EP4598953A1 - Vaccin ciblant dc dirigé contre une infection par le virus nipah - Google Patents

Vaccin ciblant dc dirigé contre une infection par le virus nipah

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Publication number
EP4598953A1
EP4598953A1 EP23783875.0A EP23783875A EP4598953A1 EP 4598953 A1 EP4598953 A1 EP 4598953A1 EP 23783875 A EP23783875 A EP 23783875A EP 4598953 A1 EP4598953 A1 EP 4598953A1
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EP
European Patent Office
Prior art keywords
amino acid
seq
antibody
acid sequence
niv
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP23783875.0A
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German (de)
English (en)
Inventor
Yves Levy
Mathieu SURENAUD
Sylvain Cardinaud
Véronique GODOT
Yadira PASTOR
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Assistance Publique Hopitaux de Paris APHP
Institut National de la Sante et de la Recherche Medicale INSERM
Universite Paris Est Creteil Val de Marne
Universite de Marne la Vallee
Original Assignee
Assistance Publique Hopitaux de Paris APHP
Institut National de la Sante et de la Recherche Medicale INSERM
Universite Paris Est Creteil Val de Marne
Universite de Marne la Vallee
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Application filed by Assistance Publique Hopitaux de Paris APHP, Institut National de la Sante et de la Recherche Medicale INSERM, Universite Paris Est Creteil Val de Marne, Universite de Marne la Vallee filed Critical Assistance Publique Hopitaux de Paris APHP
Publication of EP4598953A1 publication Critical patent/EP4598953A1/fr
Pending legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2878—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • 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
    • A61K39/12—Viral antigens
    • 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
    • A61K39/12—Viral antigens
    • A61K39/155—Paramyxoviridae, e.g. parainfluenza virus
    • 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
    • A61K40/00—Cellular immunotherapy
    • A61K40/20—Cellular immunotherapy characterised by the effect or the function of the cells
    • A61K40/24—Antigen-presenting cells [APC]
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/10—RNA viruses
    • C07K16/11—Paramyxoviridae (F); Pneumoviridae (F), e.g. respiratory syncytial virus [RSV]
    • 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
    • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
    • A61K2039/575—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 humoral response
    • 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
    • A61K2039/70—Multivalent vaccine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • 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
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/33—Fusion polypeptide fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
    • 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
    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/18011—Paramyxoviridae
    • C12N2760/18211—Henipavirus, e.g. hendra virus
    • C12N2760/18222—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • 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
    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/18011—Paramyxoviridae
    • C12N2760/18211—Henipavirus, e.g. hendra virus
    • C12N2760/18234—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • 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
    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/18011—Paramyxoviridae
    • C12N2760/18211—Henipavirus, e.g. hendra virus
    • C12N2760/18271—Demonstrated in vivo effect

Definitions

  • Nipah virus (NiV) is a recently emergent, highly pathogenic, zoonotic paramyxovirus first recognized following a 1998-99 outbreak of severe febrile encephalitis in Malaysia and Singapore (Chua, K. B., et al. "Nipah virus: a recently emergent deadly paramyxovirus.” Science 288.5470 (2000): 1432-1435.).
  • the Bangladesh strain (NiVB) has caused repeated outbreaks, varying in number, in Bangladesh and northeast India with outbreaks occurring almost every year between 2001–2015.
  • the outbreaks of NiVB have had high case fatality rate averaging about 75% (Lo, Michael K., et al. "Characterization of Nipah virus from outbreaks in Bangladesh, 2008–2010.” Emerging infectious diseases 18.2 (2012): 248.) with human-to- human transmission often observed (Gurley, Emily S., et al. "Person-to-person transmission of Nipah virus in a Bangladeshi community.” Emerging infectious diseases 13.7 (2007): 1031.). Multiple candidate vaccines exist, but all are in the preclinical stages.
