WO1993000109A1 - Procede de stimulation de la reponse immunitaire a l'aide d'hormone de croissance - Google Patents
Procede de stimulation de la reponse immunitaire a l'aide d'hormone de croissance Download PDFInfo
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- WO1993000109A1 WO1993000109A1 PCT/US1992/004489 US9204489W WO9300109A1 WO 1993000109 A1 WO1993000109 A1 WO 1993000109A1 US 9204489 W US9204489 W US 9204489W WO 9300109 A1 WO9300109 A1 WO 9300109A1
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- igf
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/61—Growth hormone [GH], i.e. somatotropin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/30—Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
- A61K2039/55516—Proteins; Peptides
Definitions
- This invention relates to improved methods and compositions for the use of growth hormone (GH) which result in the continuous presence of serum levels of GH therapeutically 10 effective in stimulating growth hormone responses in mammals or avians, including 1) increasing immune responses, such as antibody response to antigens in patients with suboptimal immune systems; and 2) novel therapeutic growth hormone administration methods and compositions that exhibit efficacy with intermittent administration.
- GH growth hormone
- GH growth hormone
- hGH is a member of a family of homologous hormones that include placental lactogens, prolactins, and other genetic and species variants or growth hormone (Nicoll, C. S., et al. (I986. Endocrine Reviews 7. 169). hGH is unusual among these in that it exhibits broad species specificity and binds to either the cloned somatogenic (Leung, D. W., et al. [I987] Nature
- prolactin receptor Boutin, J. M., et al. [I988] Cell; 53, 69.
- the cloned gene for hGH has been expressed in a secreted form in Eschericha coli (Chang, C. N., et al. [I987] Gene 55, 189) and its DNA and amino acid sequence has been reported (Goeddel, et al. [I979] Nature 281, 544; Gray, et al. [1985] Gene 39, 247).
- Human growth hormone participates in much of the regulation of normal human
- This pituitary hormone exhibits a multitude of biological effects including linear growth (somatogenesis), lactation, activation of macrophages, insulin-like and diabetogenic effects among others (Chawla, R, K. (1983) Ann. Rev. Med. 34. 519; Edwards, C. K. et al. (I988) Science 239. 769; Thomer, M. 0., et al. .1988) J. Clin. Invest. 81. 745).
- hGH Human growth hormone
- 191 amino acids molecular weight 21 ,500.
- Disulfide bonds link positions 53 and 165 and positions 182 and 189.
- hGH is a potent anabolic agent, especially due to retention of nitrogen, phosphorus, potassium, and calcium.
- hGH liver receptor D. W. Leung etal., Nature 330, 537 (1987)
- human prolactin receptor J. M. Boutin etal., Mol. Endoc ⁇ nol. 3, 1455 (1989)
- human placental lactogen receptor M. Freemark, M. Comer, G. Komer, and S. Handwerger, Endocrinol. 120, 1865 (1987)
- These homologous receptors contain a glycosylated extracellular hormone binding domain, a single transmembrane domain and a cytoplasmic domain which differs considerably in sequence and size.
- One or more receptors are assumed to play a determining role in the physiological response to hGH.
- Pegylation of Proteins hGH is given to children with growth deficiencies and proven to enhance growth.
- the half-life of the injected hGH is so short that in order to have high efficiency as a pharmaceutical, hGH has to be injected at least three times a week and more commonly daily, which makes administering hGH a bigger task than some children can tolerate.
- the short half- life of hGH is believed to be due to its small molecular weight (22,000 dalton), and rapid renal clearance, which has been found to be proportional to the molecular weight of protein in circulation.
- Pegylation meaning conjugating polyethylene glycol (PEG) to protein, was found to be an excellent way to increase the molecular weight of protein.
- PEG is an non-immunogenic, linear, uncharged polymer with three water molecules per ethylene oxide unit therefore can alter the hydrodynamic properties of the conjugated molecules dramatically (Maxfield, et al, Polymer 16,505-509 [1975]; Bailey, F. E., et al, in Nonionic Surfactants [Schick, M. J., ed] pp.794-821, 1967)).
- Several enzymes for therapeutic usage were PEGylated to increase the in vivo half-life effectively (Abuchowski, A. et al, J. Biol. Chem. 252, 3582-3586, 1977; Abuchowski, A. et al, Cancer Biochem. Biophys. 7, 175-186, 1984).
- IL-2 interleukin-2
- PEGylation of other molecules were reported to have reduced immunogenecity and toxicity (Abuchowski, A. et al, J. Biol. Chem., 252, 3578-3581, 1977).
- the patented polypeptide compositions are prepared by a process involving the steps of reacting at least one terminal carbon atom bearing a hydroxy group from polyethylene glycol or polypropylene glycol with a coupling agent to provide an activated polymer having a reactive agent to provide an activated polymer having a reactive terminal group and reacting a physiologically active immunogenic polypeptide with the activated polymer by coupling the polypeptide to the reactive terminal group of the activated polymer.
- the patent discloses the use of some 13 polyfunctional coupling moieties including (a) cyanuric chloride or fluoride, (b) an acyl azide formed by reacting the polymer with chlorocetic acid, then with diazomethane to obtain the methyl ester of the carbomethoxy ether followed by treatment with hydrazine which gives the corresponding hydrazide which is then treated with nitrous acid to give the acylazide, (c) a dihalosuccinic anhydride, (d) the p- diazobenzyl group, (e) the 3-(p-diazophenyloxy)-hydroxy propyloxy group, (f) the 1- glycydoxy-4(2-hydroxy-3-propyl) butane group, (g) carboxyamino or thiocarbonylamino benzyl linkage, (h) the 2-(hydroxy-3-carboxy) propyl linkage, (i) an w-amino derivative produced from
- PEGzymes polyethylene glycol modified enzymes
- a footnote states that, "For some enzymes such as asparaginases this coupling agent yields PEGzymes with higher specific activities.”
- Therapeutic formulations containing hormones in combination with antibodies specific for the hormone were reported to potentiate the activity of the hormone provided that the epitope specificity of the antibody is chosen appropriately. This potentiation or mimicry of hormones, such as growth hormone, is disclosed in Astor et al., EP 137234B, 10 October 1990.
- the modified bovine serum albumin exhibited a blood circulating life in rabbits similar to native bovine serum albumin except that it was not removed from circulation by the eventual development of antibodies.
- the modified bovine serum albumin exhibited substantial changes in properties, such as solubility, electrophoretic mobility in acrylamide gel, ion exchange chromatography, and sedimentation, as compared with the unmodified protein.
- Rabbits were immunized by the intravenous or by the intramuscular administration of PEG-1900-catalese.
- the intravenous administered antigen did not yield detectable antibodies against PEG-1900-catalase or native catalase whereas the ant ⁇ serum from intramuscular administered antigen contained antibodies to PEG-1900-catalase and native catalase.
- PEG-5000-catalase did not react with either antiserum.
- PEG-1900-catalase and PEG-5000-catalase retained 93% and 95%, respectively, of their enzymatic activity and PEG-5000-catalase resisted digestion by trypsin, chymotrypsin and a protease from Streptonyces griseus.
- PEG-1500-catalase and PEG-5000-catalase exhibited enhanced circulating lives in the blood of acatalasemic mice during repetitive intravenous injection and no evidence was seen of an immune response to injections of the modified enzymes.
- IGF-I Insulin-like growth factor I
- GH growth hormone
- IGF-I is reported to lower blood glucose levels in humans (Guler et al., N. Engl. J. Med.. 317: 137-140 (1987)). Additionally, IGF-I promotes growth in several metabolic conditions characterized by low IGF-I levels, such as hypophysectomized rats [Skottner etal., J. Endocr..112: 123-132 (1987)], diabetic rats [Scheiwiller etal., Nature. 323: 169-171 (1986)], and dwarf rats [Skottner et al., Endocrinology. 124: 2519-2526 (1989)].
- the kidney weight of hypophysectomized rats increases substantially upon prolonged infusions of IGF-I subcutaneously (Guler etal., Proceedings of the 1st European Congress of Endocrinology. 103: abstract 12-390 (Copenhagen, 1987))
- the kidneys of Snell dwarf mice and dwarf rats behaved similarly (van Buul-Offers etal., Pediatr. Res.. 2Q: 825-827 (1986)); Skottner etal., Endocrinology, supra.
- An additional use for IGF-I is to improve glomerular filtration and renal plasma flow (Guler et al., Proc. Natl. Acad. Sci. USA. 8_g: 2868-2872 (1989)).
- GH and IGF-I have been linked with immunoregulatory properties.
- the immune response results from interaction of antigens (foreign or non-self moieties) with host cells (lymphocytes) bearing specific receptors on the surface membrane for these antigens.
- Lymphocytes are grouped into two major classes, T-cells and B-cells.
- T-cells originate from the thymus where they mature and differentiate from bone- marrow-derived cells. The mature T-cells leave the thymus gland to continuously circulate from blood to lymph nodes and spleen and back to blood. T-cells are further subdivided into three major subsets: T-helper cells, T-suppressor cells, and T-cytolytic cells. T-helper cells
- help other cells: B-cells to secrete antibody, cytotoxic cells to become functional, and macrophages to become activated. This population of T-cells bears the CD. surface marker that is used to identify this subset in tissue and blood.
