drug is administered for about 3 to about 4 cycles.

[0199] In some embodiments, the drug is a daratumumab. In some embodiments, the drug the daratumumab is administered in accordance with the drug label. In some embodiments, the drug is administered at a dose of from about 8 mg / kg to about 16 mg / kg, preferably about 16 mg / kg. In some embodiments, the drug is administered in a pharmacologically acceptable route. In some embodiments, the drug is administered intravenously. In some embodiments, the drug is administered for about 3 to about 4 cycles.

[0200] In some embodiments, the method causes no adverse event in the subject during or after treatment. In some embodiments, the method causes no severe adverse event in the subject during or after treatment. In some embodiments, the method causes no adverse events greater than Grade 1 or 2 in severity. In some embodiments, the adverse events, if any, is limited to the list consisting of bone pain, hypocalaemia, diarrhea, dry mouth, nausea, hypokalaemia, oedema peripheral, paranesthesia, and the likes.

[0201] Described herein are uses of GPC-100 for the manufacture of a medicament for the treatment of a cancer, or a neurological disorder, or any combination thereof.THE NOVEL CXCR4 ANTAGONIST GPC-100 IS EFFECTIVE IN CELL MOBILIZATION ALONE OR IN COMBINATION WITH OTHER AGENTS.

[0202] As demonstrated in Examples 1-6, the novel CXCR4 antagonist GPC-100 is an effective hematopoietic cell mobilizer and has functional interactions between CXCR4 and P2AR, which support the combination of GPC-100 and propranolol as a novel strategy for HSPC mobilization.

[0203] GPC-100 demonstrated efficacy in disrupting CXCL12-mediated calcium signaling, cell migration and p-arrestin recruitment to CXCR4 that was comparable with AMD3100. However, GPC-100 was a better mobilizer than AMD3100 in vivo. The competitive binding assay also revealed that GPC-100 possessed superiorbinding to CXCR4 compared to AMD3100 and additional binding modes for enhanced interactions with CXCR4 compared with AMD3100.

[0204] The functional consequences of ligand binding, whether activating or inhibiting, are dependent on the structural characteristics of the ligand-receptor complex. This influences the signal transducers such as G-proteins or arrestinrecruiting GPCR kinases, which engage in the intracellular cavity of a GPCR (Gurevich Frontiers in Pharmacology 2019). For example, Jorgensen et al showed that another small molecule CXCR4 antagonist AMD11070 had a higher binding affinity to CXCR4 and greater potency to block CXCL12 induced migration than AMD3100, but AMD3100 was a better mobilizes This was thought to be due to the biased signaling of p-arrestin recruitment by AMD3100, and differences in the binding modes

[0073] ,

[0205] CXCR4 and 2AR are known to form heteromeric complexes with other GPCRs [63, 74-77], The receptor heteromerization may lead to changes in ligand binding affinity, G protein-coupling, efficacy, receptor trafficking or p-arrestin interactions

[0078] , Successful investigation of GPCR heteromerization in endogenous, unmodified native cells has been challenging due to factors such as low protein abundance and shortage of detection methods

[0062] ,

[0206] Using a highly sensitive and specific assay like PLA, the present technology is the first that uses cancer cells endogenously expressing CXCR4 and P2AR to demonstrate that the two receptors may form heteromers or are at least in close enough proximity that allows receptor crosstalk

[0079] , The detection of CXCR4 and P2AR in cancer cells is further supported using the highly sensitive and accurate pulsed interleave excitation fluorescence cross correlation spectroscopy to detect colocalization that suggests close physical interaction between CXCR4 AND ADRB2 (Sukhtankar, 2023b). Co-activation of CXCR4 and P2AR led to enhanced calcium flux and increased recruitment of p-arrestin to CXCR4. This indicates that the proximity of the two receptors has downstream functional consequences mediated by both G-protein dependent and independent pathways highlighting the importance of GPCR heteromers as druggable targets.

[0207] It is known CXCR4-mediated calcium signaling regulates cell migration and survival

[0022] , Recent studies suggest that P2AR can also utilize non-canonical, G- protein independent mechanisms for inducing calcium flux

[0080] , Therefore, it ispossible that epinephrine-induced increase in p-arrestin recruitment to CXCR4 as observed in the present technology leads to a mega-complex

[0081] that links CXCR4- 2AR- -arrestin to a calcium activating machinery.

[0208] While the role of calcium flux in HSC biology is still emerging

[0082] , calcium flux has been shown to activate the calcineurin / NFAT (nuclear factor of activated T cells) pathway and downstream gene reprogramming, leading to changes in HSC maintenance and differentiation

[0083] , Therefore, increase in calcium flux due to CXCR4- 2AR co-activation may be involved in HSC mobilization. Collectively, the present technology suggest the possibility of signaling crosstalk between CXCR4 and 2AR, opening up the opportunity for novel therapeutic approaches.

[0209] HSPC mobilization is associated with a concomitant increase in circulating WBC [84-87], In mice, propranolol significantly enhanced GPC-100-induced WBC mobilization. Previously, 2AR and CXCR4 were shown to interact physically and functionally leading to enhanced lymphocyte retention in the lymph nodes

[0026] , Similar interactions may also play a role in HSC retention by CXCR4 in BM given that both receptors are expressed on HSCs. However, due to technological limitations, such physical interactions have yet to be demonstrated in HSCs. Knight et al. and several others have discussed that propranolol can promote HSC growth and differentiation, as well as improve BM cellularity [38, 88-90], Particularly, propranolol treatment led to upregulation of CD34+HSC like gene signature and shifted cell differentiation away from myeloid bias in MM patients, which can lead to better engraftment in ASCT.

[0210] The present technology shows that propranolol improves GPC-100 induced HSPC mobilization by 2-fold. Given that clinically GPC-100 can mobilize HSPCs to PB up to 12-fold

[0023] , the increase from the addition of propranolol to GPC-100 could provide sufficient HSPCs harvest. This suggests the possibility of HSC mobilization without the use of G-CSF. It is an important finding since the elimination of G-CSF from the treatment may reduce the risk of moderate to severe side effects of G-CSF such as severe bone pain and rarely, splenic rupture

[0016] ,

[0211] MM patients have a high symptom burden and poor health-related quality of life

[0091] as well as history of treatments that negatively affect G-CSF mobilization. An alternative approach of using an oral beta blocker like propranolol eliminates the risks and burden created by daily subcutaneous G-CSF injections, as well as toxicityfrom repeated mobilization attempts. Together, these studies suggest the advantage of adding propranolol in the HSC mobilization regimen.

[0212] Addition of propranolol to G-CSF and GPC-100 (triple combination) resulted in a significant increase in viable functional HSPCs compared to G-CSF plus AMD3100. These cells were functionally capable of differentiating into myeloid and erythroid multipotent progenitors and also expressed primitive markers known for long-term repopulating capacity of HSCs. CXCR4 and P2AR are expressed on most immune cells

[0028] , Propranolol significantly increased GPC-100-induced lymphocyte mobilization.

[0213] In summary, the findings of the present technology propose the therapeutic co-targeting of CXCR4 and P2AR pathways and support the addition of propranolol to GPC-100 for HSC mobilization for ASCT in MM patients. The triple combination of GPC-100, propranolol, and G-CSF can potentially target patient populations where other mobilization regimens have failed. Propranolol could prove to be a safe, accessible, and inexpensive option to supplement the mobilization therapies for greater stem cell yields in fewer apheresis sessions and reduce the financial burden on patients and healthcare systems. This is currently being tested in a two-arm Phase II clinical trial (NCT05561751 )

[0092] with a GPC-100 plus propranolol arm and GPC-100, propranolol, and G-CSF arm.CLINICAL STUDIES SHOW THAT THE COMBINATION THERAPY OF GPC-100 AND G-CSF IN PATIENTS WITH MULTIPLE MYELOMA (MM), NON-HODGKIN’S LYMPHOMA (NHL), AND / OR HODGKIN’S DISEASE (HD) IS GENERALLY WELL TOLERATED AND IS EFFECTIVE IN CELL MOBILIZATION.

[0214] The need to mobilize cells from the marrow to PB for collection, notably CD34+ HSC for stem cell transplant and T cells for CAR-T therapy, has grown in the past few years. HSC transplants can prolong progression free survival in a variety of hematologic malignancies, the most common of which are MM, NHL, and HD (Flomenberg 2005). In addition, gene editing therapies for diseases such as sickle cell disease and p-thalassemia also use HSC transplant. CAR-T therapy has been observed to induce efficacious and durable responses in hematological cancers as well. Clinical efficacy of these therapies depends on a sufficient number of cells being infused for functional reconstitution. 2 Mobilized PB is the preferred source ofHSCs compared to bone marrow aspiration because of improved engraftment success rates, increased safety and comfort, shortened hospital stay, and lower overall cost (Beyer 1995, Devine 2004, Hartmann 1997, Smith 1997, To 1997, Vose 2002). In order to achieve this, a mobilization agent must be administered before a patient undergoes cell collection in a process called leukapheresis (Liles 2005).

[0215] Two of the mobilization agents approved by the FDA are antagonists to human CXCR4: AMD3100 (Plerixafor, or Mozobil) and BL8040 (Motixafortide). For some disease indications, these mobilization agents are used in conjunction with G- CSF, which has an orthogonal mechanism of action and is contraindicated for some autoimmune diseases, such as sickle cell disease. Both AMD3100 and BL8040 have similar efficacies and must be administered 10-14 hours prior to leukapheresis for HSC transplantation in hematological malignancies. Typically, a patient must have these agents administered the evening prior to leukapheresis and then start leukapheresis the following morning. This adds a layer of complexity and burden for patients who are already undergoing a complex procedure. There are claims that the administration of BL8040 may be more flexible due to the long residence time of CD34+ cells in the periphery. However, the effect of this on the sternness and redistribution of these stem cells to other organs is not well studied. One hint that such a state for a stem cell may not be entirely innocuous is the shortness of breath experienced by some patients on G-CSF due to the mobilized stem cells’ infiltration of the lung tissue. While the combination therapy of AMD3100 and G-CSF or BL8040 and G-CSF is an improvement relative to G-CSF alone, mobilization is still hindered in approximately 15-35% of MM patients (DiPersio 2009b). Given these factors, alternative mobilization agents with differentiated properties are needed.

[0216] GPC-100 is a potent and selective antagonist of CXCR4. In nonclinical studies, GPC-100 was shown to have distinct binding modes and a higher affinity for CXCR4 compared to AMD3100. In mice, GPC-100 was also shown to mobilize more WBC into the PB compared to AMD3100 (Sukhtankar, 2023a). Nonclinical data suggest that GPC-100 co-administered with G-CSF has synergistic effects. In a previous Phase 1 study, administration of GPC-100 at single doses from 0.10 to 4.40 mg / mL was shown to be safe and well tolerated in 64 healthy volunteers. (Sukhtankar 2023b).

[0217] As shown in Examples 10-12, which describes a randomized, open-label, double-blind, placebo-controlled, multicenter, Phase 2 Clinical Trial (NCT02104427), the combination therapy of GPC-100 and G-CSF in patients with multiple myeloma (MM), non-hodgkin’s lymphoma (NHL), and / or hodgkin’s disease (HD) is generally well tolerated and is effective in cell mobilization.

[0218] While treatment with G-CSF can be used for patients undergoing HSC transplantation (Neupogen label), its use alone yields low CD34+cell counts after each apheresis and has been shown to achieve optimal CD34+cell counts after a median of 4 apheresis days (DiPersio 2009a). In a Phase 2 study, treatment with GPC-100 in combination with G-CSF was well tolerated and resulted in achieving optimal CD34+cell counts in <2 apheresis days (mean 1.4 days). The primary endpoint of collecting >5.0*106CD34+cells / kg was met in 1 1 of 12 patients (92%) with MM (n=8) or NHL or HD (n=3) in <2 apheresis days. Of the 9 patients with MM, 8 patients (89%) mobilized >6.0*106CD34+cells / kg within a mean of 1 leukapheresis session. The only patient with MM that did not meet the primary endpoint had been treated with lenalidomide which is known to reduce stem cell yield for patients undergoing HSC transplantation (Cashen 2007). The total number of CD34+cells / kg collected after treatment with GPC-100 and G-CSF was higher in MM patients relative to NHL and HD patients, with mean cumulative cell counts of 9.00*106and 5.68*106CD34+cells / kg, respectively. The ability of GPC-100 and G-CSF to result in greater mobilization in MM patients relative to NHL and HD patients is consistent with existing data following administration of AMD3100 combined with G-CSF (Hubei 2012). With AMD3100 and G-CSF 59% of NHL patients mobilized >5.0*106cells / kg CD34+within <4 leukapheresis sessions (median of 3 sessions) and 72% of MM patients mobilized >6.0*106cells / kg CD34+within <2 leukapheresis sessions (median of 1 session) (AMD3100 or Plerixafor product label 2007).

[0219] It is important to highlight that the effects of GPC-100 and G-CSF on stem cell mobilization were achieved within 1-2 hours of treatment in contrast to AMD3100 or motixafortide (10 - 11 hours) and G-CSF (Crees et al). These differences could be due to the higher binding affinity of GPC-100 for CXCR4 (Sukhtankar, 2023). The rapid effects of GPC-100 would allow for a simplified treatment regimen that would reduce hospitalization resources as well as minimizing patient burden.

[0220] While cell mobilization with combination of G-CSF therapy and CXCR4 antagonists GPC-100 or AMD3100 is an improvement versus use of G-CSF alone, HSC mobilization can be negatively impacted in MM patients being treated with daratumumab (Hulin 2021) or lenalidomide (Popat 2009). In addition, with the negative side effects of G-CSF, such as bone pain, and the contraindication in sickle cell disease and autoimmune diseases, it is important to find other options for stem cell mobilization. There is evidence in the literature for involvement of p-adrenergic receptor signaling and beta blocker usage in hematologic cancers (Hwa 2017). Beta blockers have been shown to improve survival outcomes in MM patients (Hwa 2021 ).

[0221] In the pursuit to further optimize ASCT with GPC-100, recent preclinical studies have shown enhanced stem cell mobilization with the use of GPC-100 in combination with the beta blocker propranolol (Sukhtankar, 2023). In mice the combination of GPC-100 with propranolol was a potent mobilizer of WBC, which was further augmented with the addition of G-CSF. This effect was also recapitulated in the mobilization of mouse stem cells, as measured by analysis of the Lineage negative Seal positive and c-kit positive stem cell population and with the colony forming unit assay. The use of the triple combination of GPC-100, propranolol, and G-CSF is predicted to be best in class and can target patient populations where other treatment regimens have failed. However, mobilization with a double combination of GPC-100 and propranolol may be a treatment option when G-CSF is not tolerated.

[0222] In conclusion, the results of this phase 2 study demonstrated that administration of GPC-100 in combination with G-CSF can mobilize the optimal number of CD34+cells within 1 -2 hours and after 1 or 2 apheresis sessions in patients with MM, NHL, or HD.CLINICAL STUDY SHOWS THAT THE COMBINATION THERAPY OF COMBINATION TREATMENTS WITH GPC-100, PROPRANOLOL, AND G-CSF IS SAFE AND TOLERABLE TO PATIENTS WITH MULTIPLE MYELOMA (MM) UNDERGOING ASCT.

[0223] ASCT plays a central role in the treatment of MM. However, poor HPC mobilization occurs in 15-25% of patients. Newer therapies, such as daratumumab,may also have a negative impact on mobilization, supporting a need for an alternative mobilization regimen.

[0224] GPC-100 is a potent and selective small molecule antagonist of CXCR4. Previous clinical trials with GPC-100 alone or in combination with G-CSF have demonstrated safe and effective mobilization of stem cells. GPC-100 is characterized by faster kinetics of mobilization compared to the current FDA approved CXCR4 inhibitors, allowing same day administration and leukapheresis.

[0225] Propranolol is a non-selective beta-blocker and has been clinically shown to inhibit molecular risk markers in MM patients receiving ASCT. Other studies have also shown that propranolol can improve cellularity and reduce pro-tumorigenicity in the bone marrow. This U.S. only, open-label, multi-site Phase 2 Clinical Study (NCT05561751) evaluates the safety and migration efficacy when MM patients undergoing ASCT is treated with a combination of GPC-100, propranolol, and G- CSF.

[0226] As shown in Examples 13-14, which describes a U.S. only, open-label, multisite Phase 2 Clinical Study (NCT05561751 ), a combination treatment of GPC-100, propranolol, and G-CSF in MM patients undergoing ASCT is generally safe and tolerable, and efficiently mobilizes CD34+cells. The study also shows that the mobilization effect was present despite the negative mobilization effects of daratumumab.EXAMPLES

[0227] The reagents for the examples of the present technology are provided is Table 3.Table 3: ReagentsEXAMPLE 1 : GPC-100 SHOWS DISTINCT BINDING MODES AND HIGHERBINDING AFFINITY FOR CXCR4 COMPARED TO AMD3100.

[0228] The chemical composition of GPC-100 demonstrates distinct divergence from AMD3100 (FIG. 1A). Previous studies with various CXCR4 antagonists have identified major and minor pockets of interactions within the CXCR4 orthosteric binding site

[0049] , To understand the inactive structures of CXCR4 at a molecular level, the CXCR4 antagonist GPC-100 and AMD3100 were studied in silico docking experiments.

[0229] Briefly, the Schrodinger Small-Molecule Drug Discovery Suite was used for molecular modeling procedures, using the OPLS3e force field. The model of human CXCR4 in complex with small molecule antagonist IT11 (PDB: 3ODU) was imported and prepared using the Protein Preparation Wizard workflow. AMD3100 and GPC- 100 were prepared using LigPrep on default settings. A total of 25 and 18 different conformations were generated for AMD3100 and GPC-100, respectively. The standard workflow for ligand docking in XP (extra precision) setting was followed for AMD3100 and GPC-100 to the CXCR4 structure

[0049] , Induced Fit Docking was also performed on GPC-100 as previously described

[0050] , To ensure proper docking of the binding pocket, the residues Y116 / D171 / Y255 / E288 were selected as the centerpoint. To avoid steric conflict with the large side chain Arg188, the trim option was selected. The top 20 poses for GPC-100 with an energy window of 30 kcal / mol were saved for further analysis.

[0230] The induced-fit algorithm from Schrodinger was used for GPC-100 as previously described [49, 50], Previously validated residues with secondary amines, namely Asp97 and Asp262

[0051] , contributed to interactions of GPC-100 and AMD3100 with CXCR4. However, the phosphoryl group of GPC-100 that is absent in AMD3100 makes an ionic interaction with Arg188, and hydrogen bond with Gln200 (FIG. 1 B). These energetically favorable interactions suggest enhanced anchor points for GPC-100 that are absent in AMD3100.

[0231] Tag Lite® system (CisBio) was then used for the competitive binding assays to test whether the structural differences can translate into differences in ligand binding. After CXCR4 terbium-labeled cells were plated, 5 pL of GPC-100 or AMD3100 were added, followed by 5 pL of 20 nM red fluorescently labeled CXCR4 ligand, CXCL12, which competes with the CXCR4 inhibitors for binding to CXCR4. After a 3-h incubation at room temperature, the plate was read on a PerkinElmer Envision plate reader. Inhibitory constants (Ki) for the respective compounds were determined by plotting the normalized HTRF ratio versus the compound concentrations using nonlinear regression competitive binding “one site - fit Ki equation.” The HTRF ratio was calculated as the emission ratio of 665 nm / 620 nm proportional to the amount of CXCL12 bound to CXCR4.

[0232] Dose response curves of either GPC-100 or AMD3100 demonstrated the antagonists competitively inhibited the binding of CXCL12 to CXCR4. As shown in FIG. 2, GPC-100 has a higher affinity for CXCR4 than AMD3100. Whereas the inhibitory constant (Ki) for GPC-100 is about 1 .6 nM, the Ki for AMD3100 is about 40 nM.EXAMPLE 2: PHARMACOLOGICAL CHARACTERIZATION OF GPC-100 DEMONSTRATES ITS EFFICACY IN INHIBITING THE CXCR4 / CXCL12 AXIS AT COMPARABLE OR BETTER LEVELS THAN AMD3100.

[0233] Cell Culture: MDA-MB-231 , Namalwa and multiple myeloma cells MM.1 S from the American Type Culture Collection (ATCC) and acute myeloid leukemia cells U937 from the Korean Cell Line Bank (Seoul, Korea) were cultured in RPMI 1640with ATCC modification (Gibco, A1049101), supplemented with 10% fetal bovine serum (FBS) and 100 ll / rnl of Penicillin-Streptomycin. rO2341Calcium Flux Assay: MDA-MB-231 cells endogenously expressing CXCR4 and p?AR, or transduced with adenoviruses encoding CXCR4 for overexpression were used for calcium flux. Cells were cultured for 2 days prior to running the assay as previously described

[0060] and seeded at 8x4cells / well in a 96-well black clearbottom microplate. The following day, cells were stained with Cal-520 AM (AAT Bioquest) for 2 h at 37 °C and treated with antagonists for 30 min followed by agonist stimulation. Intracellular calcium flux was measured using a Flexstation 3 microplate reader (Molecular Devices).[02351 Migration Assay: U937 or MM.1S cells were treated with GPC-100 or AMD3100 for 30 min and 100 pl of the cell suspension was added to a transwell insert with 8-p.m pores. The transwell insert with 100 pl cell suspension was put on the lower chamber very carefully avoiding bubbles. 800 pl of serum-free media containing 0.5% BSA was added to the lower chamber of the transwell at the indicated concentration (FIGs. 5A-5B). Cells were allowed to migrate toward CXCL12 in the presence or absence of the antagonists for 4 h (MM.1S) or 24 h (LI937) at 37°C. The migration of LI937 cells was measured using PrestoBlue Cell Viability Reagent (Invitrogen). The fluorescence intensity (560 nm / 590 nm excitation / emission) was detected using a Varioskan LUX Multimode Microplate Reader. r0236 PRESTO-Tango Assay: CXCR4-Tango plasmid (Addgene plasmid # 66262)

[0061] was used to construct the CXCR4-dV2-Tango plasmid by removing V2 tail of the V2 vasopressin receptor in a Age I digestion. HTLA cells were cultured as previously described.

[0061] HTLA cells were seeded at 8X105cells / well in a 6-well plate. The following day, cells were transfected with CXCR4-dV2 Tango and pcDNA3.1-ADRB2 using Lipofectamine 3000 (Thermo Fisher Scientific). After a 48- h incubation, transfected cells were transferred to 96-well white bottom plates and incubated under serum-starvation for 4 h. Cells were pretreated with antagonist for 30 min, and then stimulated with agonist for 18 h. On day 5, cells were lysed with Steady-Gio solution (Promega) for 15 min at room temperature, and luminescence was measured with Varioskan LUX Multimode Microplate Reader.

[0237] Together, the assays potent effects of GPC-100 on CXCR4 signaling. First, calcium flux assay in MDA-MB-231 cells overexpressing CXCR4 (Table 4) yielded a robust calcium flux response when stimulated with CXCL12. Dose response titration of GPC-100 and AMD3100 led to a dose dependent inhibition of CXCL12-induced calcium flux with IC50 values of 30 nM and 35 nM, respectively (FIG. 3A). The recruitment of p-arrestin to CXCR4 was also measured, which is known to occur upon CXCL12 binding [52-54], In the PRESTO-TANGO p-arrestin assay

[0055] , both GPC-100 and AMD3100 inhibited CXCL12 mediated recruitment of p-arrestin to CXCR4 with IC50 values of 207 nM and 172 nM respectively (FIG. 3B). Directly relevant to stem cell mobilization, cell migration is a key phenotypic response upon CXCR4 activation [56-58], For this assay, U937 and MM.1S cells with high endogenous CXCR4 expression were used (FIG. 4)

[0059] , which showed a robust migration response to CXCL12 with a sub-nanomolar ECso values (FIG. 5). In LI937 cells, both GPC-100 and AMD3100 efficiently blocked CXCL12-mediated migration with ICso of 48 nM and 42 nM, respectively (FIG. 3C). In MM.1S cells, CXCL12- induced migration was blocked by GPC-100 at a substantially lower concentration than AMD3100 (compare the IC50 value of GPC-100 at 28 nM with the IC50 value of AMD3100 at 80 nM (FIG. 3D).EXAMPLE 3: ENDOGENOUSLY EXPRESSED CXCR4 AND P2AR RESIDE IN CLOSE PROXIMITY IN A MODEL CELL SYSTEM.

[0238] Previous studies in cardiomyocytes and lymphocytes suggest that CXCR4 and P2AR form heteromers. Here, CXCR4 and P2AR heteromerization were investigated in a native state, wherein the receptors are endogenously expressed. To test this, Proximity ligation assay (PLA) was applied, which allows for the detection of protein-protein interactions using endogenous and non-engineered receptors

[0062] , Because the PLA detects the amplified DNA as dots, only a few interacting molecules can produce a robust signal, making it a sensitive and specific assay. Namalwa and MDA-MB-231 cells were used as model cancer cell lines chosen based on receptor mRNA transcript levels, surface expression and cell-type diversity (Table 4, FIG. 5, and FIG. 6A-6B).

[0239] Using primary antibodies specific to the intracellular domains of CXCR4 and P2AR, a positive PLA signal (over 5 PLA events per cell) was observed in Namalwacells, indicating stable proximity of endogenous CXCR4 and P2AR receptors (FIG. 7A). To confirm specificity of receptor proximity, a knockout of CXCR4 in Namalwa was constructed and confirmed significant decrease in surface CXCR4 expression (FIG. 8A-8B). PLA signal was significantly decreased in CXCR4 knockout Namalwa cells compared to the parental cells (FIG. 7A). While these results were encouraging, the relatively low abundance of P2AR in Namalwa made detection by PLA challenging.

[0240] Next MDA-MB-231 cells that express higher levels P2AR mRNA were investigated (Table 4). In this cell system, the PLA yielded about 6 events per cell (FIG. 7B). The specificity of the PLA was confirmed in a P2AR knock-out (FIG. 8C and 8D) of MDA-MB-231 cells (FIG. 7B) suggesting that parental CXCR4 and P2AR exist in close proximity in a native cell environment. rO241]RT-qPCR for CXCR4 and ADRB2: Total RNA was isolated using rNeasy Mini Kit (Qiagen, Valencia, CA). First-strand cDNA synthesis and RT-qPCR was performed using High-capacity cDNA reverse transcription kit and Power SYBR Green PCR Master Mix, respectively (Applied Biosystems, Foster City, CA). The primer sequences are as follows:CXCR4: 5’-CCACCATCTACTCCATCATCTTC-3’ and5’-ACTTGTCCGTCATGCTTCTC-3’ ;ADRB2: 5’-CTCTTCCATCGTGTCCTTCTAC-3’ and5’-AATCTTCTGGAGCTGCCTTT-3’E; andACTS (p-actin): 5’-GGACTTCGAGCAAGAGATGG-3’ and 5’-AGCACTGTGTTGGCGTACAG-3’ .[0242 PCR conditions: 50 °C for 2 min and then 95 °C for 10 min, followed by 40 cycles of 95 °C for 15 s and 60 °C for 1 min, followed by 95 °C for 15 s, 60 °C for 1 min, and 95 °C for 1 s for melt curve analysis using QuantStudio 3 instrument (Applied Biosystems). The expression of CXCR4 and ADRB2 mRNAs was normalized to the expression of ACTB mRNA.

[0243] Construction of knock-out cells: non-targeting single guide RNA (sgControl: 5 -ACGGAGGCTAAGCGTCGCAA-3'), CXCR4-targeting sgRNA (sgCXCR4: 5'-ACTTACACTGATCCCCTCCA-3'), and ADRB2-targeting sgRNA (sgADRB2: 5’-CGTCTGCAGACGCTCGAACT-3’), and were each cloned in a pLentiCRISPRv2. Lentiviruses were produced and genetargeting was performed as previously described

[0063] , Namalwa-CXCR4 KO cells were used as a pool after puromycin selection. MDA-MB-231-ADRB2 KO clone was chosen using puromycin selection followed by limiting dilution. Flow cytometry was used to detect the surface expressions of CXCR4 and ADRB2 in the parental and KO cells with anti-CXCR4, anti-p2AR antibody or isotype control antibodies.Table 4-Expression of CXCR4 and ADRB2 mRNA measured by RT-qPCR.

