WO2008030260A2 - Traitement des infections virales de la variole au moyen d'un inhibiteur de facteur tissulaire - Google Patents

Traitement des infections virales de la variole au moyen d'un inhibiteur de facteur tissulaire Download PDF

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WO2008030260A2
WO2008030260A2 PCT/US2006/049186 US2006049186W WO2008030260A2 WO 2008030260 A2 WO2008030260 A2 WO 2008030260A2 US 2006049186 W US2006049186 W US 2006049186W WO 2008030260 A2 WO2008030260 A2 WO 2008030260A2
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factor
optionally substituted
antibody
tissue factor
para
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WO2008030260A3 (fr
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Sek Chung 'Michael' FUNG
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Genentech, Inc.
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    • 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
    • C07K16/36—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against blood coagulation factors
    • 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
    • A61K31/13—Amines
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • 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
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • 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
    • A61K31/66—Phosphorus compounds
    • 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
    • A61K39/39541—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against normal tissues, cells
    • 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

Definitions

  • Variola viral infections are serious threats to the human population and are listed as priority pathogens by the NIAID (http://www2.niaid.nih.gov/biodefense/cat.pdf)- There is growing concern that mammalian poxviruses, like monkeypox virus, may easily cross the species barrier. This is because smallpox in humans has been eradicated and vaccination against smallpox was discontinued in 1 980, rendering the majority of the human population susceptible to poxvirus infections (Lewis-Jones S. Curr Opin Infect Dis. (2004) 1 7: 81 — 89).
  • pox viruses are pathogens that may be used to carry out acts of biological terrorism, and thus cause adverse public health impact and civil disruption (Rotz LD, Khan AS, Lillibridge SR, Hughes M. Emerg Infect Dis. (2002) 8: 225-227).
  • Rotz LD Khan AS, Lillibridge SR, Hughes M. Emerg Infect Dis. (2002) 8: 225-227.
  • Vaccination against the viruses is efficacious, but no longer administered on a routine or general basis.
  • traditional vaccines suffer from rare but severe side-effects (Mayr A. Comp Immunol Microbiol Infect Dis. (2003) 26: 423-430) or are too slowly produced in the face of a terrorist act.
  • Antiviral drugs have potential but have yet to be tested (e.g., cidofovir, Bray M, et. al. J Antimicrob Chemother. (2004) 54: 1 -5). Adequate stockpiles of vaccines and antiviral drugs do not exist. Furthermore, the development of viral resistance remains a serious threat.
  • the present invention relates to novel methods of treating a patient suffering from a variola virus infection, e.g., smallpox or monkeypox, comprising administering an inhibitor of tissue factor.
  • Tissue factor is involved in the activation of FVII, FIX, and FX in the extrinsic coagulation pathway. This approach is designed to overcome the shortcomings inherent in previous approaches and prevent certain clinical outcomes including mortality and morbidity.
  • tissue Factor inhibitors may include antibodies, peptide mimetics, tissue factor ligand analogs, tissue factor pathway inhibitor (TFPI), and organic molecules that inhibit tissue factor. These tissue factor inhibitors also include those that do not bind directly to tissue factor per se but to the complexes of FVIIa-tissue factor, FX-tissue factor, FVIIa-FX-tissue factor, FIX-tissue factor, and FVIIa-FIX-tissue factor.
  • tissue factor inhibitors also include those that do not bind directly to tissue factor per se but to the complexes of FVIIa-tissue factor, FX-tissue factor, FVIIa-FX-tissue factor, FIX-tissue factor, and FVIIa-FIX-tissue factor.
  • Other aspects of the invention include the treatment of smallpox or monkeypox virus infections with a tissue factor inhibitor in combination with another antiviral agent such as, Cidofovir.
  • amino acid sequence variant refers to polypeptides having amino acid sequences that differ to some extent from a native sequence polypeptide. Ordinarily, amino acid sequence variants will possess at least about 70% homology, or at least about 80%, or at least about 90% homology to the native polypeptide. The amino acid sequence variants possess substitutions, deletions, and/or insertions at certain positions within the amino acid sequence of the native amino acid sequence.
  • identity or "homology” is defined as the percentage of amino acid residues in the candidate sequence that are identical with the residue of a corresponding sequence to which it is compared, after aligning the sequences and introducing gaps, if necessary to achieve the maximum percent identity for the entire sequence, and not considering any conservative substitutions as part of the sequence identity. Neither N- or C-terminal extensions nor insertions shall be construed as reducing identity or homology. Methods and computer programs for the alignment are well known in the art. Sequence identity can be readily calculated by known methods, including but not limited to those described in (Computational Molecular Biology, Lesk, A.
  • Methods to determine identity are designed to give the largest match between the sequences tested.
  • Computer program methods to determine identity between two sequences include, but are not limited to, the GCG program package (Devereux, J., et al., Nucleic Acids Research 1 2(1 ): 387 (1 984)), BLASTP, BLASTN, and FASTA (Atschul, S. F. et al.J Molec. Biol. 21 5: 403-410 (1 990).
  • the BLAST X program is publicly available from NCBI and other sources (BLASTManual, Altschul, S., et al, NCBI NLM NIH Bethesda, Md. 20894, Altschul, S., et al.J. MoI. Biol. 21 5: 403-410 (1 990).
  • the well-known Smith Waterman algorithm may also be used to determine identity.
