EP2994130A1 - Fgf-modulation einer in-vivo-antikörperproduktion und humorale immunität - Google Patents

Fgf-modulation einer in-vivo-antikörperproduktion und humorale immunität

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EP2994130A1
EP2994130A1 EP13884155.6A EP13884155A EP2994130A1 EP 2994130 A1 EP2994130 A1 EP 2994130A1 EP 13884155 A EP13884155 A EP 13884155A EP 2994130 A1 EP2994130 A1 EP 2994130A1
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mammal
alpha
fgf2
methyl
human
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EP2994130A4 (de
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Andrew B. BUSH
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention relates to the field of humoral immunity.
  • Organisms control antibody production at multiple steps during an immune response and this response must be carefully adjusted to the invading pathogen. If the response is excessive, autoimmune defects can damage host tissues, whereas if it is inadequate, the pathogen may persist and threaten survival. Soluble factors have been identified that stimulate the humoral immune response, but our knowledge of negative regulators of this process has been quite limited (Ravetch et al, 2000, Science 290:84). Indeed, few soluble cytokines have been identified whose loss of function leads to enhanced antibody production.
  • Extrafollicular responses are thought to be important following exposure to T- independent antigens (Fagarasan et al., 2000, Science 290:89; Martin et al., 2001.
  • B cells return to a resting state. Turning off B cell activation is necessary both for homeostatic resetting of antibody secretion and also for preventing pathologic autoimmune conditions. Little is known about the soluble factors which control the deactivation process.
  • FGF fibroblast growth factor
  • FGF2 or basic FGF
  • U.S. Patent No. 4,994,559 discloses human basic fibroblast growth factor.
  • U.S. Patent No. 5,229,501 discloses expression and use of human fibroblast growth factor receptor.
  • U.S. Patent No. 5,228,855 discloses an extracellular form of human fibroblast growth factor receptor.
  • U.S. Patent No. 5,707,632 discloses receptors for fibroblast growth factors.
  • U.S. Patent No. 5,891,655 discloses methods for identifying molecules that regulate FGF activity and oligosacharide modulators of FGF receptor activation.
  • U.S. Patent No. 6,071,885 discloses treatment of FGF-mediated conditions by administration of cardiac glycoside and aglycone derivatives thereof.
  • U.S. Patent No. 6,350,593 discloses receptors for fibroblast growth factors and methods for evaluating compositions for antagonism to fibroblast growth factors and fibroblast growth factors receptors.
  • U.S. Patent No. 6,255,454 discloses expression and use of a human fibroblast growth receptor and a soluble version of the receptor.
  • U.S. Patent No. 6,900,053 discloses antisense modulation of fibroblast growth factor receptor 2 expression.
  • FGF fibroblast growth factor
  • FGF2 is an inhibitor of the humoral immune response.
  • splenic germinal centers require FGF2 for efficient formation.
  • One embodiment of the invention provides a method for increasing humoral immune response to vaccination with an immunogen, for example, an antigen or a live or killed vaccine, in a mammal or other higher vertebrate, that includes: in conjunction with the vaccination of a mammal to the immunogen other than FGF2, inhibiting the activity of a fibroblast growth factor, such as FGF2, in the mammal, thereby increasing the humoral immune response to the antigen.
  • an immunogen for example, an antigen or a live or killed vaccine
  • FGF2 fibroblast growth factor
  • the immunogen is other than a fibroblast growth factor and other than a fibroblast growth factor receptor.
  • Another embodiment of the invention provides a method for treating an immune deficiency in a mammal, such as a human, that includes: increasing the production of endogenous antibodies in the mammal by inhibiting the activity of a fibroblast growth factor, such as FGF2, in the mammal.
  • a fibroblast growth factor such as FGF2
  • a further embodiment of the invention provides a method for treating a microbial infection in a mammal, such as a human, that includes: inhibiting the activity of a fibroblast growth factor, such as FGF2 in a mammal in need of treatment for a microbial infection, to an extent effective to increase antibody production in the mammal.
  • the inhibiting step may include or consist of administering a fibroblast growth factor antagonist, such as a FGF2 antagonist, to the mammal in an amount effective to increase antibody production in the mammal.
  • the method may further include the step of administering an antibiotic or anti-viral agent to the mammal which is active against the microbial infection.
  • Another embodiment of the invention provides a method for increasing in vivo antibody production in a mammal, such as a human, that does not have a cancer that includes the step of by inhibiting the activity of a fibroblast growth factor, such as FGF2, in the mammal.
  • a mammal such as a human
  • FGF2 fibroblast growth factor
  • the mammal is a geriatric human.
  • a still further embodiment of the invention provides a method for decreasing antibody production, such as pathological antibody production, in a mammal such as a human, in need of such reduction, by administering to the mammal, in an amount effective to decrease antibody production in the mammal, a fibroblast growth factor or agonist thereof, such as FGF2 or an FGF2 agonist, or an agonist of a receptor that binds a fibroblast growth factor such as FGF2, for example FGFR1, FGFR2 and FGFR3.