[0244] Proximity Ligation Assay (PLA): MDA-MB-231 (parental and ADRB2 knockout) and Namalwa (parental and CXCR4 knockout) cells were fixed on microscope slides and treated with lambda protein phosphatase (New England Biolabs) for 1 h at 37°C. The NaveniFlex MR kit (Navinci) was used for blocking, primary antibody incubation, and PLA. Recombinant rabbit anti-CXCR4 antibody (clone LIMB2, Abeam) and mouse anti-human P2AR antibody (clone E-3, Santa Cruz) were used as primary antibodies, while rabbit IgG and mouse lgG2b isotype (Abeam) were used as negative controls. Slides were mounted using X / ECTASHIELD Antifade Mounting Medium with DAPI and imaged using the IN Cell Analyzer 2500HS system (Molecular Devices).[02451 Statistical analyses: Data analyses were performed using GraphPad Prism and all data are presented as mean ± SEM. Comparisons of data across two dosing conditions were made using the Mann-Whitney test or multiple dosing conditions using the one-way ANOVA with Turkey’s multiple comparison test. P < 0.05 was considered statistically significant for all tests. * < 0.05, ** < 0.01 , *** < 0.001 , **** < 0.0001.EXAMPLE 4: SYNERGISTIC PHARMACOLOGY UPON CO-ACTIVATION OF CXCR4 AND 02AR THAT IS INHIBITED BY GPC-100 AND PROPRANOLOL

[0246] Functional effects of CXCR4 and P2AR proximity were evaluated in downstream signaling assays using receptor co-activation and co-inhibition. 0- arrestins act as intracellular scaffolds that mediate receptor desensitization, internalization, and G-protein independent signaling [64-66], HTLA cells overexpressing CXCR4-tango and P2AR were treated with 0-200 nM CXCL12 and 1 pM epinephrine or 100 nM CXCL12 and 0-10 pM epinephrine in two separate experiments. Under these conditions, CXCL12 alone induced 0-arrestin recruitment to CXCR4 (FIG. 9A). Epinephrine alone also induced a modest but meaningful 0- arrestin recruitment to CXCR4 (FIG. 9B). However, co-treatment of these cells with CXCL12 and epinephrine led to a significant synergistic increase of 0-arrestin recruitment compared to CXCL12-only treatment (FIG. 9C, Emax 286 ± 12.20% with co-treatment), which was blocked by GPC-100 and propranolol combination (FIG. 9C).

[0247] Treatment of MDA-MB-231 cells endogenously expressing CXCR4 and P2AR (FIG. 10) with CXCL12 or epinephrine alone elicited a modest calcium flux response. However, co-treatment with CXCL12 and epinephrine resulted in a synergistic increase in the calcium flux (FIGs. 11 A and 11 B). This was partially inhibited by the single antagonist treatment with GPC-100, AMD3100 or propranolol (FIG. 11 B). Complete blockade of calcium flux was only achieved with GPC-100 and propranolol co-treatment. In contrast, AMD3100 and propranolol co-treatment resulted in no significant reduction of synergistically increased calcium flux. These results show that the GPC-100 in the presence of propranolol was a more potent CXCR4 antagonist than AMD3100 in the presence of propranolol. These findings also suggest that CXCR4 and P2AR existing in close proximity can be co-activated to functionally regulate the downstream calcium signaling pathway, as well as affect the receptor internalization machinery, and potentially, scaffolds that mediate the G- protein independent non-canonical signaling pathways.EXAMPLE 5: GPC-100 WAS SIGNIFICANTLY MORE EFFECTIVE MOBILIZATION AGENT THAN AMD3100, AND COMBINATION TREATMENTS WITH GPC-100 AND PROPRANOLOL IN VIVO IMPROVE MOBILIZATION IN MICE

[0248] The most efficacious doses for induced mobilization were assessed for the CXCR4 antagonists GPC-100 and AMD3100. Numerous studies in mice suggest that the peak mobilization by AMD3100 (5 mg / kg, SC) at 1 hour [67-69], Mice PB WBC counts were determined at 1 hour following GPC-100 and AMD3100 administration. Our results showed that both GPC-100 and AMD3100 increased circulating WBCs as compared to the vehicle (FIG. 12A). Importantly, among the antagonists, GPC-100 was significantly more effective than AMD3100 at increasing WBCs over the vehicle baseline, such that at 1 hour post-drug, GPC-100 produced a 4.6-fold increase, whereas AMD3100 produced a 3-fold increase (FIG. 12A).

[0249] The time-course of mobilization from GPC-100 and AMD3100 was also compared from 30 min- to 6 hours post-drug. While both antagonists showed peak mobilization at 2 hours mice, GPC-100-induced mobilization was significantly greater than AMD3100 and the mobilization effect of GPC-100 was longer than AMD3100 (FIG. 12B). Based on this time-course, PB was collected at 2 hours post-GPC-100 in the following studies.

[0250] Animals: Studies were performed at a facility accredited by the Association for Assessment and Accreditation of Laboratory Animal Care and in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institute of Health. The protocol was approved by the Institutional Animal Care and Use Committee (IACUC) of Explora BioLabs (Protocol # EB17-010- 141). C57BL / 6J mice (female, 6-9 weeks old) from Jackson Laboratories and allowed to habituate for one week before handling. The mice were housed 5 per cage and had free access to food and water. Mice were randomized for each study so that all treatment groups contained similar age and weight distributions. Test articles were administered as shown in Table 5.Table 5: Dosing for in vivo mobilizationrO251]Sample collection: Mice were monitored daily and weighed prior to drug administration. Using the body weight data, mice were randomized into groups using the randomization tool in Benchling Studies. PB was collected by submental bleeding (non-terminal) or cardiac puncture (terminal). For terminal blood collection, mice were given an initial dose of 2.5-4% isoflurane in an induction chamber and a maintenance dose of 2-3% through a nose cone. A toe pinch on all four quadrants was applied to confirm the surgical plane of anesthesia. Upon completion of the blood collection from cardiac puncture, the mice were euthanized via cervical dislocation while still under the effects of isoflurane. Approximately 25 pL blood was used for CBC analysis and the remaining blood was processed for flow cytometry or colony forming unit (CFU) assay. For non-terminal submental bleeding, a 4mm lancet was used to puncture the linguofacialis vein under the chin. Blood was collected at 1 or 2 h post GPC-100 and AMD3100, and 14 h post G-CSF. For the time-course of mobilization, each mouse was bled twice. Submental bleeding was performed at 0.5 h, 1 h or 2 h after dosing and cardiac puncture was performed at 3 h, 4 h and 6 h post-dose. All doses of the treatments used in the study were well tolerated and no clinical observations were noted during the procedures. rO252 CBC analysis: Blood samples were processed for complete blood count (CBC) analysis using the Abaxis VetScan HM5 hematology analyzer, which reports 18-parameters including WBC, lymphocytes, neutrophils, monocytes, platelets, hemoglobin, RBC and morphology.

[0253] Flow cytometry: Mobilization of mouse HSC, characterized as LSK cells (Lineage- Sca-1+c-Kit+)

[0070] , was determined in two separate studies. For both studies, mononuclear cells were isolated from PB post-CBC analysis and stained with anti-lineage cocktail, c-Kit and Sca-1 antibodies for the first study (Table 6). For the second study, CD150 or CD34 antibodies were added to determine HSCs with long-term repopulating capacity (LT-HSC) (CD150+or CD34_LSK) [71 ^Sampleswere acquired with a Cytek Aurora spectral flow cytometer (Fremont, GA) and data was analyzed with CellEngine software. Gating was determined using FMO controls. The percentage of c-Kit+Sca-1+cells as a subset of parent Lin- cells were used to determine the total number of LSK cells pL of blood. For the second study, frequency of CD150+or CD34' cells were measured as a subset of parent LSK cells. Number of LSK cells in PB were normalized based on the WBC count obtained in that particular study.Table 6: Antibodies for LSK cells using flow cytometryr02541Colonv Forming Unit (CFU) Assay: 8x105mononuclear cells isolated from PB post-CBC analysis were added to tubes of semisolid methylcellulose medium (StemCell Technologies) known to support erythroid and myeloid progenitors

[0072] , Seven days later, colonies showing appearance of granulocyte-monocyte progenitors (CFU-GM) and burst forming units erythroid (BFU-E) formed and were counted by a blinded experimenter. Total CFU were calculated as a total number of CFU-GM and BFU-U colonies.

[0255] CXCR4 antagonists, GPC-100 and AMD3100, each showed more prominent mobilization in the presence of P2AR antagonist, propranolol in mice. To evaluate the impact of P2AR blockade in vivo, mice were administered propranolol.Propranolol dose was selected based on the dose titration (5-40 mg / kg, IP) when combined with GPC-100 (FIG. 13). Pretreatment with propranolol (20 mg / kg, IP) over 7 days (FIG. 14A) improved GPC-100 induced mobilization by 27% (FIG. 14B). Pretreatment with propranolol also enhanced AMD3100-induced mobilization (FIG. 14B). In particular, propranolol improved lymphocyte mobilization, but not neutrophil migration, for both antagonists (FIG. 15A and 15B). Further experiments todetermine HSPC mobilization revealed that 7-day propranolol pretreatment enhanced LSK cell mobilization by GPC-100, resulting in a 4-fold increase in circulating HSPCs (FIGs. 14C-14D).EXAMPLE 6: TRIPLE COMBINATION TREATMENTS WITH G-CSF, GPC-100 AND PROPRANOLOL IN VIVO IMPROVE MOBILIZATION IN MICE

[0256] Mobilization studies from the triple combination of G-CSF, GPC-100 or AMD3100, and propranolol was compared to the double or single combinations under the current ASCT standards of care. The triple combination (FIG. 16A) as well as the combination of G-CSF and GPC-100 induced an 8.2- and 8.4-fold increase in WBC mobilization, respectively, that was significantly greater compared to the increased WBC count by G-CSF alone (4.5-fold) or G-CSF plus AMD3100 (6.6-fold) (FIG. 16B). Together, the present findings indicated that GPC-100 mobilized more cells than AMD3100 when administered alone, with propranolol or with G-CSF. G- CSF plus AMD3100 treatment resulted in a 13-fold increase in LSK cells in PB compared to the vehicle. In comparison, G-CSF and GPC-100 combination with and without propranolol resulted in 20-fold and 24-fold increase in LSK cells, respectively (FIG. 16C, FIG. 17).

[0257] Then the functional capacity of cells mobilized by the triple combination was compared in a CFU assay. CFU assay was conducted to measure the mobilized HSPCs based on their ability to form CFU-GM and BFU-E colonies. The triple combination produced a 47-fold increase in CFUs over vehicle control compared to a 35-fold and 27-fold increase over vehicle from G-CSF plus GPC-100 and G-CSF plus AMD3100 treatments, respectively (FIG. 18A). LSK cells that express CD150 or lack CD34 are known to have long-term repopulating capacity (LT-HSC) (Purton Experimental Hematology 2022). In the present technology, the triple combination mobilized significantly more CD34’ and CD150+LSK cells compared to the standards of care (FIGs. 18B & 18C). This indicates that the addition of propranolol can improve the functional capacity of the mobilized cells. The pattern of LSK and CFU counts across the different drug combinations was consistent with the WBC count from matched samples, supporting the use of WBC counts as a surrogate marker for stem cell mobilization.EXAMPLE 7: NOVEL GPC-100 ALONE INDUCED IN VIVO MOBILIZATION SIGNIFICANTLY MORE THAN AMD3100 AND BL8040.

[0258] Time-course of WBC subset mobilization by each of GPC-100 (Burixafor, or TG-0054), AMD3100 (Plerixafor, or Mozobil), and BL8040 (Motixafortide) in mice. As shown in FIGs. 19A-19C, GPC-100 (but not BL8040) induced mobilization is significantly greater than AMD3100. Peak neutrophil mobilization for GPC-100 occurs at 2 hours post-drug, whereas for BL8040 it occurs at 4 hours. This indicates greater mobilization of cells from the hematopoietic lineage. Subset analysis for these cells will be performed for potential utility in adoptive cell therapies.

[0259] Superiority of GPC-100 over BL8040 was enhanced specifically in balb / c mouse strain. Balb / c mouse strain is used predominantly for in vivo oncology studies. For mobilization studies, C57 / BL6 strain (mentioned in other studies) is more commonly used due to preferential G-CSF mobilization in this strain and availability of co-genic mice. As shown in FIGs. 20A-20C, BL8040 does not mobilize efficiently in balb / c mice. Balb / c produce more Th2 associated cytokines with high IL4 and low I FNy, whereas C57 / BL6 produce more Th1 associated cytokines with low IL4 and high I FNy. Th2 profile is predominant in women. As used herein, “Th” means T Helper cells, which is further subdivided into “Th1” and “Th2”.

[0260] Th1 -dominated responses are involved in pathogenesis of organ-specific autoimmune disorders, Crohn’s disease, sarcoidosis, acute kidney allograft rejection, and some unexplained recurrent abortions. In contrast, allergen specific Th2 responses are responsible for atopic disorders in genetically susceptible individuals. How Th1 and Th2 immune responses or the Th1 / Th2 balance affects mobilization by CXCR4 inhibitor is not investigated. It is not clear what this finding means clinically.EXAMPLE 8: COMBINATION OF GPC-100 AND PROPRANOLOL IMPROVES MYELOID CELLS (NON-LYMPHOCYTE) MOBILIZATION IN VIVO.

[0261] As shown in FIG. 21 , myeloid cell (non-lymphocyte) mobilization by GPC-100 is further improved by addition of 7-day propranolol pretreatment. CD11 b+ myeloid cells and F4 / 80 macrophages are mobilized by GPC-100 and progranolol. Cell therapies targeting anti-tumor response from myeloid cells are currently being investigated for oncology and other therapeutic areas. See, for example, FIG. 22,describing mobilization of M1 and M2 macrophages, MDSCs, among others, in naive and tumor bearing mice.EXAMPLE 9: GPC-100 IMPROVES CELL MIGRATIONS IN CANCER BEARING MICE.

[0262] As shown in Table 7, GPC-100 mobilization enhanced in tumor bearing mice. For example, GPC-100 induced a 2.7-fold increase in circulating CXCR4 positive macrophages (F4 / 80) in naive mice, but 4.2-fold in tumor bearing mice.

[0263] GPC-100 mobilization also enhanced tumor bearing mice, which showed a 7 fold more macrophages in circulation compared to naive mice.

[0264] As shown in FIGs. 22A-22B, GPC-100 also produced greater mobilization in tumor bearing mice (CT26-colon cancer), especially for Cd11b myeloid cells.Table 7: Comparative fold change of cells in the presence of GPC-100 versus vehicle, and in tumor bearing mice (EL4 T-cell lymphoma bearing mice) verses non-tumor bearing mice.EXAMPLE 10: RANDOMIZED, OPEN-LABEL, DOUBLE-BLIND, PLACEBO- CONTROLLED, MULTICENTER, PHASE 2 CLINICAL TRIAL TO EVALUATE THE COMBINATION THERAPY OF GPC-100 AND G-CSF IN PATIENTS WITH MULTIPLE MYELOMA (MM), NON-HODGKIN’S LYMPHOMA (NHL), AND / OR HODGKIN’S DISEASE (HD).

[0265] This randomized, open-label, double-blind, placebo-controlled, multicenter, Phase 2 Clinical Trial (NCT02104427) evaluated the HSC mobilization and safety ofthe combination therapy of GPC-100 and G-CSF in patients with MM, NHL, or HD. Administration of GPC-100 resulted potent mobilization of CD34+ HSCs and CD133+ epithelial progenitor cells from bone marrow into PB. At maximal levels, GPC-100 increased the CD34+ cell counts by 3- to 14-fold from baseline levels (Sukhtankar 2023b). Nonclinical safety pharmacology and toxicology results available to date, as well as the data from the Phase 1 study, have demonstrated sufficient safety and efficacy to support further clinical development of GPC-100.

[0266] The primary purpose of this Phase 2 study was to investigate HSC mobilization by GPC-100 (3.14 mg / kg) when combined with G-CSF in patients with MM, NHL, or HD. The total number of HSCs collected in the leukapheresis product was evaluated for each patient. Interestingly, a faster kinetics of mobilization was observed with GPC-100 is combined with G-CSF compared to what was observed with GPC-100 alone. In addition, increased mobilization of lymphocytes with GPC- 100 and G-CSF were observed.[0267 Methods of Study Design: This clinical study was conducted according to the ethical principles of “good clinical practice” and the Declaration of Helsinki after obtaining a written informed consent from each patient. The protocol and its amendment, written study subject information, informed consents, and other appropriate study-related material were reviewed and approved appropriately.

[0268] Key eligibility criteria included patients aged 18 to 75 years with a confirmed diagnosis of MM, NHL, or HL, an Eastern Cooperative Oncology Group performance status of 0-1 , and potential candidates for HSC transplant.

[0269] At Day 1 , eligible patients received subcutaneous (SC) injections of 10 pg / kg / day G-CSF daily at 4:00 PM (±1 hour) as needed to reach the target collection goal of >5.0x106cells / kg. Patients could have received G-CSF for a maximum of 8 consecutive days. Beginning on Day 5, patients received intravenous 3.14 mg / kg GPC-100 over 15 minutes, beginning at 8:30 AM (±1 hour) and leukapheresis was performed (generally 2 ±1 hours after GPC-100 administration) each day as needed to reach the target collection goal of >5.0x1 o6cells / kg. Patients could have received GPC-100 for a maximum of 5 consecutive days. Leukapheresis could have been continued for a maximum of 5 sessions, if needed.

[0270] A continuous flow centrifugation device was used for peripheral stem cell collections during leukapheresis. During each leukapheresis procedure, the volumeof whole blood processed was between 18 to 24 L. The leukapheresis products were processed at the study sites for CD34+ cell enumeration.

[0271] PB samples for circulating CD34+ cells were collected prior to each dose of GPC-100 (within 30 minutes before the start of administration), pre-leukapheresis (within 30 minutes before the start of leukapheresis), post-leukapheresis (within 30 minutes after completion of leukapheresis), and 4 hours (±20 minutes) and 6 hours (±20 minutes) after completion of the GPC-100 infusion.

[0272] The demographics and baseline characteristics of this study are summarized in Table 8. A total of 12 patients were enrolled and received G-CSF and GPC-100 3.14 mg / kg as planned and completed the study. The majority of the patients (75%) had MM. All patients enrolled had an ECOG status of either Grade 0 or 1. None of the patients had bone marrow involvement nor had they undergone previous stem cell collection.Table 8 Patient demographics and baseline characteristicsEXAMPLE 11 : COMBINATION TREATMENT WITH GPC-100 AND G-CSF IS SAFE AND GENERALLY WELL-TOLERATED IN PATIENTS WITH MULTIPLE MYELOMA, NON-HODGKIN’S LYMPHOMA, AND / OR HODGKIN’S DISEASE.

[0273] Safety assessments of the combination treatment of GPC-100 and G-CSF were conducted at pre-dose and throughout the clinical study as described in Example 10. In particular, the safety assessments included the following: adverse effects (AEs), including Treatment-Emergent Adverse Events (TEAEs) and Severe Adverse Events (SAEs), physical examination findings, clinical laboratory evaluations (chemistry, hematology, urinalysis), vital signs (blood pressure, pulse rate, respiratory rate, temperature), 12-lead electrocardiograms (ECGs), pulse oximetry, and ECOG status. The sample size for this study was based on feasibility without a formal power calculation. All safety and efficacy data were descriptively analyzed.

[0274] The primary efficacy endpoint was the frequency and proportion of patients from whom a total number of CD34+ cells >5.0*106cells / kg was collected within the first 4 leukapheresis sessions. For this endpoint, each patient’s CD34+ cell number was calculated as the sum of CD34+ cell numbers collected from (up to) the first 4 leukapheresis sessions. The 95% exact confidence intervals (Cis) for the proportion of patients who mobilized the targeted collection goal were provided. The exact Cis based on the binomial distribution were constructed using SAS PROC FREQ procedure.

[0275] The average number of leukapheresis sessions required to collect >2.5 x106CD34+ cells / kg and >5.0x106CD34+ cells / kg were also evaluated.

[0276] As shown in Table 9, an administration of GPC-100 in combination with G- CSF was safe and generally well-tolerated in patients with MM, NHL, or HD. A total of 7 patients reported 10 Treatment-Emergent Adverse Events (TEAEs). There were no Severe Adverse Events (SAEs) reported during this study. No patients discontinued due to TEAEs. The number of patients with TEAEs was higher following coadministration of GPC-100 and G CSF (n=6) relative administration of G CSF alone in the initial 4 days (n=2). The majority of TEAEs were Grade 1 or 2 in severity, with a single Grade 4 TEAE of decreased platelet count that was assessedby the Investigator as unrelated to the study drug. Two drug-related TEAEs were reported that included 1 patient with Grade 2 bone pain following administration of G- CSF alone and 1 patient with Grade 1 diarrhea following coadministration of GPC- 100 and G-CSF. There were no clinically significant changes in vital signs, ECG parameters, or physical examinations during the study. Other than the expected drug effects on increasing WBC counts, changes in the other clinical laboratory parameters were generally unremarkable.Table 9 Summary of All Reported Treatment-Emergent Adverse EventsEXAMPLE 12: COMBINATION TREATMENTS WITH GPC-100 AND G-CSF IN PATIENTS DEMONSTRATE A FASTER KINETICS OF MOBILIZATION AND INCREASED LYMPHOCYTE MOBILIZATION AS COMPARED TO PATIENTS TREATED WITH GPC-100 ALONE.

[0277] Efficacy assessments of the combination treatment of GPC-100 and G-CSF were conducted as described in Example 10. Following co-ad ministrati on of GPC- 100 and G-CSF, the mean total number of CD34+cells collected over all leukapheresis sessions was 8.17*106cells / kg (Table 10). Of the 12 enrolled patients, 5 had one leukapheresis session to achieve target cell counts and 7 had two sessions to achieve target cell counts. The mean CD34+cell count from MM patients (9.00*106cells / kg) was greater than from NHL and HD patients combined (5.68*106cells / kg). Within 1 or 2 leukapheresis sessions (mean 1.4 sessions), 11 of 12 patients (92%: 8 MM and 3 NHL or HD patients) achieved the CD34+cell mobilization target of > 5.0*106cells / kg. All 8 MM patients achieved the CD34+cell mobilization cell counts of > 6.0*106cells / kg of which 6 patients achieved target cellcounts after 1 session with 2 patients achieving targets after 2 sessions. Within one leukapheresis session, all but one patient (92%) had achieved the CD34+cell mobilization target of >2.5*106cells / kg. One patient with MM who did not meet the target cell counts within 1 or 2 leukapheresis had been treated with lenalidomide, an agent known to lower CD34+cell yields (Cashen 2007), until one week prior to the study entry.Table 10 Total CD34+Cells Collected from All Leukapheresis Sessions

[0278] The change in circulating CD34+cell count in PB between the Day 4 of G- CSF administration and GPC-100 administration was used to measure the pharmacodynamics of GPC-100. The median number of PB CD34+cells increased 1.3- and 1.75-fold from pre-dose (morning after Day 4 of G-CSF and before GPC- 100 administration) to 4 hours after infusion of GPC-100 on study Day 5 (leukapheresis day 1) and Day 6 (leukapheresis day 2), respectively (Table 11). PB CD34+cell counts were relatively highest at pre-leukapheresis (1.9- and 2.1 -fold on Days 5 and 6, respectively), and returned to slightly higher than pre-dose at post- leukapheresis. On Day 6, the median number of PB CD34+cells at each sampling timepoint was approximately 50% of that on Day 5. CD34+cell count was not measured before the first administration of G-CSF (FIGs. 23A-23B). The changes in CD34+cells in PB can be graphed at each time point for as an average for all patients (FIG. 23A) or as a relative change for each individual patient (FIG. 23B). In both graphs, the peak mobilization appears to occur approximately 1 hour after GPC-100 administration. As shown in FIG. 23B, percent peak relative change in CD34+for all nine participating patients is in the range of 45 minutes ± 15 minutes (or from about 30 minutes to about 60 minutes).Table 11 Circulating CD34+Cell Count in Peripheral Blood (PB)Max = maximum; Min = minimum; N = number of patients; SD = standard deviation.EXAMPLE 13: COMBINATION TREATMENT WITH GPC-100, PROPRANOLOL, AND G-CSF IS SAFE AND TOLERABLE TO PATIENTS WITH MULTIPLE MYELOMA (MM) UNDERGOING ASCT.

[0279] In this ongoing clinical trial, around 20 participants will be enrolled across 10 sites to evaluate the safety and clinical activity of GPC-100 under a Bayesian Optimal Phase 2 (BOP2) design.

[0280] From Day 1 to Day 8, patients will self-administer 30 mg propranolol, orally, twice daily. From Day 3 to Day 7, patients will also receive SC injections of 10 pg / kg / day G-CSF every afternoon. On Day 7 and Day 8, patients will also receive a 3.14 mg / kg dose of GPC-100 via IV and undergo leukapheresis 45 minutes post drug administration. Participants may undergo additional optional days of the treatment regimen and stem cell collection, per Investigator’s discretion to meet institutional collection goal standards. Participants will be monitored for adverse event (AE) until 28 days after the last dose of GPC-100.

[0281] Preliminary results of the four patients enrolled (age range: 60-71 years old, and median age: 67 years old) show that the combination treatment of GPC-100, propranolol, and G-CSF was safe and tolerable. Of these patients, 2 patients had received 4 cycles of Daratumumab-RVd. For the other 2 patients, one received 3 cycles of Dara-R and the other 4 cycles of RVd. A total of 45 AEs of any grade were observed, 71 % of which had occurred after transplant. GPC-100 related AEs were no greater than grade 1 , and include flushing, chest tightness, stomach pain, and nausea, consistent with previous observations. No incidence of diarrhea during the mobilization and leukapheresis period was reported. No propranolol related AE wasobserved. 18% of all AEs were greater or equal to grade 3, and all occurred after the transplant.EXAMPLE 14: A COMBINATION TREATMENT OF GPC-100, PROPRANOLOL, AND G-CSF RAPIDLY MOBILIZE CD34+CELLS IN PATIENTS WITH MULTIPLE MYELOMA UNDERGOING ASCT, IN SPITE OF THE NEGATIVE MOBILIZATION EFFECTS OF DARATUMUMAB.

[0282] This U.S. only, open-label, multi-site Phase 2 Clinical Study (NCT05561751) evaluates the safety and migration efficacy when MM patients undergoing ASCT is treated with a combination of GPC-100, propranolol, and G-CSF. Methods and patient selection are described in Example 13. Migration efficacy is evaluated by measuring the proportion of patients to achieve >2 x 106CD34+cells / kg in 2 leukapheresis sessions when a combination of GPC-100, propranolol, and G-CSF is administered.

[0283] Preliminary results of the GPC-100, propranolol, and G-CSF combination treatment is promising. Table 12 and FIG. 24 show that the primary objective of reaching minimal harvest requirement achieved for all MM patients. In particular, of the four patients enrolled, every patient achieved a primary endpoint of >2x1 o6CD34+cells / kg (minimum harvest requirement) in two apheresis sessions. 75% of these patients achieved a primary endpoint of >6x106CD34+cells / kg (optimum harvest requirement) in two apheresis sessions. Here, all four patients proceeded to ASCT. Timing of when they proceed to ASCT is only a logistical detail and is not affected by GPC-100 efficacy. Median time to neutrophil engraftment was 12 days (range 11-15 days). The preliminary results show that the combination treatment regimen can sufficiently mobilize CD34+stem cells for ASCT.