  • rVSV vectors expressing Nipah virus G are prime candidates for new ‘emergency vaccines’ to be utilized for outbreak management (Foster, Stephanie L., et al. "A recombinant VSV-vectored vaccine rapidly protects nonhuman primates against lethal Nipah virus disease.” Proceedings of the National Academy of Sciences 119.12 (2022): e2200065119.), concerns remain about safety, development and inadequate transport/storage in affected areas. Thus, improving the ability of vaccines to induce strong, cellular and humoral immune responses, placing them as a new generic vaccine platform for prophylactic strategies but also at the heart of a therapeutic arsenal remains the challenge to rapidly and efficiently respond to Nipah.
  • the present invention is defined by the claims.
  • the present invention relates to antibodies that are directed against a surface antigen of an antigen presenting cell wherein the heavy chain and/or the light chain is conjugated or fused to the Nipah virus antigenic polypeptides.
  • DETAILED DESCRIPTION OF THE INVENTION Definitions: As used herein, the term "subject” or “subject in need thereof", is intended for a human or non-human mammal. Typically the patient is affected or likely to be infected with Nipah virus.
  • Nipah virus has its general meaning in the art and refers to a virus that is a member of the Paramyxoviridae family and is related to the Hendra virus (formerly called equine morbillivirus).
  • the Nipah virus was initially isolated in 1999 upon examining samples from an outbreak of encephalitis and respiratory illness among adult men in Malaysia and Singapore (see, e.g., Chua et al., Lancet. October 9, 1999;354(9186):1257-9 and Paton et al., Lancet. October 9, 1999;354(9186):1253-6).
  • Nipah virus comprises a 6-gene, 18.2-kb, negative-sense single-stranded RNA (ssRNA) genome, which encodes 9 proteins: nucleoprotein (N), phosphoprotein (P), the interferon antagonists W and V, the viral C protein, a matrix protein (M), viral fusion and glycoproteins (F and G, respectively), and a large polymerase (L).
  • ssRNA negative-sense single-stranded RNA
  • N nucleoprotein
  • P phosphoprotein
  • W and V the interferon antagonists
  • M matrix protein
  • F and G fusion and glycoproteins
  • L large polymerase
  • G protein refers to the Nipah virus glycoprotein G.
  • the G protein has a globular head domain formed of a six-bladed beta sheet-propeller, connected via a flexible stalk domain to a transmembrane anchor.
  • the G protein binds to the cellular receptors ephrin B2 and ephrin B3, mediating viral attachment. Following attachment Nipah Virus glycoprotein G undergoes a conformational change that leads to triggering of glycoprotein F which leads to membrane fusion.
  • An exemplary amino acid sequence for the G protein is represented by SEQ ID NO:1.
  • Nipah virus glycoprotein F is a class I fusion protein, with typical structural features. These include heptad repeats and a hydrophobic fusion peptide that bind to each other, forming a six-helix bundle which functions in membrane fusion processes. Nipah Virus attaches to target cells via glycoprotein G, which then undergoes a conformational change leading to triggering of Nipah virus glycoprotein F which leads to membrane fusion.
  • An exemplary amino acid sequence for the F protein is represented by SEQ ID NO:2.
  • N The encapsidated genomic RNA is termed the nucleocapsid (NC) and serves as template for transcription and replication.
  • An exemplary amino acid sequence for the N protein is represented by SEQ ID NO:3.
  • SEQ ID NO:3 >sp
  • EMBOSS Needle may be used with a BLOSUM62 matrix, a “gap open penalty” of 10, a “gap extend penalty” of 0.5, a false “end gap penalty”, an “end gap open penalty” of 10 and an “end gap extend penalty” of 0.5.
  • the “percent identity” is a function of the number of matching positions divided by the number of positions compared and multiplied by 100. For instance, if 6 out of 10 sequence positions are identical between the two compared sequences after alignment, then the identity is 60%. The % identity is typically determined over the whole length of the query sequence on which the analysis is performed. Two molecules having the same primary amino acid sequence or polynucleotide sequence are identical irrespective of any chemical and/or biological modification.