  • FIG. 1 A shows that FGF2 deficient mice respond more strongly to a Type I Thymus Independent Antigen.
  • FIG. IB shows the difference in antibody titer of FGF2 deficient animals compared to littermate controls following immunization.
  • FIG. 2A shows FGF2 transgenic mice respond more weakly to a Type I Thymus Independent Antigen.
  • FIG. 2B shows the quantification of antibody titer of FGF2 transgenic animals compared to littermate controls following immunization.
  • FIG. 3 shows that FGF2 deficiency affects germinal centers but not syndecan expression.
  • FIG. 4 shows that ectopic expression of FGF2 does not suppress germinal center formation.
  • FGF2 mutant mice FGF2 deficient mice produce more antibody to a Type I independent antigen while FGF2 over-expressing mice show suppressed antibody production to the same pathogenic stimulus.
  • germinal center formation is compromised in the absence of FGF2.
  • changes in both antibody production and germinal center formation are observed in mice lacking a single copy of FGF2, demonstrating that lymphocytes are particularly sensitive to FGF2 gene dosage.
  • FGF2 -/- mice were obtained from two academic sources. These mice display relatively benign defects in wound healing, blood pressure regulation and cortical neurogenesis and do not express detectable levels of FGF2 protein (Ortega et al, 1998. Proc Natl Acad Sci USA 95:5672; Zhou et al, 1998, Nature Medicine 4:20). Both sets of knockouts showed increases in antibody production and data in FIGS. 1 and 3 are for animals obtained from the University of Cincinnati. Heterozygous animals (mixture of 129SvEv:Black Swiss) were mated and heterozygous and null animals were compared to littermate controls. Adult mice of both sexes were used.
  • FGF2 transgenic animals exhibit bone dysplasia and disruption of endothelial homeostasis (Fulgham et al, 1999, Endothelium 6: 185; Coffin et al, 1995, Mol Biol Cell 6: 1861).
  • Animals (FVBN) heterozygous for the transgene were mated to wild type and adult animals of both sexes were compared to littermate controls. Animals were maintained in a pathogen-free facility, following institutional standards. Protocols adhered to IACUC guidelines.
  • mice were immunized intraperitoneally with 50 ug TNP-LPS (tri-nitrophenol lipopolysachharide) emulsified with complete Freund's adjuvant in PBS (200 ul final volume). Serum was harvested from retro-orbital eye bleeds. After coagulation, bleeds were centrifuged and sodium azide (0.01%) was added. ELISAs for TNP specific antisera were performed on plates coated with TNP-BSA (Biosearch) and primary antisera were bound overnight at 4°C. Goat anti-mouse IgG (all Ig isotypes) coupled to Alkaline Phosphatase was used as secondary antisera (Jackson).
  • TNP-LPS tri-nitrophenol lipopolysachharide
  • Germinal center number was scored by experimenters blind to the source of the sections. At least three serial sections were scored for each spleen. Results are based on three independent experiments from two or more animals per genotype. Data are presented from the final experiment which used the largest number of animals.
  • CD43 negative selection was carried out using anti-CD43 (Serotec) and Miltenyi microbeads according to the manufacturer's instructions.
  • Cells were cultured in RPMI 1640, 10% fetal calf serum for three days in the presence of anti- CD40 (mAb 1C10, generous gift of Hsiou-Chi Liou, Weill Medical College of Cornell University) and anti-IgM Fab '2 fragments (Jackson Immunoresearch).
  • FGFl lOOng/ml
  • Heparin lOug/ml
  • FGF2 Regulates the Humoral Immune Response
  • TNP-LPS type I independent antigen
  • FIG. 1 A data points represent average absorbance from the serum of at least five animals. Asterisks indicate statistical differences at p ⁇ .05 (student's t test).
  • FIG. IB shows the quantification of the difference in antibody titer of FGF2 deficient animals compared to littermate controls at day nineteen after immunization. Data points represent the mean absorbance +/- s.e.m. at the indicated dilutions for each genotype. Broken line between curves with corresponding vertical line delineates difference in antibody titer at the same absorbance.
  • FGF2 transgenic mice To determine whether FGF2 is sufficient to regulate antibody production, we examined the humoral immune response in FGF2 transgenic mice. These animals express a human FGF2 gene driven by the ubiquitously active promoter,
  • FGF2 protein phosphoglycerate kinase (Coffin et al., 1995, Mol Biol Cell 6: 1861). Different forms of FGF2 protein are produced from the FGF2 gene, including several high and low molecular weight isoforms. In FGF2 transgenic animals, there is a marked increase in the expression of the 18-Kd form of FGF2 in selected tissues, including spleen (Coffin et al, 1995, Mol Biol Cell 6: 1861).
  • FIG. 2B shows the quantification of antibody titer of FGF2 transgenic animals compared to littermate controls at day twenty one after immunization. Data points represent the mean absorbance +/- s.e.m. at the indicated dilutions. Broken line between curves with corresponding vertical line delineates difference in antibody titer at the same absorbance.