[0284] Table 12 and FIG. 24 also show that the combination regimen is effective in mobilizing CD34+stem cells in patients despite having received treatments that can negative impact on mobilization (i.e. treatment with daratumumab).

[0285] Table 12 and FIG. 24 also show a substantially improved mobilization kinetics from the FDA approved AMD3100 or BL8040. Whereas both AMD3100 and BL8040 require an overnight pre-treatment prior to leukapheresis, the GPC-100 regimen described here is greatly superior over existing methods because it allows for same day administration of both mobilization agent and leukapheresis, includingadministering the mobilization agent as late as from about 30 minutes to about 60 minutes prior to leukapheresis (FIG. 23B). Thus, the GPC-100, propranolol, and G- CSF combination treatment provides a substantial improvement in the health of the bone marrow stem cell niche and provides a faster mobilization profile in patients, such as those with MM seeking HSC transplants.Table 12: The combination treatment of GPC-100, propranolol, and G-CSF rapidly achieved minimum requirement in MM patients.

[0286] From the foregoing, it will be appreciated that specific embodiments of the invention have been described herein for purposes of illustration, but that various modifications may be made without deviating from the scope of the invention. Accordingly, the invention is not limited except as by the appended claims.ABBREVIATIONSUnless indicated otherwise, the following includes abbreviations for terms disclosed herein: ACKR3 (Atypical chemokine receptor 3); ACT (Adoptive cell therapy); ADCYAP1 R1 (ADCYAP receptor type I); ADCYAP1 R1 (Adenylate cyclase activating polypeptide 1 (Pituitary) Receptor Type I); AdHTS (Adenovirus high-throughput system); ADORA2B (Adenosine Receptor A2b or Adenosine A2b Receptor); ADORA3 (Adenosine a3 receptor); ADRA1A (Adrenoceptor alpha 1a); ADRB2 (Adrenoceptor beta 2); ADRB2, P2AR, or gene ADRB2 (Beta-2 adrenergic receptor); AEs (Adverse effects); ALL (Acute lymphoblastic leukemia); AML (Acute myeloid leukemia); APLNR (Apelin receptor); ARF (Alternative reading frame); ASCT (Autologous stem cell transplant); ATCC (American type culture collection);beta blocker (Beta adrenergic inhibitor); BFLI-E (Burst-forming units erythroid); BiFC (Bimolecular fluorescence complementation); BM (Bone marrow); BRET (Bioluminescence resonance energy transfer); BSA (Bovine serum albumin); C5AR1 (Complement c5a receptor 1); CALCR (Calcitonin receptor); CAR (Chimeric antigen receptor); CBC (Blood count); CBC (Complete blood count); CCR2 (C-C chemokine receptor type 2 or Chemokine (C-C Motif) Receptor 2); CCR5 (C-C chemokine receptor type 5 or Chemokine (C-C Motif) Receptor 5); CFC (Continuous flow centrifugation); CFU (Colony forming unit); CFU-GEMM (Colony-forming units multipotential); CFU-GM (Colony-forming units granulocytemacrophage); CFU-GM (Granulocyte-monocyte progenitors); CHRM1 (Cholinergic receptor muscarinic 1); CLL (Chronic lymphocytic leukemia); CMKLR1 (Chemerin chemokine-like receptor 1); CML (Chronic myeloid leukemia); COPD (Chronic obstructive pulmonary disease); CPP (Cell-penetrating peptide); CRE (Camp response element); CSCs (Cancer stem cells); CT (Computed tomography); Ct (Threshold cycles); CTLA-4 (Cytotoxic T-lymphocyte-associated antigen 4); CTRA (Conserved Transcriptional Response to Adversity); CXCL12 (C-X-C Motif Chemokine ligand 12) also known as SDF-1 ; CXCR4 (CXC receptor 4); EDNRB (Endothelin receptor type b); ELISA (Enzyme-linked immunosorbent assay); FACS (Fluorescence activated cell sorting); FBS (Fetal bovine serum); FFPE (Formalin- fixed paraffin-embedded); FRET (Fluorescence resonance energy transfer);GALR1 (Galanin receptor 1); GBM (Glioblastoma multiforme); GCGR (Glucagon receptor); GCID (Genecards identification); G-CSF (Granulocyte-colony stimulating factor); GFP (Green fluorescence protein); GPCR (G protein-coupled receptor); GPCR-HIT (GPCR heteromer identification technology); HCC (Hepatocellular carcinoma); HD (Hodgkin's disease); HGNC (Hugo gene nomenclature committee); HIV (Human immunodeficiency virus); HL (Hodgkin’s Lymphoma); HPP-CFC (High proliferative potential colony-forming cells); HRH1 (Histamine receptor hi ); HSC (Hematopoietic progenitor cells); HSCs (Hematopoietic stem cells); HTRF (Homogeneous Time Resolved Fluorescence); IACUC (Animal Care and Use Committee); Ki (Inhibitory constant); LT-HSC (Long-term repopulating capacity); MAP (Model amphipathic peptide); MDS (Myelodysplastic syndromes); MLNR (Motilin receptor); MM (Multiple myeloma); MOI (Multiplicity of infection); MOR (p-Opioid receptor); NC-IUPHAR (International Union of Basic and ClinicalPharmacology Committee on Receptor Nomenclature and Drug Classification); NFAT-RE (nuclear factor of activated T-cells response element); NGS (Next generation sequencing); NHL (Non-Hodgkin’s lymphoma); NK (Natural killer); NLS (Nuclear localization signal); NSCLC (Non-small-cell lung cancer); NTSR1 (Neurotensin receptor 1 ); OPRD (5-Opioid receptor); PB (Peripheral blood); PD-1 (Programmed cell death protein 1 ); PDC (Patient derived cell); PD-L1 (Programmed cell death ligand 1 ); PDX (Patient-derived xenograft); PET (Positron emission tomography); PET / CT (Positron emission tomography / computed tomography); PLA (Proximity ligation assay); PLA (Proximity ligation assay); Pro (Propranolol); PTGER2 (Prostaglandin E receptor 2); PTGER3 (Prostaglandin E receptor 3); RT-qPCR (Reverse transcription-quantitative PCR); RT-qPCR (Reverse transcription-quantitative polymerase chain reaction); SAEs (Severe adverse events); SCD (Sickle cell disease); SCLC (Small-cell lung cancer); SCM (Enhanced stem cell mobilization); SDF-1 (Stromal cell-derived factor 1 ), also known as CXCL12; SLE (Systemic lupus erythematosus); SLL (Small lymphocytic lymphoma); SPECT (Single-photon emission computed tomography); SPECT (Single-photon emission computed tomography); SRE (Serum response element); SRF-RE (Serum response factor response element); SSTR2 (Somatostatin receptor 2); TACR3 (Tachykinin receptor 3); TOR (T-cell receptor); TEAEs (Treatment-emergent adverse events); Th (T Helper cells), Th1 (T Helper 1 cells), Th (T Helper 2 cells), TIL (Tumor-infiltrating lymphocyte); TME (Tumor microenvironment); TR-FRET (Time-resolved FRET); VC (C-terminal fragment of Venus); VEGF (Vascular endothelial growth factor); VN (N-terminal fragments of Venus); VSMC (Vascular smooth muscle cells); WBC (White blood cell); WHIM syndrome (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis); and YFP (Yellow fluorescence protein).REFERENCES1. Cowan AJ, Green DJ, Kwok M, Lee S, Coffey DG, Holmberg LA, et al. Diagnosis and Management of Multiple Myeloma: A Review. JAMA. 2022;327(5):464- 77. doi: 10.1001 / jama.2022.0003. PubMed PMID: 35103762.2. Devarakonda S, Efebera Y, Sharma N. Role of Stem Cell Transplantation in Multiple Myeloma. Cancers (Basel). 2021 ;13(4). Epub 20210218. doi:10.3390 / cancersl 3040863. PubMed PMID: 33670709; PubMed Central PMCID: PMCPMC7922596.3. Holstein SA, McCarthy PL. Improved survival with salvage autologous stemcell transplantation in myeloma. Lancet Haematol. 2016;3(7):e306-7. doi: 10.1016 / S2352-3026(16)30058-8. PubMed PMID: 27374462.4. Li J, Zhu Y. Survival analysis of multiple myeloma patients after autologous stem cell transplantation. Stem Cell Investig. 2019;6:42. Epub 20191212. doi: 10.21037 / sci.2019.10.05. PubMed PMID: 32039264; PubMed Central PMCID: PMCPMC6987323.5. Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111 (5):2516-20. Epub 20071101. doi: 10.1182 / blood-2007-10-116129. PubMed PMID: 17975015; PubMed Central PMCID: PMCPMC2254544.6. Arora S, Majhail NS, Liu H. Hematopoietic Progenitor Cell Mobilization for Autologous Stem Cell Transplantation in Multiple Myeloma in Contemporary Era. Clin Lymphoma Myeloma Leuk. 2019;19(4):200-5. Epub 20181220. doi: 10.1016 / j.clml.2018.12.010. PubMed PMID: 30679106.7. Balassa K, Danby R, Rocha V. Haematopoietic stem cell transplants: principles and indications. Br J Hosp Med (Lond). 2019;80(1 ):33-9. doi: 10.12968 / hmed.2019.80.1.33. PubMed PMID: 30592675.8. Toor AA, Ayers J, Strupeck J, Parthasarathy M, Creech S, Rodriguez T, et al. Favourable results with a single autologous stem cell transplant following conditioning with busulphan and cyclophosphamide in patients with multiple myeloma. Br J Haematol. 2004; 124(6):769-76. doi: 10.1111 / j.1365-2141 ,2004.04837.x. PubMed PMID: 15009065.9. Tricot G, Jagannath S, Vesole D, Nelson J, Tindle S, Miller L, et al. Peripheral blood stem cell transplants for multiple myeloma: identification of favorable variables for rapid engraftment in 225 patients. Blood. 1995;85(2):588-96. PubMed PMID: 7529066.10. DiPersio JF, Stadtmauer EA, Nademanee A, Micallef IN, Stiff PJ, Kaufman JL, et al. Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma. Blood.2009;113(23):5720-6. Epub 20090410. doi: 10.1182 / blood-2008-08-174946. PubMed PMID: 19363221.11 . Demirer T, Buckner CD, Gooley T, Appelbaum FR, Rowley S, Chauncey T, et al. Factors influencing collection of peripheral blood stem cells in patients with multiple myeloma. Bone Marrow Transplant. 1996; 17(6):937-41 . PubMed PMID: 8807097.12. DiPersio JF, Micallef IN, Stiff PJ, Bolwell BJ, Maziarz RT, Jacobsen E, et al. Phase III prospective randomized double-blind placebo-controlled trial of plerixafor plus granulocyte colony-stimulating factor compared with placebo plus granulocyte colony-stimulating factor for autologous stem-cell mobilization and transplantation for patients with non-Hodgkin's lymphoma. J Clin Oncol. 2009;27(28):4767-73. Epub 20090831. doi: 10.1200 / JC0.2008.20.7209. PubMed PMID: 19720922.13. Crees ZD, Rettig MP, Jayasinghe RG, Stockerl-Goldstein K, Larson SM, Arpad I, et al. Motixafortide and G-CSF to mobilize hematopoietic stem cells for autologous transplantation in multiple myeloma: a randomized phase 3 trial. Nat Med. 2023. Epub 20230417. doi: 10.1038 / s41591-023-02273-z. PubMed PMID: 37069359.14. Hulin C, Offner F, Moreau P, Roussel M, Belhadj K, Benboubker L, et al. Stem cell yield and transplantation in transplant-eligible newly diagnosed multiple myeloma patients receiving daratumumab + bortezomib / thalidomide / dexamethasone in the phase 3 CASSIOPEIA study. Haematologica. 2021 ;106(8):2257-60. Epub 20210801 . doi: 10.3324 / haematol.2020.261842. PubMed PMID: 33657786; PubMed Central PMCID: PMCPMC8327738.15. Popat II, Saliba R, Thandi R, Hosing C, Qazilbash M, Anderlini P, et al. Impairment of filgrastim-induced stem cell mobilization after prior lenalidomide in patients with multiple myeloma. Biol Blood Marrow Transplant. 2009;15(6):718-23. Epub 20090408. doi: 10.1016 / j.bbmt.2009.02.011 . PubMed PMID: 19450756; PubMed Central PMCID: PMCPMC4352933.16. Fitzhugh CD, Hsieh MM, Bolan CD, Saenz C, Tisdale JF. Granulocyte colonystimulating factor (G-CSF) administration in individuals with sickle cell disease: time for a moratorium? Cytotherapy. 2009;11 (4):464-71. doi: 10.1080 / 14653240902849788. PubMed PMID: 19513902; PubMed Central PMCID: PMCPMC2747259.17. Daikeler T, Tichelli A, Passweg J. Complications of autologous hematopoietic stem cell transplantation for patients with autoimmune diseases. Pediatr Res.2012;71 (4 Pt 2):439-44. Epub 20120208. doi: 10.1038 / pr.2011.57. PubMed PMID: 22430379.18. Pusic I, Jiang SY, Landua S, Uy GL, Rettig MP, Cashen AF, et al. Impact of mobilization and remobilization strategies on achieving sufficient stem cell yields for autologous transplantation. Biol Blood Marrow Transplant. 2008; 14(9): 1045-56. doi: 10.1016 / j.bbmt.2008.07.004. PubMed PMID: 18721768.19. Giralt S, Costa L, SchriberJ, Dipersio J, Maziarz R, McCarty J, et al. Optimizing autologous stem cell mobilization strategies to improve patient outcomes: consensus guidelines and recommendations. Biol Blood Marrow Transplant. 2014;20(3):295-308. Epub 20131017. doi: 10.1016 / j.bbmt.2013.10.013. PubMed PMID: 24141007.20. Wu B, Chien EY, Mol CD, Fenalti G, Liu W, Katritch V, et al. Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists. Science. 2010;330(6007):1066-71 . Epub 20101007. doi: 10.1126 / science.1194396. PubMed PMID: 20929726; PubMed Central PMCID: PMCPMC3074590.21. Mezzapelle R, Leo M, Caprioglio F, Colley LS, Lamarca A, Sabatino L, et al. CXCR4 / CXCL12 Activities in the Tumor Microenvironment and Implications for Tumor Immunotherapy. Cancers (Basel). 2022; 14(9). Epub 20220506. doi: 10.3390 / cancersl 4092314. PubMed PMID: 35565443; PubMed Central PMCID: PMCPMC91 05267.22. Guo F, Wang Y, Liu J, Mok SC, Xue F, Zhang W. CXCL12 / CXCR4: a symbiotic bridge linking cancer cells and their stromal neighbors in oncogenic communication networks. Oncogene. 2016;35(7):816-26. Epub 20150511 . doi: 10.1038 / onc.2015.139. PubMed PMID: 25961926.23. Sukhtankar DD, Chang LW, Tsai CY, Cardarelli PM, Caculitan NG. Pharmacokinetics and Pharmacodynamics of Burixafor Hydrobromide (GPC-100), a Novel C-X-C Chemokine Receptor 4 Antagonist and Mobilizer of Hematopoietic Stem / Progenitor Cells, in Mice and Healthy Subjects. Clin Pharmacol Drug Dev. 2023. Epub 20230804. doi: 10.1002 / cpdd.1302. PubMed PMID: 37539772.24. Schuster MM. PD and Safety of TG-0054 Combined With G-CSF in Multiple Myeloma, Non-Hodgkin Lymphoma and Hodgkin Disease Patients (ClinicalTrials.gov Identifier: NCT02104427) https: / / clinicaltrials.gov / ct2 / show / NCT02104427?term=TG- 0054&draw=2&rank=12017 [updated April 19, 2021],25. Setia G, Hagog N, Jali lizeinali B, Funkhouser S, Pierzchanowski L, Lan F, et al. A Phase II, Open-Label Pilot Study to Evaluate the Hematopoietic Stem Cell Mobilization of TG-0054 Combined with G-CSF in 12 Patients with Multiple Myeloma, Non-Hodgkin Lymphoma or Hodgkin Lymphoma - an Interim Analysis. Blood. 2015;126(23):515-. doi: 10.1182 / blood.V126.23.515.515.26. Nakai A, Hayano Y, Furuta F, Noda M, Suzuki K. Control of lymphocyte egress from lymph nodes through beta2-adrenergic receptors. J Exp Med. 2014;211 (13):2583-98. Epub 20141124. doi: 10.1084 / jem.20141132. PubMed PMID: 25422496; PubMed Central PMCID: PMCPMC4267238.27. LaRocca TJ, Schwarzkopf M, Altman P, Zhang S, Gupta A, Gomes I, et al. beta2-Adrenergic receptor signaling in the cardiac myocyte is modulated by interactions with CXCR4. J Cardiovasc Pharmacol. 2010;56(5):548-59. doi: 10.1097 / FJC.0b013e3181f713fe. PubMed PMID: 20729750; PubMed Central PMCID: PMCPMC2978286.28. Nakai A, Leach S, Suzuki K. Control of immune cell trafficking through interorgan communication. Int Immunol. 2021 ;33(6):327-35. doi: 10.1093 / intimm / dxab009. PubMed PMID: 33751050.29. Spiegel A, Kalinkovich A, Shivtiel S, Kollet O, Lapidot T. Stem cell regulation via dynamic interactions of the nervous and immune systems with the microenvironment. Cell Stem Cell. 2008;3(5):484-92. doi: 10.1016 / j. stem.2008.10.006. PubMed PMID: 18983964.30. Saba F, Soleimani M, Kaviani S, Abroun S, Sayyadipoor F, Behrouz S, et al. G-CSF induces up-regulation of CXCR4 expression in human hematopoietic stem cells by beta-adrenergic agonist. Hematology. 2015;20(8):462-8. Epub 20141217. doi: 10.1179 / 1607845414Y.0000000220. PubMed PMID: 25517250.31. Maestroni GJM. Adrenergic Modulation of Hematopoiesis. J Neuroimmune Pharmacol. 2020; 15(1 ):82-92. Epub 20190214. doi: 10.1007 / s11481-019-09840-7. PubMed PMID: 30762159.32. Katayama Y, Battista M, Kao WM, Hidalgo A, Peired AJ, Thomas SA, et al. Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell. 2006; 124(2):407-21 . doi: 10.1016 / j.cell.2005.10.041. PubMed PMID: 16439213.33. Hanoun M, Maryanovich M, Arnal-Estape A, Frenette PS. Neural regulation of hematopoiesis, inflammation, and cancer. Neuron. 2015;86(2):360-73. doi: 10.1016 / j. neuron.2015.01.026. PubMed PMID: 25905810; PubMed Central PMCID: PMCPMC4416657.34. Schraml E, Fuchs R, Kotzbeck P, Grillari J, Schauenstein K. Acute adrenergic stress inhibits proliferation of murine hematopoietic progenitor cells via p38 / MAPK signaling. Stem Cells Dev. 2009;18(2):215-27. doi: 10.1089 / scd.2008.0072. PubMed PMID: 18444787.35. Hwa YL, Shi Q, Kumar SK, Lacy MQ, Gertz MA, Kapoor P, et al. Beta-blockers improve survival outcomes in patients with multiple myeloma: a retrospective evaluation. Am J Hematol. 2017;92(1 ):50-5. Epub 20161118. doi: 10.1002 / ajh.24582. PubMed PMID: 27733010; PubMed Central PMCID: PMCPMC5217079.36. Hwa YL, Lacy MQ, Gertz MA, Kumar SK, Muchtar E, Buadi FK, et al. Use of beta blockers is associated with survival outcome of multiple myeloma patients treated with pomalidomide. Eur J Haematol. 2021 ;106(3):433-6. Epub 20210105. doi: 10.1111 / ejh.13559. PubMed PMID: 33259093.37. Bruns I, Cadeddu RP, Brueckmann I, Frobel J, Geyh S, Bust S, et al. Multiple myeloma-related deregulation of bone marrow-derived CD34(+) hematopoietic stem and progenitor cells. Blood. 2012;120(13):2620-30. Epub 20120418. doi: 10.1182 / blood-2011-04-347484. PubMed PMID: 22517906; PubMed Central PMCID: PMCPMC3460684.38. Knight JM, Rizzo JD, Hari P, Pasquini MC, Giles KE, D'Souza A, et al. Propranolol inhibits molecular risk markers in HCT recipients: a phase 2 randomized controlled biomarker trial. Blood Adv. 2020;4(3):467-76. doi: 10.1182 / bloodadvances.2019000765. PubMed PMID: 32027744; PubMed Central PMCID: PMCPMC7013267.39. Wong GW, Boyda HN, Wright JM. Blood pressure lowering efficacy of partial agonist beta blocker monotherapy for primary hypertension. Cochrane Database Syst Rev. 2014;2014(11 ):CD007450. Epub 20141127. doi: 10.1002 / 14651858.CD007450.pub2. PubMed PMID: 25427719; PubMed Central PMCID: PMCPMC6486122.40. Nair R, Subramaniam V, Barwick BG, Gupta VA, Matulis SM, Lonial S, et al. beta adrenergic signaling regulates hematopoietic stem and progenitor cellcommitment and therapy sensitivity in multiple myeloma. Haematologica. 2022;107(9):2226-31. Epub 20220901. doi: 10.3324 / haematol.2022.280907. PubMed PMID: 35511673; PubMed Central PMCID: PMCPMC9425311.41 . Milligan G. A day in the life of a G protein-coupled receptor: the contribution to function of G protein-coupled receptor dimerization. Br J Pharmacol. 2008; 153 Suppl 1 :S216-29. doi: 10.1038 / sj.bjp.0707490. PubMed PMID: 17965750; PubMed Central PMCID: PMCPMC2268067.42. Farran B. An update on the physiological and therapeutic relevance of GPCR oligomers. Pharmacol Res. 2017;117:303-27. doi: 10.1016 / j.phrs.2017.01.008. PubMed PMID: 28087443.43. Ferre S, Navarro G, Casado V, Cortes A, Mallol J, Canela El, et al. G protein- coupled receptor heteromers as new targets for drug development. Prog Mol Biol Transl Sci. 2010;91 :41-52. doi: 10.1016 / S1877-1173(10)91002-8. PubMed PMID: 20691958.44. Gomes I, Ayoub MA, Fujita W, Jaeger WC, Pfleger KD, Devi LA. G Protein- Coupled Receptor Heteromers. Annu Rev Pharmacol Toxicol. 2016;56:403-25. doi: 10.1146 / annurev-pharmtox-011613-135952. PubMed PMID: 26514203; PubMed Central PMCID: PMCPMC5147582.45. Rozenfeld R, Devi LA. Receptor heteromerization and drug discovery. Trends Pharmacol Sci. 2010;31 (3):124-30. doi: 10.1016 / j.tips.2009.11 .008. PubMed PMID: 20060175; PubMed Central PMCID: PMCPMC2834828.46. Terrillon S, Bouvier M. Roles of G-protein-coupled receptor dimerization. EMBO Rep. 2004;5(1):30-4. doi: 10.1038 / sj.embor.7400052. PubMed PMID: 14710183; PubMed Central PMCID: PMCPMC1298963.47. Covic L, Gresser AL, Talavera J, Swift S, Kuliopulos A. Activation and inhibition of G protein-coupled receptors by cell-penetrating membrane-tethered peptides. Proc Natl Acad Sci U S A. 2002;99(2):643-8. doi: 10.1073 / pnas.022460899. PubMed PMID: 11805322; PubMed Central PMCID: PMCPMC117359.48. O'Callaghan K, Kuliopulos A, Covic L. Turning receptors on and off with intracellular pepducins: new insights into G-protein-coupled receptor drug development. J Biol Chem. 2012;287(16):12787-96. doi: 10.1074 / jbc.R112.355461 . PubMed PMID: 22374997; PubMed Central PMCID: PMCPMC3339939.49. Isbilir A, Moller J, Arimont M, Bobkov V, Perpina-Viciano C, Hoffmann C, et al. Advanced fluorescence microscopy reveals disruption of dynamic CXCR4 dimerization by subpocket-specific inverse agonists. Proc Natl Acad Sci U S A. 2020;117(46):29144-54. Epub 20201 104. doi: 10.1073 / pnas.2013319117. PubMed PMID: 33148803; PubMed Central PMCID: PMCPMC7682396.50. Miller EB, Murphy RB, Sindhikara D, Borrelli KW, Grisewood MJ, Ranalli F, et al. Reliable and Accurate Solution to the Induced Fit Docking Problem for Protein- Ligand Binding. J Chem Theory Comput. 2021 ;17(4):2630-9. Epub 20210329. doi: 10.1021 / acs.jctc.1 c00136. PubMed PMID: 33779166.51. Choi WT, Tian S, Dong CZ, Kumar S, Liu D, Madani N, et al. Unique ligand binding sites on CXCR4 probed by a chemical biology approach: implications for the design of selective human immunodeficiency virus type 1 inhibitors. J Virol. 2005;79(24): 15398-404. doi: 10.1128 / JVI.79.24.15398-15404.2005. PubMed PMID: 16306611 ; PubMed Central PMCID: PMCPMC1316031.52. Cheng ZJ, Zhao J, Sun Y, Hu W, Wu YL, Cen B, et al. beta-arrestin differentially regulates the chemokine receptor CXCR4-mediated signaling and receptor internalization, and this implicates multiple interaction sites between beta-arrestin and CXCR4. J Biol Chem. 2000;275(4):2479-85. doi: 10.1074 / jbc.275.4.2479. PubMed PMID: 10644702.53. Lagane B, Chow KY, Balabanian K, Levoye A, Harriague J, Planchenault T, et al. CXCR4 dimerization and beta-arrestin-mediated signaling account for the enhanced chemotaxis to CXCL12 in WHIM syndrome. Blood. 2008; 112(1 ):34-44. Epub 20080424. doi: 10.1182 / blood-2007-07-102103. PubMed PMID: 18436740.54. Guo S, Zhao T, Yun Y, Xie X. Recent progress in assays for GPCR drug discovery. Am J Physiol Cell Physiol. 2022;323(2):C583-C94. Epub 20220711. doi: 10.1152 / ajpcell.00464.2021. PubMed PMID: 35816640.55. Zeghal M, Laroche G, Giguere PM. Parallel Interrogation of beta-Arrestin2 Recruitment for Ligand Screening on a GPCR-Wide Scale using PRESTO-Tango Assay. J Vis Exp. 2020;(157). Epub 20200310. doi: 10.3791 / 60823. PubMed PMID: 32225148.56. Bianchi ME, Mezzapelle R. The Chemokine Receptor CXCR4 in Cell Proliferation and Tissue Regeneration. Front Immunol. 2020; 11 :2109. Epub 20200828.doi: 10.3389 / fimmu.2020.02109. PubMed PMID: 32983169; PubMed Central PMCID: PMCPMC7484992.57. Ling L, Hou J, Liu D, Tang D, Zhang Y, Zeng Q, et al. Important role of the SDF- 1 / CXCR4 axis in the homing of systemically transplanted human amnion-derived mesenchymal stem cells (hAD-MSCs) to ovaries in rats with chemotherapy-induced premature ovarian insufficiency (POI). Stem Cell Res Then 2022;13(1 ):79. Epub 20220223. doi: 10.1186 / s13287-022-02759-6. PubMed PMID: 35197118; PubMed Central PMCID: PMCPMC8867754.58. Skroblyn T, Joedicke J J , Pfau M, Kruger K, Bourquin JP, Izraeli S, et al. CXCR4 mediates leukemic cell migration and survival in the testicular microenvironment. J Pathol. 2022;258(1 ):12-25. Epub 20220606. doi: 10.1002 / path.5924. PubMed PMID: 35522562.59. Fiegl M, Samudio I, Clise-Dwyer K, Burks JK, Mnjoyan Z, Andreeff M. CXCR4 expression and biologic activity in acute myeloid leukemia are dependent on oxygen partial pressure. Blood. 2009; 113(7): 1504-12. Epub 20081028. doi: 10.1182 / blood- 2008-06-161539. PubMed PMID: 18957686; PubMed Central PMCID: PMCPMC2644078.60. Song YB, Park CO, Jeong JY, Huh WK. Monitoring G protein-coupled receptor activation using an adenovirus-based beta-arrestin bimolecular fluorescence complementation assay. Anal Biochem. 2014;449:32-41. Epub 20131220. doi: 10.1016 / j.ab.2013.12.017. PubMed PMID: 24361713.61. Kroeze WK, Sassano MF, Huang XP, Lansu K, McCorvy JD, Giguere PM, et al. PRESTO-Tango as an open-source resource for interrogation of the druggable human GPCRome. Nat Struct Mol Biol. 2015;22(5):362-9. Epub 20150420. doi: 10.1038 / nsmb.3014. PubMed PMID: 25895059; PubMed Central PMCID: PMCPMC4424118.62. Gomes I, Sierra S, Devi LA. Detection of Receptor Heteromerization Using In Situ Proximity Ligation Assay. Curr Protoc Pharmacol. 2016;75:2 16 1-2 31. Epub 20161213. doi: 10.1002 / cpph.15. PubMed PMID: 27960030; PubMed Central PMCID: PMCPMC5758307.63. Park C, Lee JW, Kim K, Seen DS, Jeong JY, Huh WK. Simultaneous activation of CXC chemokine receptor 4 and histamine receptor H1 enhances calcium signaling and cancer cell migration. Sci Rep. 2023; 13(1 ): 1894. Epub 20230202. doi:10.1038 / S41598-023-28531-1. PubMed PMID: 36732336; PubMed Central PMCID: PMCPMC9895059.64. Jean-Charles PY, Kaur S, Shenoy SK. G Protein-Coupled Receptor Signaling Through beta-Arrestin-Dependent Mechanisms. J Cardiovasc Pharmacol. 2017;70(3): 142-58. doi: 10.1097 / FJC.0000000000000482. PubMed PMID: 28328745; PubMed Central PMCID: PMCPMC5591062.65. Ranjan R, Dwivedi H, Baidya M, Kumar M, Shukla AK. Novel Structural Insights into GPCR-beta-Arrestin Interaction and Signaling. Trends Cell Biol. 2017;27(11 ):851 - 62. Epub 20170623. doi: 10.1016 / j.tcb.2O17.05.008. PubMed PMID: 28651823.66. Smit MJ, Schlecht-Louf G, Neves M, van den Bor J, Penela P, Siderius M, et al. The CXCL12 / CXCR4 / ACKR3 Axis in the Tumor Microenvironment: Signaling, Crosstalk, and Therapeutic Targeting. Annu Rev Pharmacol Toxicol. 2021 ;61 :541-63. Epub 20200921. doi: 10.1146 / annurev-pharmtox-010919-023340. PubMed PMID: 32956018.67. Broxmeyer HE, Orschell CM, Clapp DW, Hangoc G, Cooper S, Plett PA, et al. Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist. J Exp Med. 2005;201 (8):1307-18. doi: 10.1084 / jem.20041385. PubMed PMID: 15837815; PubMed Central PMCID: PMCPMC2213145.68. Hoggatt J, Singh P, Tate TA, Chou BK, Datari SR, Fukuda S, et al. Rapid Mobilization Reveals a Highly Engraftable Hematopoietic Stem Cell. Cell. 2018;172(1 - 2):191-204 e10. Epub 20171207. doi: 10.1016 / j.cell.2O17.11 .003. PubMed PMID: 29224778; PubMed Central PMCID: PMCPMC5812290.69. Redpath AN, Francois M, Wong SP, Bonnet D, Rankin SM. Two distinct CXCR4 antagonists mobilize progenitor cells in mice by different mechanisms. Blood Adv. 2017;1 (22): 1934-43. Epub 20171010. doi: 10.1 182 / bloodadvances.2017006064. PubMed PMID: 29296840; PubMed Central PMCID: PMCPMC5728142.70. Challen GA, Boles N, Lin KK, Goodell MA. Mouse hematopoietic stem cell identification and analysis. Cytometry A. 2009;75(1 ): 14-24. doi: 10.1002 / cyto.a.20674. PubMed PMID: 19023891 ; PubMed Central PMCID: PMCPMC2640229.71. Purton LE. Adult murine hematopoietic stem cells and progenitors: an update on their identities, functions, and assays. Exp Hematol. 2022;116:1-14. Epub 20221023. doi: 10.1016 / j.exphem.2022.10.005. PubMed PMID: 36283572.72. Kronstein-Wiedemann R, Tonn T. Colony Formation: An Assay of Hematopoietic Progenitor Cells. Methods Mol Biol. 2019;2017:29-40. doi: 10.1007 / 978-1 -4939-9574-5_3. PubMed PMID: 31197766.73. Jorgensen AS, Daugvilaite V, De Filippo K, Berg C, Mavri M, Benned-Jensen T, et al. Biased action of the CXCR4-targeting drug plerixafor is essential for its superior hematopoietic stem cell mobilization. Commun Biol. 2021 ;4(1 ):569. Epub 20210512. doi: 10.1038 / S42003-021 -02070-9. PubMed PMID: 33980979; PubMed Central PMCID: PMCPMC8115334.74. Dale NC, Johnstone EKM, Pfleger KDG. GPCR heteromers: An overview of their classification, function and physiological relevance. Front Endocrinol (Lausanne). 2022;13:931573. Epub 20220830. doi: 10.3389 / fendo.2022.931573. PubMed PMID: 36111299; PubMed Central PMCID: PMCPMC9468249.75. Felce JH, MacRae A, Davis SJ. Constraints on GPCR Heterodimerization Revealed by the Type-4 Induced-Association BRET Assay. Biophys J. 2019;116(1 ):31-41 . Epub 20181 122. doi: 10.1016 / j.bpj.2018.09.034. PubMed PMID: 30558888; PubMed Central PMCID: PMCPMC6341220.76. Pin JP, Kniazeff J, Prezeau L, Liu JF, Rondard P. GPCR interaction as a possible way for allosteric control between receptors. Mol Cell Endocrinol. 2019;486:89-95. Epub 20190305. doi: 10.1016 / j.mce.2019.02.019. PubMed PMID: 30849406.77. Lan TH, Kuravi S, Lambert NA. Internalization dissociates beta2-adrenergic receptors. PLoS One. 2011 ;6(2):e17361 . Epub 20110222. doi: 10.1371 / journal. pone.0017361. PubMed PMID: 21364942; PubMed Central PMCID: PMCPMC3043075.78. Milligan G. G protein-coupled receptor hetero-dimerization: contribution to pharmacology and function. Br J Pharmacol. 2009;158(1 ):5-14. Epub 20090320. doi: 10.1111 / j.1476-5381.2009.00169.x. PubMed PMID: 19309353; PubMed Central PMCID: PMCPMC2795239.79. Alam MS. Proximity Ligation Assay (PLA). Methods Mol Biol. 2022;2422:191- 201. doi: 10.1007 / 978-1 -0716-1948-3_13. PubMed PMID: 34859407.80. Galaz-Montoya M, Wright SJ, Rodriguez GJ, Lichtarge O, Wensel TG. beta(2)- Adrenergic receptor activation mobilizes intracellular calcium via a non-canonical cAMP-independent signaling pathway. J Biol Chem. 2017;292(24):9967-74. Epub20170425. doi: 10.1074 / jbc.M117.7871 19. PubMed PMID: 28442571 ; PubMed Central PMCID: PMCPMC5473248.81. Nguyen AH, Thomsen ARB, Cahill TJ, 3rd, Huang R, Huang LY, Marcink T, et al. Structure of an endosomal signaling GPCR-G protein-beta-arrestin megacomplex. Nat Struct Mol Biol. 2019; 26( 12): 1 123-31 . Epub 20191118. doi: 10.1038 / s41594-019- 0330-y. PubMed PMID: 31740855; PubMed Central PMCID: PMCPMC7108872.82. Snoeck HW. Calcium regulation of stem cells. EMBO Rep. 2020;21 (6):e50028. Epub 20200517. doi: 10.15252 / embr.202050028. PubMed PMID: 32419314; PubMed Central PMCID: PMCPMC7271657.83. Fric J, Lim CX, Mertes A, Lee BT, Vigano E, Chen J, et al. Calcium and calcineurin-NFAT signaling regulate granulocyte-monocyte progenitor cell cycle via Flt3-L. Stem Cells. 2014;32(12):3232-44. doi: 10.1002 / stem.1813. PubMed PMID: 25100642; PubMed Central PMCID: PMCPMC4282522.84. Vater A, Sahlmann J, Kroger N, Zollner S, Lioznov M, Maasch C, et al. Hematopoietic stem and progenitor cell mobilization in mice and humans by a first-in- class mirror-image oligonucleotide inhibitor of CXCL12. Clin Pharmacol Ther. 2013;94(1): 150-7. Epub 20130319. doi: 10.1038 / clpt.2013.58. PubMed PMID: 23588307.85. Almeida-Neto C, Rocha V, Moreira FR, Hamasaki DT, Farias MC, Arrifano AM, et al. Validation of a formula predictive of peripheral blood stem cell yield and successful collection in healthy allogeneic donors. Hematol Transfus Cell Ther. 2020;42(2): 164-5 e5. Epub 20190723. doi: 10.1016 / j.htct.2O19.04.004. PubMed PMID: 31439517; PubMed Central PMCID: PMCPMC7248504.86. Abraham M, Biyder K, Begin M, Wald H, Weiss ID, Galun E, et al. Enhanced unique pattern of hematopoietic cell mobilization induced by the CXCR4 antagonist 4F-benzoyl-TN 14003. Stem Cells. 2007;25(9):2158-66. Epub 20070524. doi: 10.1634 / stemcells.2007-0161. PubMed PMID: 17525235.87. Lee H, Che J-H, Oh JE, Chung SS, Jung HS, Park KS. Bone marrow stem / progenitor cell mobilization in C57BL / 6J and BALB / c mice. lar. 2014;30(1 ): 14-20. doi: 10.5625 / lar.2014.30.1 .14.88. Alamo IG, Kannan KB, Bible LE, Loftus TJ, Ramos H, Efron PA, et al. Daily propranolol administration reduces persistent injury-associated anemia after severe trauma and chronic stress. J Trauma Acute Care Surg. 2017;82(4):714-21 . doi:10.1097 / TA.0000000000001374. PubMed PMID: 28099381 ; PubMed Central PMCID: PMCPMC5360508.89. Alamo IG, Kannan KB, Loftus TJ, Ramos H, Efron PA, Mohr AM. Severe trauma and chronic stress activates extramedullary erythropoiesis. J T rauma Acute Care Surg. 2017;83(1 ): 144-50. doi: 10.1097 / TA.0000000000001537. PubMed PMID: 28452894; PubMed Central PMCID: PMCPMC5484090.90. Miller ES, Apple CG, Kannan KB, Funk ZM, Efron PA, Mohr AM. The effects of selective beta-adrenergic blockade on bone marrow dysfunction following severe trauma and chronic stress. Am J Surg. 2020;220(5): 1312-8. Epub 20200725. doi: 10.1016 / j.amjsurg.2020.06.058. PubMed PMID: 32741547; PubMed Central PMCID: PMCPMC7680292.91. Johnsen AT, Tholstrup D, Petersen MA, Pedersen L, Groenvold M. Health related quality of life in a nationally representative sample of haematological patients. Eur J Haematol. 2009;83(2):139-48. Epub 20090305. doi: 10.1111 / j.1600- 0609.2009.01250.x. PubMed PMID: 19284418; PubMed Central PMCID: PMCPMC2730555.92. GPCR Therapeutics I. Ph2, Study to Assess the Safety and Efficacy of GPC100 and Propranolol With and Without G-CSF for the Mobilization of Stem Cells in Patients With Multiple Myeloma Undergoing Autologous Stem Cell Transplant (ClinicalTrials.gov Identifier: NCT05561751 ) https: / / cJinicaltrials.gov / ct2 / show / NCT055617517term-GPC-100&draw=2&rank- 12023 [updated February 16, 2023],Abraham M, Pereg Y, Bulvik B, Klein S, Mishalian I, Wald H, Eizenberg O, Beider K, Nagler A, Golan R, Vainstein A, Aharon A, Galun E, Caraco Y, Or R, Peled A. Single Dose of the CXCR4 Antagonist BL-8040 Induces Rapid Mobilization for the Collection of Human CD34+ Cells in Healthy Volunteers. Clin Cancer Res. 2017 Nov 15;23(22):6790-6801. doi: 10.1158 / 1078-0432. CCR-16-2919. Epub 2017 Aug 23. PMID: 28835380.AMD3100 or Plerixafor product label 2007. https: / / www.accessdata.fda.gov / drugsatfda_docs / label / 2017 / 02231 1 s018lbl.pdf Beyer J, et al. Hematopoietic rescue after high-dose chemotherapy using autologous peripheral-blood progenitor cells or bone marrow: a randomized comparison. J Clin Oncol. 1995;13(6):1328-35.Braadland et al., 2014. Braadland PR, Ramberg H, Grytli HH, Tasken KA. beta- Adrenergic Receptor Signaling in Prostate Cancer. Front Oncol. 2014;4:375. doi: 10.3389 / fonc.2014.00375Bushlin et al., 2012. Bushlin I, Gupta A, Stockton SD, Jr., Miller LK, Devi LA. Dimerization with cannabinoid receptors allosterical ly modulates delta opioid receptor activity during neuropathic pain. PLoS One. 2012;7(12):e49789. doi: 10.1371 / journal, pone.0049789Callen et al., 2012. Callen L, Moreno E, Barroso-Chinea P, et al. Cannabinoid receptors CB1 and CB2 form functional heteromers in brain. J Biol Chem. Jun 15 2012;287(25):20851 -65. doi: 10.1074 / jbc. M 111 .335273Cashen, A., Lazarus, H. & Devine, S. Mobilizing stem cells from normal donors: is it possible to improve upon G-CSF?. Bone Marrow Transplant 39, 577-588 (2007). https: / / doi.Org / 10.1038 / sj.bmt.1705616.Chatterjee et al., 2014. Chatterjee S, Behnam Azad B, Nimmagadda S. The intricate role of CXCR4 in cancer. Adv Cancer Res. 2014;124:31-82. doi: 10.1016 / B978-0-12- 411638-2.00002-1Choy et al., 2016. Choy C, Raytis JL, Smith DD, et al. Inhibition of beta2-adrenergic receptor reduces triple-negative breast cancer brain metastases: The potential benefit of perioperative beta-blockade. Oncol Rep. Jun 2016;35(6):3135-42. doi: 10.3892 / or.2016.4710Debnath et al., 2013. Debnath B, Xu S, Grande F, Garofalo A, Neamati N. Small molecule inhibitors of CXCR4. Theranostics. 2013;3(1):47-75. doi:10.7150 / thno.5376 Decaillot et al., 2008. Decaillot FM, Rozenfeld R, Gupta A, Devi LA. Cell surface targeting of mu-delta opioid receptor heterodimers by RTP4. Proc Natl Acad Sci U S A. Oct 14 2008; 105(41 ): 16045-50. doi:10.1073 / pnas.0804106105Decaillot et al., 2011. Decaillot FM, Kazmi MA, Lin Y, Ray-Saha S, Sakmar TP, Sachdev P. CXCR7 / CXCR4 heterodimer constitutively recruits beta-arrestin to enhance cell migration. J Biol Chem. Sep 16 2011 ;286(37):32188-97. doi: 10.1074 / jbc. M 111 .277038Devine SM, et al. Rapid mobilization of CD34+cells following administration of the CXCR4 antagonist AMD3100 to patients with multiple myeloma and non-Hodgkin's lymphoma. J Clin Oncol. 2004;22(6): 1095-102.DiPersio JF, Micallef IN, Stiff PJ, Bolwell BJ, Maziarz RT, Jacobsen E, et al. Phase III prospective randomized double-blind placebo-controlled trial of plerixafor plus granulocyte colony-stimulating factor compared with placebo plus granulocyte colonystimulating factor for autologous stem-cell mobilization and transplantation for patients with non-Hodgkin's lymphoma. J Clin Oncol. 2009b;27(28):4767-73. Epub 20090831. doi: 10.1200 / JCO.2008.20.7209. PubMed PMID: 19720922.DiPersio JF, Stadtmauer EA, Nademanee A, Micallef IN, Stiff PJ, Kaufman JL, et al. Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma. Blood. 2009a; 113(23):5720-6. Epub 20090410. doi: 10.1182 / blood-2008-08-174946. PubMed PMID: 19363221.Domanska et al. , 2013. Domanska UM, Kruizinga RC, Nagengast WB, et al. A review on CXCR4 / CXCL12 axis in oncology: no place to hide. Eur J Cancer. Jan 2013;49(1):219-30. doi:10.1016 / j.ejca.2012.05.005Ferre et al., 2009. Ferre S, Navarro G, Casado V, Cortes A, Mallol J, Canela El, et al. G protein-coupled receptor heteromers as new targets for drug development. Prog Mol Biol Transl Sci. 2010;91 :41 -52. doi: 10.1016 / S1877-1173(10)91002-8. PubMed PMID: 20691958.Fitzpatrick, 2004. Fitzpatrick JM. 'Urology: Today's Advances, Tomorrow's Clinical Practice', Cannes, November 2003. Current thinking in prostatic diseases: insights into dual 5alpha-reductase inhibitor therapy in BPH and prostate cancer. Prostate Cancer Prostatic Dis. 2004;7(2):91-2. doi: 10.1038 / sj.pcan.4500724Flomenberg N, et al. The use of AMD3100 plus G-CSF for autologous hematopoietic progenitor cell mobilization is superior to G-CSF alone. Blood. 2005;106(5): 1867-74.Frederick et al., 2015. Frederick AL, Yano H, Trifilieff P, et al. Evidence against dopamine D1 / D2 receptor heteromers. Mol Psychiatry. Nov 2015;20(11 ):1373-85. doi:10.1038 / mp.2014.166Fung J J, Chiou V, Lee J, et al. GPC-100 Is a Novel CXCR4 Inhibitor That Leads to Improved in Vitro Potency and In Vivo Efficacy in Stem Cell Mobilization When Combined with a Beta-Blocker. Blood. 2022; 140(Supplement 1 ):4489-4490.Gregorio et al., 2017. Gregorio GG, Masureel M, Hilger D, et al. Single-molecule analysis of ligand efficacy in beta(2)AR-G-protein activation. Nature. Jul 6 2017;547(7661 ):68-73. doi: 10.1038 / nature22354Guidotti et al., 2017. Guidotti G, Brambilla L, Rossi D. Cell-Penetrating Peptides: From Basic Research to Clinics. Trends Pharmacol Sci. Apr 2017;38(4):406-424. doi: 10.1016 / j.tips.2017.01.003Gurevich Frontiers in Pharmacology 2019. Gurevich VV, Gurevich EV. GPCR Signaling Regulation: The Role of GRKs and Arrestins. Front Pharmacol. 2019; 10: 125. doi:10.3389 / fphar.2019.00125Hansen et al. , 2009. Hansen JL, Hansen JT, SpeerschneiderT, et al. Lack of evidence for AT 1 R / B2R heterodimerization in COS-7, HEK293, and NIH3T3 cells: how common is the AT1 R / B2R heterodimer? J Biol Chem. Jan 16 2009;284(3):1831-9. doi: 10.1074 / jbc. M804607200Hartmann O, et al. Peripheral blood stem cell and bone marrow transplantation for solid tumors and lymphomas: hematologic recovery and costs. A randomized, controlled trial. Ann Intern Med. 1997;126(8):600-7.Hubei K, et al. European data on stem cell mobilization with plerixafor in nonHodgkin’s lymphoma, Hodgkin’s lymphoma, and multiple myeloma patients. A subgroup analysis of the European Consortium of stem cell mobilization. Bone Marrow Transplant. 2012; 47: 1046-1050.Korbling M and Anderlini P. Peripheral blood stem cell versus bone marrow allotransplantation: does the source of hematopoietic stem cells matter? Blood. 2001 ;98(10):2900-8.Kristensen et al., 2016. Kristensen M, Nielsen HM. Cell-penetrating peptides as tools to enhance non-injectable delivery of biopharmaceuticals. Tissue Barriers. Apr-Jun 2016;4(2):e1178369. doi: 10.1080 / 21688370.2016.1178369Kroeze et al., 2015. Kroeze WK, Sassano MF, Huang XP, et al. PRESTO-Tango as an open-source resource for interrogation of the druggable human GPCRome. Nat Struct Mol Biol. May 2015;22(5):362-9. doi:10.1038 / nsmb.3014LaRocca et al., 2010. LaRocca TJ, Schwarzkopf M, Altman P, et al. beta2-Adrenergic receptor signaling in the cardiac myocyte is modulated by interactions with CXCR4. J Cardiovasc Pharmacol. Nov 2010;56(5):548-59. doi : 10.1097 / FJC.0b013e3181 f713fe Law et al., 2005. Law HK, Cheung CY, Ng HY, et al. Chemokine up-regulation in SARS-coronavirus-infected, monocyte-derived human dendritic cells. Blood. Oct 1 2005;106(7):2366-74. doi: 10.1 182 / blood-2004-10-4166Leonard, Alexis; Weiss, Mitchell J.. Hematopoietic stem cell collection for sickle cell disease gene therapy. Current Opinion in Hematology 31 (3):p 104-114, May 2024. | DOI: 10.1097 / MOH.0000000000000807Liang J, Seghiri M, Singh PK, Seo HG, Lee JY, Jo Y, Song YB, Park C, Zalicki P, Jeong JY, Huh WK, Caculitan NG, Smith AW. The p2-adrenergic receptor associates with CXCR4 multimers in human cancer cells. Proc Natl Acad Sci U S A. 2024 Apr 2;121 (14):e2304897121. doi: 10.1073 / pnas.2304897121 . Epub 2024 Mar 28. PMID: 38547061 ; PMCID: PMC10998613.Liles WC, et al. Augmented mobilization and collection of CD34+hematopoietic cells from normal human volunteers stimulated with granulocyte-colony-stimulating factor by single-dose administration of AMD3100, a CXCR4 antagonist. Transfusion. 2005;45(3):295-300.Lohse et al., 2012. Lohse MJ, Nuber S, Hoffmann C. Fluorescence / bioluminescence resonance energy transfer techniques to study G-protein-coupled receptor activation and signaling. Pharmacol Rev. Apr 2012;64(2):299-336. doi: 10.1124 / pr.110.004309 Peled et al., 2012. Peled A, Wald O, Burger J. Development of novel CXCR4-based therapeutics. Expert Opin Investig Drugs. Mar 2012;21 (3):341-53. doi: 10.1517 / 13543784.2012.656197Pello et al., 2008. Pello R, Martin MA, Carelli V, et al. Mitochondrial DNA background modulates the assembly kinetics of OXPHOS complexes in a cellular model of mitochondrial disease. Hum Mol Genet. Dec 15 2008;17(24):4001-11 . doi:10.1093 / hmg / ddn303Pfeiffer et al., 2002. Pfeiffer M, Koch T, Schroder H, Laugsch M, Hollt V, Schulz S. Heterodimerization of somatostatin and opioid receptors cross-modulates phosphorylation, internalization, and desensitization. J Biol Chem. May 31 2002;277(22): 19762-72. doi: 10.1074 / jbc. M 110373200Pfleger and Eidne, 2006. Pfleger KD, Seeber RM, Eidne KA. Bioluminescence resonance energy transfer (BRET) for the real-time detection of protein-protein interactions. Nat Protoc. 2006;1 (1):337-45. doi:10.1038 / nprot.2006.52Purton Experimental Hematology, 2022. urton LE. Adult murine hematopoietic stem cells and progenitors: an update on their identities, functions, and assays. Exp Hematol. Dec 2022;116:1-14. doi:10.1016 / j.exphem.2022.10.005Rios et al., 2006. Rios C, Gomes I, Devi LA. mu opioid and CB1 cannabinoid receptor interactions: reciprocal inhibition of receptor signaling and neuritogenesis. Br J Pharmacol. Jun 2006;148(4):387-95. doi:10.1038 / sj.bjp.0706757Roccaro et al., 2014. Roccaro AM, Sacco A, Jimenez C, et al. C1013G / CXCR4 acts as a driver mutation of tumor progression and modulator of drug resistance in lymphoplasmacytic lymphoma. Blood. Jun 26 2014;123(26):4120-31 . doi:10.1182 / blood-2014-03-564583Schots R, et al. The absolute number of circulating CD34+cells predicts the number of hematopoietic stem cells that can be collected by apheresis. Bone Marrow Transplant. 1996;17(4):509-15.Schwella N, et al. Impact of preleukapheresis cell counts on collection results and correlation of progenitor-cell dose with engraftment after high-dose chemotherapy in patients with germ cell cancer. J Clin Oncol. 1996;14(4): 1114-21. Smith TJ, et al. Economic analysis of a randomized clinical trial to compare filgrastim-mobilized peripheral-blood progenitor-cell transplantation and autologous bone marrow transplantation in patients with Hodgkin's and non-Hodgkin's lymphoma. J Clin Oncol. 1997; 15(1 ):5-10.Stefan et al., 2007. tefan E, Wiesner B, Baillie GS, et al. Compartmentalization of cAMP-dependent signaling by phosphodiesterase-4D is involved in the regulation of vasopressin-mediated water reabsorption in renal principal cells. J Am Soc Nephrol. Jan 2007; 18(1): 199-212. doi:10.1681 / ASN.2006020132Sukhtankar, 2023a. Sukhtankar DD, Fung JJ, Kim MN, et al. GPC-100, a novel CXCR4 antagonist, improves in vivo hematopoietic cell mobilization when combined with propranolol. PLoS One. 2023; 18(10):e0287863. doi: 10.1371 / journal, pone.0287863Sukhtankar, 2023b. Sukhtankar DD, Chang LW, Tsai CY, Cardarelli PM, Caculitan NG. Pharmacokinetics and Pharmacodynamics of Burixafor Hydrobromide (GPC-100), a Novel C-X-C Chemokine Receptor 4 Antagonist and Mobilizer of Hematopoietic Stem / Progenitor Cells, in Mice and Healthy Subjects. Clin Pharmacol Drug Dev. Nov 2023; 12(11 ): 1114-1120. doi: 10.1002 / cpdd.1302To LB, et al. The biology and clinical uses of blood stem cells. Blood. 1997;89(7):2233- 58.Vose JM, et al. Autologous transplantation for aggressive non-Hodgkin's lymphoma: results of a randomized trial evaluating graft source and minimal residual disease. J Clin Oncol. 2002;20(9):2344-52.Walenkamp et al., 2017. 1. Walenkamp AME, Lapa C, Herrmann K, Wester HJ. CXCR4 Ligands: The Next Big Hit? J Nucl Med. Sep 2017;58(Suppl 2):77S-82S. doi: 10.2967 / jnumed.116.186874Wang et al., 2015a. Wang LP, Jin J, Lv FF, et al. Norepinephrine attenuates CXCR4 expression and the corresponding invasion of MDA-MB-231 breast cancer cells via beta2-adrenergic receptors. Eur Rev Med Pharmacol Sci. Apr 2015; 19(7): 1170-81 .Xu et al., 2017. Xu X, Li D, Li X, Shi Q, Ju X. Mesenchymal stem cell conditioned medium alleviates oxidative stress injury induced by hydrogen peroxide via regulating miR143 and its target protein in hepatocytes. BMC Immunol. Dec 19 2017; 18(1 ):51 . doi: 10.1186 / s12865-017-0232-xENUMERATED EMBODIMENTSEmbodiment 1 . A method of mobilizing a cell in a subject, the method comprising: blocking CXCR4 signaling and beta-adrenergic receptor signaling in the subject.Embodiment 2. A method of inducing cell mobilization in a subject, the method comprising: blocking CXCR4 signaling and beta-adrenergic receptor signaling in the subject.Embodiment 3. A method of enhancing apheresis by inducing cell mobilization in a subject, the method comprising: blocking CXCR4 signaling and beta-adrenergic receptor signaling in the subject.Embodiment 4. A method of enhancing apheresis by mobilizing a cell in a subject, the method comprising: blocking CXCR4 signaling and beta-adrenergic receptor signaling in the subject.Embodiment 5. The method of any of embodiments 1-4, wherein the cell is a stem cell.Embodiment 6. The method of any of embodiments 1-5, wherein the cell is a LSK (Lin-Sca1 +c-Kit+) cell.Embodiment 7. The method of embodiment 6, wherein the LSK cell is a longterm repopulating hematopoietic stem cell (LT-HSC).Embodiment 8. The method of embodiment 7, wherein the LT-HSC is aCD150+, CD34-, or CD48+ LSK cell.Embodiment 9. The method of any of embodiments 1-8, wherein the blocking CXCR4 signaling comprises administration of a CXCR4 inhibitor to the subject. Embodiment 10. The method of embodiment 9, wherein the CXCR4 inhibitor forms an ionic interaction with Arg 188 on CXCR4.Embodiment 11. The method of embodiment 9 or 10, wherein the CXCR4 inhibitor forms a hydrogen bond with Gln200 on CXCR4.Embodiment 12. The method of any one of embodiments 9-11 , wherein the CXCR4 inhibitor has a higher binding affinity to CXCL12 than AMD3100.Embodiment 13. The method of any one of embodiments 9-12, wherein the CXCR4 inhibitor has a lower inhibitory constant (Ki) than AMD3100.Embodiment 14. The method of any one of embodiments 9-13, wherein the CXCR4 inhibitor has at least a 2-fold lower inhibitory constant than AMD3100. Embodiment 15. The method of any one of embodiments 9-14, wherein the CXCR4 inhibitor inhibits CXCL12-induced calcium flux at an equal or greater level as AMD3100.Embodiment 16. The method of any one of embodiments 9-15, wherein the CXCR4 inhibitor inhibits CXCL12-induced p-arrestin recruitment at an equal or greater level as AMD3100.Embodiment 17. The method of any one of embodiments 9-16, wherein the CXCR4 inhibitor inhibits CXCL12-induced migration of cancer cells at an equal or greater level as AMD3100.Embodiment 18. The method of any one of embodiments 9-17, wherein the CXCR4 inhibitor inhibits CXCL12-induced migration of LI937 and MM.1S cells at an equal or greater level as AMD3100.Embodiment 19. The method of any one of embodiments 9-18, wherein the CXCR4 inhibitor inhibits calcium flux induced by CXCL12 and epinephrine. Embodiment 20. The method of any one of embodiments 9-19, wherein the blocking of the beta-adrenergic receptor signaling inhibits calcium flux and / or cell migration induced by CXCL12 and epinephrine.Embodiment 21. The method of any one of any one of embodiments 9-19, wherein the blocking of the propranolol inhibits calcium flux and / or cell migration induced by CXCL12 and epinephrine.Embodiment 22. The method of any one of embodiments 1-21 , wherein blocking CXCR4 signaling and beta-adrenergic receptor signaling in the subject induces an enhanced amount of long-term repopulating hematopoietic stem cell (LT-HSC) mobilization relative to the amount of LT-HSC mobilization induced by the CXCR4 inhibitor and G-CSF only.Embodiment 23. The method of any one of embodiments 1-22, wherein blocking CXCR4 signaling and beta-adrenergic receptor signaling in the subject mobilizes a LT-HSC by an amount enhanced relative to the amount of LT-HSC mobilization induced by the CXCR4 inhibitor and G-CSF only.Embodiment 24. The method of any one of embodiments 22 or 23, wherein the LT-HSC expresses CD150.Embodiment 25. The method of any one of embodiments 22 or 23, wherein the LT-HSC does not express CD34.Embodiment 26. The method of any one of embodiments 22 or 23, wherein the LT-HSC expresses CD48.Embodiment 27. The method of any one of embodiments 1-26, further comprising administration of G-CSF.Embodiment 28. The method of embodiment 27, wherein the CXCR4 inhibitor, the beta-adrenergic receptor inhibitor, and the G-CSF induces an enhanced amount of cell mobilization relative to the amount of cell mobilization induced by the CXCR4 inhibitor and G-CSF only.Embodiment 29. The method of embodiment 27, wherein the CXCR4 inhibitor, the beta-adrenergic receptor inhibitor, and the G-CSF mobilizes a cell by an amount enhanced relative to the amount of cell mobilization induced by the CXCR4 inhibitor and G-CSF only.Embodiment 30. The method of any one of embodiments 1-29, wherein the blocking beta-adrenergic receptor signaling is performed before the blocking CXCR4 signaling.Embodiment 31. The method of any one of embodiments 1 -30, wherein the blocking beta-adrenergic receptor signaling continues after the blocking CXCR4 signaling is terminated.Embodiment 32. The method of any one of embodiments 1-31 , wherein the blocking CXCR4 signaling comprises administration of a CXCR4 inhibitor to the subject.Embodiment 33. The method of any one of embodiments 1-32, wherein the blocking beta-adrenergic receptor signaling comprises administration of a beta- adrenergic receptor inhibitor to the subject.Embodiment 34. The method of embodiment 33, wherein the beta-adrenergic receptor inhibitor is an ADRB2 inhibitor.Embodiment 35. The method of any one of embodiments 33 or 34, wherein the beta-adrenergic receptor inhibitor is selected from the group consisting of alprenolol, atenolol, betaxolol, bupranolol, butoxamine, carazolol, carvedilol, CGP 12177, cicloprolol, ICI 118551 , ICYP, labetalol, levobetaxolol, levobunolol, LK 