  • a first amino acid sequence having at least 80% of identity with a second amino acid sequence means that the first sequence has 80; 81; 82; 83; 84; 85; 86; 87; 88; 89; 90; 91; 92; 93; 94; 95; 96; 97; 98; 99 or 100% of identity with the second amino acid sequence.
  • conjugate or interchangeably “conjugated polypeptide” is intended to indicate a composite or chimeric molecule formed by the covalent attachment of one or more polypeptides.
  • conjugation means that the polypeptide and the non-peptide moiety are either directly covalently joined to one another, or else are indirectly covalently joined to one another through an intervening moiety or moieties, such as a bridge, spacer, or linkage moiety or moieties.
  • a particular conjugate is a fusion protein.
  • fusion protein indicates a protein created through the attaching of two or more polypeptides which originated from separate proteins. In particular fusion proteins can be created by recombinant DNA technology and are typically used in biological research or therapeutics. Fusion proteins can also be created through chemical covalent conjugation with or without a linker between the polypeptides portion of the fusion proteins.
  • the two or more polypeptide are fused directly or via a linker.
  • the term "directly” means that the first amino acid at the N-terminal end of a first polypeptide is fused to the last amino acid at the C-terminal end of a second polypeptide.
  • This direct fusion can occur naturally as described in (Vigneron et al., Science 2004, PMID 15001714), (Warren et al., Science 2006, PMID 16960008), (Berkers et al., J. Immunol.2015a, PMID 26401000), (Berkers et al., J.
  • linker has its general meaning in the art and refers to an amino acid sequence of a length sufficient to ensure that the proteins form proper secondary and tertiary structures.
  • the linker is a peptidic linker which comprises at least one, but less than 30 amino acids e.g., a peptidic linker of 2-30 amino acids, preferably of 10-30 amino acids, more preferably of 15-30 amino acids, still more preferably of 19-27 amino acids, most preferably of 20-26 amino acids.
  • the linker has 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 13; 14; 15; 16; 17; 18; 19; 20; 21; 22; 23; 24; 25; 26; 27; 28; 29; 30 amino acid residues.
  • linkers are those which allow the compound to adopt a proper conformation.
  • linker sequences (1) will adopt a flexible extended conformation, (2) will not exhibit a propensity for developing ordered secondary structure which could interact with the functional domains of fusion proteins, and (3) will have minimal hydrophobic or charged character which could promote interaction with the functional protein domains.
  • antibody refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antigen binding site that immunospecifically binds to an antigen.
  • two heavy chains are linked to each other by disulfide bonds, and each heavy chain is linked to a light chain by a disulfide bond. There are two types of light chains, lambda (1) and kappa (k).
  • the heavy chain classes which determine the functional activity of an antibody molecule: IgM, IgD, IgG, IgA and IgE. Each chain contains distinct sequence domains.
  • the light chain includes two domains, a variable domain (VL) and a constant domain (CL).
  • the heavy chain includes four domains, a variable domain (VH) and three constant domains (CH1, CH2 and CH3, collectively referred to as CH).
  • the variable regions of both light (VL) and heavy (VH) chains determine binding recognition and specificity to the antigen.
  • the constant region domains of the light (CL) and heavy (CH) chains confer important biological properties such as antibody chain association, secretion, trans- placental mobility, complement binding, and binding to Fc receptors (FcR).
  • the Fv fragment is the N-terminal part of the Fab fragment of an immunoglobulin and consists of the variable portions of one light chain and one heavy chain.
  • the specificity of the antibody resides in the structural complementarity between the antibody combining site and the antigenic determinant.
  • Antibody combining sites are made up of residues that are primarily from the hypervariable or complementarity determining regions (CDRs). Occasionally, residues from non-hypervariable or framework regions (FR) can participate in the antibody binding site, or influence the overall domain structure and hence the combining site.
  • Complementarity Determining Regions or CDRs refer to amino acid sequences that together define the binding affinity and specificity of the natural Fv region of a native immunoglobulin binding site.