  • FIG. 1 FGF2 deficiency affects germinal centers but not syndecan expression.
  • FGF2 +/+, +/-, -/- mice were immunized i.p. with 50 ug TNP-LPS.
  • A-C Spleens were stained for expression of germinal centers with peanut agglutinin two weeks after immunization.
  • D-F Expression of syndecan-1 was determined by monoclonal antibody anti-CD 138 (BD).
  • FGF2 is one of the more widely expressed members of the FGF family of ligands, with strong expression in multiple tissues.
  • functional studies have demonstrated that both FGF-1 and FGF2 are present in the spleen in forms which can stimulate liver cell proliferation (Suzuki et al., 1992, Biochem Biophys Res Commun 186: 1192).
  • FGF-1 constitutes a plausible candidate because it structurally resembles FGF2 and also is expressed in the spleen (Suzuki et al, 1992, Biochem Biophys Res Commun 186: 1192).
  • studies with FGF- 1/2 double knock out mice suggest that the mild wound healing and neural phenotypes in FGF2 null mice are not a result of FGF-1 substituting for FGF2 (Miller et al, 2000, Mol Cell Biol 20:2260).
  • the type I independent antigen lipopolysaccharide is a key pathogenic substance in the cell wall of gram negative bacteria.
  • the repeating epitope in this molecule leads to massive engagement of receptors on the surface of B cells, including the BCR, TLR2 and TLR4 (Yang et al, 1998, Nature 395:284; Takeuchi et al, 1999, Immunity 11 :443).
  • B cell evolution has developed rapid and vigorous pre-existing defenses against such frequent threats and consequently, antibody secretion in response to this stimulus is robust.
  • the greater response in the absence of FGF2 demonstrates that FGF2 negatively regulates the primary humoral immune response.
  • FC DRIIB FC DRIIB
  • FGF2 may regulate a step subsequent to the expression of syndecan- 1, such as plasmablast migration, full terminal differentiation, or metabolic function of antibody secreting cells in the bone marrow. Consistent with this latter idea, FGF2 is strongly expressed by multiple cell types in the bone marrow (Brunner et al, 1993, Blood 81 :631; Chou et al, 2003, Leuk Res 27:499.).
  • FGF2 may control antibody production either by directly signaling to B cells or indirectly by affecting cells which regulate plasma cell activity.
  • the direct model is consistent with our data showing decreased proliferation in response to FGF signaling of primary mature B lymphocytes (Table 3). While the reduction in cell number is modest, it should be borne in mind that few substances can overcome the strong growth and survival signals turned on by simultaneous CD40 and BCR engagement. In agreement with a direct mode of action, a previous study reported that FGF receptors exist on normal human peripheral blood B cells (Genot, et al., 1989, Cell Immunol 122:424). However, the possibility that other cell types could mediate the observed effects cannot presently be excluded.
  • TNF receptor null animals lack germinal centers but produce substantial antibody titers in response to vesicular stomatitis virus (Karrer et al., 2000, J Immunol 164:768). Similarly, TNF-a null animals display dramatic alterations in splenic morphology but their antibody production to LPS is unaffected (Pasparakis et al, 1996, J Exp Med 184: 1397).
  • FGF2 plays two distinct and complementary roles in the humoral immune response. FGF2 facilitates germinal center formation, thereby contributing to the generation of activated B cells which defend against pathogenic stimuli. On the other hand, FGF2 reduces plasma cell activity and in so doing provides a limit on antibody production. Since FGF2 exerts opposing forces at different times during the B cell response, its activities in the immune system are certainly complex. Such complexity is consistent with observations in other tissues, where FGF signaling can stimulate radically different effects depending on its temporal and spatial locus of action.
  • Influenza vaccine (Nguyen ML et al Infect Immun. 2009 Nov;77(l l):4714-23.
  • the major neutralizing antibody responses to recombinant anthrax lethal and edema factors are directed to non-cross- reactive epitopes);
  • Influenza Vaccine in geriatric patients (Frasca D, Diaz, A, Romero, M et al. Vaccine. 2010 Oct 22. Intrinsic defects in B cell response to seasonal influenza vaccination in elderly humans.); and Anthrax vaccine (Nguyen ML et al Infect Immun. 2009 Nov;77(l l):4714-23.
  • the major neutralizing antibody responses to recombinant anthrax lethal and edema factors are directed to non-cross-reactive epitopes.).
  • the invention may, for example, be used to increase antibody production and/or humoral immunity in patients, such as human patients, suffering from
  • immunodeficiencies including but not limited to: Common variable immunodeficiency (Rezaei N et al Clin Vaccine Immunol. 2008 Apr; 15 (4): 607- 11 Serum bactericidal antibody responses to meningococcal polysaccharide vaccination as a basis for clinical classification of common variable immunodeficiency); primary immunodeficiency disorder (PIDD), Ig deficiency, IgG deficiency; and HIV disease (Acquired Immune Deficiency Syndrome).