204-545, metoprolol, nadolol, NIHP, NIP, propafenone, propranolol, sotalol, SR59230A, and timolol.Embodiment 36. The method of embodiment 35, wherein the beta-adrenergic receptor inhibitor is selected from the group consisting of propranolol, nadolol, and ICI 118551.Embodiment 37. The method of embodiment 36, wherein the beta-adrenergic receptor inhibitor is propranolol.Embodiment 38. The method of any one of embodiments 9-37, wherein the CXCR4 inhibitor is selected from the group consisting of ALX40-4C, AMD070 (AMD11070, X4P-001 ), AMD3100 (Plerixafor, or Mozobil), AMD3465, ATI 2341 , BKT140 (BL-8040; TF14016; 4F-Benzoyl-TN 14003), CTCE-9908, CX549, D-[Lys3] GHRP-6, FC122, FC131 , GMI-1359, GSK812397, GSTNT21 MP, isothiourea-1 a, isothiourea-1 t (IT1t), KRH-1636, KRH-3955, LY2510924, MSX-122, N-[11C]Methyl- AMD3465, POL6326, SDF-1 l-9[P2G] dimer, SDFI P2G, T134, T140, T22, TC 14012, GPC-100 (Burixafor, or TG-0054), USL311 , viral macrophage inflammatory protein-ll (vMIP-11), WZ811 , [64Cu]-AMD3100, [64Cu]-AMD3465, [68Ga]pentixafor, [90Y]pentixather, [99mTc]02-AMD3100, [177Lu]pentixather, Ulocuplumab (MDX1338 / BMS-936564), AD-214, LY2624587, PF-06747143, POL6326. MB1707, and 508MC1 (Compound 26).Embodiment 39. The method of embodiment 38, wherein the CXCR4 inhibitor is selected from the group consisting of AD-214, AMD070 (AMD11070, X4P-001),AMD3100 (Plerixafor, or Mozobil), BKT140 (BL-8040; TF14016; 4F-Benzoyl- TN14003), CTCE-9908, LY2510924, LY2624587, T140, GPC-100 (Burixafor, or TG- 0054), PF-06747143, POL6326, and ulocuplumab (MDX1338 / BMS-936564).Embodiment 40. The method of embodiment 39, wherein the CXCR4 inhibitor is GPC-100 (Burixafor, or TG-0054).Embodiment 41. The method of embodiment 39, wherein the CXCR4 inhibitor is AMD3100 (Plerixafor, or Mozobil).Embodiment 42. The method of embodiment 39, wherein the CXCR4 inhibitor is ulocuplumab (MDX1338 / BMS-936564).Embodiment 43. The method of any one of embodiments 33-42, wherein the administration of the CXCR4 inhibitor and beta-adrenergic receptor inhibitor to the subject comprises administration of GPC-100 (Burixafor, or TG-0054) and propranolol.Embodiment 44. The method of any one of embodiments 33-42, wherein the administration of the CXCR4 inhibitor beta-adrenergic receptor inhibitor to the subject comprises administration of AMD3100 (Plerixafor, or Mozobil) and propranolol.Embodiment 45. The method of any one of embodiments 33-42, wherein the administration of the CXCR4 inhibitor beta-adrenergic receptor inhibitor to the subject comprises administration of ulocuplumab (MDX1338 / BMS-936564) and propranolol.Embodiment 46. The method of any one of embodiments 27-42, wherein the administration of a combination of the CXCR4 inhibitor and the G-CSF induces an enhanced amount of cell mobilization relative to the amount of cell mobilization induced by the CXCR4 inhibitor only.Embodiment 47. The method of any one of embodiments 27-42, wherein the administration of a combination of the CXCR4 inhibitor and the G-CSF mobilizes a cell by an amount enhanced relative to the amount of cell mobilization induced by the CXCR4 inhibitor only.Embodiment 48. The method of any one of embodiments 27-42, wherein the administration of a combination of the CXCR4 inhibitor and the G-CSF induces an enhanced amount of apheresis relative to the amount of apheresis induced by the CXCR4 inhibitor only.Embodiment 49. The method of any one of embodiments 27-42, wherein the administration of a combination of the CXCR4 inhibitor and the beta-adrenergic receptor inhibitor induces an enhanced amount of cell mobilization relative to the amount of cell mobilization induced by the CXCR4 inhibitor only.Embodiment 50. The method of any one of embodiments 27-42, wherein the administration of a combination of the CXCR4 inhibitor and the beta-adrenergic receptor inhibitor mobilizes a cell by an amount enhanced relative to the amount of cell mobilization induced by the CXCR4 inhibitor only.Embodiment 51. The method of any one of embodiments 27-42, wherein the administration of a combination of the CXCR4 inhibitor and the beta-adrenergic receptor inhibitor induces an enhanced amount of apheresis relative to the amount of apheresis induced by the CXCR4 inhibitor only.Embodiment 52. The method of any one of embodiments 27-42, wherein the administration of a combination of the CXCR4 inhibitor, the beta-adrenergic receptor inhibitor, and the G-CSF induces an enhanced amount of cell mobilization relative to the amount of cell mobilization induced by the CXCR4 inhibitor and the beta- adrenergic receptor inhibitor only.Embodiment 53. The method of any one of embodiments 27-42, wherein the administration of a combination of the CXCR4 inhibitor, the beta-adrenergic receptor inhibitor, and the G-CSF mobilizes a cell by an amount enhanced relative to the amount of cell mobilization induced by the CXCR4 inhibitor and the beta-adrenergic receptor inhibitor only.Embodiment 54. The method of any one of embodiments 27-42, wherein the administration of a combination of the CXCR4 inhibitor and the beta-adrenergic receptor inhibitor, and the G-CSF induces an enhanced amount of apheresis relative to the amount of apheresis induced by the CXCR4 inhibitor and the beta-adrenergic receptor inhibitor only.Embodiment 55. The method of any one of embodiments 27-42, wherein the administration of a combination of GPC-100 (Burixafor, or TG-0054) and the G-CSF induces an enhanced amount of cell mobilization relative to the amount of cell mobilization induced by AMD3100 (Plerixafor, or Mozobil) and the G-CSF.Embodiment 56. The method of any one of embodiments 27-42, wherein the administration of a combination of the GPC-100 (Burixafor, or TG-0054) and the G-CSF mobilizes a cell by an amount enhanced relative to the amount of cell mobilization induced by the AMD3100 (Plerixafor, or Mozobil) and the G-CSF. Embodiment 57. The method of any one of embodiments 27-42, wherein the administration of a combination of the GPC-100 (Burixafor, or TG-0054) and the G- CSF induces an enhanced amount of apheresis relative to the amount of apheresis induced by the AMD3100 (Plerixafor, or Mozobil) and the G-CSF.Embodiment 58. The method of any one of embodiments 47-57, wherein an enhanced amount of cell mobilization or apheresis is measured by a method selected from the group consisting of complete blood count (CBC) analysis, flow cytometry, and colony forming unit (CFU) assay.Embodiment 59. The method of embodiment 58, wherein the enhanced amount of cell mobilization or apheresis is measured by flow cytometry.Embodiment 60. The method of embodiment 59, wherein the flow cytometry is performed on (Lin-Scal+c-Kit+) LSK cells.Embodiment 61 . The method of embodiment 58, wherein the enhanced amount of cell mobilization or apheresis is measured by colony forming unit (CFU) assay. Embodiment 62. The method of any one of embodiments 1-61 , wherein the subject has a CXCR4 protomer in the cell.Embodiment 63. The method of any one of embodiments 1-62, wherein the subject has an ADRB2 protomer in the cell.Embodiment 64. The method of any one of embodiments 1-63, wherein the subject has a CXCR4 protomer and an ADRB2 protomer in the cell.Embodiment 65. The method of embodiment 64, wherein the subject has a CXCR4-ADRB2 heteromer in the cell.Embodiment 66. The method of embodiment 65, wherein: i) the CXCR4-ADRB2 heteromer has an enhanced amount of downstream calcium mobilization relative to downstream calcium mobilization from a CXCR4 protomer or ADRB2 protomer; and ii) the administered combination of inhibitors suppresses the enhanced downstream calcium mobilization from said CXCR4-ADRB2 heteromer in the stem cell.Embodiment 67. The method of any one of embodiments 5-66, wherein the stem cell is selected from the group consisting of a hematopoietic stem cell, a hematopoietic progenitor cell, a mesenchymal stem cell, an endothelial progenitorcell, a neural stem cell, an epithelial stem cell, a skin stem cell, and a cancer stem cell.Embodiment 68. The method of embodiment 67, wherein the stem cell is a hematopoietic stem cell or a hematopoietic progenitor cell.Embodiment 69. The method of embodiment 68, wherein the hematopoietic stem cell or the hematopoietic progenitor cell is mobilized from bone marrow to peripheral blood (PB).Embodiment 70. The method of embodiment 69, wherein the mobilized hematopoietic stem cell or hematopoietic progenitor cell is collected for transplantation to a patient having cancer.Embodiment 71. The method of embodiment 70, wherein the cancer is selected from the group consisting of lymphoma, leukemia, and myeloma.Embodiment 72. The method of embodiment 71 , wherein the cancer is nonHodgkin’s lymphoma (NHL), Hodgkin’s Disease (HD) or Hodgkin’s Lymphoma (HL), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), multiple myeloma (MM), or Burkitt’s Lymphoma.Embodiment 73. The method of any one of embodiments 5-66, wherein the stem cell is a mesenchymal stem cell.Embodiment 74. The method of embodiment 73, wherein the mesenchymal stem cell is mobilized from bone marrow to PB.Embodiment 75. The method of embodiment 74, wherein the mesenchymal stem cell is mobilized for treatment of a condition selected from the group consisting of neurological disorder, cardiac ischemia, myocardial infarction, diabetes, tissue repair, bone and cartilage disease, autoimmune disease, graft versus host disease, Crohn’s disease, multiple sclerosis, systemic lupus erythematosus, and systemic sclerosis.Embodiment 76. The method of any one of embodiments 5-66, wherein the stem cell is a cancer stem cell.Embodiment 77. The method of embodiment 76, wherein the cancer stem cell is mobilized into blood.Embodiment 78. The method of embodiment 76 or 77, wherein the cancer stem cell is mobilized for treatment of a cancer.Embodiment 79. The method of any one of embodiments 5-66, wherein the cell is an immune cell.Embodiment 80. The method of embodiment 79, wherein the immune cell is a white blood cell (WBC).Embodiment 81. The method of embodiment 80, wherein the WBC is a lymphocyte.Embodiment 82. The method of embodiment 81 , wherein the lymphocyte is selected from the group consisting of a T cell, a B cell, and a natural killer (NK) cell.Embodiment 83. The method of embodiment 82, wherein the lymphocyte is a T cell.Embodiment 84. The method of embodiment 82, wherein the lymphocyte is a natural killer (NK) cell.Embodiment 85. The method of embodiment 80, wherein the WBC is a granulocyte.Embodiment 86. The method of embodiment 85, wherein the granulocyte is selected from the group consisting of a neutrophile, an eosinophile, and a basophile.Embodiment 87. The method of embodiment 86, wherein the granulocyte is a neutrophile.Embodiment 88. The method of embodiment 81 , wherein the WBC is a monocyte.Embodiment 89. The method of any one of embodiments 79-88, wherein the immune cell is mobilized from bone marrow to PB.Embodiment 90. The method of any one of claims 79-88, wherein the immune cell is mobilized from spleen to PB.Embodiment 91. The method of any one of claims 79-88, wherein the immune cell is mobilized from thymus to PB.Embodiment 92. The method of any one of embodiments 79-88, wherein the immune cell is mobilized from lymph node to PB.Embodiment 93. The method of any one of embodiments 79-88, wherein the mobilized immune cell is used for adoptive cell therapy (ACT).Embodiment 94. The method of embodiment 93, wherein the adoptive cell therapy (ACT) is chimeric antigen receptor (CAR) T cell therapy.Embodiment 95. The method of embodiment 93, wherein the adoptive cell therapy (ACT) is netural killer (NK) cell therapy.Embodiment 96. The method of embodiment 93, wherein the adoptive cell therapy (ACT) is engineered T-cell receptor (TCR) therapy.Embodiment 97. The method of embodiment 93, wherein the adoptive cell therapy (ACT) is tumor-infiltrating lymphocyte (TIL) therapy.Embodiment 98. A method of preparing a subject for a treatment, the method comprising: blocking a CXCR4 in the subject, blocking a beta-adrenergic receptor in the subject, or blocking the CXCR4 inhibitor and the beta-adrenergic receptor in the subject.Embodiment 99. The method of embodiment 98, wherein the blocking of the CXCR4 is achieved through an ionic interaction with Arg188 on CXCR4; and / or wherein the blocking of the CXCR4 is achieved through a hydrogen bond with Gln200 on CXCR4; and / or any combination thereof.Embodiment 100. A method of treatment to a subject in need thereof, the method comprising: blocking a CXCR4 in the subject, blocking a beta-adrenergic receptor in the subject, or blocking the CXCR4 inhibitor and the beta-adrenergic receptor in the subject.Embodiment 101 . The method of embodiment 100, wherein the blocking of the CXCR4 is achieved through an ionic interaction with Arg188 on CXCR4; and / or wherein the blocking of the CXCR4 is achieved through a hydrogen bond with Gln200 on CXCR4; and / or any combination thereof.Embodiment 102. A method of preparing a subject for a treatment, the method comprising administering an effective amount of: a CXCR4 inhibitor, a beta-adrenergic receptor inhibitor, or a combination thereof.Embodiment 103. A method to qualify a subject for treatment, the method comprising administering an effective amount of:a CXCR4 inhibitor, a beta-adrenergic receptor inhibitor, or a combination thereof.Embodiment 104. A method of treatment to a subject in need thereof, the method comprising administering an effective amount of: a CXCR4 inhibitor, a beta-adrenergic receptor inhibitor, or a combination thereof.Embodiment 105. Use of GPC-100 for the manufacture of a medicament for the treatment of a cancer, or a neurological disorder, or any combination thereof.Embodiment 106. The method of any one of embodiment 98 to the embodiment immediately above, wherein the treatment further comprises administering an effective amount of: a beta-adrenergic receptor inhibitor, or a G-CSF, or a lenalidomide, or a daratumumab, or a velacade, or a dexamethasone, or a cyclophosphamide, or bortezombil, or combinations thereof.Embodiment 107. The method of any one of embodiment 98 to the embodiment immediately above, wherein the subject is pre-treated with an administration of an effective amount of: a beta-adrenergic receptor inhibitor, or a G-CSF, or a lenalidomide, or a daratumumab, or a velacade, or a dexamethasone, or a cyclophosphamide, or bortezombil, orcombinations thereof.Embodiment 108. The method of any one of embodiment 98 to the embodiment immediately above, wherein the treatment comprises one or more of: an apheresis step; or a leukapheresis step; or a peripheral blood collection step; or a cell transplant step, wherein the cell is optionally a stem cell, wherein the cell is optionally a hematopoietic progenitor cell (HSC), wherein the cell is optionally a T cell, or combinations thereof; and / or a CAR-T therapy step; or a combinations thereof.Embodiment 109. The method of any one of embodiment 98 to the embodiment immediately above, further comprising administering of an effective amount of G-CSF. Embodiment 110. The method of any one of embodiments 98 to the embodiment immediately above, wherein the subject present symptoms of or is diagnosed with a cancer, or a neurological disorder, or any combination thereof; and / or wherein the cancer is selected from the group consisting of lymphoma, leukemia, and myeloma; and / or wherein the subject present symptoms of or is diagnosed with a hematologic malignancy; and / or wherein the cancer is selected from the group consisting of non-Hodgkin's lymphoma (NHL), Hodgkin's Disease (HD) or Hodgkin's Lymphoma (HL), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), multiple myeloma (MM), Burkitt's Lymphoma; and / or wherein the cancer is HD; and / or wherein the cancer is NHL; and / or wherein the cancer is AML; and / or wherein the cancer is ALL; and / or wherein the cancer is MM; and / or wherein the neurological disorder is selected from the group consisting of neurological disorder, cardiac ischemia, myocardial infarction, diabetes, tissue repair,bone and cartilage disease, autoimmune disease, graft versus host disease, Crohn’s disease, multiple sclerosis, systemic lupus erythematosus, and systemic sclerosis; and / or wherein the subject is a human.Embodiment 111. The method of any one of embodiments 98 to the embodiment immediately above, wherein the subject is in need of Autologous Stem Cell Transplant (ASCT); wherein the treatment is Autologous Stem Cell Transplant (ASCT).Embodiment 112. The method of any one of embodiments 98 to the embodiment immediately above, wherein: the CXCR4 inhibitor forms an ionic interaction with Arg188 on CXCR4, or the CXCR4 inhibitor forms a hydrogen bond with Gln200 on CXCR4, or any combination thereof; and / or wherein: the CXCR4 inhibitor has a higher binding affinity to CXCL12 than AMD3100, or the CXCR4 inhibitor has a lower inhibitory constant (Ki) than AMD3100, or the CXCR4 inhibitor has at least a 2-fold lower inhibitory constant than AMD3100.Embodiment 113. The method of any one of embodiments 98 to the embodiment immediately above, wherein the CXCR4 inhibitor: is selected from the group consisting of ALX40-4C, AMD070 (AMD11070, X4P-001 ), AMD3100 (Plerixafor, or Mozobil), AMD3465, ATI 2341 , BKT140 (BL-8040; TF14016; 4F-Benzoyl-TN 14003), CTCE-9908, CX549, D-[Lys3] GHRP-6, FC122, FC131 , GMI-1359, GSK812397, GSTNT21 MP, isothiourea-1 a, isothiourea-11 (IT1t), KRH-1636, KRH-3955, LY2510924, MSX-122, N-[1 ICJMethyl- AMD3465, POL6326, SDF-1 l-9[P2G] dimer, SDFI P2G, T134, T140, T22, TC 14012, GPC-100 (Burixafor, or TG-0054), LISL311 , viral macrophage inflammatory protein-ll (vMIP-11), WZ811 , [64Cu]-AMD3100, [64Cu]-AMD3465, [68Ga]pentixafor,[90Y]pentixather, [99mTc]02-AMD3100, [177Lu]pentixather, Ulocuplumab (MDX1338 / BMS-936564), AD-214, LY2624587, PF-06747143, POL6326, MB1707, 508MC1 (Compound 26), and the derivatives and similars thereof, and / or is selected from the group consisting of AD-214, AMD070 (AMD11070, X4P-001), AMD3100 (Plerixafor, or Mozobil), BKT140 (BL-8040; TF14016; 4F- Benzoyl-TN14003), CTCE-9908, LY2510924, LY2624587, T140, GPC-100 (Burixafor, or TG-0054), PF-06747143, POL6326, and ulocuplumab (MDX1338 / BMS-936564), and the derivatives and similars thereof; and / or is ulocuplumab (MDX1338 / BMS-936564); and / or is AMD3100 (Plerixafor, or Mozobil); and / or is BL8040; and / or is GPC-100 (Burixafor, or TG-0054); and / or wherein the beta-adrenergic receptor inhibitor: is an ADRB2 inhibitor, and / or is selected from the group consisting of alprenolol, atenolol, betaxolol, bupranolol, butoxamine, carazolol, carvedilol, CGP 12177, cicloprolol, ICI 118551 , ICYP, labetalol, levobetaxolol, levobunolol, LK 204-545, metoprolol, nadolol, NIHP, NIP, propafenone, propranolol, sotalol, SR59230A, timolol, and the derivatives and similars thereof, and / or is selected from the group consisting of propranolol, nadolol, and ICI 118551 , and / or is propranolol.Embodiment 114. The method of embodiment 113, wherein the CXCR4 inhibitor is GPC-100, or AMD3100, or BL8040, preferably GPC-100; and / or wherein the beta-adrenergic receptor inhibitor is propranolol.Embodiment 115. The method of any one of embodiment 98 to the embodiment immediately above, wherein: the effective amount of the CXCR inhibitor is: a pharmacologically effective dose with clinically acceptable severe adverse effects, or from about 30 mg / kg to about 0.01 mg / kg, orfrom about 30 mg / kg to about 0.07 mg / kg, or from about 25 mg / kg to about 0.07 mg / kg, or from about 20 mg / kg to about 0.07 mg / kg, or from about 15 mg / kg to about 0.07 mg / kg, or from about 10 mg / kg to about 0.07 mg / kg, or from about 9 mg / kg to about 0.07 mg / kg, or from about 8 mg / kg to about 0.07 mg / kg, or from about 7 mg / kg to about 0.07 mg / kg, or from about 6 mg / kg to about 0.07 mg / kg, or from about 5 mg / kg to about 0.07 mg / kg, or from about 4.40 mg / kg to about 0.07 mg / kg, or from about 3.14 mg / kg to about 0.07 mg / kg, or from about 2.24 mg / kg to about 0.07 mg / kg, or from about 1.12 mg / kg to about 0.07 mg / kg, or from about 0.56 mg / kg to about 0.07 mg / kg, or from about 0.28 mg / kg to about 0.07 mg / kg, or from about 0.14 mg / kg to about 0.07 mg / kg, or from about 0.10 mg / kg, to about 0.07 mg / kg, or from about 30 mg / kg to about 0.10 mg / kg, or from about 25 mg / kg to about 0.10 mg / kg, or from about 20 mg / kg to about 0.10 mg / kg, or from about 15 mg / kg to about 0.10 mg / kg, or from about 10 mg / kg to about 0.10 mg / kg, or from about 9 mg / kg to about 0.10 mg / kg, or from about 8 mg / kg to about 0.10 mg / kg, or from about 7 mg / kg to about 0.10 mg / kg, or from about 6 mg / kg to about 0.10 mg / kg, or from about 5 mg / kg to about 0.10 mg / kg, or from about 4.40 mg / kg to about 0.10 mg / kg, or from about 3.14 mg / kg to about 0.10 mg / kg, or from about 2.24 mg / kg to about 0.10 mg / kg, or from about 1.12 mg / kg to about 0.10 mg / kg, or from about 0.56 mg / kg to about 0.10 mg / kg, orfrom about 0.28 mg / kg to about 0.10 mg / kg, or from about 0.14 mg / kg to about 0.10 mg / kg, or about 4.40 mg / kg, or about 3.14 mg / kg, or about 2.24 mg / kg, or about 1.12 mg / kg, or about 0.56 mg / kg, or about 0.28 mg / kg, or about 0.14 mg / kg, or about 0.10 mg / kg, or about 0.07 mg / kg, orCXCR4 inhibitor is administered: in a pharmacologically acceptable route, or orally, or subcutaneously, or intravenously; and / or the duration of CXCR4 inhibitor administration is: from about 1 minute to about 30 minutes, or from about 5 minute to about 20 minutes, or from about 10 minute to about 18 minutes, or about 15 minutes; and / or the time of CXCR4 inhibitor administration is: in the morning, or from about 7:00 AM to about 7 PM, or from about 7: 30 AM to about 12:30 PM, or from about 7:30 AM to about 9:30 AM, or at about 8:30 AM; and / or the last dose of CXCR4 inhibitor prior to the apheresis and / or the leukapheresis is administered at: from about 120 hours to about 30 minutes, or from about 72 hours to about 30 minutes, or from about 24 hours to about 30 minutes, or from about 14 hours to about 30 minutes, orfrom about 13 hours to about 30 minutes, or from about 13 hours to about 30 minutes, or from about 12 hours to about 30 minutes, or from about 11 hours to about 30 minutes, or from about 10 hours to about 30 minutes, or from about 9 hours to about 30 minutes, or from about 8 hours to about 30 minutes, or from about 7 hours to about 30 minutes, or from about 6 hours to about 30 minutes, or from about 5 hours to about 30 minutes, or from about 4 hours to about 30 minutes, or from about 3 hours to about 30 minutes, or from about 2 hours to about 30 minutes, or from about 90 minutes to about 30 minutes, or from about 60 minutes to about 30 minutes, or from about 45 minutes to about 30 minutes, or about 11 hours, or about 10 hours, or about 9 hours, or about 8 hours, or about 7 hours, or about 6 hours, or about 5 hours, or about 4 hours, or about 3 hours, or about 2 hours, or about 90 minutes, or about 60 minutes, or about 45 minutes, or about 30 minutes, before the apheresis and / or the leukapheresis treatment begins; and / orCXCR4 inhibitor is administered once, twice, or three times, four times,or more than four times; and / orCXCR4 inhibitor is administered no more than once, no more than twice, or no more than three times, or no more than four times, or no more than five times; and / orCXCR4 inhibitor is administered for one day, two days, or three days, or four days, or more than four days; and / orCXCR4 inhibitor is administered no more than one day, no more than two days, or no more than three days, or no more than four days, or no more than five days; and / or the apheresis and / or the leukapheresis treatment comprises from about 1 to about 5 sessions, preferably from about 1 to 2 sessions, more preferably 1 session; and / orCXCR4 inhibitor is administered once daily; and / orCXCR4 inhibitor is administered: from about 7 days to about 11 days of the administration of the propranolol, or from about 9 days to about 11 days of the administration of the propranolol, or from about 7 days to about 8 days of the administration of the propranolol; or on day-7 of the administration of the propranolol, or on day-8 of the administration of the propranolol; and / or a first dose of CXCR4 inhibitor is administered: from about 7 days to about 11 days of the administration of the propranolol, or from about 7 days to about 8 days of the administration of the propranolol, or on day-7 of the administration of the propranolol, or on day-8 of the administration of the propranolol; and / or a second dose of CXCR4 inhibitor is administered: from about 7 days to about 11 days of the administration of the propranolol, or from about 9 days to about 11 days of the administration of thepropranolol, or on day-9 of the administration of the propranolol, or on day-10 of the administration of the propranolol, or on day-11 of the administration of the propranolol; and / or from about 0.1 mg / kg to about 4.4 mg / kg of CXCR4 inhibitor is administered intravenously once daily, for one day or up to five days, preferably the last dose of CXCR4 inhibitor prior to the apheresis and / or the leukapheresis is administered at from about 30 minutes to about 60 minutes before the apheresis and / or the leukapheresis treatment begins; and / or