US20140079637A1 - Methods and compositions for improving antiangiogenic therapy with anti-integrins - Google Patents

Methods and compositions for improving antiangiogenic therapy with anti-integrins Download PDF

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US20140079637A1
US20140079637A1 US14/006,669 US201214006669A US2014079637A1 US 20140079637 A1 US20140079637 A1 US 20140079637A1 US 201214006669 A US201214006669 A US 201214006669A US 2014079637 A1 US2014079637 A1 US 2014079637A1
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Prior art keywords
integrin
agent
beta
antibody
tumor
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Warren Shawn Carbonell
Manish Kumar Aghi
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University of California San Diego UCSD
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University of California San Diego UCSD
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    • 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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • 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
    • A61K38/18—Growth factors; Growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2839—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the integrin superfamily
    • C07K16/2842—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the integrin superfamily against integrin beta1-subunit-containing molecules, e.g. CD29, CD49
    • 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
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • 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
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • 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
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/15011—Lentivirus, not HIV, e.g. FIV, SIV
    • C12N2740/15041—Use of virus, viral particle or viral elements as a vector
    • C12N2740/15043—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector

Definitions

  • the present invention comprises, in general, pharmaceutical compositions for inhibiting tumor cell growth, comprising: a first agent which is an inhibitor of VEGF activity, such as VEGF signaling and/or binding to the VEGF receptor; and a second agent which blocks beta-1 integrin.
  • the blocking of beta-1 integrin can be blocking of cell attachment, blocking of beta-integrin intracellular signaling that occurs after cell attachment, or both.
  • the agents used are compositions of matter, such as peptides or small molecules. They may be antibodies or antibody-like molecules. The combination of agents has a synergistic effect, i.e. is more effective than either agent separately.
  • the agents may be in a single composition or a matched pair of compositions.
  • FIG. 8 is a bar graph showing expression of annexin and Ki67 apoptosis markers at different concentrations of AIIB2 in an antiangiogenesis resistant glioblastoma cell line.
  • FIG. 12 is a bar graph showing cell growth over time of GBM cells subjected to hypoxia for 2 days followed by growth at normoxia. Cells were given IgG (control) and different concentrations of AIIB2.
  • FIG. 13 is a line graph showing tumor growth over time for U87MG glioma tumors measured biweekly with control IgG (10 mg/kg) (diamonds), bevacizumab (10 mg/kg) (squares), or low-dose alternating combination therapy of bevacizumab (1 mg/kg) and AIIB2 (1 mg/kg) (circles).
  • VEGF refers to vascular endothelial growth factor, also referred to as vasoendothelial growth factor, having an exemplary amino acid sequence at Genbank Accession Number AAA35789, described further at Leung, et al. “Vascular endothelial growth factor is a secreted angiogenic mitogen,” Science 246 (4935), 1306-1309 (1989). VEGF is a dimeric, disulfide-linked 46-kDa glycoprotein related to Platelet-Derived Growth Factor (“PDGF”).
  • PDGF Platelet-Derived Growth Factor
  • VEGFR-I also known as flt-1
  • VEGFR-2 also known as KDR3
  • VEGFR-3 VEGF receptor
  • the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FRs are those of a human immunoglobulin sequence.
  • the humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.
  • Fc immunoglobulin constant region
  • antibody further includes various forms of modified or altered antibodies, such as various fragments such as an Fv fragment, an Fv fragment containing only the light and heavy chain variable regions, an Fv fragment linked by a disulfide bond (Brinkmann, et al. Proc. Natl. Acad. Sci. USA, 90: 547-551 (1993)), a Fab or (Fab)′2 fragment containing the variable regions and parts of the constant regions, a single-chain antibody and the like (Bird et al., Science 242: 424-426 (1988); Huston et al., Proc. Nat. Acad. Sci. USA 85: 5879-5883 (1988)).
  • fragments such as an Fv fragment, an Fv fragment containing only the light and heavy chain variable regions, an Fv fragment linked by a disulfide bond (Brinkmann, et al. Proc. Natl. Acad. Sci. USA, 90: 547-551 (1993)