  • antibody herein is used in the broadest sense and specifically covers intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g. bispecific antibodies) formed from at least two intact antibodies, and antibody fragments, so long as they exhibit the desired biological activity.
  • monoclonal antibody refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. In contrast to polyclonal antibody preparations which include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen.
  • the modifier "monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
  • the monoclonal antibodies to be used in accordance with the present invention may be made by the hybridoma method first described by Kohler et al, Nature, 256:495 (1 975), or may be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567).
  • the "monoclonal antibodies” may also be isolated from phage antibody libraries using the techniques described in Clackson et al., Nature, 352:624-628 (1 991 ) and Marks et al., / MoI. Biol., 222:581 -597 (1 991 ), for example.
  • the monoclonal antibodies herein specifically include "chimeric" antibodies in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (U.S. Pat. No. 4,816,567; and Morrison et al, Proc. Natl. Acad. Sc/. USA, 81 :6851 -6855 (1 984)).
  • antibody fragments comprise a portion of an intact antibody comprising the antigen-binding or variable region thereof.
  • antibody fragments include Fab, Fab 2, and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules; and multispecific antibodies formed from antibody fragment(s).
  • An "intact” antibody is one which comprises an antigen-binding variable region as well as a light chain constant domain (CL) and heavy chain constant domains, CHI , CH2 and CH3.
  • the constant domains may be native sequence constant domains (e.g. human native sequence constant domains) or amino acid sequence variant thereof.
  • the intact antibody may have one or more effector functions.
  • Antibody effector functions refer to those biological activities attributable to the Fc region (a native sequence Fc region or amino acid sequence variant Fc region) of an antibody.
  • Examples of antibody effector functions include Cl q binding; complement dependent cytotoxicity; Fc receptor binding; antibody-dependent cell- mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors (e.g. B cell receptor; BCR), etc.
  • variable refers to the fact that certain portions of the variable domains differ extensively in sequence among antibodies and are used in the binding and specificity of each particular antibody for its particular antigen. However, the variability is not evenly distributed throughout the variable domains of antibodies. It is concentrated in three segments called hypervariable regions both in the light chain and the heavy chain variable domains. These hypervariable regions are also called complementarity determining regions or CDRs. The more highly conserved portions of variable domains are called the framework regions (FRs).
  • FRs framework regions
  • hypervariable regions in each chain are held together in close proximity by the FRs and, with the hypervariable regions from the other chain, contribute to the formation of the antigen-binding site of antibodies (see Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1 991 )).
  • hypervariable region when used herein refers to the amino acid residues of an antibody which are responsible for antigen-binding.
  • the hypervariable region generally comprises amino acid residues from a "complementarity determining region" or 11 CDR" (e.g. residues 24-34 (Ll ), 50-56 (L2) and 89-97 (L3) in the light chain variable domain and 31 -35 (Hl ), 50-65 (H2) and 95-102 (H3) in the heavy chain variable domain; Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md.
  • This region consists of a dimer of one heavy chain and one light chain variable domain in tight, non-covalent association. It is in this configuration that the three hypervariable regions of each variable domain interact to define an antigen-binding site on the surface of the VH-VL dimer. Collectively, the six hypervariable regions confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three hypervariable regions specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site. [Para 23] "Single-chain Fv" or "scFv” antibody fragments comprise the V H and V L domains of antibody, wherein these domains are present in a single polypeptide chain.
  • the Fv polypeptide further comprises a polypeptide linker between the V H and VL domains which enables the scFv to form the desired structure for antigen binding.
  • a polypeptide linker between the V H and VL domains which enables the scFv to form the desired structure for antigen binding.
  • diabodies refers to small antibody fragments with two antigen- binding sites, which comprise a variable heavy domain (VH) connected to a variable light domain (VO in the same polypeptide chain (VH-VL).
  • VH variable heavy domain
  • VH-VL variable light domain
  • linker that is too short to allow pairing between the two domains on the same chain, the domains are forced to pair with the complementary domains of another chain and create two antigen-binding sites.
  • Diabodies are described more fully in, for example, EP 404,097; WO 93/1 1 1 61 ; and Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444- 6448 (1 993).
  • a “single-domain antibody” is synonymous with “dAb” and refers to an immunoglobulin variable region polypeptide wherein antigen binding is effected by a single variable region domain.
  • a “single-domain antibody” as used herein includes i) an antibody comprising heavy chain variable domain (VH), or antigen binding fragment thereof, which forms an antigen binding site independently of any other variable domain, ii) an antibody comprising a light chain variable domain (VL), or antigen binding fragment thereof, which forms an antigen binding site independently of any other variable domain, iii) an antibody comprising a VH domain polypeptide linked to another VH or a VL domain polypeptide (e.g., VH-VH or VHx-VL), wherein each V domain forms an antigen binding site independently of any other variable domain, and iv) an antibody comprising VL domain polypeptide linked to another VL domain polypeptide (VL-VL), wherein each V domain forms an antigen binding site independently of any other variable domain
  • Humanized forms of non-human (e.g., rodent) antibodies are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin.
  • Humanized antibodies are human immunoglobulins wherein the hypervariable regions are replaced by residues from a hypervariable region of a non-human species, such as mouse, rat, rabbit or nonhuman primate having the desired specificity, affinity, and capacity.
  • framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues.