wherein: the effective amount of GPC-100 is: from about 30 mg / kg to about 0.07 mg / kg, or from about 25 mg / kg to about 0.07 mg / kg, or from about 20 mg / kg to about 0.07 mg / kg, or from about 15 mg / kg to about 0.07 mg / kg, or from about 10 mg / kg to about 0.07 mg / kg, or from about 9 mg / kg to about 0.07 mg / kg, or from about 8 mg / kg to about 0.07 mg / kg, or from about 7 mg / kg to about 0.07 mg / kg, or from about 6 mg / kg to about 0.07 mg / kg, or from about 5 mg / kg to about 0.07 mg / kg, or from about 4.40 mg / kg to about 0.07 mg / kg, or from about 3.14 mg / kg to about 0.07 mg / kg, or from about 2.24 mg / kg to about 0.07 mg / kg, or from about 1.12 mg / kg to about 0.07 mg / kg, or from about 0.56 mg / kg to about 0.07 mg / kg, or from about 0.28 mg / kg to about 0.07 mg / kg, or from about 0.14 mg / kg to about 0.07 mg / kg, or from about 0.10 mg / kg, to about 0.07 mg / kg, or from about 30 mg / kg to about 0.10 mg / kg, or from about 25 mg / kg to about 0.10 mg / kg, or from about 20 mg / kg to about 0.10 mg / kg, or from about 15 mg / kg to about 0.10 mg / kg, orfrom about 10 mg / kg to about 0.10 mg / kg, or from about 9 mg / kg to about 0.10 mg / kg, or from about 8 mg / kg to about 0.10 mg / kg, or from about 7 mg / kg to about 0.10 mg / kg, or from about 6 mg / kg to about 0.10 mg / kg, or from about 5 mg / kg to about 0.10 mg / kg, or from about 4.40 mg / kg to about 0.10 mg / kg, or from about 3.14 mg / kg to about 0.10 mg / kg, or from about 2.24 mg / kg to about 0.10 mg / kg, or from about 1.12 mg / kg to about 0.10 mg / kg, or from about 0.56 mg / kg to about 0.10 mg / kg, or from about 0.28 mg / kg to about 0.10 mg / kg, or from about 0.14 mg / kg to about 0.10 mg / kg, or about 4.40 mg / kg, or about 3.14 mg / kg, or about 2.24 mg / kg, or about 1.12 mg / kg, or about 0.56 mg / kg, or about 0.28 mg / kg, or about 0.14 mg / kg, or about 0.10 mg / kg, or about 0.07 mg / kg, orGPC-100 is administered: in a pharmacologically acceptable route, or orally, or subcutaneously, or intravenously; and / or the duration of GPC-100 administration is: from about 1 minute to about 30 minutes, or from about 5 minute to about 20 minutes, or from about 10 minute to about 18 minutes, or about 15 minutes; and / or the time of GPC-100 administration is:in the morning, or from about 7:00 AM to about 7 PM, or from about 7: 30 AM to about 12:30 PM, or from about 7:30 AM to about 9:30 AM, or at about 8:30 AM; and / or the last dose of GPC-100 prior / or the leukapheresis is administered at: from about 120 hours to about 30 minutes, or from about 72 hours to about 30 minutes, or from about 24 hours to about 30 minutes, or from about 14 hours to about 30 minutes, or from about 13 hours to about 30 minutes, or from about 13 hours to about 30 minutes, or from about 12 hours to about 30 minutes, or from about 11 hours to about 30 minutes, or from about 10 hours to about 30 minutes, or from about 9 hours to about 30 minutes, or from about 8 hours to about 30 minutes, or from about 7 hours to about 30 minutes, or from about 6 hours to about 30 minutes, or from about 5 hours to about 30 minutes, or from about 4 hours to about 30 minutes, or from about 3 hours to about 30 minutes, or from about 2 hours to about 30 minutes, or from about 90 minutes to about 30 minutes, or from about 60 minutes to about 30 minutes, or from about 45 minutes to about 30 minutes, or about 11 hours, or about 10 hours, or about 9 hours, or about 8 hours, or about 7 hours, or about 6 hours, or about 5 hours, orabout 4 hours, or about 3 hours, or about 2 hours, or about 90 minutes, or about 60 minutes, or about 45 minutes, or about 30 minutes, before the apheresis and / or the leukapheresis treatment begins; and / orGPC-100 is administered once, twice, or three times, four times, or more than four times; and / orGPC-100 is administered no more than once, no more than twice, or no more than three times, or no more than four times, or no more than five times; and / orGPC-100 is administered for one day, two days, or three days, or four days, or more than four days; and / orGPC-100 is administered no more than one day, no more than two days, or no more than three days, or no more than four days, or no more than five days; and / or the apheresis and / or the leukapheresis treatment comprises from about 1 to about 5 sessions, preferably from about 1 to 2 sessions, more preferably 1 session; and / orGPC-100 is administered once daily; and / orGPC-100 is administered: from about 7 days to about 11 days of the administration of the propranolol, or from about 9 days to about 11 days of the administration of the propranolol, or from about 7 days to about 8 days of the administration of the propranolol; or on day-7 of the administration of the propranolol, or on day-8 of the administration of the propranolol; and / or a first dose of GPC-100 is administered: from about 7 days to about 11 days of the administration of thepropranolol, or from about 7 days to about 8 days of the administration of the propranolol, or on day-7 of the administration of the propranolol, or on day-8 of the administration of the propranolol; and / or a second dose of GPC-100 is administered: from about 7 days to about 11 days of the administration of the propranolol, or from about 9 days to about 11 days of the administration of the propranolol, or on day-9 of the administration of the propranolol, or on day-10 of the administration of the propranolol, or on day-1 1 of the administration of the propranolol; and / or from about 0.1 mg / kg to about 4.4 mg / kg of GPC-100 is administered intravenously once daily, for one day or up to five days, preferably the last dose of GPC-100 prior to the apheresis and / or the leukapheresis is administered at from about 30 minutes to about 60 minutes before the apheresis and / or the leukapheresis treatment begins; and / or wherein: the effective amount of AMD3100 is: from about 10 pg / kg to about 480 pg / kg, or from about 40 pg / kg to about 480 pg / kg, or from about 80 pg / kg to about 480 pg / kg, or from about 40 pg / kg to about 480 pg / kg and administered subcutaneously; or from about 80 pg / kg to about 480 pg / kg and administered subcutaneously; or about 40 pg / kg and administered subcutaneously; or about 80 pg / kg and administered subcutaneously; or about 480 pg / kg and administered subcutaneously; or from about 10 pg / kg to about 80 pg / kg and administered intravenously; or from about 20 pg / kg to about 80 pg / kg and administered intravenously; orfrom about 40 pg / kg to about 80 pg / kg and administered intravenously; or about 10 pg / kg and administered intravenously; or about 20 pg / kg and administered intravenously; or about 40 pg / kg and administered intravenously; or about 80 pg / kg and administered intravenously; and / orAMD3100 is administered: in a pharmacologically acceptable route, or subcutaneously, or intravenously; and / or the last dose of the AMD3100 inhibitor prior to the start of apheresis and / or the start of leukapheresis is administered at: from about 120 hours to about 10 hours, or from about 72 hours to about 10 hours, or from about 24 hours to about 10 hours, or from about 14 hours to about 10 hours, or from about 13 hours to about 10 hours, or from about 13 hours to about 10 hours, or from about 12 hours to about 10 hours, or from about 11 hours to about 10 hours, or about 12 hours, or about 11 hours, or about 10 hours, before the apheresis and / or the leukapheresis treatment begins; and / orAMD3100 is administered once daily; and / orAMD3100 is administered once, twice, three times, four times, or more than four times; and / orAMD3100 is administered no more than five times, no more than four times, or no more than three times, no more than twice, or no more than once; and / or AMD3100 is administered at from about 10 pg / kg to about 480 pg / kg mg / kg, intravenously or subcutaneously, preferably subcutaneously, once daily, for one day or up to five days, preferably the last dose of AMD3100 prior to the apheresisand / or the leukapheresis is administered at least about 10 hours before the apheresis and / or the leukapheresis treatment begins, or preferably at from about 12 hours to about 10 hours before the apheresis and / or the leukapheresis treatment begins; and / or wherein: the effective amount of BL8040 is: from about 0.5 mg / kg to about 2.0 mg / kg, or from about 0.75 mg / kg to about 2.0 mg / kg, or from about 1.0 mg / kg to about 2.0 mg / kg, or from about 1 .25 mg / kg to about 2.0 mg / kg, or from about 1.5 mg / kg to about 2.0 mg / kg, or about 0.5 mg / kg; or about 0.75 mg / kg; or about 1 mg / kg; or about 1.5 mg / kg; and / orBL8040 is administered: in a pharmacologically acceptable route, or subcutaneously, or intravenously; and / or the last dose of the BL8040 prior to the start of apheresis and / or the start of leukapheresis is administered at: from about 120 hours to about 10 hours, or from about 72 hours to about 10 hours, or from about 24 hours to about 10 hours, or from about 14 hours to about 10 hours, or from about 13 hours to about 10 hours, or from about 13 hours to about 10 hours, or from about 12 hours to about 10 hours, or from about 11 hours to about 10 hours, or about 12 hours, or about 11 hours, or about 10 hours, before the apheresis and / or the leukapheresis treatment begins;and / orBL8040 is administered once daily; and / orBL8040 is administered once, twice, three times, four times, or more than four times; and / orBL8040 is administered no more than five times, no more than four times, or no more than three times, no more than twice, or no more than once; and / orBL8040 is administered at from about 1.5 mg / kg subcutaneously, once daily, for one day or up to five days, preferably the last dose of BL8040 prior to the apheresis and / or the leukapheresis is administered at least 10 hours before the apheresis and / or the leukapheresis treatment begins, preferably at from about 12 hours to about 10 hours before the apheresis and / or the leukapheresis treatment begins; and / or wherein: the effective amount of the beta-adrenergic receptor inhibitor is: a pharmacologically effective dose with clinically acceptable severe adverse effects, or from about 10 mg daily to about 480 mg daily, or from about 20 mg daily to about 480 mg daily, or from about 30 mg daily to about 480 mg daily, or from about 40 mg daily to about 480 mg daily, or from about 50 mg daily to about 480 mg daily, or from about 60 mg daily to about 480 mg daily, or from about 70 mg daily to about 480 mg daily, or from about 80 mg daily to about 480 mg daily, or from about 120 mg daily to about 480 mg daily, or from about 160 mg daily to about 480 mg daily, or from about 200 mg daily to about 480 mg daily, or from about 240 mg daily to about 480 mg daily, or from about 280 mg daily to about 480 mg daily, or from about 320 mg daily to about 480 mg daily, or from about 360 mg daily to about 480 mg daily, or from about 400 mg daily to about 480 mg daily, or from about 440 mg daily to about 480 mg dailyfrom about 10 mg daily to about 480 mg daily, or from about 10 mg daily to about 450 mg daily, or from about 10 mg daily to about 420 mg daily, or from about 10 mg daily to about 390 mg daily, or from about 10 mg daily to about 360 mg daily, or from about 10 mg daily to about 330 mg daily, or from about 10 mg daily to about 300 mg daily, or from about 10 mg daily to about 270 mg daily, or from about 10 mg daily to about 240 mg daily, or from about 10 mg daily to about 210 mg daily, or from about 10 mg daily to about 180 mg daily, or from about 10 mg daily to about 150 mg daily, or from about 10 mg daily to about 120 mg daily, or from about 10 mg daily to about 90 mg daily, or from about 10 mg daily to about 60 mg daily, or from about 10 mg daily to about 30 mg daily, or from about 10 mg daily to about 90 mg daily, or from about 10 mg daily to about 60 mg daily, or from about 10 mg daily to about 30 mg daily, or from about 20 mg daily to about 480 mg daily, or from about 20 mg daily to about 450 mg daily, or from about 20 mg daily to about 440 mg daily, or from about 20 mg daily to about 410 mg daily, or from about 20 mg daily to about 400 mg daily, or from about 20 mg daily to about 370 mg daily, or from about 20 mg daily to about 360 mg daily, or from about 20 mg daily to about 330 mg daily, or from about 20 mg daily to about 320 mg daily, or from about 20 mg daily to about 290 mg daily, or from about 20 mg daily to about 280 mg daily, or from about 20 mg daily to about 250 mg daily, or from about 20 mg daily to about 240 mg daily, or from about 20 mg daily to about 210 mg daily, orfrom about 20 mg daily to about 200 mg daily, or from about 20 mg daily to about 170 mg daily, or from about 20 mg daily to about 160 mg daily, or from about 20 mg daily to about 130 mg daily, or from about 20 mg daily to about 120 mg daily, or from about 20 mg daily to about 90 mg daily, or from about 20 mg daily to about 80 mg daily, or from about 20 mg daily to about 50 mg daily, or from about 20 mg daily to about 40 mg daily, or from about 20 mg daily to about 160 mg daily, or from about 20 mg daily to about 130 mg daily, or from about 20 mg daily to about 120 mg daily, or from about 20 mg daily to about 100 mg daily, or from about 20 mg daily to about 80 mg daily, or from about 20 mg daily to about 70 mg daily, or from about 20 mg daily to about 40 mg daily, or about 20 mg daily, or about 40 mg daily, or about 60 mg daily, or about 80 mg daily, and / orBETA-adrenergic receptor inhibitor is administered: in a pharmacologically acceptable route, or orally; and / orBETA-adrenergic receptor inhibitor is administered once daily, or twice daily, or three times daily, or four times daily; and / orBETA-adrenergic receptor inhibitor is administered: from about 7 hours to about 12 hours apart about 12 hours apart, or about 11 hours apart, or about 10 hours apart, or about 9 hours apart, or about 8 hours apart, or about 7 hours apart, orabout 6 hours apart, or about 5 hours apart, or about 4 hours apart, or about 3 hours apart; and / orBETA-adrenergic receptor inhibitor is administered at about 30 mg orally, twice daily at from about 7 hours to about 12 hours apart; and / or wherein: the effective amount of the ADRB2 inhibitor is: a pharmacologically effective dose with clinically acceptable severe adverse effects, or from about 10 mg daily to about 480 mg daily, or from about 20 mg daily to about 480 mg daily, or from about 30 mg daily to about 480 mg daily, or from about 40 mg daily to about 480 mg daily, or from about 50 mg daily to about 480 mg daily, or from about 60 mg daily to about 480 mg daily, or from about 70 mg daily to about 480 mg daily, or from about 80 mg daily to about 480 mg daily, or from about 120 mg daily to about 480 mg daily, or from about 160 mg daily to about 480 mg daily, or from about 200 mg daily to about 480 mg daily, or from about 240 mg daily to about 480 mg daily, or from about 280 mg daily to about 480 mg daily, or from about 320 mg daily to about 480 mg daily, or from about 360 mg daily to about 480 mg daily, or from about 400 mg daily to about 480 mg daily, or from about 440 mg daily to about 480 mg daily, or from about 10 mg daily to about 480 mg daily, or from about 10 mg daily to about 450 mg daily, or from about 10 mg daily to about 420 mg daily, or from about 10 mg daily to about 390 mg daily, or from about 10 mg daily to about 360 mg daily, or from about 10 mg daily to about 330 mg daily, orfrom about 10 mg daily to about 300 mg daily, or from about 10 mg daily to about 270 mg daily, or from about 10 mg daily to about 240 mg daily, or from about 10 mg daily to about 210 mg daily, or from about 10 mg daily to about 180 mg daily, or from about 10 mg daily to about 150 mg daily, or from about 10 mg daily to about 120 mg daily, or from about 10 mg daily to about 90 mg daily, or from about 10 mg daily to about 60 mg daily, or from about 10 mg daily to about 30 mg daily, or from about 10 mg daily to about 90 mg daily, or from about 10 mg daily to about 60 mg daily, or from about 10 mg daily to about 30 mg daily, or from about 20 mg daily to about 480 mg daily, or from about 20 mg daily to about 450 mg daily, or from about 20 mg daily to about 440 mg daily, or from about 20 mg daily to about 410 mg daily, or from about 20 mg daily to about 400 mg daily, or from about 20 mg daily to about 370 mg daily, or from about 20 mg daily to about 360 mg daily, or from about 20 mg daily to about 330 mg daily, or from about 20 mg daily to about 320 mg daily, or from about 20 mg daily to about 290 mg daily, or from about 20 mg daily to about 280 mg daily, or from about 20 mg daily to about 250 mg daily, or from about 20 mg daily to about 240 mg daily, or from about 20 mg daily to about 210 mg daily, or from about 20 mg daily to about 200 mg daily, or from about 20 mg daily to about 170 mg daily, or from about 20 mg daily to about 160 mg daily, or from about 20 mg daily to about 130 mg daily, or from about 20 mg daily to about 120 mg daily, or from about 20 mg daily to about 90 mg daily, orfrom about 20 mg daily to about 80 mg daily, or from about 20 mg daily to about 50 mg daily, or from about 20 mg daily to about 40 mg daily, or from about 20 mg daily to about 160 mg daily, or from about 20 mg daily to about 130 mg daily, or from about 20 mg daily to about 120 mg daily, or from about 20 mg daily to about 100 mg daily, or from about 20 mg daily to about 80 mg daily, or from about 20 mg daily to about 70 mg daily, or from about 20 mg daily to about 40 mg daily, or about 20 mg daily, or about 40 mg daily, or about 60 mg daily, or about 80 mg daily, and / orADRB2 inhibitor is administered: in a pharmacologically acceptable route, or orally; and / orADRB2 inhibitor is administered once daily, or twice daily, or three times daily, or four times daily; and / orADRB2 inhibitor is administered: from about 7 hours to about 12 hours apart, or about 12 hours apart, or about 11 hours apart, or about 10 hours apart, or about 9 hours apart, or about 8 hours apart, or about 7 hours apart, or about 6 hours apart, or about 5 hours apart, or about 4 hours apart, or about 3 hours apart; and / orADRB2 inhibitor is administered at about 30 mg orally, twice daily at from about 7 hours to about 12 hours apart; and / orwherein: the effective amount of propranolol is: from about 10 mg daily to about 480 mg daily, or from about 20 mg daily to about 480 mg daily, or from about 30 mg daily to about 480 mg daily, or from about 40 mg daily to about 480 mg daily, or from about 50 mg daily to about 480 mg daily, or from about 60 mg daily to about 480 mg daily, or from about 70 mg daily to about 480 mg daily, or from about 80 mg daily to about 480 mg daily, or from about 120 mg daily to about 480 mg daily, or from about 160 mg daily to about 480 mg daily, or from about 200 mg daily to about 480 mg daily, or from about 240 mg daily to about 480 mg daily, or from about 280 mg daily to about 480 mg daily, or from about 320 mg daily to about 480 mg daily, or from about 360 mg daily to about 480 mg daily, or from about 400 mg daily to about 480 mg daily, or from about 440 mg daily to about 480 mg daily, or from about 10 mg daily to about 480 mg daily, or from about 10 mg daily to about 450 mg daily, or from about 10 mg daily to about 420 mg daily, or from about 10 mg daily to about 390 mg daily, or from about 10 mg daily to about 360 mg daily, or from about 10 mg daily to about 330 mg daily, or from about 10 mg daily to about 300 mg daily, or from about 10 mg daily to about 270 mg daily, or from about 10 mg daily to about 240 mg daily, or from about 10 mg daily to about 210 mg daily, or from about 10 mg daily to about 180 mg daily, or from about 10 mg daily to about 150 mg daily, or from about 10 mg daily to about 120 mg daily, or from about 10 mg daily to about 90 mg daily, orfrom about 10 mg daily to about 60 mg daily, or from about 10 mg daily to about 30 mg daily, or from about 10 mg daily to about 90 mg daily, or from about 10 mg daily to about 60 mg daily, or from about 10 mg daily to about 30 mg daily, or from about 20 mg daily to about 480 mg daily, or from about 20 mg daily to about 450 mg daily, or from about 20 mg daily to about 440 mg daily, or from about 20 mg daily to about 410 mg daily, or from about 20 mg daily to about 400 mg daily, or from about 20 mg daily to about 370 mg daily, or from about 20 mg daily to about 360 mg daily, or from about 20 mg daily to about 330 mg daily, or from about 20 mg daily to about 320 mg daily, or from about 20 mg daily to about 290 mg daily, or from about 20 mg daily to about 280 mg daily, or from about 20 mg daily to about 250 mg daily, or from about 20 mg daily to about 240 mg daily, or from about 20 mg daily to about 210 mg daily, or from about 20 mg daily to about 200 mg daily, or from about 20 mg daily to about 170 mg daily, or from about 20 mg daily to about 160 mg daily, or from about 20 mg daily to about 130 mg daily, or from about 20 mg daily to about 120 mg daily, or from about 20 mg daily to about 90 mg daily, or from about 20 mg daily to about 80 mg daily, or from about 20 mg daily to about 50 mg daily, or from about 20 mg daily to about 40 mg daily, or from about 20 mg daily to about 160 mg daily, or from about 20 mg daily to about 130 mg daily, or from about 20 mg daily to about 120 mg daily, or from about 20 mg daily to about 100 mg daily, or from about 20 mg daily to about 80 mg daily, orfrom about 20 mg daily to about 70 mg daily, or from about 20 mg daily to about 40 mg daily, or about 20 mg daily, or about 40 mg daily, or about 60 mg daily, or about 80 mg daily, and / or propranolol is administered: in a pharmacologically acceptable route, or orally; and / or propranolol is administered once daily, or twice daily, or three times daily, or four times daily; and / or propranolol is administered: from about 7 hours to about 12 hours apart, or about 12 hours apart, or about 11 hours apart, or about 10 hours apart, or about 9 hours apart, or about 8 hours apart, or about 7 hours apart, or about 6 hours apart, or about 5 hours apart, or about 4 hours apart, or about 3 hours apart; and / or propranolol is administered at about 30 mg orally, twice daily at from about 7 hours to about 12 hours apart; and / or wherein: the effective amount of G-CSF is: from about 1 ug / kg to about 70 ug / kg twice daily by intravenous injection, or from about 1 ug / kg to about 40 ug / kg daily by subcutaneous injection, or from about 3 ug / kg to about 40 ug / kg daily by continuous subcutaneous injection, orfrom about 10 ug / kg daily to about 40 ug / kg daily, or about 10 ug / kg daily; and / orG-CSF is administered: in a pharmacologically acceptable route, or intravenously, or subcutaneously, or continuous subcutaneously; and / or the last dose of the G-CSF inhibitor prior to the start of apheresis and / or the start of leukapheresis is administered at: from about 120 hours to about 10 hours, or from about 72 hours to about 10 hours, or from about 24 hours to about 10 hours, or from about 14 hours to about 10 hours, or from about 13 hours to about 10 hours, or from about 13 hours to about 10 hours, or from about 12 hours to about 10 hours, or from about 11 hours to about 10 hours, or about 12 hours, or about 11 hours, or about 10 hours, before the apheresis and / or the leukapheresis treatment begins; and / orG-CSF is administered once daily; and / orG-CSF is administered once, twice, three times, four times, five times, six times, seven times, eight times, or more than eight times; and / orG-CSF is administered no more than eight times, no more than seven times, no more than six times, no more than five times, no more than four times, or no more than three times, no more than twice, or no more than once; and / orG-CSF is administered at about 10 ug / kg daily by intravenous injection, or subcutaneous injection, or continuous subcutaneous injection, for about four days, preferably at least about 10 hours prior to the apheresis and / or the leukapheresis. Embodiment 116. The method of any one of embodiment 98 to the embodiment immediately above,wherein the subject is administered a drug that interferes with CD34+cell mobilization, wherein the drug is a lenalidomide, wherein the lenalidomide is administered: in accordance with the drug label, and / or at a dose of from about 8 mg / kg to about 16 mg / kg, preferably about 16 mg / kg, and / or in a pharmacologically acceptable route, or intravenously, or for about 3 to about 4 cycles; and / or wherein the drug is a daratumumab, wherein the daratumumab is administered: in accordance with the drug label, and / or at a dose of from about 8 mg / kg to about 16 mg / kg, preferably about 16 mg / kg, and / or in a pharmacologically acceptable route, or intravenously, or for about 3 to about 4 cyclesEmbodiment 117. The method of any one of embodiment 98 to the embodiment immediately above, wherein the method causes: no adverse event in the subject during or after treatment, or no severe adverse event in the subject during or after treatment, or no adverse events greater than Grade 1 or 2 in severity, or the adverse events, if any, is limited to the list consisting of bone pain, hypocalaemia, diarrhea, dry mouth, nausea, hypokalaemia, oedema peripheral, paranesthesia, and the likes.