  • Common variable immunodeficiency Rezaei N et al Clin Vaccine Immunol. 2008 Apr; 15 (4): 607- 11 Serum bactericidal antibody responses to meningococcal polysaccharide vaccination as a basis for clinical classification of common variable immunodeficiency
  • PIDD primary immunodeficiency disorder
  • Ig deficiency IgG deficiency
  • HIV disease Acquired Immune Deficiency Syndrome
  • One embodiment of the invention provides a method for increasing the humoral immune response to vaccination with an immunogen, for example, an antigen or a live vaccine, in a mammal, that includes: in conjunction with the vaccination of a mammal to the immunogen other than FGF2, inhibiting the activity of FGF2 in the mammal, thereby increasing the humoral immune response to the antigen.
  • an immunogen for example, an antigen or a live vaccine
  • the immunogen is other than a fibroblast growth factor and other than a fibroblast growth factor receptor.
  • the mammal may be a human, such as a geriatric human.
  • the mammal which may be human, may have an immune deficiency, such as but not limited to Common variable immunodeficiency; primary immunodeficiency disorder (PIDD), an immunoglobulin deficiency such as IgG deficiency, and HIV disease.
  • an immune deficiency such as but not limited to Common variable immunodeficiency; primary immunodeficiency disorder (PIDD), an immunoglobulin deficiency such as IgG deficiency, and HIV disease.
  • PIDD primary immunodeficiency disorder
  • IgG deficiency immunoglobulin deficiency
  • HIV disease HIV disease.
  • Another embodiment of the invention provides a method for treating an immune deficiency in a mammal, such as a human, that includes: increasing the production of endogenous antibodies in the mammal by inhibiting the activity of FGF2 in the mammal.
  • the mammal does not have cancer.
  • the immune deficiency may be, for example, but is not limited to: Common variable
  • immunodeficiency primary immunodeficiency disorder (PIDD), an immunoglobulin deficiency such as IgG deficiency, and HIV disease.
  • PIDD primary immunodeficiency disorder
  • immunoglobulin deficiency such as IgG deficiency
  • HIV disease HIV disease.
  • Non-human mammals also suffer from immunodeficiencies and may be treated according to the invention.
  • the method may be used to treat immunodeficiency associated with feline
  • immunodeficiency virus in a cat, such as a domesticated cat.
  • a further embodiment of the invention provides a method for treating a microbial infection in a mammal, such as a human, that includes: administering an FGF2 antagonist to a mammal in need of treatment for a microbial infection, wherein the FGF2 antagonist is administered in an amount effective to increase antibody production in the mammal.
  • the method may further include the step of: administering an antibiotic or anti-viral agent to the mammal which is active against the microbial infection.
  • the antibiotic or anti-viral agent is administered such that the effect of the antibiotic or antiviral agent and that of the FGF2 antagonist are temporally overlapping in the mammal.
  • the microbial infection may, for example, be a bacterial infection, a viral infection or a eukaryotic parasite infection.
  • the method may further include the step of determining that the mammal has a microbial infection prior to administering the FGF2 antagonist.
  • Another embodiment of the invention provides a method for increasing in vivo antibody production in a mammal, such as a human, that does not have a cancer, which includes the step of inhibiting the activity of FGF2 in the mammal.
  • the mammal is a geriatric human or non-human mammal, such as a geriatric domesticated dog or cat.
  • a related embodiment provides a method for enhancing the production of antisera or polyclonal antibodies generally against a desired immunogen in a non-human mammal that includes the steps of: inhibiting FGF2 activity in the non-human mammal according to any of methods and ways described herein and immunizing the non-human mammal with an immunogen that is not a fibroblast growth factor or a fibroblast growth factor receptor, whereby the production of antibodies against the immunogen in the mammal is enhanced, increased and/or accelerated versus a comparable immunization without the inhibition of FGF2 activity.
  • the method may further include the step of retrieving the polyclonal sera from the non-human mammal and optionally the step of isolating.
  • the immunizing step may, for example, include more than one temporally separated immunization with the immunogen and may, for example, be aided by inclusion of an immunization adjuvant.
  • the methods for production of antisera and polyclonal antibodies are well known and long-established in the art. See, for example, U.S. Pat. No. 5,440,021.
  • the increase in antibody production in response to inhibition of FGF2 activity in a mammal is a general characteristic of the invention which is not limited to the type of FGF2 inhibitor that is administered to the mammal to inhibit the activity of FGF2.
  • Preferred types of inhibitors of FGF2 activity include antibodies and binding fragments thereof, both monoclonal and polyclonal, which bind to FGF2 and block its interaction with FGF binding receptors and antibodies, both monoclonal and polyclonal, which bind to an FGF receptor such as FGFR1, FGFR2 and FGFR3 and block binding of the ligand (FGF2) to the receptor.
  • FGF2 ligand
  • a single chain, monoclonal scFv antibody that neutralizes FGF2 may be used such as that described in Tao et al, Selection and characterization of a human neutralizing antibody to human fibroblast growth factor-2, Biochem Biophys Res Commun. 2010 Apr 9;394(3):767-73.