  • humanized antibodies may comprise residues that are not found in the human antibody or in the non-human antibody. These modifications are made to further refine antibody performance.
  • 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
  • Variola virus the etiological agent of smallpox, belongs to the family Poxviridae, subfamily Chordopoxvirinae, and genus orthopoxvirus, which includes cowpox virus, vaccinia virus (VV), monkeypox virus (MPXV), and several other animal poxviruses that cross-react serologically.
  • the poxviruses contain single, linear, double-stranded DNA molecules of 1 30-to-375-kb pairs and replicate in cell cytoplasm. They are shaped like bricks on electron micrographs and measure about 300 by 250 by 200 nm.
  • There are two classic forms of smallpox namely variola major and variola minor, each of which confers immunity against the other (Kuiken T, et al. Curr Opin Biotech. 14: 641 -646).
  • Variola virus and also monkeypox virus are now ranked high on the list of biological agents that may be used as a bioweapon because of the high mortality rate and to date the vast majority of the population lacks protective immunity (LeDuc JW, et. al. Emerg Infect Dis. (2002) 8:743-745).
  • MPXV monkeypox virus
  • MVA modified vaccinia virus Ankara
  • Cidofovir acyclic nucleotide analogue
  • HPMPC acyclic nucleotide analogue
  • VISTIDE® acyclic nucleotide analogue
  • Cidofovir is licensed for the treatment of cytomegalovirus retinitis in patients with HIV infection. It is not currently approved for treatment of variola virus infections in humans, but has been shown to be also active against a number of poxviruses, including vaccinia-, variola-, monkeypox-, and cowpox virus.
  • MPXV infection model has been established in cynomolgus macaques (Macaca fasciculahs).
  • MPXV is an orthopoxvirus closely related to variola virus and can cause a smallpox-like disease in humans with a mortality rate of approximately 10% and a human-to-human transmission rate of around 50%. The disease is endemic in the rainforests of central and western Africa. Animal antibody surveys in the Democratic Republic of Congo suggested that squirrels and monkeys play a role in the life cycle of the virus.
  • MPXV infection in cynomolgus macaques causes a disease very similar to smallpox. Different infection protocols have been described including intramuscular, intravenous and respiratory inoculation. Since MPXV, like variola virus has evolved primarily as a respiratory pathogen, it is probably most suitable for pathogenesis studies and for the evaluation of intervention strategies against smallpox and MPXV.
  • multifocal areas of necrosis were found that involved the terminal airways, the alveolar spaces and the interstitium.
  • the bronchial and bronchiolar epithelia exhibited multifocal hyperplasia and vacuolation. In some areas, the mucosal epithelium was eroded and necrotic and sloughed in the lumen.
  • Multifocal Iy the alveolar spaces were filled by eosinophilic fibrilar material (fibrin), eosinophilic amorphous material (edema), foamy macrophages, degenerative neutrophils and necrotic cellular debris. In association with these areas small necrotic vessels were apparent.
  • the peribronchial fibrous connective tissue was expanded by abundant number of extravasated red blood cells (hemorrhage), edema, increased number of fibroblasts and infiltrates of mixed inflammatory cells.
  • the fibrinolytic system was activated to dissolve the fibrin thrombi, resulting in consumption of plasminogen as it was converted into plasmin, and the formation of fibrin degradation products (FDP) including D-dimers as plasmin degrades fibrin clots.
  • FDP fibrin degradation products
  • mice infected with a cowpox virus that lack a functional serpin gene show decreased pulmonary hemorrhage, reduced inflammation and an absence of alveolar edema (Thompson JP, et. al. Virology. (1993) 197:328-338). Furthermore, heparin treatment of mice that are intravenously infected with a high dose of VV circumvents coagulation and fibrin loss (Sottnek HM, et al. Lab Invest. (1 975) 33:514-521 ) [Para 43] Etiologic agents such as variola virus and monkeypox virus, which cause lung injury with abundant deposition of fibrin in alveolar spaces, can result in death at two different phases.
  • the present invention is designed to address the problem of treatment in individuals who have already contracted the disease and no longer can be treated with prophylactic methods. Therefore, the present invention relates to an alternative intervention strategy for the treatment of serious variola viral infections.
  • the present invention relates to the use of tissue factor inhibitors as a therapy to fill this unmet medical need.
  • Another aspect of the invention is to provide other benefits such as shortened stays in the ICU, reduction in the time of hospitalization, shortened time on assisted ventilation, reduced incidence of complications, such tracheitis, necrotizing glositis, lymphadenitis, splenitis with lymphoid depletion, multifocal hyperplasia and vacuolation of the bronchial epithelia, reduction in the mortality rates associated with these severe viral infections, and reduction in the number or severity of morbidities.
  • One embodiment of the present invention is a tissue factor inhibitor that binds to human TF or the TF-Factor Vila (FVIIa) complex preventing binding and/or activation of Factor X (FX) and Factor IX (FIX), thereby inhibiting thrombin generation.
  • FX Factor X
  • FIX Factor IX
  • One aspect of the invention is an anti-tissue factor antibody.
  • Antibodies useful in the present invention may bind tissue factor, blocking or inhibiting the action of Factor VII, Factor Vila, Factor IX or Factor X.
  • the antibody may be monoclonal and may be chimeric, humanized, or human.