Claims

CLAIMSI / We claim:

1. A method of mobilizing a cell in a subject, the method comprising: blocking CXCR4 signaling and beta-adrenergic receptor signaling in the subject.

2. A method of inducing cell mobilization in a subject, the method comprising: blocking CXCR4 signaling and beta-adrenergic receptor signaling in the subject.

3. A method of enhancing apheresis by inducing cell mobilization in a subject, the method comprising: blocking CXCR4 signaling and beta-adrenergic receptor signaling in the subject.

4. A method of enhancing apheresis by mobilizing a cell in a subject, the method comprising: blocking CXCR4 signaling and beta-adrenergic receptor signaling in the subject.

5. The method of any of Claims 1 -4, wherein the cell is a stem cell.

6. The method of any of Claims 1-5, wherein the cell is a LSK (Lin-Sca1+c-Kit+) cell.

7. The method of Claim 6, wherein the LSK cell is a long-term repopulating hematopoietic stem cell (LT-HSC).

8. The method of Claim 7, wherein the LT-HSC is a CD150+, CD34-, or CD48+ LSK cell.

9. The method of any of Claims 1-8, wherein the blocking CXCR4 signaling comprises administration of a CXCR4 inhibitor to the subject.

10. The method of Claim 9, wherein the CXCR4 inhibitor forms an ionic interaction with Arg188 on CXCR4.

11. The method of Claim 9 or 10, wherein the CXCR4 inhibitor forms a hydrogen bond with Gln200 on CXCR4.

12. The method of any one of Claims 9-1 1 , wherein the CXCR4 inhibitor has a higher binding affinity to CXCL12 than AMD3100.

13. The method of any one of Claims 9-12, wherein the CXCR4 inhibitor has alower inhibitory constant (Ki) than AMD3100.

14. The method of any one of Claims 9-13, wherein the CXCR4 inhibitor has at least a 2-fold lower inhibitory constant than AMD3100.

15. The method of any one of Claims 9-14, wherein the CXCR4 inhibitor inhibits CXCL12-induced calcium flux at an equal or greater level as AMD3100.

16. The method of any one of Claims 9-15, wherein the CXCR4 inhibitor inhibits CXCL12-induced ?-arrestin recruitment at an equal or greater level as AMD3100.

17. The method of any one of Claims 9-16, wherein the CXCR4 inhibitor inhibits CXCL12-induced migration of cancer cells at an equal or greater level as AMD3100.

18. The method of any one of Claims 9-17, wherein the CXCR4 inhibitor inhibits CXCL12-induced migration of U937 and MM.1 S cells at an equal or greater level as AMD3100.

19. The method of any one of Claims 9-18, wherein the CXCR4 inhibitor inhibits calcium flux induced by CXCL12 and epinephrine.

20. The method of any one of Claims 9-19, wherein the blocking of the beta- adrenergic receptor signaling inhibits calcium flux and / or cell migration induced by CXCL12 and epinephrine.21 . The method of any one of any one of Claims 9-19, wherein the blocking of the propranolol inhibits calcium flux and / or cell migration induced by CXCL12 and epinephrine.

22. The method of any one of Claims 1-21 , wherein blocking CXCR4 signaling and beta-adrenergic receptor signaling in the subject induces an enhanced amount of long-term repopulating hematopoietic stem cell (LT-HSC) mobilization relative to the amount of LT-HSC mobilization induced by the CXCR4 inhibitor and G-CSF only.

23. The method of any one of Claims 1-22, wherein blocking CXCR4 signaling and beta-adrenergic receptor signaling in the subject mobilizes a LT-HSC by an amount enhanced relative to the amount of LT-HSC mobilization induced by the CXCR4 inhibitor and G-CSF only.

24. The method of any one of Claims 22 or 23, wherein the LT-HSC expresses25. The method of any one of Claims 22 or 23, wherein the LT-HSC does not express CD34.

26. The method of any one of Claims 22 or 23, wherein the LT-HSC expresses CD48.

27. The method of any one of Claims 1-26, further comprising administration of G- CSF.

28. The method of Claim 27, wherein the CXCR4 inhibitor, the beta-adrenergic receptor inhibitor, and the G-CSF induces an enhanced amount of cell mobilization relative to the amount of cell mobilization induced by the CXCR4 inhibitor and G-CSF only.

29. The method of Claim 27, wherein the CXCR4 inhibitor, the beta-adrenergic receptor inhibitor, and the G-CSF mobilizes a cell by an amount enhanced relative to the amount of cell mobilization induced by the CXCR4 inhibitor and G-CSF only.

30. The method of any one of Claims 1-29, wherein the blocking beta-adrenergic receptor signaling is performed before the blocking CXCR4 signaling.

31. The method of any one of Claims 1-30, wherein the blocking beta-adrenergic receptor signaling continues after the blocking CXCR4 signaling is terminated.

32. The method of any one of Claims 1-31 , wherein the blocking CXCR4 signaling comprises administration of a CXCR4 inhibitor to the subject.

33. The method of any one of Claims 1-32, wherein the blocking beta-adrenergic receptor signaling comprises administration of a beta-adrenergic receptor inhibitor to the subject.

34. The method of Claim 33, wherein the beta-adrenergic receptor inhibitor is an ADRB2 inhibitor.

35. The method of any one of Claims 33 or 34, wherein the beta-adrenergic receptor inhibitor is selected from the group consisting of alprenolol, atenolol, betaxolol, bupranolol, butoxamine, carazolol, carvedilol, CGP 12177, cicloprolol, ICI 118551 , ICYP, labetalol, levobetaxolol, levobunolol, LK 204-545, metoprolol, nadolol, NIHP, NIP, propafenone, propranolol, sotalol, SR59230A, and timolol.

36. The method of Claim 35, wherein the beta-adrenergic receptor inhibitor is- 150 -selected from the group consisting of propranolol, nadolol, and ICI 118551 .

37. The method of Claim 36, wherein the beta-adrenergic receptor inhibitor is propranolol.

38. The method of any one of Claims 9-37, wherein the CXCR4 inhibitor is selected from the group consisting of ALX40-4C, AMD070 (AMD11070, X4P-001 ), AMD3100 (Plerixafor, or Mozobil), AMD3465, ATI 2341 , BKT140 (BL-8040; TF14016; 4F-Benzoyl-TN 14003), CTCE-9908, CX549, D-[Lys3] GHRP-6, FC122, FC131 , GMI-1359, GSK812397, GSTNT21 MP, isothiourea-1 a, isothiourea-11 (IT1t), KRH-1636, KRH-3955, LY2510924, MSX-122, N- [11 C]Methyl-AMD3465, POL6326, SDF-1 l-9[P2G] dimer, SDFI P2G, T134, T140, T22, TC 14012, GPC-100 (Burixafor, or TG-0054), USL311 , viral macrophage inflammatory protein-ll (vMIP-11 ), WZ811 , [64Cu]-AMD3100, [64Cu]-AMD3465, [68Ga]pentixafor, [90Y]pentixather, [99mTc]02-AMD3100, [177Lu]pentixather, Ulocuplumab (MDX1338 / BMS-936564), AD-214,LY2624587, PF-06747143, POL6326. MB1707, and 508MC1 (Compound 26).

39. The method of Claim 38, wherein the CXCR4 inhibitor is selected from the group consisting of AD-214, AMD070 (AMD11070, X4P-001 ), AMD3100 (Plerixafor, or Mozobil), BKT140 (BL-8040; TF14016; 4F-Benzoyl-TN14003), CTCE-9908, LY2510924, LY2624587, T140, GPC-100 (Burixafor, or TG-0054), PF-06747143, POL6326, and ulocuplumab (MDX1338 / BMS-936564).

40. The method of Claim 39, wherein the CXCR4 inhibitor is GPC-100 (Burixafor, or TG-0054).

41. The method of Claim 39, wherein the CXCR4 inhibitor is AM D3100 (Plerixafor, or Mozobil).

42. The method of Claim 39, wherein the CXCR4 inhibitor is ulocuplumab (MDX1338 / BMS-936564).

43. The method of any one of Claims 33-42, wherein the administration of the CXCR4 inhibitor and beta-adrenergic receptor inhibitor to the subject comprises administration of GPC-100 (Burixafor, or TG-0054) and propranolol.

44. The method of any one of Claims 33-42, wherein the administration of the CXCR4 inhibitor beta-adrenergic receptor inhibitor to the subject comprises administration of AMD3100 (Plerixafor, or Mozobil) and propranolol.

45. The method of any one of Claims 33-42, wherein the administration of theCXCR4 inhibitor beta-adrenergic receptor inhibitor to the subject comprises administration of ulocuplumab (MDX1338 / BMS-936564) and propranolol.

46. The method of any one of Claims 27-42, wherein the administration of a combination of the CXCR4 inhibitor and the G-CSF induces an enhanced amount of cell mobilization relative to the amount of cell mobilization induced by the CXCR4 inhibitor only.

47. The method of any one of Claims 27-42, wherein the administration of a combination of the CXCR4 inhibitor and the G-CSF mobilizes a cell by an amount enhanced relative to the amount of cell mobilization induced by the CXCR4 inhibitor only.

48. The method of any one of Claims 27-42, wherein the administration of a combination of the CXCR4 inhibitor and the G-CSF induces an enhanced amount of apheresis relative to the amount of apheresis induced by the CXCR4 inhibitor only.

49. The method of any one of Claims 27-42, wherein the administration of a combination of the CXCR4 inhibitor and the beta-adrenergic receptor inhibitor induces an enhanced amount of cell mobilization relative to the amount of cell mobilization induced by the CXCR4 inhibitor only.

50. The method of any one of Claims 27-42, wherein the administration of a combination of the CXCR4 inhibitor and the beta-adrenergic receptor inhibitor mobilizes a cell by an amount enhanced relative to the amount of cell mobilization induced by the CXCR4 inhibitor only.

51. The method of any one of Claims 27-42, wherein the administration of a combination of the CXCR4 inhibitor and the beta-adrenergic receptor inhibitor induces an enhanced amount of apheresis relative to the amount of apheresis induced by the CXCR4 inhibitor only.

52. The method of any one of Claims 27-42, wherein the administration of a combination of the CXCR4 inhibitor, the beta-adrenergic receptor inhibitor, and the G-CSF induces an enhanced amount of cell mobilization relative to the amount of cell mobilization induced by the CXCR4 inhibitor and the beta- adrenergic receptor inhibitor only.

53. The method of any one of Claims 27-42, wherein the administration of a combination of the CXCR4 inhibitor, the beta-adrenergic receptor inhibitor, andthe G-CSF mobilizes a cell by an amount enhanced relative to the amount of cell mobilization induced by the CXCR4 inhibitor and the beta-adrenergic receptor inhibitor only.

54. The method of any one of Claims 27-42, wherein the administration of a combination of the CXCR4 inhibitor and the beta-adrenergic receptor inhibitor, and the G-CSF induces an enhanced amount of apheresis relative to the amount of apheresis induced by the CXCR4 inhibitor and the beta-adrenergic receptor inhibitor only.

55. The method of any one of Claims 27-42, wherein the administration of a combination of GPC-100 (Burixafor, or TG-0054) and the G-CSF induces an enhanced amount of cell mobilization relative to the amount of cell mobilization induced by AMD3100 (Plerixafor, or Mozobil) and the G-CSF.

56. The method of any one of Claims 27-42, wherein the administration of a combination of the GPC-100 (Burixafor, or TG-0054) and the G-CSF mobilizes a cell by an amount enhanced relative to the amount of cell mobilization induced by the AMD3100 (Plerixafor, or Mozobil) and the G-CSF.

57. The method of any one of Claims 27-42, wherein the administration of a combination of the GPC-100 (Burixafor, or TG-0054) and the G-CSF induces an enhanced amount of apheresis relative to the amount of apheresis induced by the AMD3100 (Plerixafor, or Mozobil) and the G-CSF.

58. The method of any one of Claims 47-57, wherein an enhanced amount of cell mobilization or apheresis is measured by a method selected from the group consisting of complete blood count (CBC) analysis, flow cytometry, and colony forming unit (CFU) assay.

59. The method of Claim 58, wherein the enhanced amount of cell mobilization or apheresis is measured by flow cytometry.

60. The method of Claim 59, wherein the flow cytometry is performed on (Lin- Scal+c-Kit+) LSK cells.61 . The method of Claim 58, wherein the enhanced amount of cell mobilization or apheresis is measured by colony forming unit (CFU) assay.

62. The method of any one of Claims 1-61 , wherein the subject has a CXCR4 protomer in the cell.

63. The method of any one of Claims 1-62, wherein the subject has an ADRB2protomer in the cell.

64. The method of any one of Claims 1-63, wherein the subject has a CXCR4 protomer and an ADRB2 protomer in the cell.

65. The method of Claim 64, wherein the subject has a CXCR4-ADRB2 heteromer in the cell.

66. The method of Claim 65, wherein: i) the CXCR4-ADRB2 heteromer has an enhanced amount of downstream calcium mobilization relative to downstream calcium mobilization from a CXCR4 protomer or ADRB2 protomer; and ii) the administered combination of inhibitors suppresses the enhanced downstream calcium mobilization from said CXCR4-ADRB2 heteromer in the stem cell.

67. The method of any one of Claims 5-66, wherein the stem cell is selected from the group consisting of a hematopoietic stem cell, a hematopoietic progenitor cell, a mesenchymal stem cell, an endothelial progenitor cell, a neural stem cell, an epithelial stem cell, a skin stem cell, and a cancer stem cell.

68. The method of Claim 67, wherein the stem cell is a hematopoietic stem cell or a hematopoietic progenitor cell.

69. The method of Claim 68, wherein the hematopoietic stem cell or the hematopoietic progenitor cell is mobilized from bone marrow to peripheral blood (PB).

70. The method of Claim 69, wherein the mobilized hematopoietic stem cell or hematopoietic progenitor cell is collected for transplantation to a patient having cancer.

71. The method of Claim 70, wherein the cancer is selected from the group consisting of lymphoma, leukemia, and myeloma.

72. The method of Claim 71 , wherein the cancer is non-Hodgkin's lymphoma (NHL), Hodgkin's Disease (HD) or Hodgkin's Lymphoma (HL), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), multiple myeloma (MM), or Burkitt's Lymphoma.

73. The method of any one of Claims 5-66, wherein the stem cell is a mesenchymal stem cell.

74. The method of Claim 73, wherein the mesenchymal stem cell is mobilized from bone marrow to PB.

75. The method of Claim 74, wherein the mesenchymal stem cell is mobilized fortreatment of a condition selected from the group consisting of neurological disorder, cardiac ischemia, myocardial infarction, diabetes, tissue repair, bone and cartilage disease, autoimmune disease, graft versus host disease, Crohn's disease, multiple sclerosis, systemic lupus erythematosus, and systemic sclerosis.

76. The method of any one of Claims 5-66, wherein the stem cell is a cancer stem cell.

77. The method of Claim 76, wherein the cancer stem cell is mobilized into blood.

78. The method of Claim 76 or 77, wherein the cancer stem cell is mobilized for treatment of a cancer.

79. The method of any one of Claims 5-66, wherein the cell is an immune cell.

80. The method of Claim 79, wherein the immune cell is a white blood cell (WBC).81 . The method of Claim 80, wherein the WBC is a lymphocyte.

82. The method of Claim 81 , wherein the lymphocyte is selected from the group consisting of a T cell, a B cell, and a natural killer (NK) cell.

83. The method of Claim 82, wherein the lymphocyte is a T cell.

84. The method of Claim 82, wherein the lymphocyte is a natural killer (NK) cell.

85. The method of Claim 80, wherein the WBC is a granulocyte.

86. The method of Claim 85, wherein the granulocyte is selected from the group consisting of a neutrophile, an eosinophile, and a basophile.

87. The method of Claim 86, wherein the granulocyte is a neutrophile.

88. The method of Claim 81 , wherein the WBC is a monocyte.

89. The method of any one of Claims 79-88, wherein the immune cell is mobilized from bone marrow to PB.

90. The method of any one of claims 79-88, wherein the immune cell is mobilized from spleen to PB.91 . The method of any one of claims 79-88, wherein the immune cell is mobilized from thymus to PB.

92. The method of any one of Claims 79-88, wherein the immune cell is mobilized from lymph node to PB.

93. The method of any one of Claims 79-88, wherein the mobilized immune cell is used for adoptive cell therapy (ACT).

94. The method of Claim 93, wherein the adoptive cell therapy (ACT) is chimericantigen receptor (CAR) T cell therapy.

95. The method of Claim 93, wherein the adoptive cell therapy (ACT) is netural killer (NK) cell therapy.

96. The method of Claim 93, wherein the adoptive cell therapy (ACT) is engineered T-cell receptor (TCR) therapy.

97. The method of Claim 93, wherein the adoptive cell therapy (ACT) is tumorinfiltrating lymphocyte (TIL) therapy.

98. A method of preparing a subject for a treatment, the method comprising: blocking a CXCR4 in the subject, blocking a beta-adrenergic receptor in the subject, or blocking the CXCR4 inhibitor and the beta-adrenergic receptor in the subject.

99. The method of Claim 98, wherein the blocking of the CXCR4 is achieved through an ionic interaction with Arg188 on CXCR4; and / or wherein the blocking of the CXCR4 is achieved through a hydrogen bond with Gln200 on CXCR4; and / or any combination thereof.

100. A method of treatment to a subject in need thereof, the method comprising: blocking a CXCR4 in the subject, blocking a beta-adrenergic receptor in the subject, or blocking the CXCR4 inhibitor and the beta-adrenergic receptor in the subject.

101. The method of Claim 100, wherein the blocking of the CXCR4 is achieved through an ionic interaction with Arg188 on CXCR4; and / or wherein the blocking of the CXCR4 is achieved through a hydrogen bond with Gln200 on CXCR4; and / or any combination thereof.

102. A method of preparing a subject for a treatment, the method comprising administering an effective amount of: a CXCR4 inhibitor, a beta-adrenergic receptor inhibitor, or a combination thereof.

103. A method to qualify a subject for treatment, the method comprisingadministering an effective amount of: a CXCR4 inhibitor, a beta-adrenergic receptor inhibitor, or a combination thereof.

104. A method of treatment to a subject in need thereof, the method comprising administering an effective amount of: a CXCR4 inhibitor, a beta-adrenergic receptor inhibitor, or a combination thereof.

105. Use of GPC-100 for the manufacture of a medicament for the treatment of a cancer, or a neurological disorder, or any combination thereof.

106. The method of any one of Claim 98 to the Claim immediately above, wherein the treatment further comprises administering an effective amount of: a beta-adrenergic receptor inhibitor, or a G-CSF, or a lenalidomide, or a daratumumab, or a velacade, or a dexamethasone, or a cyclophosphamide, or bortezombil, or combinations thereof.

107. The method of any one of Claim 98 to the Claim immediately above, wherein the subject is pre-treated with an administration of an effective amount of: a beta-adrenergic receptor inhibitor, or a G-CSF, or a lenalidomide, or a daratumumab, or a velacade, or a dexamethasone, or a cyclophosphamide, or bortezombil, orcombinations thereof.

108. The method of any one of Claim 98 to the Claim immediately above, wherein the treatment comprises one or more of: an apheresis step; or a leukapheresis step; or a peripheral blood collection step; or a cell transplant step, wherein the cell is optionally a stem cell, wherein the cell is optionally a hematopoietic progenitor cell (HSC), wherein the cell is optionally a T cell, or combinations thereof; and / or a CAR-T therapy step; or a combinations thereof.

109. The method of any one of Claim 98 to the Claim immediately above, further comprising administering of an effective amount of G-CSF.

110. The method of any one of Claims 98 to the Claim immediately above, wherein the subject present symptoms of or is diagnosed with a cancer, or a neurological disorder, or any combination thereof; and / or wherein the cancer is selected from the group consisting of lymphoma, leukemia, and myeloma; and / or wherein the subject present symptoms of or is diagnosed with a hematologic malignancy; and / or wherein the cancer is selected from the group consisting of nonHodgkin's lymphoma (NHL), Hodgkin's Disease (HD) or Hodgkin's Lymphoma (HL), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), multiple myeloma (MM), Burkitt's Lymphoma; and / or wherein the cancer is HD; and / or wherein the cancer is NHL; and / or wherein the cancer is AML; and / or wherein the cancer is ALL; and / or wherein the cancer is MM; and / or wherein the neurological disorder is selected from the group consistingof neurological disorder, cardiac ischemia, myocardial infarction, diabetes, tissue repair, bone and cartilage disease, autoimmune disease, graft versus host disease, Crohn’s disease, multiple sclerosis, systemic lupus erythematosus, and systemic sclerosis; and / or wherein the subject is a human.

111. The method of any one of Claims 98 to the Claim immediately above, wherein the subject is in need of Autologous Stem Cell Transplant (ASCT); wherein the treatment is Autologous Stem Cell Transplant (ASCT).

112. The method of any one of Claims 98 to the Claim immediately above, wherein: the CXCR4 inhibitor forms an ionic interaction with Arg188 on CXCR4, or the CXCR4 inhibitor forms a hydrogen bond with Gln200 on CXCR4, or any combination thereof; and / or wherein: the CXCR4 inhibitor has a higher binding affinity to CXCL12 than AMD3100, or the CXCR4 inhibitor has a lower inhibitory constant (Ki) than AMD3100, or the CXCR4 inhibitor has at least a 2-fold lower inhibitory constant than AMD3100.

113. The method of any one of Claims 98 to the Claim immediately above, wherein the CXCR4 inhibitor: is selected from the group consisting of ALX40-4C, AMD070 (AMD11070, X4P-001 ), AMD3100 (Plerixafor, or Mozobil), AMD3465, ATI 2341 , BKT140 (BL-8040; TF14016; 4F-Benzoyl-TN14003), CTCE-9908, CX549, D- [Lys3] GHRP-6, FC122, FC131 , GMI-1359, GSK812397, GSTNT21 MP, isothiourea-1 a, isothiourea-11 (IT1t), KRH-1636, KRH-3955, LY2510924, MSX- 122, N-[11 C]Methyl-AMD3465, POL6326, SDF-1 l-9[P2G] dimer, SDFI P2G, T134, T140, T22, TC 14012, GPC-100 (Burixafor, or TG-0054), USL311 , viral macrophage inflammatory protein-ll (vMIP-11 ), WZ811 , [64Cu]-AMD3100,[64Cu]-AMD3465, [68Ga]pentixafor, [90Y]pentixather, [99mTc]02-AMD3100, [177Lu]pentixather, Ulocuplumab (MDX1338 / BMS-936564), AD-214,LY2624587, PF-06747143, POL6326, MB1707, 508MC1 (Compound 26), and the derivatives and similars thereof, and / or is selected from the group consisting of AD-214, AMD070 (AM D11070, X4P-001 ), AMD3100 (Plerixafor, or Mozobil), BKT140 (BL-8040; TF14016; 4F-Benzoyl-TN 14003), CTCE-9908, LY2510924, LY2624587, T140, GPC-100 (Burixafor, or TG-0054), PF-06747143, POL6326, and ulocuplumab (MDX1338 / BMS-936564), and the derivatives and similars thereof; and / or is ulocuplumab (MDX1338 / BMS-936564); and / or is AMD3100 (Plerixafor, or Mozobil); and / or is BL8040; and / or is GPC-100 (Burixafor, or TG-0054); and / or wherein the beta-adrenergic receptor inhibitor: is an ADRB2 inhibitor, and / or is selected from the group consisting of alprenolol, atenolol, betaxolol, bupranolol, butoxamine, carazolol, carvedilol, CGP 12177, cicloprolol, ICI 118551 , ICYP, labetalol, levobetaxolol, levobunolol, LK 204-545, metoprolol, nadolol, NIHP, NIP, propafenone, propranolol, sotalol, SR59230A, timolol, and the derivatives and similars thereof, and / or is selected from the group consisting of propranolol, nadolol, and ICI 118551 , and / or is propranolol.

114. The method of Claim 113, wherein the CXCR4 inhibitor is GPC-100, or AMD3100, or BL8040, preferably GPC-100; and / or wherein the beta-adrenergic receptor inhibitor is propranolol.