  • the light and heavy chains of an immunoglobulin each have three CDRs, designated L-CDR1, L-CDR2, L- CDR3 and H- CDR1, H-CDR2, H-CDR3, respectively.
  • An antigen-binding site therefore, typically includes six CDRs, comprising the CDRs set from each of a heavy and a light chain V region.
  • Framework Regions refer to amino acid sequences interposed between CDRs.
  • variable regions of the light and heavy chains typically comprise 4 framework regions and 3 CDRs of the following sequence: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4.
  • residues in antibody variable domains are conventionally numbered according to a system devised by Kabat et al. This system is set forth in Kabat et al., 1987, in Sequences of Proteins of Immunological Interest, US Department of Health and Human Services, NIH, USA (Kabat et al., 1992, hereafter “Kabat et al.”).
  • Kabat residue designations do not always correspond directly with the linear numbering of the amino acid residues in SEQ ID sequences.
  • the actual linear amino acid sequence may contain fewer or additional amino acids than in the strict Kabat numbering corresponding to a shortening of, or insertion into, a structural component, whether framework or complementarity determining region (CDR), of the basic variable domain structure.
  • CDR complementarity determining region
  • the correct Kabat numbering of residues may be determined for a given antibody by alignment of residues of homology in the sequence of the antibody with a “standard” Kabat numbered sequence.
  • the CDRs of the heavy chain variable domain are located at residues 31- 35 (H-CDR1), residues 50-65 (H-CDR2) and residues 95-102 (H-CDR3) according to the Kabat numbering system.
  • the CDRs of the light chain variable domain are located at residues 24-34 (L-CDR1), residues 50-56 (L-CDR2) and residues 89-97 (L-CDR3) according to the Kabat numbering system.
  • the CDRs have been determined using CDR finding algorithms from www.bioinf.org.uk - see the section entitled « How to identify the CDRs by looking at a sequence » within the Antibodies pages.
  • the term “immunoglobulin domain” refers to a globular region of an antibody chain (such as e.g. a chain of a heavy chain antibody or a light chain), or to a polypeptide that essentially consists of such a globular region.
  • Fc region is used to define the C-terminal region of an immunoglobulin heavy chain, including native sequence Fc region and variant Fc regions.
  • the human IgG heavy chain Fc region is generally defined as comprising the amino acid residue from position C226 or from P230 to the carboxyl-terminus of the IgG antibody. The numbering of residues in the Fc region is that of the EU index of Kabat.
  • the C-terminal lysine (residue K447) of the Fc region may be removed, for example, during production or purification of the antibody.
  • composition of antibodies of the invention may comprise antibody populations with all K447 residues removed, antibody populations with no K447 residues removed, and antibody populations having a mixture of antibodies with and without the K447 residue.
  • the term "chimeric antibody” refers to an antibody which comprises a VH domain and a VL domain of a non-human antibody, and a CH domain and a CL domain of a human antibody.
  • a “chimeric antibody” is an antibody molecule in which (a) the constant region (i.e., the heavy and/or light chain), or a portion thereof, is altered, replaced or exchanged so that the antigen binding site (variable region) is linked to a constant region of a different or altered class, effector function and/or species, or an entirely different molecule which confers new properties to the chimeric antibody, e.g., an enzyme, toxin, an agonist molecule, e.g., CD40 Ligand, hormone, growth factor, drug, etc.; or (b) the variable region, or a portion thereof, is altered, replaced or exchanged with a variable region having a different or altered antigen specificity.
  • Chimeric antibodies also include primatized and in particular humanized antibodies. Furthermore, chimeric antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine antibody performance. For further details, see Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol.2:593- 596 (1992). (see U.S. Pat. No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984)).
  • humanized antibody include antibodies which have the 6 CDRs of a murine antibody, but humanized framework and constant regions. More specifically, the term “humanized antibody”, as used herein, may include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences. As used herein the term “human monoclonal antibody”, is intended to include antibodies having variable and constant regions derived from human immunoglobulin sequences.