  • the antibody may also be a single-domain antibody. Examples of such antibodies of the invention that inhibit TF function by effectively blocking FX binding or access to TF molecules, include H36.D2.B7 (secreted by hybridoma ATCC HB-I 2255) and humanized clones of this antibody.
  • Other anti-TF antibodies useful in the invention include those disclosed in U.S. Pat. No.
  • Antibodies may also be directed to Factor VII, Factor Vila, Factor X, or Factor IX thereby inhibiting tissue factor by blocking the ligand necessary for activation. Examples of such antibodies have been disclosed in 5,506,1 34 and 6,835,81 7.
  • Peptide mimetics include fragments of tissue factor that bind Factor VII, Factor Vila, Factor IX, Factor X, or Factor Xa, thereby blocking their activation.
  • Tissue factor ligand analogs include modified Factor VII, Factor IX, or Factor X, that bind tissue factor, preventing the binding of the corresponding wild-type ligands to tissue factor and thus inhibiting activation.
  • the antibodies of the present invention may be generated by any suitable method known in the art.
  • the antibodies of the present invention may comprise polyclonal antibodies. Methods of preparing polyclonal antibodies are known to the skilled artisan (Harlow, et al., Antibodies: a Laboratory Manual, (Cold spring Harbor Laboratory Press, 2nd ed. (1 988), which is hereby incorporated herein by reference in its entirety).
  • antibodies may be generated by administering an immunogen comprising the antigen of interest to various host animals including, but not limited to, rabbits, mice, rats, etc., to induce the production of sera containing polyclonal antibodies specific for the antigen.
  • Antibodies directed to other antigens such as Factor VII, Factor Vila, Factor IX, Factor Xa, and Factor X may be generated in a similar manner.
  • the antibodies useful in the present invention comprise monoclonal antibodies. Monoclonal antibodies may be prepared using hybridoma technology, such as those described by Kohler and Milstein, Nature, 256:495 (1 975) and U.S. Pat. No. 4,376, 1 10, by Harlow, et al., Antibodies: A Laboratory Manual, (Cold spring Harbor Laboratory Press, 2.sup.nd ed.
  • Such antibodies may be of any immunoglobulin class including IgG, IgM, IgE, IgA, IgD and any subclass thereof.
  • the hybridoma producing the antibodies of this invention may be cultivated in vitro or in vivo.
  • a host such as a mouse, a humanized mouse, a mouse with a human immune system, hamster, rabbit, camel or any other appropriate host animal, is typically immunized with an immunogen to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the antigen of interest. Alternatively, lymphocytes may be immunized in vitro with the antigen.
  • Hybridoma technology is well known in the art.
  • the monoclonal antibodies may be made by recombinant DNA methods, such as those described in U.S. Pat. No. 4,81 6,567.
  • the antibodies may be monovalent antibodies. Methods for preparing monovalent antibodies are well known in the art. For example, one method involves recombinant expression of immunoglobulin light chain and modified heavy chain. The heavy chain is truncated generally at any point in the Fc region so as to prevent heavy chain cross-linking. Alternatively, the relevant cysteine residues are substituted with another amino acid residue or are deleted so as to prevent cross-linking.
  • Antibody fragments which recognize specific epitopes may be generated by known techniques.
  • Fab and F(ab')2 fragments of the invention may be produced by proteolytic cleavage of immunoglobulin molecules, using enzymes such as papain (to produce Fab fragments) or pepsin (to produce F(ab')2 fragments).
  • F(ab')- 2 fragments contain the variable region, the light chain constant region and the CHl domain of the heavy chain.
  • a chimeric antibody is a molecule in which different portions of the antibody are derived from different animal species, such as antibodies having a variable region derived from a murine monoclonal antibody and a human immunoglobulin constant region.
  • Methods for producing chimeric antibodies are known in the art. See e.g., Morrison, Science 229:1 202 (1 985); Oi et al., BioTechniques 4:214 (1986); Gillies et al., (1989) J. Immunol. Methods 125:191 -202; U.S. Pat. Nos. 5,807,71 5; 4,81 6,567; and 4,816397, which are incorporated herein by reference in their entirety.
  • Humanized antibodies are antibody molecules generated in a non-human species that bind the desired antigen having one or more complementarity determining regions (CDRs) from the non-human species and framework (FR) regions from a human immunoglobulin molecule.
  • CDRs complementarity determining regions
  • FR framework
  • framework residues in the human framework regions will be substituted with the corresponding residue from the CDR donor antibody to alter, preferably improve, antigen binding.
  • framework substitutions are identified by methods well known in the art, e.g., by modeling of the interactions of the CDR and framework residues to identify framework residues important for antigen binding and sequence comparison to identify unusual framework residues at particular positions. (See, e.g., Queen et al., U.S. Pat. No.
  • Antibodies can be humanized using a variety of techniques known in the art including, for example, CDR-grafting (EP 239,400; PCT publication WO 91 /09967; U.S. Pat. Nos. 5,225,539; 5,530,101 ; and 5,585,089), veneering or resurfacing (EP 592,106; EP 519,596; Padlan, Molecular Immunology 28(4/5):489-498 (1 991 ); Studnicka et al., Protein Engineering 7(6):805-814 (1 994); Roguska. et al., PNAS 91 :969-973 (1 994)), and chain shuffling (U.S. Pat. No. 5,565,332).