  • Fab or (Fab)′2 fragment
  • tumors and metastases may be deprived of an adequate blood supply resulting in tumor cell growth arrest and possibly regression, including tumor cell death.
  • the methods have a variety of uses in scientific research and health care wherein vascularization is a contributing factor in disease processes, especially cancer.
  • enhancement of vascularization for repair or replacement of tissue may be achieved by potentiating both angiogenesis and adhesive vessel co-option simultaneously or sequentially.
  • anti-beta-1 compositions can be a monotherapy for 3L GBM who have failed Bevacizmab.
  • vascular niche a niche for insulin gene expression and beta cell proliferation.
  • vascular mural cells require the ⁇ 1 integrin subunit for proper adhesion to vessels and for maintaining vessel stability.
  • carcinoma cells appear to hijack the brain's VBM for essential functions during brain metastasis.
  • inhibiting angiogenesis in circumscribed, well-established CNS melanoma metastases causes reversion to growth by vascular co-option. This suggests a continuum for vessel utilization by tumor cells which may represent a viable target for therapeutic exploitation.
  • ⁇ 1 integrins In addition to the apoptotic mechanism described in vitro, inhibition of vascular co-option may have also attenuated growth.
  • tumors were analyzed in the MMTV/PyMT transgenic model of breast cancer.
  • Conditional deletion of ⁇ 1 integrin after induction of tumorigenesis resulted in impairment of FAK phosphorylation and proliferation consistent with a reliance on anchorage-dependent signaling for tumor growth.
  • Single chain recombinant antibodies may also be used, as described, for example in U.S. Pat. No. 5,840,300 to Williams et al, entitled “Methods and compositions comprising single chain recombinant antibodies,” hereby incorporated by reference for purposes of describing methods useful in the preparation of such compositions.
  • Kappa, heavy, and lambda immunoglobulin chains are amplified separately and are subsequently combined as single chains, using recombinant PCR, i.e., the splicing by overlap extension (SOE) PCR method, wherein the single chains comprise a heavy chain plus a kappa chain or a heavy chain plus a lambda chain.
  • SOE overlap extension
  • KDR-bp KDR-binding protein
  • Lys49PLA2 catalytically inactive PLA2 homologue
  • RNAi lentivirus The preparation of competent virus from DNA vectors involves packaging the construct into a cell line.
  • Packaging an RNAi lentivirus is essentially the same as packaging a lentivirus carrying a cDNA.
  • DNA vectors are transiently transfected into a packaging cell line-such as human 293 cells, and after 2-3 days the supernatant will contain the virus.
  • Spheroidal tumor cell growth in culture is a surrogate for stem-like phenotype and can be promoted/enriched by stressors such as hypoxia and acid pH.
  • Knockdown of beta1 in both a classic glioma cell line (U87MG) and the BRG3 bevacizumab resistant line significantly impaired spheroid formation (data not shown)
  • AIIB2 also inhibited spheroidal growth of U87MG glioma cells induced by 48 hours of hypoxia (data not shown).
  • beta1 integrin In addition to impairment of spheroidal growth, inhibition of beta1 integrin promoted reversal of EMT as demonstrated by a significant increase in tumor cell area and a 50% decrease in the mesenchymal receptor c-met (data not shown).
  • beta1 integrin may inhibit growth of tumors by 1) preventing vessel co-option and perivascular invasion (or invasion upon any classical ECM substrate), 2) reducing viability of tumor cells after insults such as IR and hypoxia possibly by promoting apoptosis, 3) directly inhibiting tumor cell proliferation, 4) directly inhibiting angiogenesis by targeting proliferating and migrating endothelial cells and 5) reversing the aggressive stem-like phenotype including epithelial to mesenchymal transition (EMT).
  • EMT epithelial to mesenchymal transition

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  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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EP3067369A1 (en) 2015-03-11 2016-09-14 Institut d'Investigació Biomèdica de Bellvitge (IDIBELL) Methods and compositions for the treatment of anti-angiogenic resistant cancer
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CA2830908A1 (en) 2012-09-27
CN103561761A (zh) 2014-02-05
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WO2012129448A1 (en) 2012-09-27
AU2012230809A1 (en) 2013-10-10
US20180236073A1 (en) 2018-08-23
EP2688585A1 (en) 2014-01-29
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ES2699532T3 (es) 2019-02-11
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