- T-cytolytic cells are responsible for killing target cells such as virally infected cells, tumor cells, and aliografts. Suppressor T-cells act to limit and terminate the immune response. The cytolytic and suppressor T-cell populations are identified by the CD g surface marker.
- the B-cells also derive from immature precursors found in the bone marrow. When mature, the B-cells migrate to all lymphoid organs except the thymus. B-cells interact with antigens by way of antibody molecules bound to their plasma membranes that act as receptor proteins. This surface immunoglobulin is used as a marker to identify B- cells in tissue and blood. Following interaction with antigen and T-helper cells, the B-cells differentiate into antibody-forming cells called plasma cells. These plasma cells secrete antibody into the extracellular matrix. The antibody diffuses into capillaries and circulates via normal blood flow. Thus, the serum immunoglobulin level reflects the cellular dynamics of the immune response.
- the B-cell reaction to vaccine is the production of appropriate immunoglobulins, which are intended to confer immunity against the disease.
- a particular B-cell will be differentiated to produce one particular type of antibody, and such production is caused by the presence in the body of one particular type of antigen.
- the animal or human will have a number of different B-cells that can produce its particular immunoglobulins when the appropriate antigen is present.
- the immune response to antigen is insufficient to confer immunity. That is, a quantity of immunoglobulins is generated (or a number of B-cells are potentiated) that is insufficient to confer effective immunity. It has been known since 1967 that a connection exists between the anterior pituitary and the immune system, and specifically with GH. Two groups of investigators concluded from their studies that GH controls the growth of lymphoid tissue (Pierpaoli and Sorkin, Nature. 215: 834 (1967); Baroni, Experientia. 22: 282 (1967)). Subsequently, immunologic function was restored in the pituitary dwarf mouse by a combination of bovine somatotropic hormone and thyroxin (Baroni etal., Immunol.. 17: 303-314 (1969)).
- mice with hereditary GH deficiency develop an impairment of the immune system associated with thymic atrophy, immunodeficiency, and wasting, resulting in a shortened life expectancy (Frabris ef al., Clin. EXP. Immunol..2: 209-225 (1971)). It has been shown that an age-associated decline in the plasma concentration of thymulin (a thymic hormone) occurs and that plasma thymulin concentration increases in bGH-treated middle-aged and old dogs (Goff etal., Clin. Exp. Immunol.. 6J3: 580-587 (1987)). The authors suggest that exogenous GH may be useful for restoring some immune functions in aged individuals.
- hGH prednisolone
- Cc /B1/6J mice administration of hGH to Cc /B1/6J mice was found to reverse the inhibitory effect of prednisolone on thymus and spleen cellularity and on natural killer activity; administration of hGH without prednisolone had no effect, although at higher doses it induced a decrease of thymic parameters and natural killer activity with no effect on spleen cellularity, and relative weights (Franco et al., Acta Endocrinolo ⁇ ica. 123: 339-344 (1990)). It has also been shown that GH induces T-cell proliferation in the thymus (Murphy et al., FASEB Meeting Abstract.
- IGF-I produced locally in tissues such as the thymus or inflammatory sites might affect the growth and function of IGF-l-receptor- bearing T- lymphocytes (Tapson etal., J. Clin. Invest..22: 950-957 (1988)).
- a statistically significant increase in thymus and spleen weight of hypophysectomized rats infused for 18 days with IGF-I was observed as compared to control or treatment with GH (Froesch et al., in Growth Hormone Basic and Clinical Aspects, eds. 0. Isaksson etal., p. 321-326 (1987)).
- IGF-I was found to repopulate the bone marrow cavity with hematopoietic cells [Froesch etal., supra], stimulate erythropoiesis in hypophysectomized rats [Kurtz etal., Proc. Natl. Acad. Sci. .USA..25: 7825-7829 (1988)], and enhance the maturation of mo ⁇ hologically recognizable granulocytic and erythroid progenitors in suspension cultures of marrow cells (Merchav etal., J. Clin. Invest..21: 791 (1988)).
- IGF-l is a growth-promoting factor for lymphocytes (Schimpff etal., Acta EndocrinoL. 102: 21-25 (1983)). B-cells, but not T-cells, have recently been shown to possess receptors for IGF-I (Stuart etal., J. Clinical Endo. and Met.. 72: 1117- 1122 (1991)). Also, IGF-I, as a chemotactic for resting and activated T-cells, stimulates an increase in thymidine inco ⁇ oration into resting and activated T-cells. Normal T-cell lines show augmentation of basal colony formation in response to IGF-I (Geffner et al., supra).
- IGF-I insulin growth factor-I receptor-bearing T lymphocytes.
- IGF-I is reported to suppress in a dose- dependent manner IL-2-induced prolrferative responses and in vitro antibody responses of splenocytes (Hunt and Eardley, J. Immunol.. 136: 3994-3999 (1986)).
- continuous GH presence can be achieved by the use of a catheter, insulin pump or implanted diffusion device which slowly administers a dose of GH which results in the stimulation of the immune system leading to an improved immune response.
- continuous presence of GH is achieved by coupling of GH to other macromolecules that results in an improved half-life of GH thereby facilitating the continuous presence of a therapeutically effective amount of GH.
- GH growth hormone binding protein
- covalently attached polymers such as polyethelene glycol, polypropylene glycol or carbohydrates
- other macromolecules such as proteins, lipids, or glycolipids that reduce clearance and are not immunogenic.
- GH human growth hormone
- PEG polyethyleneglycol
- the present invention provides a method for stimulating a mammal's or avian's immune system comprising administering to the mammal or avian an immune-stimulating effective amount of a GH containing composition.
- GH may be used in combination with IGF-I in a method of immune stimulation.
- the invention provides a method for increasing a mammal's or avian's antibody response to an im unogen comprising administering to the mammal or avian the immunogen and an effective amount of GH and IGF-I.
- This use of GH, PEG-GH, with or without IGF-I may be considered as an endocrine or hormonal adjuvant for the immunization process.
- this administration is concurrent and is followed by boosts of immunogen at shortened intervals relative to immunization methods when no GH and IGF-l are given. Therefore, the invention provides co-administration of effective amounts of IGF-I and GH for stimulating the immune system.
- This hormonal adjuvant that is the use of GH or of GH plus IGF-I as an adjuvant to promote the immune response, is applicable to any antigenic substance.
- the antigen is derived from microorganisms, viruses and tumors.
- a method is provided of increasing the amount of immunoglobulin produced by B-cells of a human or other mammalian subject in response to an immunogen, where said subject suffers from a condition in which insufficient immunoglobulin production occurs, comprising administering to the subject an effective amount of GH and IGF- I, the amount being effective to increase the production of immunoglobulin.
- the invention provides a method of increasing the T-cell responsiveness in a human or other mammalian subject in response to an immunogen, where said subject suffers from a condition in which insufficient T-helper or T-cytolytic activity occurs, comprising administering to the subject an effective amount of GH and IGF-I, the amount being effective to increase the T-helper or T-cytolytic activity.
- the intermittent administration of GH is not a therapeutically effective use of GH to stimulate the immune system. Stimulation of the immune system requires the continuous presence of GH. Intermittent administration of GH can result in the continuous presence of GH when the GH is complexed with itself or with another macromolecule such that the GH is not cleared from the plasma. Intermittent GH use is defined as administration every 3 or more days, preferably every 6 or more days.
- This unexpected use of GH in combination with a macromolecule such as PEG or covalent attachment to other large polymers results in a therapeutic composition that may be administered at intermittent intervals yet results in the continuous presence of GH in the plasma. Continuous presence GH results in the unexpected stimulation of the immune system.
- a second unexpected result of using GH complexed with a macromolecule is the stimulation of the growth of other tissues such as bone and muscle when compared to GH not complexed to a macromolecule and intermittently administered every 6 or more days.
- GH secreted by administered GH secreting tumor cells has been shown to stimulate growth (Kelley, Biochem Pharmacol., 38705, 1989). Growth hormone and growth hormone receptor have been shown to be present within the cells of the immune system. However there has been no indication that GH administration would result in a therapeutically useful stimulation of the immune system of mammals or birds.
- the administration of GH alone, or GH in combination with IGF-I stimulates the immune system, most preferably when GH is continuously present in the blood plasma and body tissue fluids. Su ⁇ risingly, the continuous presence of GH results in the stimulation of immune responsive tissues, such as the thymus and spleen.
- a preferred form of GH is GH in combination with a macromolecule that increases the plasma half-life of the GH.
- Such macromolecules include polyethylene glycol, polypropylene glycol, carbohycrates, lipids, and proteins.
- proteins include the GH binding proteins, antibodies and albumin.
- the most preferred form of GH is pegylated GH.
- Preferred formulations for administration to induce the continuous effective plasma concentrations of GH include GH with one or more pegylated lysine or methionine residues.