  • the human antibodies of the present invention may include amino acid residues not encoded by human immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo).
  • the term "human monoclonal antibody”, as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.
  • the term “immune response” refers to a reaction of the immune system to an antigen in the body of a host, which includes generation of an antigen-specific antibody and/or cellular cytotoxic response.
  • the immune response to an initial antigenic exposure is typically, detectable after a lag period of from several days to two weeks; the immune response to subsequent stimulus (secondary immune response) by the same antigen is more rapid than in the case of the primary immune response.
  • An immune response to a transgene product may include both humoral (e.g., antibody response) and cellular (e.g., cytolytic T cell response) immune responses that may be elicited to an immunogenic product encoded by the transgene.
  • the level of the immune response can be measured by methods known in the art (e.g., by measuring antibody titre).
  • APCs or "Antigen Presenting Cells” denotes cells that are capable of activating T-cells, and include, but are not limited to, certain macrophages, B cells and dendritic cells.
  • DCs refer to any member of a diverse population of morphologically similar cell types found in lymphoid or non-lymphoid tissues. These cells are characterized by their distinctive morphology, high levels of surface MHC-class II expression (Steinman, et al., Ann. Rev. Immunol. 9:271 (1991); incorporated herein by reference for its description of such cells).
  • CD40 has its general meaning in the art and refers to human CD40 polypeptide receptor. In some embodiments, CD40 is the isoform of the human canonical sequence as reported by UniProtKB-P25942 (also referred as human TNR5).
  • CD40L has its general meaning in the art and refers to human CD40L polypeptide, for example, as reported by UniProtKB-P25942, including its CD40- binding domain of SEQ ID NO:4. CD40L may be expressed as a soluble polypeptide and is the natural ligand of CD40 receptor.
  • CD40 agonist antibody is intended to refer to an antibody that increases CD40 mediated signaling activity in the absence of CD40L in a cell-based assay, such as the B cell proliferation assay.
  • the CD40 agonist antibody (i) it induces the proliferation of B cell, as measured in vitro by flow cytometric analysis, or by analysis of replicative dilution of CFSE-labeled cells; and/or (ii) induces the secretion of cytokines, such as IL-6, IL-12, or IL-15, as measured in vitro with a dendritic cell activation assay.
  • cytokines such as IL-6, IL-12, or IL-15
  • the term “Langerin” has its general meaning in the art and refers to human C- type lectin domain family 4 member K polypeptide.
  • Langerin is the isoform of the human canonical sequence as reported by UniProtKB- Q9UJ71 (also referred as human CD207).
  • treatment refers to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of patient at risk of contracting the disease or suspected to have contracted the disease as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse.
  • the treatment may be administered to a patient having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a patient beyond that expected in the absence of such treatment.
  • therapeutic regimen is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy.
  • a therapeutic regimen may include an induction regimen and a maintenance regimen.
  • the phrase “induction regimen” or “induction period” refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease.
  • the general goal of an induction regimen is to provide a high level of drug to a patient during the initial period of a treatment regimen.
  • An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both.
  • maintenance regimen refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a patient during treatment of an illness, e.g., to keep the patient in remission for long periods of time (months or years).
  • a maintenance regimen may employ continuous therapy (e.g., administering a drug at a regular interval, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., pain, disease manifestation, etc.]).
  • the term “pharmaceutical composition” refers to a composition described herein, or pharmaceutically acceptable salts thereof, with other agents such as carriers and/or excipients.
  • the pharmaceutical compositions as provided herewith typically include a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical-Sciences, Sixteenth Edition, E. W.
  • the term “vaccination” or “vaccinating” means, but is not limited to, a process to elicit an immune response in a subject against a particular antigen.
  • the term “vaccine composition” is intended to mean a composition which can be administered to humans or to animals in order to induce an immune system response; this immune system response can result in the activation of certain cells, in particular APCs, T lymphocytes and B lymphocytes.