  • Antibodies contain one or more antigen binding sites that specifically binds with an antigen.
  • Antibodies include, but are not limited to polyclonal, monoclonal, chimeric, and humanized antibodies.
  • Immunologically active portions include
  • Immunologically active portions can be incorporated into multivalent from such as diabodies, triabodies, and the like.
  • Antibodies further include antigen binding fragments displayed on phage, and antibody conjugates.
  • an "isolated antibody” is an antibody that (1) has been partially, substantially, or fully purified from a mixture of components; (2) has been identified and separated and/or recovered from a component of its natural environment; (3) is monoclonal; (4) is free of other proteins from the same species; (5) is expressed by a cell from a different species; or (6) does not occur in nature. Isolated antibodies may, for example, be used as inhibitors of FGF2 activity according to the invention.
  • isolated antibodies include an anti-FGF2 antibody that has been affinity purified using FGF2, an anti-FGF2 antibody that has been made by a hybridoma or other cell line in vitro, a human anti- FGF2 antibody isolated from a library such as a phage library, and a human anti-FGF2 antibody derived from a transgenic mouse.
  • Naturally occurring antibody molecules are composed of two identical heavy chains and two light chains.
  • Each light chain is usually covalently linked to a heavy chain by an interchain disulfide bond, and the two heavy chains are further linked to one another by multiple disulfide bonds at the hinge region.
  • the individual chains fold into domains having similar sizes (about 110-125 amino acids) and structures, but different functions.
  • the light chain comprises one variable domain (V L ) and one constant domain (C L ).
  • the heavy chain comprises one variable domain (V H ) and, depending on the class or isotype of antibody, three or four constant domains (C H I , C H 2, C H 3 and C H 4).
  • the isotypes are IgA, IgD, IgE, IgG, and IgM, with IgA and IgG further subdivided into subclasses or subtypes.
  • the portion of an antibody consisting of V L and V H domains is designated "Fv” and constitutes the antigen-binding site.
  • a single chain Fv (scFv) is an engineered protein containing a V L domain and a V H domain on one polypeptide chain, wherein the N terminus of one domain and the C terminus of the other domain are joined by a flexible linker.
  • Fab refers to the portion of the antibody consisting of V L -C L (i.e., a light chain) and V H -C H 1 (also designated "Fd").
  • Antibodies include without limitation single variable domains (sVDs) and antigen binding proteins that comprise sVDs.
  • sVD binding sites can be obtained from antigen specific Fv regions (which comprise both V H and V L domains). Often, it can be shown that the binding affinity and specificity of an Fv region is contributed primarily by one of the variable domains. Alternatively, the scFv can be obtained directly.
  • Direct sources of sVDs include mammals (e.g., camelids) that naturally express antibodies containing only V H domain.
  • phage display libraries can be constructed to express only a single variable domain. For example, a human domain antibody phage display library is commercially available from Domantis (Cambridge, UK).
  • the antibody variable domains show considerable amino acid sequence variablity from one antibody to the next, particularly at the location of the antigen binding site.
  • Three regions, called “complementarity-determining regions” (CDRs) are found in each of V L and V H -
  • the CDRs of an antibody are often referred to as
  • Fc is the designation for the portion of an antibody which comprises paired heavy chain constant domains.
  • the Fc comprises C H 2 and C H 3 domains.
  • the Fc of an IgA or an IgM antibody further comprises a C H domain.
  • the Fc is associated with Fc receptor binding, activation of complement-mediated cytotoxicity and antibody-dependent cellular-cytotoxicity.
  • complex formation requires Fc constant domains.
  • antibodies of the invention include, but are not limited to, naturally occurring antibodies, bivalent fragments such as (Fab') 2 , monovalent fragments such as Fab, single chain antibodies, single chain Fv (scFv), single domain antibodies, multivalent single chain antibodies, diabodies, triabodies, and the like that bind specifically with antigens.
  • Antibody fragments also include polypeptides with amino acid sequences substantially similar to the amino acid sequence of the variable or hypervariable regions of the antibodies of the invention. Substantially the same amino acid sequence is defined herein as a sequence with at least 70%, at least about 80%, at least about 90%>, at least about 95% or at least about 99% homology or identity to a compared amino acid sequence, as determined by the FASTA search method in accordance with Pearson and Lipman, Proc. Natl. Acad. Sci. USA 85:2444-2448 (1988).
  • Antibodies that may be employed as inhibitors according to the invention also include "chimeric" antibodies and binding fragments thereof. Such antibodies generally comprise variable domains of one antibody and constant domains of a different antibody. Typically, to minimize host immune responses against the antibody and to enhance host responses against the antibody target by retaining antibody effector functions, the constant domains of a chimeric antibody are taken from the same species to which the chimeric antibody will be administered.
  • Antibodies that may be employed as inhibitors according to the invention also include "humanized" antibodies.
  • Humanized variable domains are constructed in which amino acid sequences which comprise one or more complementarity determining regions (CDRs) of non-human origin are grafted to human framework regions (FRs).