- the present invention represents an unexpected finding that not only are the spleen and thymus weights increased upon administration of GH containing compositions, but also the function of the thymus, spleen, or lymph nodes, as indicated by increased size and cell numbers in response to IGF-I.
- the increase in cell number and responsiveness translates to an increased production of antibody by these cells in response to an antigen.
- This method would be useful in treating patients having compromised immune systems such as AIDS patients, in whom increased antibody response to antigens would ward off, or decrease the severity of, infectious diseases and in whom vaccines could be made more effective.
- figure 1A is a plot of the spleen weight gain in rats following treatment with various doses of excipient, GH or GH plus GHBP for 7 days; figure 1B is the same spleen data plotted as a percent of whole body weight.
- Figure 2 is a graph of thymus weight in hypox rats following treatment with various doses of hGH, PEG-1 hGH or PEG-2 hGH.
- Figure 3 is a graph of whole body weight gain after 24 days in hypox rats receiving treatment with excipient, PEG-5 daily, every 3 days or every 6 days; or hGH daily, every 3 days or every 6 days.
- Figure 4 is a graph of the thymus weight following the same treatment as in figure 3.
- Figure 5 is a time plot for 16 days of whole body weight gain following treatment with excipient, hGH every 6 days, hGH daily, PEG-hGH daily or PEG-hGH every six days. All groups received 0.1mg/kg day of hGH.
- Figure 6 is a graph of body weight gain in aged rats treated with excipient, IGF-I, hGH, or IGF-I plus hGH.
- Figures 7A, 7B, and 7C provide graphs on the splenocyte number, splenic T-cell population number, and splenic B-cell number, respectively, after 7-day IGF-I treatment or excipient treatment.
- Figures 8A, 8B, and 8C provide graphs on the splenocyte number, splenic T-cell population number, and splenic B-cell number, respectively, after 14-day IGF-I, GH or excipient treatment.
- Figure 9 represents a graph of the number of thymocytes after 14-day IGF-I treatment, hGH treatment, IGF-I control treatment, and hGH control treatment.
- Figure 10 represents a graph of the mitogenic responses 14 days after initial excipient or IGF-I or hGH treatment of mice using the mitogens LPS (Fig. 10A), Con A (Fig. 10B), or PWM (Fig.10C).
- Figures 11 A, 11 B, and 11C provide graphs on the splenocyte number, splenic T-cell population number, and splenic B-cell number, respectively, after 14-day treatment with excipient, IGF-I, hGH, and IGF-I plus hGH.
- Figure 12 represents a graph of the number of thymocytes after 14-day IGF-I treatment, hGH treatment, and IGF-I plus hGH treatment.
- Figures 13A, 13B, and 13C represent graphs of splenic lymphocyte number, splenic T- cell subpopulation number, and splenic B-cell number, respectively, 7 days after the end of excipient, IGF-I, hGH, and IGF-I plus hGH treatment.
- Figure 14 represents a graph of the number of thymocytes 7 days after the end of excipient, IGF-I, hGH, and IGF-I plus hGH treatment.
- Figure 15 represents a graph of the mitogenic responses 7 days after the end of excipient, IGF-I, hGH, or IGF-I plus hGH treatment of mice using the mitogens LPS (Fig. 15A), Con A (Fig. 15B), or PWM (Fig. 15C).
- Figures 16A and 16B represent graphs of the lymph node cell number and lymph node T-cell populations, respectively, 7 days after the end of excipient, IGF-I, hGH, and IGF-I plus hGH treatment.
- Figures 17A, 17B, and 17C provide graphs on the splenic lymphocyte number, splenic T-cell population number, and splenic B-cell number, respectively, 21 days after the end of excipient, IGF- 1, hGH, and IGF-I plus hGH treatment.
- Figure 18 represents a graph of the number of thymocytes 21 days after the end of excipient, IGF-I, hGH, and IGF-I plus hGH treatment.
- Figure 19 represents a graph of the mitogenic responses 21 days after the end of excipient, IGF-I, hGH, or IGF-I plus hGH treatment of mice using the mitogens LPS (Fig. 19A), Con A (Fig. 19B), or PWM (Fig. 19C).
- Figure 20 shows the concentration of anti-dinitrophenyl-ovalbumin IgG (Fig. 20A) and total IgG (Fig. 20B) in ⁇ g/ml in the serum of mice as a function of the number of weeks since the first immunization with dinitrophenyl-ovalbumin conjugate (Day 0, designated AG), wherein at week 3 (Day 20) the mice were boosted with conjugate and given excipient or IGF-I.
- Figure 21 shows the weight gain changes for mice with and without transplanted bone marrow and treated with excipient or 40 ⁇ g or 120 ⁇ g of IGF-I.
- Figures 22A, 22B, and 22C show graphs of peripheral blood lymphocyte B-cells, T-cell subpopulations, and H/S ratio, respectively, 14 days after irradiation of mice with transplanted bone marrow and treated with excipient, 40 ⁇ g IGF-I, or 120. ⁇ g IGF- 1.
- Figures 23A, 23B, and 23C show graphs of splenic lymphocyte number, splenic T-cell subpopulations and splenic B-cell number, respectively, 14 days after irradiation of mice with transplanted bone marrow and treated with excipient, 40 ⁇ g IGF-I, or 120 ⁇ g IGF- 1.
- Figure 24 represents a graph of the mitogenic responses 14 days after irradiation of mice with transplanted bone marrow and treated with excipient, 40 ⁇ g IGF-I, or 120 ⁇ g IGF-I using the mitogens LPS (Fig. 24A), Con A (Fig. 24B), or PWM (Fig. 24C).
- Figures 25A, 25B, and 25C show graphs of peripheral blood lymphocyte B-cells, T-cell subpopulations, and H/S ratio, respectively, 21 days after irradiation of mice with transplanted bone marrow and treated with excipient, 40 ⁇ g IGF-I, or 120 ⁇ g IGF- 1.
- Figures 26A, 26B, and 26C show graphs of total splenocyte number, T-cell subpopulations and splenic B-cell number, respectively, 21 days after irradiation of mice with transplanted bone marrow and treated with excipient, 40 ⁇ g IGF-I, or 120 ⁇ g IGF- 1.
- Figure 27 represents a graph of the mitogenic responses 21 days after irradiation of mice with transplanted bone marrow and treated with excipient, 40 ⁇ g IGF-I, or 120 ⁇ g IGF-I using the mitogens LPS (Fig. 27A), Con A (Fig. 27B), or PWM (Fig. 27C).
- Figure 28 represents a graph of thymic lymphocyte number 14 days (Fig. 28A) or 21 days (Fig. 28B) after irradiation of mice with transplanted bone marrow and treated with excipient, 40 ⁇ g IGF-I, or 120 ⁇ g IGF-I.
- stimulating an immune system refers to increasing the immune function of a mammal or avian, whether the increase is due to antibody mediation or cell mediation, and whether the immune system is endogenous to the host treated with GH or GH plus IGF-I or is transplanted from a donor to the host recipient given GH or GH plus IGF-I (such as bone marrow transplants).
- the stimulation may result from an increased number of splenic cells such as splenic lymphocyte number, splenic T-cell population number (T-cell, CD 4 and CD g ), or splenic B-cell number, or from an increased number of thymocytes.
- Other cells involved in the immune system response include natural killer cells, macrophages, and neutrophils.
- the stimulation may be due to an increase in antibody production in response to an immunogen.
- the expressions "compromised immune system” and “condition in which insufficient immunoglobulin production occurs” signify the immune system of humans as well as animals that have a smaller antibody response to antigens than normal, whether because their spleen size is smaller than it should be, whether the spleen is only partially functional, whether drugs such as chemotherapeutic agents are suppressing the normal immune function, whether the animal is functionally IGF-I (or GH) deficient, or due to any other factor.
- Examples include aged patients, patients undergoing chemotherapy or radiation therapy, recovering from a major illness, or about to undergo surgery, patients with AIDS, patients with congenital and acquired B-cell deficiencies such as hypogammaglobulinemia, common varied agammaglobulinemia, and selective immunoglobulin deficiencies, e.g., IgA deficiency, patients infected with a virus such as rabies with an incubation time shorter than the immune response of the patient, and patients with hereditary disorders such as diGeorge syndrome.
- the mammals and avians potentially affected herein include mammals and avians of economic importance such as bovine, ovine, and porcine animals, as well as chickens and turkeys. The mammals may exhibit a splenic atrophy and subsequent loss in B-cel!
- IGF-I insulin-like growth factor from any species, including bovine, ovine, porcine, equine, avian, and preferably human, in native-sequence or in variant form, and from any source, whether natural, synthetic, or recombinant.
- Preferred herein for animal use is that form of IGF-I from the particular species being treated, such as porcine IGF- I to treat pigs, ovine IGF-I to treat sheep, bovine IGF-I to treat cattle, etc.