  • the term "antigen” refers to a molecule capable of being specifically bound by an antibody or by a T cell receptor (TCR) if processed and presented by MHC molecules.
  • An antigen is additionally capable of being recognized by the immune system and/or being capable of inducing a humoral immune response and/or cellular immune response leading to the activation of B- and/or T-lymphocytes.
  • An antigen can have one or more epitopes or antigenic sites (B- and T- epitopes).
  • adjuvant refers to a compound that can induce and/or enhance the immune response against an antigen when administered to a subject or an animal.
  • the term "adjuvant” means a compound, which enhances both innate immune response by affecting the transient reaction of the innate immune response and the more long-lived effects of the adaptive immune response by activation and maturation of the antigen-presenting cells (APCs) especially Dendritic cells (DCs).
  • APCs antigen-presenting cells
  • DCs Dendritic cells
  • therapeutically effective amount is meant a sufficient amount of the active ingredient of the present invention to induce an immune response at a reasonable benefit/risk ratio applicable to the medical treatment.
  • the first object of the present invention relates to an antibody that is directed against a surface antigen of an antigen presenting cell wherein the heavy chain and/or the light chain is conjugated or fused to a polypeptide having at least 80% of identity with the amino acid sequence that ranges from the amino acid residue (Q) at position 71 to the amino acid residue (T) at position 602 in SEQ ID NO:1 “(Niv(G) B ectodomain”).
  • the light chain of the antibody is conjugated or fused to the polypeptide having at least 80% of identity with the amino acid sequence that ranges from the amino acid residue (Q) at position 71 to the amino acid residue (T) at position 602 in SEQ ID NO:1 (Niv(G)B ectodomain).
  • the heavy chain of the antibody is conjugated or fused to the polypeptide having at least 80% of identity with the amino acid sequence that ranges from the amino acid residue (Q) at position 71 to the amino acid residue (T) at position 602 in SEQ ID NO:1 (Niv(G)B ectodomain).
  • the heavy chain and/or the light chain of the antibody is conjugated or fused to the Niv(G)B ectodomain via its C-terminal. In some embodiments, the heavy chain and/or the light chain of the antibody is fused to the N-terminal of the Niv(G)B ectodomain. In some embodiments, the heavy chain and/or the light chain of the antibody is conjugated to the Niv(G) B ectodomain by using chemical coupling. Several methods are known in the art for the attachment or conjugation of an antibody to its conjugate moiety.
  • linker types that have been used to conjugate a moiety to an antibody include, but are not limited to, hydrazones, thioethers, esters, disulfides and peptide-containing linkers, such as valine-citruline linker.
  • a linker can be chosen that is, for example, susceptible to cleavage by low pH within the lysosomal compartment or susceptible to cleavage by proteases, such as proteases preferentially expressed in tumor tissue such as cathepsins (e.g., cathepsins B, C, D).
  • the peptide is covalently attached to lysine or cysteine residues on the antibody, through N- hydroxysuccinimide ester or maleimide functionality respectively.
  • TDCs cysteine-based site-specific conjugation called ‘‘THIOMABs’’ (TDCs) that are claimed to display an improved therapeutic index as compared to conventional conjugation methods. Conjugation to unnatural amino acids that have been incorporated into the antibody is also being explored for ADCs; however, the generality of this approach is yet to be established (Axup et al., 2012).
  • Fc-containing polypeptide engineered with an acyl donor glutamine-containing tag e.g., Gin-containing peptide tags or Q- tags
  • an endogenous glutamine that are made reactive by polypeptide engineering (e.g., via amino acid deletion, insertion, substitution, or mutation on the polypeptide).
  • a transglutaminase can covalently crosslink with an amine donor agent (e.g., a small molecule comprising or attached to a reactive amine) to form a stable and homogenous population of an engineered Fc-containing polypeptide conjugate with the amine donor agent being site-specifically conjugated to the Fc- containing polypeptide through the acyl donor glutamine-containing tag or the accessible/exposed/reactive endogenous glutamine (WO 2012059882).