  • a humanized antibody has one or more amino acid residues introduced into it from a source that is non-human. These non-human amino acid residues are often referred to as "import" residues, which are typically taken from an "import” variable domain. Humanization can be essentially performed following the methods of Winter and co-workers (Jones et al., Nature, 321 :522-525 (1 986); Reichmann et al., Nature, 332:323-327 (1 988); Verhoeyen et al., Science, 239:1 534- 1 536 (1 988), by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody.
  • humanized antibodies are chimeric antibodies (U.S. Pat. No. 4,816,567), wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non-human species.
  • humanized antibodies are typically human antibodies in which some CDR residues and possible some FR residues are substituted from analogous sites in rodent antibodies.
  • Human antibodies are particularly desirable for therapeutic treatment of human patients.
  • Human antibodies can be made by a variety of methods known in the art including phage display methods described above using antibody libraries derived from human immunoglobulin sequences. See also, U.S. Pat. Nos. 4,444,887 and 4,71 6,1 1 1 ; and PCT publications WO 98/46645, WO 98/50433, WO 98/24893, WO 98/ 16654, WO 96/34096, WO 96/33735, and WO 91 / 10741 ; each of which is incorporated herein by reference in its entirety.
  • Human antibodies can also be single-domain antibodies having a VH or VL domain that functions independently of any other variable domain. These antibodies are typically selected from antibody libraries expressed in phage. These antibodies and methods for isolating such antibodies are described in U.S. Pat. No.
  • Human antibodies can also be produced using transgenic mice which are incapable of expressing functional endogenous immunoglobulins, but which can express human immunoglobulin genes.
  • the human heavy and light chain immunoglobulin gene complexes may be introduced randomly or by homologous recombination into mouse embryonic stem cells.
  • the human variable region, constant region, and diversity region may be introduced into mouse embryonic stem cells in addition to the human heavy and light chain genes.
  • the mouse heavy and light chain immunoglobulin genes may be rendered nonfunctional separately or simultaneously with the introduction of human immunoglobulin loci by homologous recombination. In particular, homozygous deletion of the JH region prevents endogenous antibody production.
  • the modified embryonic stem cells are expanded and microinjected into blastocysts to produce chimeric mice. The chimeric mice are then bred to produce homozygous offspring which express human antibodies.
  • the transgenic mice are immunized in the normal fashion with a selected antigen, e.g., all or a portion of a polypeptide of the invention. Monoclonal antibodies directed against the antigen can be obtained from the immunized, transgenic mice using conventional hybridoma technology.
  • the human immunoglobulin transgenes harbored by the transgenic mice rearrange during B cell differentiation, and subsequently undergo class switching and somatic mutation.
  • this technology for producing human antibodies see Lonberg and Huszar, Int. Rev. Immunol. 1 3:65-93 (1 995).
  • this technology for producing human antibodies and human monoclonal antibodies and protocols for producing such antibodies see, e.g., PCT publications WO 98/24893; WO 92/01047; WO 96/34096; WO 96/33735; European Patent No. 0 598 877; U.S.
  • human MAbs could be made by immunizing mice transplanted with human peripheral blood leukocytes, splenocytes or bone marrows (e.g., Trioma techniques of XTL).
  • Completely human antibodies which recognize a selected epitope can be generated using a technique referred to as "guided selection.”
  • a selected non-human monoclonal antibody e.g., a mouse antibody, is used to guide the selection of a completely human antibody recognizing the same epitope. (Jespers et al., Bio/technology 1 2:899-903 (1 988)).
  • antibodies to the polypeptides of the invention can, in turn, be utilized to generate anti-idiotype antibodies that "mimic" polypeptides of the invention using techniques well known to those skilled in the art. (See, e.g., Greenspan & Bona, FASEB J. 7(5):437-444; (1 989) and Nissinoff, J. Immunol. 147(8):2429-2438 (1991 )).
  • antibodies which bind to and competitively inhibit polypeptide multimerization and/or binding of a polypeptide of the invention to a ligand can be used to generate anti-idiotypes that "mimic" the polypeptide multimerization and/or binding domain and, as a consequence, bind to and neutralize polypeptide and/or its ligand.
  • anti-idiotypes or Fab fragments of such anti-idiotypes can be used in therapeutic regimens to neutralize polypeptide ligand.
  • anti-idiotypic antibodies can be used to bind a polypeptide of the invention and/or to bind its ligands/receptors, and thereby block its biological activity.
  • the antibodies of the present invention may be bispecific antibodies.
  • Bispecific antibodies are monoclonal, preferably human or humanized, antibodies that have binding specificities for at least two different antigens.
  • one of the binding specificities may be directed towards tissue factor, the other may be for any other antigen, and preferably for a cell-surface protein, receptor, receptor subunit, tissue-specific antigen, virally derived protein, virally encoded envelope protein, bacterially derived protein, or bacterial surface protein, etc.
  • Bispecific antibodies may also comprise two or more single-domain antibodies.
  • bispecific antibodies are based on the co-expression of two immunoglobulin heavy-chain/light-chain pairs, where the two heavy chains have different specificities (Milstein and Cuello, Nature, 305:537-539 (1 983). Because of the random assortment of immunoglobulin heavy and light chains, these hybridomas (quadromas) produce a potential mixture of ten different antibody molecules, of which only one has the correct bispecific structure. The purification of the correct molecule is usually accomplished by affinity chromatography steps. Similar procedures are disclosed in WO 93/08829, published May 1 3, 1 993, and in Traunecker et al., EMBO J., 10:3655-3659 (1 991 ).