- human native-sequence, mature IGF-I is human native-sequence, mature IGF-I, more preferably without a N-terminal methk>nine, prepared, e.g., by the process described in EP 230,869 published August 5, 1987; EP 128,733 published December 19, 1984; or EP 288,451 published October 26, 1988. More preferably, this native-sequence IGF-I is recombinantly produced and is available from Genentech, Inc., South San Francisco, CA for clinical investigations. Also preferred for use is IGF-I that has a specific activity greater than about 14,000 units/mg as determined by radioreceptor assay using placenta membranes, such as that available from KabiGen AB, Sweden.
- IGF-I variants are those described in PCT WO 87/01038 published February 26, 1987 and in PCT WO 89/05822 published June 29, 1989, i.e., those wherein at least the glutamic acid residue is absent at position 3 from the N-terminus of the mature molecule or those having a deletion of up to five amino acids at the N-terminus.
- the most preferred variant has the first three amino acids from the N-terminus deleted (variously designated as brain IGF, tIGF-l, des(1-3)-IGF-l, ordes-IGF-l).
- Recombinant human IGF-I [available commercially from KabiGen AB, Sweden,
- the IGF-I was dissolved at 5 mg/ml in 10 mM citrate buffer and 126 mM NaCI, pH 6.0. This IGF-I was administered to three species, i.e., rat, rabbit, and mouse, to observe its effects on spleen and thymus weight. Dose-response studies were performed in the mouse and rat, and IGF-I was given to the rabbit with similar effects. In addition, B- and T-cell numbers and responses to mitogenic stimulation were evaluated in the mice.
- IGF-I deficiency Two animal models of GH deficiency and therefore IGF-I deficiency were used to demonstrate the effect of IGF-I on spleen and thymic weight and size.
- a third model of GH and IGF-I deficiency is the aged animal. Aged (18-month-old) rats were used to demonstrate the effect of IGF-I on spleen and thymic size, cellulants architecture, and in vitro response to mitogens. Also, adult ovariectomized rats, with normal serum IGF-I concentrations, were used to demonstrate the effect of IGF-I on spleen and thymus in an animal that was not IGF-I deficient .
- GH refers to growth hormone from any species, including bovine, ovine, porcine, equine, avian, and preferably human (hGH), in native-sequence or in variant form, and from any source, whether natural, synthetic, or recombinant.
- hGH human growth hormone
- hGH recombinant hGH
- rhGH recombinant hGH
- Nutropin recombinant hGH
- Another suitable hGH candidate is an hGH variant that is a placental form of GH with pure somatogenic and no lactogenic activity.
- GH variants are described in WO/90/04788 published 3 May 1990.
- other molecules which have the same activity are included within the functional meaning of growth hormone, for example fragments of GH or antibody specific for GH receptor which stimulates a GH response.
- any other therapeutic agent that causes a continuous expression of GH by manipulating endogenous GH secretion will fall within the functional definition of GH.
- an increase in continuous expression of GH may be achieved by the administration of steroid hormones, for example estrogen and testosterone. The use of such agents that increases the endogenous production of GH resulting in the continuous presence of GH thereby stimulating the immune system, and other responsive tissues.
- the expression “intermittent administration” or the term “intermittent” both refer to the therapeutic use by injection, or other suitable methods, such as lung or nasal administration, of GH or GH plus IGF-I formulation in a short time interval, generally less than 60 minutes, preferably less than 30 minutes and most preferably in less than 10 minutes.
- This intermittent bolus delivery of the GH containing therapeutic composition may be every three or more days, preferably every 4, 5, 6 or more days, and most preferably every 7, 8, 9, 10, 12, 14, 16, 18, 21 , 24 or more days.
- the expression “continuous presence” refers to a therapeutically effective plasma, serum or intracellular fluid concentration of GH or a GH variant.
- the GH is present in detectable amounts, at a concentration sufficient to stimulate GH responsive tissues, and the level present is not below a level the GH responsive tissues respond to as GH free.
- the expression “increasing antibody response to an immunogen” refers to raising the serum immunoglobulin (IgG, IgA or IgM) titer of an animal in response to a boost of the antigen against which the antibody is directed. Indicators of increased antibody response include an increase in the production of antibodies to booster shots of immunogen, as well as an increase in the number of B-cells in the patient.
- the immunogen can be any that raise antibodies directed thereto, but preferably is a virus, including a vaccine, or a bacterium.
- the invention is particularly useful for those instances where the mammal or avian is infected with a virus that has an incubation time that is shorter than the immune response of the mammal or avian, such as, e.g., rabies.
- the IGF-I herein decreases the interval between primary and secondary immunizations or between secondary immunization and subsequent boosts of immunogen.
- the invention is also useful in promoting immunization through the use of GH or GH plus IGF-I as hormonal adjuvants to increase both the rate of antibody production, and the amount or magnitude of the immune response.
- This hormonal adjuvant also increases the cellular immune response.
- the expression "increasing the T-cell responsiveness to an immunogen" in a subject suffering from a condition in which insufficient T-help or T-cytolytic activity occurs refers to raising the level of T-he!per and/or T-cytolytic cell activity of the mammal in response to an immunogen to which T- cells are responsive, including viral antigens, tumors, bacteria, etc.
- a subject with insufficient T-help or T-cytolytic activity is a mammal that has less than the normal number of T-helper and/or T- cytolytic cells (as determined, e.g., by CD 4 /CDg markers) necessary to, for example, secrete antibodies, activate macrophages, and kill target cells such as virally infected or tumor cells.
- the expression "restore immunity" in a mammal means to bring the level of immunity of the mammal back to normal, whether by restoring splenic or thymic cells or by increasing T- cell responsiveness or the amount of immunoglobulin produced by B- cells.
- the expression mammal refers to any mammal but especially primates, bovine, ovine, canine, feline, equine and rodentia. Specifically it includes human, cows, horses, rats, mice, rabbits, monkeys, cats, dogs and pigs.
- the present invention clearly shows that the s.c. administration of hGH as a continuous infusion or PEG-GH as daily or infrequent intermittent injections are optimal modes of GH delivery to affect the growth of the thymus and to stimulate the immune system.
- PEG-GH is a particularly attractive method of practicing this invention. In one example we show that only 2 injections of PEG-5 hGH 6 days apart leads to a large overgrowth of the thymus. In another example, we show that small doses of hGH given for 24 days are ineffective at stimulating thymic growth, yet the same doses of PEG-5 hGH greatly increase thymic size.
- PEG-5 hGH should be delivered as infrequent injections, in the rat at intervals of every 6 days.
- intermittent GH administration of PEG-hGH results in superior growth stimulation.
- met-less hGH also has the desired efficacy when it is pegylated.
- GHBP in combination with GH results in similar stimulation of GH responses and it may be administered intermittently. High level continuous infusion of GH will achieve similar stimulation but with the use of substantially greater amounts of GH.
- the mechanism of the enhanced effect of continuous hGH on thymic growth is unknown. It is known that optimal GH responses are seen on whole body or bone growth after pulsatile GH delivery. One might therefore predict that the growth of the thymus would also be optimal with a pulsatile method of hGH administration.
- There are enzyme systems in the liver where different isozymes are produced depending on the pattern of GH exposure, some are optimally stimulated by continuous GH exposure.
- the mechanism of how the liver senses continuous or pulsatile patterns is unknown. The magnitude of this effect was quite su ⁇ rising as it was possible to administer GH in different patterns that had an equal effect on whole body growth yet an almost all or none effect on the thymus.
- the thymus is restored in weight and in function by IGF-1, GH, or IGF-1 + GH administration; that this increased mass is accompanied by an increased number of thymocytes, and that the cells produced are true precursor cells for T-cells.
- the increased mass of the thymus, its rejuvenation in fact, found in the present invention is translated into a positive beneficial effect on the immune system as determined by antibody production, B-cell count or T-cell count.
- This invention provides the basis for a mode of administration of met hGH, metless hGH, and particularly of PEG-5 hGH (both met hGH and metless hGH) which appears to be the most effective form of hGH at producing this response.
- PEG-hGH since it can produce the response equivalent to that of a continuous mode of administration, but using infrequent injections, seems the most effective and practical way to stimulate those hGH responsive tissues that preferentially respond to continuous hGH presence.
- the su ⁇ rising finding that the response of the thymus to GH is very dependent on the pattern of GH administration is that the response of the thymus is optimal under a continuous exposure to GH.
- Other growth responses to GH for example those of the whole body or of bone growth, previously were found optimal when GH was given in a pulsatile manner.
- a single cysteine mutant of hGH was made by site-directed mutagenesis, secreted by £ coli 16C9 strain and purified on an anion-exchange column.
- PEG-maleimide was made by reacting monomethoxy-PEG amine with suIfo-MBs in 0.1 M Na-phosphate pH 7.5 for one hour at room temp and buffer changed to phosphate buffer pH 6.2.
- the product hGH was characterized by SDS-PAGE, gel filtration, NMR, tryptic mapping, LC-mass spectrophotometry, and in vitro biological assay.
- the extent of PEGylation was first shown by SDS-PAGE and gel filtration and then analysed by NMR, which has a specific abso ⁇ tion peak for the hydrogen of PEG and the number of PEG group on each molecule can be calculated.