  • CDRs complementarity determining regions
  • FRs human framework regions
  • Variable domains have a high degree of structural homology, allowing easy identification of amino acid residues within variable domains which corresponding to CDRs and FRs. See, e.g., Kabat, E. A., et al, 1991 , Sequences of Proteins of Immunological Interest. 5th ed. National Center for Biotechnology
  • CDRs are most easily grafted onto different FRs by first amplifying individual FR sequences using overlapping primers which include desired CDR sequences, and joining the resulting gene segments in subsequent amplification reactions. Grafting of a CDR onto a different variable domain can further involve the substitution of amino acid residues which are adjacent to the CDR in the amino acid sequence or packed against the CDR in the folded variable domain structure which affect the conformation of the CDR.
  • Humanized variable domains of the invention therefore include human domains which comprise one or more non-human CDRs as well as such domains in which additional substitutions or replacements have been made to preserve or enhance binding characteristics.
  • Antibodies with variable domains that have been made less immunogenic by replacing surface-exposed residues so as to make the antibody appear as self to the immune system may also be employed as inhibitors (Padlan, E. A., 1991, Mol. Immunol. 28, 489-98). Antibodies have been modified by this process with no loss of affinity (Roguska et al, 1994, Proc. Natl. Acad. Sci. USA 91, 969-973). Because the internal packing of amino acid residues in the vicinity of the antigen binding site remains unchanged, affinity is preserved. Substitution of surface-exposed residues according to the invention for the purpose of reduced immunogenicity does not mean substitution of CDR residues or adjacent residues which influence binding characteristics.
  • variable domains that are essentially human as when the recipient of the antibody is human.
  • Human antibodies comprise human VH and VL framework regions (FWs) as well as human complementary determining regions (CDRs).
  • FWs human VH and VL framework regions
  • CDRs human complementary determining regions
  • the entire VH and VL variable domains are human or derived from human sequences.
  • the antibodies can be obtained directly from human cells, for example by creating human hybridomas.
  • human antibodies can be obtained from transgenic animals into which unrearranged human Ig gene segments have been introduced and in which the endogenous mouse Ig genes have been inactivated (reviewed in Briiggemann and Taussig, 1997, Curr. Opin. Biotechnol. 8, 455-58).
  • Preferred transgenic animals contain very large contiguous Ig gene fragments that are over 1 Mb in size (Mendez et al., 1997, Nature Genet. 15, 146-56) but human Mabs of moderate affinity can be raised from transgenic animals containing smaller gene loci (See, e.g., Wagner et al, 1994, Eur. J. Immunol. 42, 2672-81; Green et al, 1994, Nature Genet. 7, 13-21).
  • Human antibodies can also be obtained from libraries of antibody VH and/or VL domains.
  • a variable domain library can be obtained from human genomic sequences, or from peripheral blood lymphocyte expressing productively rearranged variable region genes.
  • the human gene library can be synthetic.
  • variable domain libraries can be created which comprise human framework regions with one or more CDRs that are synthesized to include random or partial random sequences.
  • a human VH variable domain library can be created in which members are encoded by a human VH gene segment and a synthetic sequence for the CDR3H region (i.e., a synthetic D H -JH gene segment).
  • a human VL variable domain may be encoded by a human VL gene segment and a synthetic sequence for the CDR3L region (i.e., a synthetic J L gene segment).
  • the human frameworks may be synthetic in that they have a consensus sequence derived from known human antibody sequences or subgroups of human sequences.
  • one or more CDRs is obtained by amplification from human lymphocytes expressing rearranged variable domains and then recombined into a particular human framework.
  • variable domains In order to screen libraries of variable domains, it is common to employ phage display libraries wherein combinations of human heavy and light chain variable domains are displayed on the surface of filamentous phage (see, e.g., McCafferty et al, 1990, Nature 348, 552-54; Aujame et al, 1997, Human Antibodies 8, 155-68). Combinations of variable domains are typically displayed on filamentous phage in the form of Fabs or scFvs. The library is screened for phage bearing combinations of variable domains having desired antigen binding characteristics. Preferred single domain and variable domain combinations display high affinity for a selected antigen and little cross-reactivity to other related antigens.
  • binding domains of the invention include those for which binding characteristics have been improved by mutating CDRs and/or FW regions by direct mutation, methods of affinity maturation, or chain shuffling. It is understood that amino acid residues that are primary determinants of binding of single domain antibodies can be within Kabat defined CDRs, but may include other residues as well.
  • residues important for antigen binding can also potentially include amino acids that would otherwise be located at the interface of a V H -V L heterodimer.
  • phage display is used to screen such mutants to identify those having the desired binding characteristics (see, e.g., Yang et al, J. Mol. Biol, 254: 392-403 (1995)). Mutations can be made in a variety of ways. One way is to randomize individual residues or
  • mutations may be induced over a range of CDR residues by error prone PCR methods (see, e.g., Hawkins et al, J. Mol. Biol, 226: 889-896 (1992)).