  • Antibody variable domains with the desired binding specificities can be fused to immunoglobulin constant domain sequences.
  • the fusion preferably is with an immunoglobulin heavy-chain constant domain, comprising at least part of the hinge, CH2, and CH3 regions. It may have the first heavy-chain constant region (CHl ) containing the site necessary for light-chain binding present in at least one of the fusions.
  • DNAs encoding the immunoglobulin heavy-chain fusions and, if desired, the immunoglobulin light chain are inserted into separate expression vectors, and are co-transformed into a suitable host organism.
  • DNAs encoding the immunoglobulin heavy-chain fusions and, if desired, the immunoglobulin light chain are inserted into separate expression vectors, and are co-transformed into a suitable host organism.
  • Heteroconjugate antibodies are also contemplated by the present invention.
  • Heteroconjugate antibodies are composed of two covalently joined antibodies. Such antibodies have, for example, been proposed to target immune system cells to unwanted cells (U.S. Pat. No. 4,676,980).
  • the antibodies may be prepared in vitro using known methods in synthetic protein chemistry, including those involving cross-linking agents.
  • immunotoxins may be constructed using a disulfide exchange reaction or by forming a thioester bond. Examples of suitable reagents for this purpose include iminothiolate and methyl-4- mercaptobutyrimidate and those disclosed, for example, in U.S. Pat. No.
  • Ar is optionally substituted carbocyclic aryl or optionally substituted heteroaryl; HET is optionally substituted N, O or S; each X, each Y, each X', each Y' and each Z are each independently hydrogen; halogen; hydroxyl; sulfhydryl; amino; optionally substituted alkyl preferably; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted alkoxy; optionally substituted alkylthio; optionally substituted alkylsulfinyl; optionally substituted alkylsulfonyl; or optionally substituted alkylamino; m and n each is independently an integer of from 0 to 4; p is 1 or 2; and pharmaceutically acceptable salts thereof.
  • each R 1 is independently halogen; amino; hydroxy; nitro; carboxy; sulfhydryl; optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted alkoxy; optionally substituted alkylthio; optionally substituted alkylsulfinyl; optionally substituted alkylsulfonyl; optionally substituted alkylamino; optionally substituted alkanoyl; optionally substituted carbocyclic aryl; or optionally substituted aralkyl; and q is an integer of from 0 to 5; and pharmaceutically acceptable salts thereof.
  • W is hydrogen, optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted alkoxy; optionally substituted alkylthio; optionally substituted alkylsulfinyl; optionally substituted alkylsulfonyl; optionally substituted alkylamino; optionally substituted alkanoyl; optionally substituted carbocyclic aryl; or optionally substituted aralkyl; R 1 is independently halogen; amino; hydroxy; nitro; carboxy; sulfhydryl; optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted alkoxy; optionally substituted alkylthio; optionally substituted alkylsulfinyl; optionally substituted
  • R 1 is independently halogen; amino; hydroxy; nitro; carboxy; sulfhydryl; optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted alkoxy; optionally substituted alkylthio; optionally substituted alkylsulfinyl; optionally substituted alkylsulfonyl; optionally substituted alkylamino; optionally substituted alkanoyl; optionally substituted carbocyclic aryl; or optionally substituted aralkyl; and q is an integer of from 0 to 5; and pharmaceutically acceptable salts thereof.
  • the mixture is refluxed for 24 hours, and then an additional 2 liters of methanol is added, and the solution concentrated under reduced pressure at 35 0 C. 1 liter of toluene is added to the concentrate, and the resulting solution concentrated, and the toluene addition and concentration repeated.
  • the resulting intermediate is then dissolved in 1 liter of dry toluene, p-toluenesulfonic acid monohydrate (0.50 g) is added and the mixture is refluxed. Resulting methanol is removed, e.g. via a Dean-Stark trap or molecular sieves.
  • the TF:Vlla complex was aliquoted and stored at -70°C until needed.
  • Purified human factors VII, Vila, and FX were obtained from Enyzme Research Laboratories, Inc. The following buffer was used for all FXa and FVIIa assays: 25 mM Hepes-NaOH, 5 mM CaCI 2 , 1 50 mM NaCI, 0.1 % BSA, pH 7.5.
  • [Para 81 ] Mabs were tested for their capacity to block TF:Vlla-mediated activation of FX to FXa.
  • the FX activation was determined in two discontinuous steps. In the first step (FX activation), FX conversion to FXa was assayed in the presence of Ca +2 . In the second step (FXa activity assay), FX activation was quenched by EDTA and the formation of FXa was determined using a FXa-specific chromogenic substrate (S- 2222). The S-2222 and S-2288 (see below) chromogens were obtained from Chromogenix (distributed by Pharmacia Hepar Inc.).
  • FX activation was conducted in 1 .5 mL microfuge tubes by incubating the reaction with 0.08 nM TF:Vlla, either pre- incubated with an anti-rhTF antibody or a buffer control. The reaction was subsequently incubated for 30 minutes at 37 0 C, then 30 nM FX was added followed by an additional incubation for 10 minutes at 37°C. FXa activity was determined in 96-well titer plates. Twenty microlitres of sample was withdrawn from step one and admixed with an equal volume of EDTA (500 mM) in each well, followed by addition of 0.144 ml_ of buffer and 0.01 6 ml. of 5 mM S-2222 substrate.