- Polyacrylamide gel electrophoresis in 10% SDS was run in reduced condition and gel filtration was run on Superose 12 with PBS or 10mM Tris-HCI pH 8.0, 100mM NaCI as elution buffer. To demonstrate which residue was PEGylated, tryptic mapping was performed.
- PEGylated hGH was digested with trypsin at the protein/enzyme ratio of 100 to 1 in mg basis at 37C for 4 hr in 100mM sodium acetate, 10 mM Tris-HCI, 1mM calcium chloride, pH 8.3 and acdified to pH ⁇ 4 to stop digestion before separating on HPLC Nucleosil C-18(4.6mmX150mm, 5u,100A) and the chromatogram was compared to that of non- PEGyfated starting material. Each peak can then be analysed by mass spectrometry to verify the size of the fragment in the peak. We found the fragment(s) that carry PEG group usually are not retained on the HPLC column after injection and disappear from the chromatograph.
- PEGylated hGH was assayed for its ability to bind to the hGH binding protein (hGHBP) and this binding was compared to the binding of non-PEGylated hGHBP as described (REF) as an in vitro biological assay.
- the various PEGylation methods used produced mainly three kinds of PEGylated wild-type hGH, with apparent molecular weight of 30K, 40K, and 100K on reduced SDS- PAGE. Whereas in the size exclusion chromatography, the corresponding molecular weight of this three PEGylated hGH are 35K, 51 K, and 250K which should be close to their native hydrodynamic volume. These were designated PEG-hGH-1 , -2 and -3.
- PEG-hGH-1 and -2 both had the N-terminal 9- amino-acid fragment missing from the chromatogram and possibly pegylated, which could be confirmed by the mass spectrometry of the big molecular species found in the flow-through of the LC.
- PEG-hGH-1 may have one PEG on the N- terminal amine
- PEG-hGH-2 may have two PEG on the N-terminal amine, forming a tertiary amide.
- the PEG-hGH-3 has about 5 PEG group per molecule based upon the NMR result, and on the tryptic map, at least 5 peptide fragments were missing, meaning they are pegylated.
- the sites for adding PEG groups to hGH were N-terminal Met, K38, K41, K70, K140, K145, K158 and K168.
- Two lysines (K) which appeared to not be pegylated were K115 and K172.
- the GH or GH plus IGF-I is directly administered to the mammal or avian by any suitable technique, including parenterally, and can be administered locally or systemically.
- the specific route of administration will depend, e.g., on the medical history of the patient, including any perceived or anticipated side effects using IGF-I.
- parenteral administration include subcutaneous, intramuscular, intravenous, intraarterial, and intraperitoneal administration.
- the administration of GH or GH plus IGF-I is by continuous infusion (using, e.g., minipumps such as osmotic pumps or insulin pumps), or by injection using, e.g., intravenous intramuscular or subcutaneous means.
- the administration is subcutaneous for GH or GH plus IGF-I.
- the administration may also be as a single bolus or by slow-release depot formulation.
- the GH or GH plus IGF-I is administered continuously by infusion or by bolus for those formulations having a long plasma half-life.
- the GH or GH plus IGF-I is suitably administered together with any one or more of their binding proteins.
- IGFBP-2 Used with IGF-I for example, IGFBP-2, IGF- BP-4, or most preferably, IGFBP-3, which is described in WO 89/09268 published October 5, 1989 and by Martin and Baxter, J. Biol. Chem.. 261: 8754-8760 (1986).
- This glycosylated protein is an acid- stable component of about 53 Kd on a non-reducing SDS-PAGE gel of a 125-150 Kd glycoprotein complex found in human plasma that carries most of the endogenous IGFs and is also regulated by GH.
- the IGF-I is also suitably coupled to a receptor or antibody or antibody fragment for administration.
- the GH or GH plus IGF-I compositions to be used in the therapy will be formulated and dosed in a fashion consistent with good medical practice, taking into account the clinical condition of the individual patient (especially the side effects of treatment with GH or GH plus IGF-I), the site of delivery of the IGF-I composition, the method of administration, the scheduling of administration, and other factors known to practitioners.
- the "effective amount" of IGF-I for pu ⁇ oses herein is thus determined by such considerations.
- the total pharmaceutically effective amount of the IGF-I administered parenterally per dose will be in the range of about l ⁇ g/kg/day to 10 mg/kg/day of patient body weight, although, as noted above, this will be subject to therapeutic discretion. More preferably, this dose is at least 0.01 mg/kg/day, and most preferably for humans between about 0.01 and 1 mg/kg/day for the hormone.
- the IGF-I is typically administered at a dose rate of about 1 ⁇ g/kg/hour to about 50 ⁇ g/kg/hour, either by 1-4 injections per day or by continuous subcutaneous infusions, for example, using a mini-pump. An intravenous bag solution may also be employed.
- the key factor in selecting an appropriate dose is the result obtained, as measured by increases in antibody production, increases in splenocyte orthymocyte number, increases in splenic B-cells, etc.
- IGF-I is also suitably administered by sustained-release systems.
- sustained-release compositions include semi-permeable polymer matrices in the form of shaped articles, e.g., films, or microcapsules.
- Sustained-release matrices include polylactides (U.S. Pat. No.3,773,919, EP 58,481), copolymers of L-glutamic acid and gamma- ethyl-L-glutamate (U.
- Sustained-release IGF-I compositions also include liposomally entrapped IGF-I.
- Liposomes containing IGF-I are prepared by methods known per se: DE 3,218,121; Epstein etal., Proc. Natl. Acad. Sci. U.S.A., 22: 3688- 3692 (1985); Hwang et al., Proc. Natl. Acad. Sci. U.S.A., 7J: 4030- 4034 (1980); EP 52,322; EP 36,676; EP 88,046; EP 143,949; EP 142,641; Japanese Pat. Appin.83-118008; U.S. Pat. Nos.4,485,045 and 4,544,545; and EP 102,324. Ordinarily, the liposomes are of the small (about 200-800 Angstroms) unilamellartype in which the lipid content is greater than about 30 mol. percent cholesterol, the selected proportion being adjusted for the optimal IGF-I therapy.
- the GH or GH plus IGF-I is formulated generally by mixing it at the desired degree of purity, in a unit dosage injectable form (solution, suspension, or emulsion), with a pharmaceutically acceptable carrier, i.e., one that is non-toxic to recipients at the dosages and concentrations employed and is compatible with other ingredients of the formulation.
- a pharmaceutically acceptable carrier i.e., one that is non-toxic to recipients at the dosages and concentrations employed and is compatible with other ingredients of the formulation.
- the formulation preferably does not include oxidizing agents and other compounds that are known to be deleterious to polypeptides.
- the formulations are prepared by contacting the GH or GH plus IGF-I uniformly and intimately with liquid carriers or finely divided solid carriers or both. Then, if necessary, the product is shaped into the desired formulation.
- the carrier is a parenteral carrier, more preferably a solution that is isotonic with the blood of the recipient. Examples of such carrier vehicles include water, saline, Ringer's solution, and dextrose solution. Non-aqueous vehicles such as fixed oils and ethyl oleate are also useful herein, as well as liposomes.
- the carrier suitably contains minor amounts of additives such as substances that enhance isotonicity and chemical stability.
- additives such as substances that enhance isotonicity and chemical stability.
- Such materials are non-toxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, succinate, acetic acid, and other organic acids or their salts; antioxidants such as ascorbic acid; low molecular weight (less than about ten residues) polypeptides, e.g., polyarginine or tripeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids, such as glycine, glutamic acid, aspartic acid, or arginine; monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbi
- the GH or GH plus IGF-I is typically formulated in such vehicles at a concentration of about 0.1 mg/ml to 100 mg/ml, preferably 1-10 mg/ml, at a pH of about 3 to 8.
- GH is generally stable at a pH of 6.5 to 8, more preferably 7.2 to 7.8.
- Full-length IGF-I is generally stable at a pH of no more than about 6; des(1-3)-IGF-l is stable at about 3.2 to 5. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of IGF-I salts.
- the IGF-I preferably the full-length IGF-I
- a suitable carrier vehicle to form a pharmaceutical composition that does not contain cells.
- the buffer used for formulation wiil depend on whether the composition will be employed immediately upon mixing or stored for later use. If employed immediately, the full- length IGF-I can be formulated in mannitol, glycine, and phosphate, pH 7.4. If this mixture is to be stored, it is formulated in a buffer at a pH of about 6, such as citrate, with a surfacant that increases the solubility of the GH at this pH, such as 0.1% polysorbate 20 or poloxamer 188. The final preparation may be a stable liquid or lyophilized solid. GH or GH plus IGF-I to be used for therapeutic administration must be sterile.
- Sterility is readily accomplished by filtration through sterile filtration membranes (e.g., 0.2 micron membranes).
- Therapeutic IGF-I compositions generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.
- GH or GH plus IGF-I or IGF-I alone ordinarily will be stored in unit or multi-dose containers, for example, sealed ampoules or vials, as an aqueous solution or as a lyophilized formulation for reconstitution.
- a lyophilized formulation 10-ml vials are filled with 5 ml of sterile-filtered 1% (w/v) aqueous IGF-I solution, and the resulting mixture is lyophilized.