  • phage display vectors containing heavy and light chain variable region genes may be propagated in mutator strains of E. coli (see, e.g., Low et al, J. Mol. Biol, 250: 359-368 (1996)).
  • Inhibitors that may be used according to the invention also include antigen binding proteins engineered from non-immunoglobulin scaffolds.
  • affibodies which are derived from an immuno globulin-binding domain of S. aureus protein A, possess no disulfide bonds and display reversible folding.
  • fibronectin which has an antibody-like structure and displays CDR-like loops. In contrast to antibodies, the fibronectin domain structure does not rely on disulfide bonds, yet displays high thermodynamic stability. Binding sites can be engineered into such scaffolds by, for example, diversifying codons at specified positions and screening for binding to a desired antigen.
  • Codons can be randomized in loops, flat surfaces, cavities, or combinations of such locations. Further, peptide sequences can be inserted, usually in loops. Target-binding variants of resulting libraries can be isolated using selection of screening techniques that are well known in the art, not limited to phage display, ribosome display, bacteria or yeast surface display, and the like. For antigen-binding proteins intended for therapy, various strategies are available for minimizing potential immunogenicity. Human scaffolds can be employed, and immunogenicity can be minimized, for example, by PEGylation or T-cell epitope engineering (i.e., minimizing T- cell reactive sequences).
  • Antigen-binding proteins from non-immunoglobulin scaffolds often can be produced more economically than immunoglobulin-type proteins.
  • the absence of disulfide bonds or free cysteines allows for expression of functional molecules in the reducing environment of the bacterial cytoplasm, which usually gives higher yields than periplasmic expression, and is more convenient than refolding in vitro.
  • Binz, H. K. et al. discloses a variety of such antigen-specific binding proteins and techniques for their development.
  • the identification or selection of antibodies or other molecules that inhibit binding of FGF2 or other FGFs to their receptors may be performed according to routine ligand-receptor binding assays, comparing binding in presence and absence of test agent, since the full sequences of FGF2 and its receptors are known in various mammals such as human. See, for example, U.S. Pat. No. 5,440,021 for ligand-receptor binding assays.
  • Another preferred type of inhibitor of FGF2 activity is a soluble FGF2- binding receptor or soluble portion of an FGF-binding receptor, such as a soluble form of FGFRl, FGFR2 and FGFR3.
  • the soluble receptor sequence may, for example match the species in which it will be administered, i.e., a human receptor sequence may be used for a human recipient and so on.
  • FP-1039 is a soluble fusion protein consisting of the extracellular domains of human FGFRl linked to the Fc region of human
  • Immunoglobulin Gl (IgGl), which may be used as an FGF2 inhibitor/antagonist according to the invention (Five Prime Therapeutics, Inc., San Francisco, CA; Keer et al, ASCO 2010, Abstract no. TPS260).
  • FGF2 activity may also be inhibited according to the invention by vaccinating the subject mammal against FGF2 itself or against FGFRl, FGFR2 and/or FGFR3.
  • a peptide vaccine targeting the heparin-binding portion of FGF2 can be used to generate a specific anti-FGF2 antibody response in a mammal according the method of Plum et. al., Generation of a specific immunological response to FGF2 does not affect wound healing or reproduction, Immunopharmacol Immunotoxicol. 2004 Feb;26(l):29- 41.
  • a composition for intravenous administration for example, to a human, may include 0.1 to 20 mg, such as 0.1 to 10 mg, of the polypeptide, and this may be a daily dose. More generally, dosages from 0.1 mg to about 100 mg per subject per day for one or more days may be used.
  • Methods for preparing administrable compositions are well known to those skilled in the art and are described in more detail in such publications as Remington's Pharmaceutical Science, 19th ed., Mack Publishing Company, Easton, Pa. (1995).
  • Polypeptides for administration to a subject may, for example, be provided in lyophilized form and rehydrated with sterile water before administration.
  • the solution of polypeptide may then be added to an infusion bag containing 0.9% sodium chloride, USP, and, for example administered at a dosage of from 0.5 to 15 mg/kg body weight.
  • the polypeptide can be administered as a bolus injection, for example, at a dosage of 0.5 to 30 mg/kg body weight.
  • FGF2 activity inhibitors include, for example, antisense oligonucleotides targeting FGF2 or one or more of FGFR1, FGFR2 and
  • FGFR3 FGFR3.
  • Still further suitable inhibitors are small molecule inhibitors, for example cardiac glycosides or aglycone derivatives as described in U.S. Pat. No. 6,071,885 and
  • TKI258 also known as CHIR-258 described in Sarker et al., Clin Cancer Res,
  • the invention also provides embodiments in which antibody production in vivo is purposefully reduced in a mammal, such as a human, by increasing FGF2 activity in the mammal, for example, by administration of FGF2 to the mammal or administration of an agonist of FGF2 or an agonist of an FGF2 receptor, such as FGFR1, FGFR2 or
  • the peptide sequence may, for example at least substantially or identically match the species in which it will be administered, i.e., a human receptor sequence may be used for a human recipient and so on.