115. The method of any one of Claim 98 to the Claim immediately above, wherein: the effective amount of the CXCR inhibitor is: a pharmacologically effective dose with clinically acceptable severe adverse effects, or from about 30 mg / kg to about 0.01 mg / kg, orfrom about 30 mg / kg to about 0.07 mg / kg, or from about 25 mg / kg to about 0.07 mg / kg, or from about 20 mg / kg to about 0.07 mg / kg, or from about 15 mg / kg to about 0.07 mg / kg, or from about 10 mg / kg to about 0.07 mg / kg, or from about 9 mg / kg to about 0.07 mg / kg, or from about 8 mg / kg to about 0.07 mg / kg, or from about 7 mg / kg to about 0.07 mg / kg, or from about 6 mg / kg to about 0.07 mg / kg, or from about 5 mg / kg to about 0.07 mg / kg, or from about 4.40 mg / kg to about 0.07 mg / kg, or from about 3.14 mg / kg to about 0.07 mg / kg, or from about 2.24 mg / kg to about 0.07 mg / kg, or from about 1.12 mg / kg to about 0.07 mg / kg, or from about 0.56 mg / kg to about 0.07 mg / kg, or from about 0.28 mg / kg to about 0.07 mg / kg, or from about 0.14 mg / kg to about 0.07 mg / kg, or from about 0.10 mg / kg, to about 0.07 mg / kg, or from about 30 mg / kg to about 0.10 mg / kg, or from about 25 mg / kg to about 0.10 mg / kg, or from about 20 mg / kg to about 0.10 mg / kg, or from about 15 mg / kg to about 0.10 mg / kg, or from about 10 mg / kg to about 0.10 mg / kg, or from about 9 mg / kg to about 0.10 mg / kg, or from about 8 mg / kg to about 0.10 mg / kg, or from about 7 mg / kg to about 0.10 mg / kg, or from about 6 mg / kg to about 0.10 mg / kg, or from about 5 mg / kg to about 0.10 mg / kg, or from about 4.40 mg / kg to about 0.10 mg / kg, or from about 3.14 mg / kg to about 0.10 mg / kg, or from about 2.24 mg / kg to about 0.10 mg / kg, or from about 1.12 mg / kg to about 0.10 mg / kg, or from about 0.56 mg / kg to about 0.10 mg / kg, orfrom about 0.28 mg / kg to about 0.10 mg / kg, or from about 0.14 mg / kg to about 0.10 mg / kg, or about 4.40 mg / kg, or about 3.14 mg / kg, or about 2.24 mg / kg, or about 1.12 mg / kg, or about 0.56 mg / kg, or about 0.28 mg / kg, or about 0.14 mg / kg, or about 0.10 mg / kg, or about 0.07 mg / kg, orCXCR4 inhibitor is administered: in a pharmacologically acceptable route, or orally, or subcutaneously, or intravenously; and / or the duration of CXCR4 inhibitor administration is: from about 1 minute to about 30 minutes, or from about 5 minute to about 20 minutes, or from about 10 minute to about 18 minutes, or about 15 minutes; and / or the time of CXCR4 inhibitor administration is: in the morning, or from about 7:00 AM to about 7 PM, or from about 7: 30 AM to about 12:30 PM, or from about 7:30 AM to about 9:30 AM, or at about 8:30 AM; and / or the last dose of CXCR4 inhibitor prior to the apheresis and / or the leukapheresis is administered at: from about 120 hours to about 30 minutes, or from about 72 hours to about 30 minutes, or from about 24 hours to about 30 minutes, or from about 14 hours to about 30 minutes, orfrom about 13 hours to about 30 minutes, or from about 13 hours to about 30 minutes, or from about 12 hours to about 30 minutes, or from about 11 hours to about 30 minutes, or from about 10 hours to about 30 minutes, or from about 9 hours to about 30 minutes, or from about 8 hours to about 30 minutes, or from about 7 hours to about 30 minutes, or from about 6 hours to about 30 minutes, or from about 5 hours to about 30 minutes, or from about 4 hours to about 30 minutes, or from about 3 hours to about 30 minutes, or from about 2 hours to about 30 minutes, or from about 90 minutes to about 30 minutes, or from about 60 minutes to about 30 minutes, or from about 45 minutes to about 30 minutes, or about 11 hours, or about 10 hours, or about 9 hours, or about 8 hours, or about 7 hours, or about 6 hours, or about 5 hours, or about 4 hours, or about 3 hours, or about 2 hours, or about 90 minutes, or about 60 minutes, or about 45 minutes, or about 30 minutes, before the apheresis and / or the leukapheresis treatment begins; and / orCXCR4 inhibitor is administered once, twice, or three times, fourtimes, or more than four times; and / orCXCR4 inhibitor is administered no more than once, no more than twice, or no more than three times, or no more than four times, or no more than five times; and / orCXCR4 inhibitor is administered for one day, two days, or three days, or four days, or more than four days; and / orCXCR4 inhibitor is administered no more than one day, no more than two days, or no more than three days, or no more than four days, or no more than five days; and / or the apheresis and / or the leukapheresis treatment comprises from about 1 to about 5 sessions, preferably from about 1 to 2 sessions, more preferably 1 session; and / orCXCR4 inhibitor is administered once daily; and / orCXCR4 inhibitor is administered: from about 7 days to about 11 days of the administration of the propranolol, or from about 9 days to about 11 days of the administration of the propranolol, or from about 7 days to about 8 days of the administration of the propranolol; or on day-7 of the administration of the propranolol, or on day-8 of the administration of the propranolol; and / or a first dose of CXCR4 inhibitor is administered: from about 7 days to about 11 days of the administration of the propranolol, or from about 7 days to about 8 days of the administration of the propranolol, or on day-7 of the administration of the propranolol, or on day-8 of the administration of the propranolol; and / or a second dose of CXCR4 inhibitor is administered: from about 7 days to about 11 days of the administration of the propranolol, or from about 9 days to about 11 days of the administrationof the propranolol, or on day-9 of the administration of the propranolol, or on day-10 of the administration of the propranolol, or on day-11 of the administration of the propranolol; and / or from about 0.1 mg / kg to about 4.4 mg / kg of CXCR4 inhibitor is administered intravenously once daily, for one day or up to five days, preferably the last dose of CXCR4 inhibitor prior to the apheresis and / or the leukapheresis is administered at from about 30 minutes to about 60 minutes before the apheresis and / or the leukapheresis treatment begins; and / or wherein: the effective amount of GPC-100 is: from about 30 mg / kg to about 0.07 mg / kg, or from about 25 mg / kg to about 0.07 mg / kg, or from about 20 mg / kg to about 0.07 mg / kg, or from about 15 mg / kg to about 0.07 mg / kg, or from about 10 mg / kg to about 0.07 mg / kg, or from about 9 mg / kg to about 0.07 mg / kg, or from about 8 mg / kg to about 0.07 mg / kg, or from about 7 mg / kg to about 0.07 mg / kg, or from about 6 mg / kg to about 0.07 mg / kg, or from about 5 mg / kg to about 0.07 mg / kg, or from about 4.40 mg / kg to about 0.07 mg / kg, or from about 3.14 mg / kg to about 0.07 mg / kg, or from about 2.24 mg / kg to about 0.07 mg / kg, or from about 1.12 mg / kg to about 0.07 mg / kg, or from about 0.56 mg / kg to about 0.07 mg / kg, or from about 0.28 mg / kg to about 0.07 mg / kg, or from about 0.14 mg / kg to about 0.07 mg / kg, or from about 0.10 mg / kg, to about 0.07 mg / kg, or from about 30 mg / kg to about 0.10 mg / kg, or from about 25 mg / kg to about 0.10 mg / kg, or from about 20 mg / kg to about 0.10 mg / kg, or from about 15 mg / kg to about 0.10 mg / kg, orfrom about 10 mg / kg to about 0.10 mg / kg, or from about 9 mg / kg to about 0.10 mg / kg, or from about 8 mg / kg to about 0.10 mg / kg, or from about 7 mg / kg to about 0.10 mg / kg, or from about 6 mg / kg to about 0.10 mg / kg, or from about 5 mg / kg to about 0.10 mg / kg, or from about 4.40 mg / kg to about 0.10 mg / kg, or from about 3.14 mg / kg to about 0.10 mg / kg, or from about 2.24 mg / kg to about 0.10 mg / kg, or from about 1.12 mg / kg to about 0.10 mg / kg, or from about 0.56 mg / kg to about 0.10 mg / kg, or from about 0.28 mg / kg to about 0.10 mg / kg, or from about 0.14 mg / kg to about 0.10 mg / kg, or about 4.40 mg / kg, or about 3.14 mg / kg, or about 2.24 mg / kg, or about 1.12 mg / kg, or about 0.56 mg / kg, or about 0.28 mg / kg, or about 0.14 mg / kg, or about 0.10 mg / kg, or about 0.07 mg / kg, orGPC-100 is administered: in a pharmacologically acceptable route, or orally, or subcutaneously, or intravenously; and / or the duration of GPC-100 administration is: from about 1 minute to about 30 minutes, or from about 5 minute to about 20 minutes, or from about 10 minute to about 18 minutes, or about 15 minutes; and / or the time of GPC-100 administration is:in the morning, or from about 7:00 AM to about 7 PM, or from about 7: 30 AM to about 12:30 PM, or from about 7:30 AM to about 9:30 AM, or at about 8:30 AM; and / or the last dose of GPC- prior to the apheresis and / or the leukapheresis is administered at: from about 120 hours to about 30 minutes, or from about 72 hours to about 30 minutes, or from about 24 hours to about 30 minutes, or from about 14 hours to about 30 minutes, or from about 13 hours to about 30 minutes, or from about 13 hours to about 30 minutes, or from about 12 hours to about 30 minutes, or from about 11 hours to about 30 minutes, or from about 10 hours to about 30 minutes, or from about 9 hours to about 30 minutes, or from about 8 hours to about 30 minutes, or from about 7 hours to about 30 minutes, or from about 6 hours to about 30 minutes, or from about 5 hours to about 30 minutes, or from about 4 hours to about 30 minutes, or from about 3 hours to about 30 minutes, or from about 2 hours to about 30 minutes, or from about 90 minutes to about 30 minutes, or from about 60 minutes to about 30 minutes, or from about 45 minutes to about 30 minutes, or about 11 hours, or about 10 hours, or about 9 hours, or about 8 hours, or about 7 hours, or about 6 hours, or about 5 hours, orabout 4 hours, or about 3 hours, or about 2 hours, or about 90 minutes, or about 60 minutes, or about 45 minutes, or about 30 minutes, before the apheresis and / or the leukapheresis treatment begins; and / orGPC-100 is administered once, twice, or three times, four times, or more than four times; and / orGPC-100 is administered no more than once, no more than twice, or no more than three times, or no more than four times, or no more than five times; and / orGPC-100 is administered for one day, two days, or three days, or four days, or more than four days; and / orGPC-100 is administered no more than one day, no more than two days, or no more than three days, or no more than four days, or no more than five days; and / or the apheresis and / or the leukapheresis treatment comprises from about 1 to about 5 sessions, preferably from about 1 to 2 sessions, more preferably 1 session; and / orGPC-100 is administered once daily; and / orGPC-100 is administered: from about 7 days to about 11 days of the administration of the propranolol, or from about 9 days to about 11 days of the administration of the propranolol, or from about 7 days to about 8 days of the administration of the propranolol; or on day-7 of the administration of the propranolol, or on day-8 of the administration of the propranolol; and / or a first dose of GPC-100 is administered:from about 7 days to about 11 days of the administration of the propranolol, or from about 7 days to about 8 days of the administration of the propranolol, or on day-7 of the administration of the propranolol, or on day-8 of the administration of the propranolol; and / or a second dose of GPC-100 is administered: from about 7 days to about 11 days of the administration of the propranolol, or from about 9 days to about 11 days of the administration of the propranolol, or on day-9 of the administration of the propranolol, or on day-10 of the administration of the propranolol, or on day-11 of the administration of the propranolol; and / or from about 0.1 mg / kg to about 4.4 mg / kg of GPC-100 is administered intravenously once daily, for one day or up to five days, preferably the last dose of GPC-100 prior to the apheresis and / or the leukapheresis is administered at from about 30 minutes to about 60 minutes before the apheresis and / or the leukapheresis treatment begins; and / or wherein: the effective amount of AMD3100 is: from about 10 pg / kg to about 480 pg / kg, or from about 40 pg / kg to about 480 pg / kg, or from about 80 pg / kg to about 480 pg / kg, or from about 40 pg / kg to about 480 pg / kg and administered subcutaneously; or from about 80 pg / kg to about 480 pg / kg and administered subcutaneously; or about 40 pg / kg and administered subcutaneously; or about 80 pg / kg and administered subcutaneously; or about 480 pg / kg and administered subcutaneously; or from about 10 pg / kg to about 80 pg / kg and administered intravenously; or from about 20 pg / kg to about 80 pg / kg and administeredintravenously; or from about 40 pg / kg to about 80 pg / kg and administered intravenously; or about 10 pg / kg and administered intravenously; or about 20 pg / kg and administered intravenously; or about 40 pg / kg and administered intravenously; or about 80 pg / kg and administered intravenously; and / or AMD3100 is administered: in a pharmacologically acceptable route, or subcutaneously, or intravenously; and / or the last dose of the AMD3100 inhibitor prior to the start of apheresis and / or the start of leukapheresis is administered at: from about 120 hours to about 10 hours, or from about 72 hours to about 10 hours, or from about 24 hours to about 10 hours, or from about 14 hours to about 10 hours, or from about 13 hours to about 10 hours, or from about 13 hours to about 10 hours, or from about 12 hours to about 10 hours, or from about 11 hours to about 10 hours, or about 12 hours, or about 11 hours, or about 10 hours, before the apheresis and / or the leukapheresis treatment begins; and / orAMD3100 is administered once daily; and / orAMD3100 is administered once, twice, three times, four times, or more than four times; and / orAMD3100 is administered no more than five times, no more than four times, or no more than three times, no more than twice, or no more than once; and / orAMD3100 is administered at from about 10 pg / kg to about 480pg / kg mg / kg, intravenously or subcutaneously, preferably subcutaneously, once daily, for one day or up to five days, preferably the last dose of AMD3100 prior to the apheresis and / or the leukapheresis is administered at least about 10 hours before the apheresis and / or the leukapheresis treatment begins, or preferably at from about 12 hours to about 10 hours before the apheresis and / or the leukapheresis treatment begins; and / or wherein: the effective amount of BL8040 is: from about 0.5 mg / kg to about 2.0 mg / kg, or from about 0.75 mg / kg to about 2.0 mg / kg, or from about 1 .0 mg / kg to about 2.0 mg / kg, or from about 1 .25 mg / kg to about 2.0 mg / kg, or from about 1 .5 mg / kg to about 2.0 mg / kg, or about 0.5 mg / kg; or about 0.75 mg / kg; or about 1 mg / kg; or about 1.5 mg / kg; and / orBL8040 is administered: in a pharmacologically acceptable route, or subcutaneously, or intravenously; and / or the last dose of the BL8040 prior to the start of apheresis and / or the start of leukapheresis is administered at: from about 120 hours to about 10 hours, or from about 72 hours to about 10 hours, or from about 24 hours to about 10 hours, or from about 14 hours to about 10 hours, or from about 13 hours to about 10 hours, or from about 13 hours to about 10 hours, or from about 12 hours to about 10 hours, or from about 11 hours to about 10 hours, or about 12 hours, or about 11 hours, orabout 10 hours, before the apheresis and / or the leukapheresis treatment begins; and / orBL8040 is administered once daily; and / orBL8040 is administered once, twice, three times, four times, or more than four times; and / orBL8040 is administered no more than five times, no more than four times, or no more than three times, no more than twice, or no more than once; and / orBL8040 is administered at from about 1.5 mg / kg subcutaneously, once daily, for one day or up to five days, preferably the last dose of BL8040 prior to the apheresis and / or the leukapheresis is administered at least 10 hours before the apheresis and / or the leukapheresis treatment begins, preferably at from about 12 hours to about 10 hours before the apheresis and / or the leukapheresis treatment begins; and / or wherein: the effective amount of the beta-adrenergic receptor inhibitor is: a pharmacologically effective dose with clinically acceptable severe adverse effects, or from about 10 mg daily to about 480 mg daily, or from about 20 mg daily to about 480 mg daily, or from about 30 mg daily to about 480 mg daily, or from about 40 mg daily to about 480 mg daily, or from about 50 mg daily to about 480 mg daily, or from about 60 mg daily to about 480 mg daily, or from about 70 mg daily to about 480 mg daily, or from about 80 mg daily to about 480 mg daily, or from about 120 mg daily to about 480 mg daily, or from about 160 mg daily to about 480 mg daily, or from about 200 mg daily to about 480 mg daily, or from about 240 mg daily to about 480 mg daily, or from about 280 mg daily to about 480 mg daily, or from about 320 mg daily to about 480 mg daily, orfrom about 360 mg daily to about 480 mg daily, or from about 400 mg daily to about 480 mg daily, or from about 440 mg daily to about 480 mg daily from about 10 mg daily to about 480 mg daily, or from about 10 mg daily to about 450 mg daily, or from about 10 mg daily to about 420 mg daily, or from about 10 mg daily to about 390 mg daily, or from about 10 mg daily to about 360 mg daily, or from about 10 mg daily to about 330 mg daily, or from about 10 mg daily to about 300 mg daily, or from about 10 mg daily to about 270 mg daily, or from about 10 mg daily to about 240 mg daily, or from about 10 mg daily to about 210 mg daily, or from about 10 mg daily to about 180 mg daily, or from about 10 mg daily to about 150 mg daily, or from about 10 mg daily to about 120 mg daily, or from about 10 mg daily to about 90 mg daily, or from about 10 mg daily to about 60 mg daily, or from about 10 mg daily to about 30 mg daily, or from about 10 mg daily to about 90 mg daily, or from about 10 mg daily to about 60 mg daily, or from about 10 mg daily to about 30 mg daily, or from about 20 mg daily to about 480 mg daily, or from about 20 mg daily to about 450 mg daily, or from about 20 mg daily to about 440 mg daily, or from about 20 mg daily to about 410 mg daily, or from about 20 mg daily to about 400 mg daily, or from about 20 mg daily to about 370 mg daily, or from about 20 mg daily to about 360 mg daily, or from about 20 mg daily to about 330 mg daily, or from about 20 mg daily to about 320 mg daily, or from about 20 mg daily to about 290 mg daily, or from about 20 mg daily to about 280 mg daily, orfrom about 20 mg daily to about 250 mg daily, or from about 20 mg daily to about 240 mg daily, or from about 20 mg daily to about 210 mg daily, or from about 20 mg daily to about 200 mg daily, or from about 20 mg daily to about 170 mg daily, or from about 20 mg daily to about 160 mg daily, or from about 20 mg daily to about 130 mg daily, or from about 20 mg daily to about 120 mg daily, or from about 20 mg daily to about 90 mg daily, or from about 20 mg daily to about 80 mg daily, or from about 20 mg daily to about 50 mg daily, or from about 20 mg daily to about 40 mg daily, or from about 20 mg daily to about 160 mg daily, or from about 20 mg daily to about 130 mg daily, or from about 20 mg daily to about 120 mg daily, or from about 20 mg daily to about 100 mg daily, or from about 20 mg daily to about 80 mg daily, or from about 20 mg daily to about 70 mg daily, or from about 20 mg daily to about 40 mg daily, or about 20 mg daily, or about 40 mg daily, or about 60 mg daily, or about 80 mg daily, and / orBETA-adrenergic receptor inhibitor is administered: in a pharmacologically acceptable route, or orally; and / orBETA-adrenergic receptor inhibitor is administered once daily, or twice daily, or three times daily, or four times daily; and / orBETA-adrenergic receptor inhibitor is administered: from about 7 hours to about 12 hours apart about 12 hours apart, or about 11 hours apart, or about 10 hours apart, orabout 9 hours apart, or about 8 hours apart, or about 7 hours apart, or about 6 hours apart, or about 5 hours apart, or about 4 hours apart, or about 3 hours apart; and / orBETA-adrenergic receptor inhibitor is administered at about 30 mg orally, twice daily at from about 7 hours to about 12 hours apart; and / or wherein: the effective amount of the ADRB2 inhibitor is: a pharmacologically effective dose with clinically acceptable severe adverse effects, or from about 10 mg daily to about 480 mg daily, or from about 20 mg daily to about 480 mg daily, or from about 30 mg daily to about 480 mg daily, or from about 40 mg daily to about 480 mg daily, or from about 50 mg daily to about 480 mg daily, or from about 60 mg daily to about 480 mg daily, or from about 70 mg daily to about 480 mg daily, or from about 80 mg daily to about 480 mg daily, or from about 120 mg daily to about 480 mg daily, or from about 160 mg daily to about 480 mg daily, or from about 200 mg daily to about 480 mg daily, or from about 240 mg daily to about 480 mg daily, or from about 280 mg daily to about 480 mg daily, or from about 320 mg daily to about 480 mg daily, or from about 360 mg daily to about 480 mg daily, or from about 400 mg daily to about 480 mg daily, or from about 440 mg daily to about 480 mg daily, or from about 10 mg daily to about 480 mg daily, or from about 10 mg daily to about 450 mg daily, or from about 10 mg daily to about 420 mg daily, orfrom about 10 mg daily to about 390 mg daily, or from about 10 mg daily to about 360 mg daily, or from about 10 mg daily to about 330 mg daily, or from about 10 mg daily to about 300 mg daily, or from about 10 mg daily to about 270 mg daily, or from about 10 mg daily to about 240 mg daily, or from about 10 mg daily to about 210 mg daily, or from about 10 mg daily to about 180 mg daily, or from about 10 mg daily to about 150 mg daily, or from about 10 mg daily to about 120 mg daily, or from about 10 mg daily to about 90 mg daily, or from about 10 mg daily to about 60 mg daily, or from about 10 mg daily to about 30 mg daily, or from about 10 mg daily to about 90 mg daily, or from about 10 mg daily to about 60 mg daily, or from about 10 mg daily to about 30 mg daily, or from about 20 mg daily to about 480 mg daily, or from about 20 mg daily to about 450 mg daily, or from about 20 mg daily to about 440 mg daily, or from about 20 mg daily to about 410 mg daily, or from about 20 mg daily to about 400 mg daily, or from about 20 mg daily to about 370 mg daily, or from about 20 mg daily to about 360 mg daily, or from about 20 mg daily to about 330 mg daily, or from about 20 mg daily to about 320 mg daily, or from about 20 mg daily to about 290 mg daily, or from about 20 mg daily to about 280 mg daily, or from about 20 mg daily to about 250 mg daily, or from about 20 mg daily to about 240 mg daily, or from about 20 mg daily to about 210 mg daily, or from about 20 mg daily to about 200 mg daily, or from about 20 mg daily to about 170 mg daily, or from about 20 mg daily to about 160 mg daily, orfrom about 20 mg daily to about 130 mg daily, or from about 20 mg daily to about 120 mg daily, or from about 20 mg daily to about 90 mg daily, or from about 20 mg daily to about 80 mg daily, or from about 20 mg daily to about 50 mg daily, or from about 20 mg daily to about 40 mg daily, or from about 20 mg daily to about 160 mg daily, or from about 20 mg daily to about 130 mg daily, or from about 20 mg daily to about 120 mg daily, or from about 20 mg daily to about 100 mg daily, or from about 20 mg daily to about 80 mg daily, or from about 20 mg daily to about 70 mg daily, or from about 20 mg daily to about 40 mg daily, or about 20 mg daily, or about 40 mg daily, or about 60 mg daily, or about 80 mg daily, and / orADRB2 inhibitor is administered: in a pharmacologically acceptable route, or orally; and / orADRB2 inhibitor is administered once daily, or twice daily, or three times daily, or four times daily; and / orADRB2 inhibitor is administered: from about 7 hours to about 12 hours apart, or about 12 hours apart, or about 11 hours apart, or about 10 hours apart, or about 9 hours apart, or about 8 hours apart, or about 7 hours apart, or about 6 hours apart, or about 5 hours apart, or about 4 hours apart, orabout 3 hours apart; and / orADRB2 inhibitor is administered at about 30 mg orally, twice daily at from about 7 hours to about 12 hours apart; and / or wherein: the effective amount of propranolol is: from about 10 mg daily to about 480 mg daily, or from about 20 mg daily to about 480 mg daily, or from about 30 mg daily to about 480 mg daily, or from about 40 mg daily to about 480 mg daily, or from about 50 mg daily to about 480 mg daily, or from about 60 mg daily to about 480 mg daily, or from about 70 mg daily to about 480 mg daily, or from about 80 mg daily to about 480 mg daily, or from about 120 mg daily to about 480 mg daily, or from about 160 mg daily to about 480 mg daily, or from about 200 mg daily to about 480 mg daily, or from about 240 mg daily to about 480 mg daily, or from about 280 mg daily to about 480 mg daily, or from about 320 mg daily to about 480 mg daily, or from about 360 mg daily to about 480 mg daily, or from about 400 mg daily to about 480 mg daily, or from about 440 mg daily to about 480 mg daily, or from about 10 mg daily to about 480 mg daily, or from about 10 mg daily to about 450 mg daily, or from about 10 mg daily to about 420 mg daily, or from about 10 mg daily to about 390 mg daily, or from about 10 mg daily to about 360 mg daily, or from about 10 mg daily to about 330 mg daily, or from about 10 mg daily to about 300 mg daily, or from about 10 mg daily to about 270 mg daily, or from about 10 mg daily to about 240 mg daily, or from about 10 mg daily to about 210 mg daily, or from about 10 mg daily to about 180 mg daily, orfrom about 10 mg daily to about 150 mg daily, or from about 10 mg daily to about 120 mg daily, or from about 10 mg daily to about 90 mg daily, or from about 10 mg daily to about 60 mg daily, or from about 10 mg daily to about 30 mg daily, or from about 10 mg daily to about 90 mg daily, or from about 10 mg daily to about 60 mg daily, or from about 10 mg daily to about 30 mg daily, or from about 20 mg daily to about 480 mg daily, or from about 20 mg daily to about 450 mg daily, or from about 20 mg daily to about 440 mg daily, or from about 20 mg daily to about 410 mg daily, or from about 20 mg daily to about 400 mg daily, or from about 20 mg daily to about 370 mg daily, or from about 20 mg daily to about 360 mg daily, or from about 20 mg daily to about 330 mg daily, or from about 20 mg daily to about 320 mg daily, or from about 20 mg daily to about 290 mg daily, or from about 20 mg daily to about 280 mg daily, or from about 20 mg daily to about 250 mg daily, or from about 20 mg daily to about 240 mg daily, or from about 20 mg daily to about 210 mg daily, or from about 20 mg daily to about 200 mg daily, or from about 20 mg daily to about 170 mg daily, or from about 20 mg daily to about 160 mg daily, or from about 20 mg daily to about 130 mg daily, or from about 20 mg daily to about 120 mg daily, or from about 20 mg daily to about 90 mg daily, or from about 20 mg daily to about 80 mg daily, or from about 20 mg daily to about 50 mg daily, or from about 20 mg daily to about 40 mg daily, or from about 20 mg daily to about 160 mg daily, or from about 20 mg daily to about 130 mg daily, orfrom about 20 mg daily to about 120 mg daily, or from about 20 mg daily to about 100 mg daily, or from about 20 mg daily to about 80 mg daily, or from about 20 mg daily to about 70 mg daily, or from about 20 mg daily to about 40 mg daily, or about 20 mg daily, or about 40 mg daily, or about 60 mg daily, or about 80 mg daily, and / or propranolol is administered: in a pharmacologically acceptable route, or orally; and / or propranolol is administered once daily, or twice daily, or three times daily, or four times daily; and / or propranolol is administered: from about 7 hours to about 12 hours apart, or about 12 hours apart, or about 11 hours apart, or about 10 hours apart, or about 9 hours apart, or about 8 hours apart, or about 7 hours apart, or about 6 hours apart, or about 5 hours apart, or about 4 hours apart, or about 3 hours apart; and / or propranolol is administered at about 30 mg orally, twice daily at from about 7 hours to about 12 hours apart; and / or wherein: the effective amount of G-CSF is: from about 1 ug / kg to about 70 ug / kg twice daily by intravenous injection, or from about 1 ug / kg to about 40 ug / kg daily bysubcutaneous injection, or from about 3 ug / kg to about 40 ug / kg daily by continuous subcutaneous injection, or from about 10 ug / kg daily to about 40 ug / kg daily, or about 10 ug / kg daily; and / orG-CSF is administered: in a pharmacologically acceptable route, or intravenously, or subcutaneously, or continuous subcutaneously; and / or the last dose of the G-CSF inhibitor prior to the start of apheresis and / or the start of leukapheresis is administered at: from about 120 hours to about 10 hours, or from about 72 hours to about 10 hours, or from about 24 hours to about 10 hours, or from about 14 hours to about 10 hours, or from about 13 hours to about 10 hours, or from about 13 hours to about 10 hours, or from about 12 hours to about 10 hours, or from about 11 hours to about 10 hours, or about 12 hours, or about 11 hours, or about 10 hours, before the apheresis and / or the leukapheresis treatment begins; and / orG-CSF is administered once daily; and / orG-CSF is administered once, twice, three times, four times, five times, six times, seven times, eight times, or more than eight times; and / orG-CSF is administered no more than eight times, no more than seven times, no more than six times, no more than five times, no more than four times, or no more than three times, no more than twice, or no more than once; and / orG-CSF is administered at about 10 ug / kg daily by intravenousinjection, or subcutaneous injection, or continuous subcutaneous injection, for about four days, preferably at least about 10 hours prior to the apheresis and / or the leukapheresis.

116. The method of any one of Claim 98 to the Claim immediately above, wherein the subject is administered a drug that interferes with CD34+cell mobilization, wherein the drug is a lenalidomide, wherein the lenalidomide is administered: in accordance with the drug label, and / or at a dose of from about 8 mg / kg to about 16 mg / kg, preferably about 16 mg / kg, and / or in a pharmacologically acceptable route, or intravenously, or for about 3 to about 4 cycles; and / or wherein the drug is a daratumumab, wherein the daratumumab is administered: in accordance with the drug label, and / or at a dose of from about 8 mg / kg to about 16 mg / kg, preferably about 16 mg / kg, and / or in a pharmacologically acceptable route, or intravenously, or for about 3 to about 4 cycles117. The method of any one of Claim 98 to the Claim immediately above, wherein the method causes: no adverse event in the subject during or after treatment, or no severe adverse event in the subject during or after treatment, or no adverse events greater than Grade 1 or 2 in severity, or the adverse events, if any, is limited to the list consisting of bone pain, hypocalaemia, diarrhea, dry mouth, nausea, hypokalaemia, oedema peripheral, paranesthesia, and the likes.

Images