- the infusion solution is prepared by reconstituting the lyophilized IGF-I using bacteriostatic Water-for-lnjection.
- hGH is stable at a higher pH than IGF-I, e.g., 7.4-7.8.
- GH high-affinity growth hormone binding protein
- a well characterized such binding protein is the high-affinity growth hormone binding protein (GHBP) constituting the extracellular domain of the GH receptor that circulates in blood and functions as a GHBP in several species [Ymer and Herington, Mol. Cell. Endocrino.. 41: 153 (1985); Smith and Talamantes, Endocrinology. 123: 1489-1494 (1988); Emtner and Roos, Ada Endocrinolooica (Cooenh...
- GHBP high-affinity growth hormone binding protein
- the doses of both GH and IGF-I can be less if used together than if IGF-I is administered alone. It is noted that practitioners devising doses of both IGF-I and GH should take into account the known side effects of treatment with these hormones.
- the side effects include sodium retention and expansion of extracellular volume [Ikkos etal., Acta EndocrinoL (Copenhagen), 2: 341-361 (1959); Bigiieri etal., J. Clin. EndocrinoL Metab.. 21: 361- 370 (1961)], as well as hyperinsuiinemia and hyperglycemia.
- the major apparent side effect of IGF-I is hypoglycemia (Guler etal., Proc. Natl.
- the GH and or IGF-I is administered in conjunction with ⁇ i.e., before, at the same time as, or after) a vaccine, such as an AIDS vaccine (for example, a gp120 or gp160 vaccine or a cocktail of gp receptor-based vaccines), either during initial immunization or during a boost of the vaccine, to ensure increased antibody response.
- a vaccine such as an AIDS vaccine (for example, a gp120 or gp160 vaccine or a cocktail of gp receptor-based vaccines), either during initial immunization or during a boost of the vaccine, to ensure increased antibody response.
- a vaccine such as an AIDS vaccine (for example, a gp120 or gp160 vaccine or a cocktail of gp receptor-based vaccines)
- a vaccine such as an AIDS vaccine (for example, a gp120 or gp160 vaccine or a cocktail of gp receptor-based vaccines)
- the GH alone or with IGF-l is given at
- GH, GH plus IGF-I, or IGF-I may be therapeutically used to stimulate the immune system, particularly the lymphocytic portion of the immune system following immunosuppresive/cytotoxic therapy associated with transplantation, cancer therapy, and the treatment of autoimmune diseases.
- These compounds could be used to restore the lymphocytic arm of the immune system in a manner analogous to the way G-CSF is used to restore the phagocytic arm of the immune system.
- Corticosteroids lead to a marked increase in the propensity for viral and fungal infection.
- GH, GH plus IGF-l, of IGF-l alone could be used to mitigate this increased propensity to infections.
- these compounds could be used to improve the treatment of other chronic viral diseases such as chronic hepatitis, cytomeglovirus, myocarditis and encephalitis.
- Such human patients might include those who are aged, underfed, malnourished, or ill.
- Diagnosing GH and IGF-I levels in a patient can be accomplished by any standard technique, but is typically done by subjecting a blood sample to an ELISA or RIA test using anti-IGF-l antibodies such as described in Furlanetto etal., J. Clin. Invest..22: 648-657 (1977); Bala and Bhaumick, J. Clin. Endocrin. and Metabo 49: 770-777 (1979); and Zapf etal., J. Clin. Invest..22: 1321-1330 (1981). Methods for precisely determining the presence of GH and GHBP are described in 07/615,538, filed 19 November 1990. The invention will be more fully understood by reference to the following examples.
- the hGH used was rhGH (Nutropin, Lot N9267AX, G042A) dissolved in sterile water.
- the GHBP (1-238) used was expressed in EColi, and dissolved in the rhGH excipient.
- the excipient minipumps and the excipient injections both contained the rhGH excipient. All injections (0.1 ml) were given subcutaneously in the nape of the neck.
- the minipumps used were purchased from Alza (Alzet minipumps, Model 2001 , pump rate 1.03 ul/h), and were implanted s.c. on the back under ketamine/xylazine anesthesia. The rats were sacrificed after 7 days (7 injections) and organs harvested.
- the 4 GH treated groups all had similar weight gains and there was no overgrowth of the liver, spleen or the kidney.
- the thymus showed a large absolute and relative growth response, but only to continuous GH (Table II).
- FIG 1 A and 1B the weight of spleen in rats receiving hGH or hGH plus GHBP for 7 days is illustrated.
- Measured in this series of experiments were spleen growth over 7 days in dwarf rats (dw/dw) for hGH alone at 5 doses (32, 8, 4, 2, 0.5, & 0.125 mg/kg/daiy) or hGH at 4 doses (8, 4, 2, 0.5, & 0.125 mg/kg/day) plus GHBP (at 2x the GH doses on a weight basis i.e. 16, 8, 4,1, 0.5 mg/kg/day Of GHBP).
- the spleen shows a huge growth response to GH + GHBP with the responses for GH and GH + GHBP being non-parallel.
- the high dose complex induced splenic overgrowth in 7 days the spleen grew from 300 to 900 mg, spleens in non-GH deficient 150g rats average 500 mg.
- the maximum response to GH plus GHBP was greater than for GH alone. As the maximum response was different and the curves are not parallel an exact potency estimate cannot be obtained. But 2 mg/kg/day of GH + GHBP gave equivalent growth responses to 32 mg/kg/day of GH alone, suggesting a 16-fold potency difference.
- the PEG-hGH groups showed relative overgrowth of the thymus. Only the PEG treated groups showed relative organ overgrowth and the only organs showing statistically significant relative growth compared to excipient injected controls were the spleen and the thymus.
- the dose response curves shown in the figure 2 illustrate the non-parallel nature of this response (non-parallel compared to hGH treatment).
- 48 female hypox rats purchased from Taconic, Germantown, New York
- 85-105 g were weighed 5 times over 9 days to establish growth stasis (weight gain or loss of less than 7 grams). They ate pelleted lab diet and drank water ad libitum. They were group housed (6/cage) in a room controlled for lighting and temperature. They were then randomized into 8 groups of 6 rats per group based on their initial body weight.
- Met-less rhGH (Nutropin) was pegylated by the method of Abuchowski et al. (Abuchowski, A. et al, J. Biol. Chem.252, 3582-3586, 1977; Abuchowski, A. et al, Cancer Biochem. Biophys.7, 175-186, 1984).
- Four forms of the PEG-5 rhGH were assayed, a broad pool as well as 3 pools based on arbitrary cuts of, early, mid, and late from a Sepharose- fractionating sizing column. The broad pool and the 3 pools were tested in the rats for 11 days by s.c. injections of material from the 4 batches of PEG-5 hGH.
- the organ weight responses were similar to those seen in the previous examples. When the weights of the liver, spleen, kidney and heart were expressed relative to body weight there was no dose-related effect of the PEG-hGH forms. The only relative organ weight showing a dose response relationship was the thymus.
- the absolute thymic weight was greatly increased by PEG-hGH, for the broad pool (equivalent to the preparations of PEG-hGH used in the previous examples) the absolute thymus weight was increased for 60 ⁇ g of PEG-5 rhGH to 512 ⁇ 83 mg, and for 20 ⁇ g of this material to 401 ⁇ 99 mg, with the relative weights being 0.41 ⁇ 0.05% and 0.36 ⁇ 0.08%, respectively.
- IGF-I Recombinant human IGF-I [available commercially from KabiGen AB, Sweden (specific activity > 14,000 U/mg by radioreceptor assay using placental membranes) or available for clinical investigations from Genentech, Inc., South San Francisco] was employed in all the IGF-I experiments detailed in the examples.
- the IGF-I was dissolved at 5 mg/ml in 10 mM citrate buffer and 126 mM NaCI, pH 6.0.
- This IGF-I was administered to three species, i.e., rat, rabbit, and mouse, to observe its effects on spleen and thymus weight. Dose-response studies were performed in the mouse and rat, and IGF-I was given to the rabbit with similar effects. In addition, B- and T-cell numbers and responses to mitogenic stimulation were evaluated in the mice.
- Rats Two animal models of GH deficiency and therefore IGF-I deficiency were used to demonstrate the effect of IGF-I on spleen and thymic weight and size.
- a third model of GH and IGF-I deficiency is the aged animal.
- Aged (18-month-old) rats were used to demonstrate the effect of IGF-I on spleen and thymic size, cellulants architecture, and in vitro response to mitogens.
- adult ovariectomized rats with normal serum IGF-I concentrations, were used to demonstrate the effect of IGF-I on spleen and thymus in an animal that was not IGF-I deficient .
- IGF-I, GH, or IGF-I plus GH were administered for 14 days to aged 18-month-old rats to determine whether IGF-I could induce functional changes in spleen and thymus in this model of thymic regression.
- HSD Harlan Sprague Dawley
- the treatment groups were: (1) excipient pumps, excipient injections, (2) IGF-I pumps, excipient injections, (3) IGF-I pumps, GH injections, (4) excipient pumps, GH injections, and (5) young rats.