  • This aspect of the invention finds practical application is the suppression of antibody production in acutely toxic states.
  • response to invading pathogens can lead to pathological autoimmune effects, with lymphocyte activity spiraling out of control.
  • administration of FGF2 attenuates the uncontrolled secretion of antibody.
  • autoimmune antibodies are observed in both systemic lupus erythematosus (Cohen D et al., Diagnosis and management of the antiphospho lipid syndrome. BMJ. 2010 May 14;340:c2541) and diverse arthritic disease (Calero I, et al., B cell therapies for rheumatoid arthritis: beyond B cell depletion. Rheum Dis Clin North Am 2010
  • rheumatoid arthritis including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and juvenile idiopathic arthritis.
  • increasing FGF2 activity in a mammal may be used to decrease or maintain a decreased level of antibody production in organ transplant patients, such as human organ transplant patients in order to decrease negative immune responses to and increase tolerance to the transplanted organ in the patient.
  • one embodiment of the invention provides a method for decreasing antibody production, such as pathological antibody production, in a mammal such as a human in need thereof by administering to the mammal FGF2 or an FGF2 agonist or an agonist of a receptor that binds FGF2 such as FGFR1, FGFR2 and FGFR3 in an amount effect to decrease antibody production in the mammal.
  • the mammal may have and be in need of treatment for systemic lupus erythematosus and diverse arthritic disease, including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and juvenile idiopathic arthritis and the method decreases the production of autoimmune antibodies in these mammals thereby treating the condition.
  • the mammal is an organ transplant patient such as a human organ transplant patient and the method reduces antibody response against the transplanted organ.
  • fibroblast growth factors and their receptors are well characterized in humans and non-human mammals.
  • the following sequences are known and form part of this disclosure: Human FGF2 (NCBI Reference Sequence NM 002006.4; SEQ ID NO: l peptide, SEQ ID NO:2 nucleotide), Human FGFR1 (GenBank Accession No. M34185.1; SEQ ID NO:3 peptide, SEQ ID NO:4 nucleotide), Human FGFR2 (NCBI Reference Sequence NM 000141.4; SEQ ID NO:5 peptide, SEQ ID NO:6 nucleotide), Human FGFR3 (NCBI Reference Sequence
  • the invention also provides methods for increasing endogenous antibody production in mammals such as humans by administering any of the following enumerated compounds or pharmacologically acceptable salts thereof: [000105] 1. BIBF1120 (Vargatef) Boehringer Ingelheim,
  • BIBF 1120 triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy.
  • AZD2171 a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer.
  • AZD4547 an orally bioavailable, potent, and selective inhibitor of the fibroblast growth factor receptor tyrosine kinase family.
  • TSU-68 (SU6668) inhibits local tumor growth and liver metastasis of human colon cancer xenografts via anti- angio genesis.
  • ENMD-2076 an oral inhibitor of angiogenic and proliferation kinases, has activity in recurrent, platinum resistant ovarian cancer.
  • FP1039 (fusion protein) Five Prime, Human Genome Sciences, Glaxo Smith Kline.
  • FP 1039 comprises the extracellular domain of human fibroblast growth factor receptor lc (FGFR1) linked to the Fc portion of human IgGl .
  • the molecule is designed to trap FGFR1 ligands and prevent binding to FGF receptors.
  • Harding et al Preclinical efficacy of FP- 1039 (FGFR1 :Fc) in endometrial carcinoma models with activating mutations in FGFR2. 101st Annual Meeting of the American Association for Cancer Research. : abstr. 2597, 17 Apr 2010
  • the compounds or pharmacologically acceptable sales thereof may, for example, be administered in therapeutically effective amounts to a mammal such as a human in need of increasing endogenous antibody production who is not in need of treatment for a cancer.
  • the mammal may have an immune deficiency such as a humoral immune deficiency or any of the immune deficiencies described herein.
  • the mammal may, for example, be geriatric.
  • the compounds or pharmaceutically acceptable salts thereof may for example, be administered in an amount effective to increase endogenous antibody production in conjunction with a vaccination with an immunogen (other than FGF2 or an FGF) to improve the humoral immune response to the vaccination.
  • the compounds or pharmaceutically acceptable salts thereof may for example, be
  • the mammal may be one that is not in need of treatment for cancer.
  • the invention also provides corresponding first and second medical uses for each of the methods of treatment described in this disclosure.
  • the invention provides the use of the agents for treatment of the conditions described and also provides use of the agents for the manufacture of medicaments for the treatment of the conditions described.
  • Non-human mammals with which the invention may be used include, for example, livestock animals, such as Bovidae, for example cows and sheep, and swine, also Equidae such as horses, canines such as companion domesticated dogs and felines such as companion domesticated cats, primates, Lagomorphs such as rabbits and
  • Rodentia such as rats and mice.
  • the invention is also applicable in birds such as foul, for example, chickens, turkeys and quail, ducks and geese. Accordingly, the invention provides corresponding embodiments and variations as described herein for mammals but applied to avians, such as the aforementioned avians.

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