  • Mabs may be further screened by an FVMa specific assay.
  • H36 antibody did not significantly block TF/Vlla activity toward the S-2288 substrate when the antibody was either pre-incubated with TF (prior to Vila addition) or added to TF pre-incubated with Vila (prior to adding the antibody). This indicates that H36 does not interfere with the interaction (binding) between TF and FVIIa, and that H36 also does not inhibit TF:Vlla activity toward a peptide substrate.
  • Clot reactions were initiated by addition of lipidated rhTF in the presence of Ca + +. Clot time was monitored by an automated coagulation timer (MLA Electra 800). PT assays were initiated by injecting 0.2 mL of lipidated rhTF (in a buffer of 50 mM Tris-HCI, pH 7.5, containing 0.1 % BSA, 14.6 mM
  • the cuvettes each contained 0.1 mL of the plasma preincubated with either 0.01 mL of buffer (control sample) or antibody (experimental sample) for 1 -2 minutes.
  • the inhibition of TF-mediated coagulation by the H36.D2 antibody was calculated using a TF standard curve in which the log [TF] was plotted against log clot time.
  • H36.D2 antibody substantially inhibits TF-initiated coagulation in human plasma.
  • the H36.D2 antibody increased PT times significantly, showing that the antibody is an effective inhibitor of TF-initiated coagulation (up to approximately 99% inhibition).
  • H36.D2 binding to native and non- native rhTF was performed by a simplified dot blot assay. Specifically, rhTF was diluted to 30 ⁇ g/mL in each of the following three buffers: 10 mM Tris-HCI, pH 8.0; 10 mM Tris-HCI, pH 8.0 and 8 M urea; and 10 mM Tris-HCI, pH 8.0, 8 M urea and 5 mM dithiothreitol.
  • the membrane was probed with H36.D2 antibody, followed by incubation with a goat anti-mouse IgG peroxidase conjugate (obtained from Jackson ImmunoResearch Laboratories, Inc.). After incubation with ECL Western Blotting reagents in accordance with the manufacturer's instructions (Amersham), the membrane was wrapped with plastic film (Saran Wrap) and exposed to X-ray film for various times.
  • H36.D2 Mab binds a conformational epitope on native TF in the presence of Tris buffer or Tris buffer with 8M urea. (See U.S. Pat. No. 6,555,319) The autoradiogram was exposed for 40 seconds.
  • [Para 9O] A lethal intratracheal infection model in cynomolgus monkeys ⁇ Macaca fascicularis) with monkeypox virus (MPXV) is used. This model is appropriate to study the possible efficacy of an anti-TF antibody to decrease the severity of lung injury caused by pox virus infection because of the similarity to human small pox infection. MPXV causes a disease similar to human smallpox. This model has been shown to measure differences in protective efficacies of classical and new generation candidate smallpox vaccines (Stittelaar KJ, et. al. J Virol. (2005) 79:7845-7851 ).
  • the intratracheal MPXV infection in macaques is currently the only available respiratory infection model in human primates for smallpox.
  • the cynomolgus macaque provides unique advantages as a model due to the close similarity to humans of its pulmonary anatomy and gas exchange, resemblance of the MPXV model to human monkeypox and human smallpox and bronchopnemonia, the ability to use human reagents, and the availability of specific reagents including macaque microarrays.
  • MPXV like variola virus, has evolved primarily as a respiratory pathogen which replicates massively in the lungs.
  • the MPXV strain is MSF#6 and may be obtained from various laboratories around the world.
  • Group 2 consists of 6 macaques administered an Irrelevant lgG4 and MPXV virus.
  • Group 3 consists of 6 macaques administered anti-TF antibody and MPXV virus.
  • Group 3 receives an intravenous injection of anti-TF antibody (5 mg/kg body weight) at 1 2 hours before virus inoculation, and lower doses (0.5 mg/kg body weight) at 1 and 2 dpi (days after inoculation of virus). This dose of anti-TF antibody is chosen based on the effective dose (5 mg/kg over 34 hrs in a bacteria-induced acute lung injury study in baboons) and the half life of the antibody (3-7 days) obtained from the preclinical safety studies in normal cynomolgus monkeys.
  • Group 1 serves as a challenge control, whereas Group 2 receives a control/irrelevant human lgG4 antibody.
  • the irrelevant human lgG4 is tested for negative reactivity and neutralization activity against MPXV by immunochemical assays and in vitro neutralization assay.
  • Groups 1 , 2 and 3 are inoculated intratracheal ⁇ with a lethal dose of MPXV, such as strain MSF#6 (10 7 pfu).
  • the macaques are euthanized at when they are moribund, which is 1 2.6 dpi for untreated animals. At 28 dpi all animals will be euthanized.
  • This first experiment is designed to show prophylactic use of an anti-TF molecule with a "saturating" dosage schedule.
  • Experiment 2 shows the effect of an anti-TF antibody on the coagulation cascade, inflammatory response, viral dynamics, and lung damage during the course of monkeypox virus infection in cynomolgus monkeys.
  • Group 1 consists of 4 macaques per time point (3 dpi, 7 dpi, and 1 3 dpi) administered an irrelevant lgC4 and MPXV.