- the IGF-I was loaded into two minipumps so that 1.150 mg/rat/day of IGF-I or 0.8 mg/kg/day of des-IGF-l was delivered sc as a continuous infusion.
- the rhGH (Nutropin brand, Genentech, Inc.
- IGF-I 10 mM citrate buffer and 126 mM NaCI, pH 6.0
- IGF-I excipient The treatments continued for 14 days. The animals not receiving GH were injected (0.1 ml) with hGH vehicle each day.
- a blood sample was taken, and the liver, kidneys, heart, spleen, and thymus were removed, blotted dry, and immediately weighed.
- the spleen and thymus were immediately placed in buffer and then cells were obtained by digestion or physical rupture. The cells were counted and then plated out at uniform density.
- the thymic cells were cultured with IL-1 (2 U/ml) and phytohemaglutinin (PHA) (5 ⁇ g/ml) and thymidine inco ⁇ oration was measured as described by Maizel etal., J. Exp. Med.. 153: 470-476 (1981).
- the spleens were similarly treated and two tests of function were performed.
- a very dramatic effect of IGF-I treatment was the large fall in blood urea nitrogen (BUN) levels from 20.7 ⁇ 2.4 mg/dL in controls to 13.8 ⁇ 1.8 mg/dL after IGF-I treatment; hGH had no effect.
- BUN blood urea nitrogen
- a lowered BUN indicates an anabolic metabolic state.
- the body weight gain data, the increased organ weights, the lowered BUN, and the lowered blood enzyme levels all indicate that IGF-I was producing an anabolic state where protein synthesis was predominant over protein breakdown.
- the effect of IGF-I was clearly greater than that of hGH.
- the cells from the harvested organs were dispersed and their response to mitogens was measured.
- Table III shows some of the data for the thymus and spleen.
- the wet weight of the thymus was increased by IGF-I but not by hGH. Normal, young, 60-day-old Fischer rats were run as positive controls.
- Values are Means and Standard diviations.
- IGF-I plus hGH was also an effective way to increase thymic cell number.
- the number of cells in the spleen was not significantly increased by IGF-I or GH treatment, although the mean values of the IGF-l-treated groups were higher. Therefore, IGF-I could increase the wet weight of the thymus and also the number of cells capable of being harvested. Then, any functional effect of the increased tissue mass and cell number was tested in vitro by measuring the responses of the dispersed thymocytes to mitogens, as shown in Table IV below. TABLE IV Thymic cells from young and old F344 rats. Untreated old rats all had insufficient thymic cells to run the assays.
- the tissue from the old rats showed a tendency toward increased activity with IGF-I alone compared to that from the younger animals, although this effect was not statistically significant.
- the PHA response for IGF-I plus GH was increased 3.7-foId and for the PHA plus IL-1 combination the response was increased 4-fold.
- the increased thymic tissue produced by IGF-I is functional tissue, in that it can respond to mitogens.
- IGF-l-treated old rats had an in vitro activity that was improved up to 4-fold. Therefore, according to the functional tests used, the thymus of the older rats was essentially restored to that of a much younger animal. In the thymus the effect of aging appeared to have been reversed.
- des-IGF-l The weight gains with des-IGF-l seemed less than in the first study, but were still superior to the response to bGH.
- the kidney and spleen showed large responses to des-IGF-l, and no significant response to GH.
- des-IGF-l returned the blood cell counts toward those in the younger animals, with the combination of des-IGF-l and bGH being the most effective treatment.
- des-IGF-l tended to increase the white blood cell (WBC) and the lymphocyte number when combined with bGH. This change is similar in amount to that seen in Example IV, in man.
- WBC white blood cell
- thymus weight was increased at sacrifice in the des-IGF-l-treated rats.
- This experiment was designed to test the origin and type of increased cell number in the thymus. This discrimination of the origin and type of cells was achieved by FACS analysis (described further below) using PNA as the specific marker for true thymocytes.
- PNA positive thymocytes are believed to be young precursor cells for T-cells.
- the young rats had 5-fold more thymic cells than the old rats.
- the number of cells in the thymus was increased about 4.5-fold using des-IGF-l alone or in combination with bGH. By itself, bGH increased cell number only two-fold.
- the pumps delivered either 0.364 mg of des-IGF-l/kg/day or 1.18 mg IGF- l/kg/day for 7 days. Control animals received excipient-filled pumps. The animals were sacrificed at day 7 and the thymus and spleen were dissected.
- mice were chosen as the model, in this case retired breeder male mice, which are a model of accelerated aging.
- the effect of IGF-I as an anabolic agent as well as an effector of immune tissue growth and function was studied in the adult aged mice.
- the effect of hGH and a combination of IGF-I and hGH on cell number and mitogenic stimulation was evaluated.
- mice 9 months old or older and weighing approximately 25 to 35 g (Harlan Sprague Dawley, San Diego, CA). Animals were housed in single cages and given food (Purina Rodent Chow 5010, St. Louis, MO) and water, ad libitum. All animals were weighed before being grouped into treatment groups (based on their body weight) using a randomization program. Animals were identified with stainless steel ear tags and were acclimated for at least one week.
- IGF-I was administered by sc-implanted osmotic minipump (for 7-day studies, Alzet Model 2001 , pump rate approximately 1 ⁇ l/hr.; for 14-day studies, two Alzet Model 2002 minipumps, pump rate approximately 0.5 ⁇ l/hr; Alza, Palo Alto, CA).
- the pumps were loaded with solution per the manufacturer's instructions, and the filled pumps were then incubated in sterile saline overnight in the refrigerator.
- the pumps were filled with either the IGF-I excipient or the desired concentration of IGF-I (5 mg/ml formulated as described above), i.e., 7.5, 30, or 120 ⁇ g IGF-l/day/7 days for 6 animals per group for the first seven-day treatment study and 120 ⁇ g IGF- l/day 7 days for 5 animals per group for the second seven-day treatment study and the 14-day treatment study.
- rhGH (Nutropin brand) was administered by itself in an amount of 9.6, 48, or 240 ⁇ g hGH/day/14 days via two Alzet Model 2002 osmotic minipumps (0.5 ⁇ l/hr/14 days) implanted sc to 5 animals per group, or by itself via 240 ⁇ g hGH for 14 days via sc injection, 5 animals/group.
- IGF-I was administered in a dose of 120 ⁇ g by two Alzet 2002 minipumps and GH was administered by daily sc 240- ⁇ g injections into 5 animals/group.
- mice were anesthetized with an ip injection of approximately 0.4 ml of avertin (2,2,2-tribromoethanol and tert- amyl alcohol in phosphate buffered saline (PBS)).
- PBS phosphate buffered saline
- the dorsal scapular region was then clipped of hair and a small incision was made.
- a close hemostat was then inserted into the incision and pushed posteriorly.
- a minipump was then inserted into the pocket and the incision was closed with stainless steel wound clips, and a sc injection of 7500 U of penicillin was given. Animals were inspected daily and their body weights recorded.
- lymph nodes, spleen and thymus were dispersed using sintered glass slides to form single cell suspensions. The cells were then washed, in Eagle's minimal essential medium
- IGF-I caused significant growth of the spleen and the thymus after 7 days of treatment with IGF-I.
- the first experiment there was a clear dose-related effect of IGF-I on the spleen (excipient 105 ⁇ 14, low dose 124 ⁇ 21 ; medium dose 145 ⁇ 58; high dose 193 ⁇ 23 mg; excipient vs. high-dose IGF-I, p ⁇ 0.001).
- Thymus weight was unchanged in the first experiment; this was probably due to the thymus being dissected differently by different dissectors.
- lymphocyte number was increased, but mitogenic response was depressed.
- lymphocyte populations from control and treated animals were examined 7 and 21 days after 14-day treatment with hGH, IGF-I, or the combination of IGF-I and hGH.
- mice Seven days post-treatment the IGF-I- and IGF-I- plus hGH-treated mice had significantly elevated splenocyte numbers compared to either control, or hGH-treated mice (Fig. 13). A statistical increase in B-cell number was observed in both IGF-l-treated groups.
- T-cell number was significant in the IGF-I only group, but not in the combination of hGH plus IGF-I group.
- both CD 4 + and CD g + T-cell populations were elevated in this group compared to controls.
- both groups of IGF-l-treated mice had elevated thymocyte numbers compared to hGH-treated or control mice (Fig. 14).
- IGF-I, alone or in combination with hGH produced an increase in peripheral lymph node cell numbers (Fig. 16). No alteration in node T-cell number or CD 4 :CDg ratios was observed following these treatment regimes.
- the pu ⁇ ose of this experiment was to evaluate the immune function in male mice (retired breeders) immunized with dinitrophenyl-ovalbumin and treated with IGF-I.
- DNPOA dinitrophenyl-ovalbumin mixed with alum
- the DNPOA was mixed before use by adding 50 ⁇ l of DNPOA (1 mg/ml) to 2.45 ml of sterile PBS, pH 7.0 and 2.50 ml of aluminum hydroxide abso ⁇ tive gel (Rehsorptar brand, sold by Armor Pharmaceutical Col, IL, 20 mg/ml). The DNPOA was mixed for approximately 30 minutes prior to injection. The day of DNPOA immunization is designated as Day 0.
- IgG IgG anti-DNP antibodies in the test mouse sera were measured by ELISA
- the plates were washed three times with PBS/0.02% Tween 20, and 0.1 ml of 1 :250 dilution of horseradish peroxidase-conjugated Fab-specific goat-anti-mouse IgG (Cappel Labs) was added to each well. Plates were again incubated two hours and washed. After washing, 0.1 ml of 0.2 mg/ml OPD, 0.01% hydrogen peroxide in 0.05 M citrate buffer was added to each well, the reaction was stopped with 2 M hydrogen peroxide after 30 minutes, and the optical density was read at 490 nm on a Microtect plate reader.
- Figure 20 shows the concentration of total (Fig. 20B) and OA-specific (Fig. 20A) IgG in the serum of excipient- or IGF-l-treated mice.
- IGF-I treatment significantly increased the secondary IgG response to antigen at every time point examined. While there was a trend toward elevation in total IgG levels in the IGF-I group, the values were not statistically increased compared to controls. Thus, IGF-I functions to boost the memory response of the mammal. It is noted that exposure to IgG after a secondary immunization produces a longer improvement in antibody production.
- the pu ⁇ ose of this experiment is to determine the effects of IGF-I treatment of mice on repopulation of the spleen and thymus following bone marrow transplantation.
- mice Male BALB c mice, 19-26 g and 6-7 weeks old (Charles River, San Diego, CA), were used in the study. The animals were group housed in polypropylene cages with food (Purina).
- Rodent Chow 5010, St. Louis, MO Rodent Chow 5010, St. Louis, MO
- water, ad libitum All animals were weighed the day of pump implantation and randomized into groups. Animals were identified by stainless-steel ear tags.
- IGF excipient (0.58 ⁇ 0.03 ⁇ l/hr./14 days) filled with IGF excipient or 200 ⁇ l of rIGF-l described above diluted to achieve a daily, continuous delivery of approximately 40 or 120 ⁇ g/day/14 days.
- Femurs and tibias were removed from 40 donor animals. The bone marrow was flushed out with PBS. Cells were centrifuged and washed with saline. Viable cells were counted and diluted with saline to achieve 10 cell/0.25 ml.
- IGF-I increases the rate of peripheral cell repopulation and supports an important therapeutic role for this molecule following syngenic bone marrow transplantation. It is anticipated that the use of GH to stimulate IGF-I production will result in a similar response following syngenic bone marrow transplantation. Administration of both GH and IGF-I is expected to increase the rate and extent of such bond marrow transplantation.
- GH be delivered to maintain continuous presence in the blood and intracellular fluids.
- the present invention establishes for the first time that GH and IGF-I have an additive effect when both are co-administered.
- GH has previously been administered as a daily or every 2-day pulsatile or bolus injection route, since it was assumed and had been shown superior to short term continuous GH infusion.
- the longer term continuous presence of GH in the plasma has been found superior for stimulating many if not most GH responsive tissues.
- the continuous presence of GH for 3 or more, preferably 6 or more and most preferably 14 or more days stimulates GH responsive tissue better than pulsatile administration.
- GH may be continuously administered by catheter or various minipumps that deliver a constant amount of GH.
- GH formulated to have a long half-life has been found to result in a superior GH response, when administered every 6 days or more.
- the tissues and cells of the immune system have been found to respond to GH or GH plus IGF-l treatment to increase both the rate or response and the magnitude of the immune response.
- the intermittent administration of PEG-GH has been found to give the best GH response when administered every 6 days.
- IGF-I was isolated and named first as a "somatomedin" to indicate that it mediated the whole-body growth-promoting activity of GH. It was later named IGF-I in recognition of its insulin-like metabolic activities. It is therefore su ⁇ rising that IGF-I, a molecule considered to be a metabolic regulator of somatic growth, was shown to have similar growth factor activity on cells of the immune system as many of the interleukins.
- GH receptors IGF-I receptors
- insulin receptors are present on cells of the immune system.
- the functional effect in vivo of these receptors and the activity of their ligands on the immune system was unknown until the present invention.
- the effects of insulin and GH on the immune system have been taken to be insignificant (see, e.g., Snow, J. Immunol.. 135: 776-778 (1985)).
- Most tissues in the body have receptors for GH, IGF-I, and insulin where these hormones act to regulate the basic metabolic functions of cells, for example, glucose uptake or amino acid transport.
- the receptors that have been demonstrated to be present in immune tissue could function to control these activities, rather than act to influence their differentiation, growth, and the immunological activities.
- Recent literature has recognized that the role of IGF-I in affecting immune cytology or function is unknown (see Fu etal., J. Immunol.. 146: 1602-1608 (1991)).
- the thymus involutes with age in most animals; it reaches a maximal size and then begins involuting in man after puberty. This involution is associated with a decline in the activity of the immune system.
- This invention therefore provides in one aspect a means of stimulating the immune system of an aged human to restore the thymic tissue to that of a much younger person.
- the combination of an agent that has anabolic activity on the major internal organs, with improvement of hematology and immune function, makes GH or GH plus IGF-I an attractive drug for treating adult or aged humans.
- the ability to rejuvenate the thymus and therefore boost the immune system is seen as providing a range of therapeutic opportunities.
- Such opportunities include common varied agammaglobulinemia in which B-cells fail to mature into Ig secretory cells and the serum contains less than 250 mg/dl compared to 1000 mg/dl that is the normal concentration. IGF-I produced significant increases in serum Ig levels (Fig. 20) and may be useful in this disease.
- a further use of the invention would be to administer the IGF-I to a patient who suffers from a hereditary illness that results in an impaired immune system.
- An example of such a patient would be a child suffering from congenital thymic aplasia (diGeorge syndrome) in which the thymus is atrophied and T-cells are severely diminished, leading to opportunistic infections that are often fatal. The reason for this disease is unknown.
- IGF-I might be expected to give an improved size, cellularity, and responsiveness of the thymus in these patients.
- the course of treatment would be intermittent, with, for example, a predicted 14- day period of treatment being given followed by a resting period of more than 21 days between exposures to IGF-I.
- AIDS acquired immunodeficiency syndrome
- Patients with AIDS have no T-cell immunity and inversed T4/T8 ratios.
- IGF-I has been shown to increase T-cell mitogen responsiveness and specifically enhance CD 4 + cell number (Figs.5, 10, 11) and as such may be a useful drug in the treatment of AIDS.
- Another use of the invention is to give a patient a course of IGF-I treatment during his or her recovery from major illnesses or following surgery when an infection or relapse might be expected.
- An enhanced immune response would be expected to aid such a patient to mount an immune challenge to the infection or relapse.
- GH or IGF-I administration is as an immunoadjuvant. Whenever immunizing a mammal or avian, priming with GH and or IGF-I to accelerate the immunization process is clearly indicated in the present invention. In the above examples, the effectiveness of IGF-I has been demonstrated as follows:
- mice (1) in three species (mouse, rat, and rabbit); (2) in both sexes (male and female rats); and (3) in several animal models, including animals made surgically GH and IGF-I deficient (hypophysectomized rats), animals with hereditary GH and IGF-I deficiency (dwarf rats), normal animals (ovariectomized rats), normally aged animals that are IGF-I deficient (18- month-old rats), animals showing accelerated aging (retired breeder mice), and animals with reduced immune function (the aged animals).
- mice data herein may be extrapolated to avians, horses, cows, and other mammals, correcting for the body weight of the avian or mammal in accordance with recognized veterinary and clinical procedures. Humans are believed to respond in this manner as well. IGF-I receptors have been demonstrated on human lymphocytes [Kozak etal., Cell Immunol.. 109: 318 (1987)], and evidence of similar responses in man is demonstrated in Example IV. Thus, it would be reasonably expected that in man IGF-I would have a beneficial restorative effect on immune function in all patients.
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Abstract
Procédés de stimulation de tissus réagissant à l'hormone de croissance d'un mammifère ou d'un oiseau, en particulier de tissus de réponse immunitaire chez des mammifères à l'immunité atteinte, consistant à administrer de l'hormone de croissance ou de l'hormone de croissance plus du facteur-I de croissante insulinoïde. De préférence, l'hormone de croissance ici mentionnée est de l'hormone de croissance conjuguée à du polyéthylène glycol (PEG).
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US72335991A | 1991-06-28 | 1991-06-28 | |
US723,359 | 1991-06-28 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1993000109A1 true WO1993000109A1 (fr) | 1993-01-07 |
Family
ID=24905890
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1992/004489 WO1993000109A1 (fr) | 1991-06-28 | 1992-05-29 | Procede de stimulation de la reponse immunitaire a l'aide d'hormone de croissance |
Country Status (3)
Country | Link |
---|---|
AU (1) | AU2147192A (fr) |
PT (1) | PT100629A (fr) |
WO (1) | WO1993000109A1 (fr) |
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