  • Croup 2 consists of 4 macaques per time point (3 dpi, 7 dpi, and 1 3 dpi) administered anti-TF antibody and MPXV.
  • Experiment 3 shows the effect of anti-TF antibody on post-exposure antiviral treatment with Cidofovir on the coagulation cascade, inflammatory response, viral dynamics, lung injury, and disease severity and survival during the course of MPXV infection in cynomolgus monkeys.
  • Group 1 consists of 4 macaques administered MPXV.
  • Group 2 consists of 6 macaques administered Cidofovir and MPXV.
  • Croup 3 consists of 6 macaques administered an irrelevant lgG4 antibody and MPXV.
  • Group 4 consists of 6 macaques administered anti-TF antibody plus MPXV.
  • Group 5 consists of 6 macaques administered anti-TF antibody plus Cidofovir and MPXV.
  • Histopathology endpoints for lung injury are based on histological evaluation of postmortem lung tissue. Per macaque, one lung is inflated with 10% neutral-buffered formalin and samples are selected in a standard manner from cranial, medial, and caudal parts of the lung. Influenza virus antigen expression in the lung is determined by immunohistochemistry (Kuiken T, et al. Veterinary Pathology. (2003) 40:304-310; Rimmelzwaan et al.. J Virol (2001 ) 75; 6687-6691 ), and scored per animal as the number of positive fields per 100 fields (Haagmans BL, et al. Nat Med. (2004) 1 0:290-293).
  • Inflammatory lesions are scored in a semiquantitative manner, based on the number and size of inflammatory foci and the severity of inflammation. The presence of polymerized fibrin and collagen within these foci are assessed by use of phosphotungstic acid-hematoxylin stain and Masson's trichrome stain, respectively.
  • Virology endpoints for virus replication and excretion are based on virological examination of swabs collected during the experiment and lung tissue collected at necropsy. Nasal swabs and pharyngeal swabs are collected under ketamine anesthesia at 0, 1 , 2, 3, 5, 7, 10, and 14 dpi. Lung specimens for virological examination are collected at necropsy. Both lung specimens and swabs are tested for the presence and quantity of influenza virus RNA by use of a quantitative real time PCR assay.
  • Biochemical endpoints tor inflammation and the coagulation cascade are measured in broncho-alveolar lavage fluid (BALF) collected at necropsy, and in serum collected under ketamine anesthesia at 0, 1 , 2, 3, 5, 7, 10, and 1 3 dpi.
  • BALF broncho-alveolar lavage fluid
  • Cytokines (TNF-rl , IL-I , IL-6, IL-8, TCF- , and VECF), which are implicated in the pathogenesis of acute lung injury, are measured in BALF by commercial ELISA kits.
  • Anti-TF antibody levels and anti-coagulant activities are measured by established assays. Sensitive ELISAs are used to measure TF and anti-TF antibody. Procoagulant activity in plasma and BALF are determined by prothrombin time (PT), and by ELISAs for fibrinogen, FDP, and thrombin-antithrombin (TAT) complexes. Anti- TF antibody levels are compared statistically to pro-coagulant and fibrinolytic activity in plasma and BALF at the end of the experiments.
  • PT prothrombin time
  • TAT thrombin-antithrombin
  • proteomics By proteomics, a search for proteins and peptides that are differentially expressed in the lung tissue of different experimental groups is done. Because of the enormous complexity of the proteome and the dynamic range of proteins, samples may be pre-fractionated by, e.g., nano liquid chromatography techniques. The resulting fractions are compared by, e.g., Fourier transform mass spectrometry. The resulting peptides that are differentially expressed can be identified by MS/MS approaches.

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Abstract

La présente invention concerne de nouveaux procédés destinés au traitement d'infections virales de la variole, telles que la petite vérole et l'orthopoxvirose simienne, par l'administration d'un inhibiteur de facteur tissulaire.
PCT/US2006/049186 2005-12-22 2006-12-21 Traitement des infections virales de la variole au moyen d'un inhibiteur de facteur tissulaire WO2008030260A2 (fr)

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US9168314B2 (en) 2010-06-15 2015-10-27 Genmab A/S Human antibody drug conjugates against tissue factor
TWI806844B (zh) * 2016-11-30 2023-07-01 美商Ｎｖｍ動力股份有限公司 非暫時性計算機可讀儲存媒體及其校準寫入操作方法

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US10532065B2 (en) 2014-12-19 2020-01-14 Nagasaki University Bisphosphonic acid derivative and application for same
US20230218548A1 (en) * 2020-03-19 2023-07-13 Eumentis Therapeutics, Inc. Nitro-aminoadamantane compounds for the treatment of betacoronavirus infections

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US9150658B2 (en) 2008-12-09 2015-10-06 Genmab A/S Human antibodies against tissue factor and methods of use thereof
US9714297B2 (en) 2008-12-09 2017-07-25 Genmab A/S Human antibodies against tissue factor and methods of use thereof
US9168314B2 (en) 2010-06-15 2015-10-27 Genmab A/S Human antibody drug conjugates against tissue factor
US9492565B2 (en) 2010-06-15 2016-11-15 Genmab A/S Human antibody drug conjugates against tissue factor
TWI806844B (zh) * 2016-11-30 2023-07-01 美商Ｎｖｍ動力股份有限公司 非暫時性計算機可讀儲存媒體及其校準寫入操作方法

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