  • an amine donor agent e.g., a small molecule comprising or attached to a reactive amine
  • the heavy chain and/or the light chain of the antibody is conjugated to the Niv(G)B ectodomain by a dockerin domain or multiple domains to permit non-covalent coupling to cohesin fusion proteins as described in US20160031988A1 and US20120039916A1.
  • the heavy chain and/or light of the antibody is fused to the Niv(G) B ectodomain to form a fusion protein.
  • the Niv(G)B ectodomain is fused either directly or via a linker to the heavy and/or light chain.
  • the term "directly" means that the first amino acid at the N-terminal end of the Niv(G)B ectodomain is fused to the last amino acid at the C-terminal end of the heavy or light chain. This direct fusion can occur naturally as described in (Vigneron et al., Science 2004, PMID 15001714), (Warren et al., Science 2006, PMID 16960008), (Berkers et al., J. Immunol.2015a, PMID 26401000), (Berkers et al., J.
  • the N-terminal of the Niv(G)B ectodomain is fused to the C-terminal of the heavy chain directly or via a linker.
  • the linker is selected from the group consisting of SEQ ID NO:5 (FlexV1), SEQ ID NO:6 (f1), SEQ ID NO:7 (f2), SEQ ID NO:8 (f3), or SEQ ID NO:9 (f4), as described below.
  • the antibody of the present invention comprises: - a heavy chain of the antibody that is conjugated or fused to the polypeptide having at least 80% of identity with the amino acid sequence that ranges from the amino acid residue (Q) at position 71 to the amino acid residue (T) at position 602 in SEQ ID NO:1 (Niv(G)B ectodomain) and - a light chain is conjugated or fused to the polypeptide having at least 80% of identity with the amino acid sequence that ranges from the amino acid residue (K) at position 45 to the amino acid
  • the C-terminal of the light chain of the antibody is conjugated or fused to the N-terminal of the the polypeptide having at least 80% of identity with the amino acid sequence that ranges from the amino acid residue (K) at position 45 to the amino acid residue (I) at position 90 in SEQ ID NO:2 (“predicted epitope-rich peptide Niv(F) B ”), and the C- terminal of the heavy chain of the antibody is conjugated or fused to the N-terminal of the polypeptide having at least 80% of identity with the amino acid sequence that ranges from the amino acid residue (Q) at position 71 to the amino acid residue (T) at position 602 in SEQ ID NO:1 (Niv(G) B ectodomain).
  • the antibody of the present invention comprises: - a heavy chain of the antibody that is conjugated or fused to the polypeptide having at least 80% of identity with the amino acid sequence that ranges from the amino acid residue (Q) at position 71 to the amino acid residue (T) at position 602 in SEQ ID NO:1 (Niv(G)B ectodomain) and - a light chain is conjugated or fused to the polypeptide having at least 80% of identity with the amino acid sequence that ranges from the amino acid residue (I) at position 318 to the amino acid residue (L) at position 355 in SEQ ID NO:3 (“predicted epitope- rich peptide Niv(N) B ”).
  • the C-terminal of the light chain of the antibody is conjugated or fused to the N-terminal of the polypeptide having at least 80% of identity with the amino acid sequence that ranges from the amino acid residue (I) at position 318 to the amino acid residue (L) at position 355 in SEQ ID NO:3 (“predicted epitope-rich peptide Niv(N) B ”) and the C- terminal of the heavy chain of the antibody is conjugated or fused to the N-terminal of the polypeptide having at least 80% of identity with the amino acid sequence that ranges from the amino acid residue (Q) at position 71 to the amino acid residue (T) at position 602 in SEQ ID NO:1 (Niv(G) B ectodomain).
  • the antibody of the present invention comprises: - a heavy chain of the antibody that is conjugated or fused to the polypeptide having at least 80% of identity with the amino acid sequence that ranges from the amino acid residue (Q) at position 71 to the amino acid residue (T) at position 602 in SEQ ID NO:1 (Niv(G)B ectodomain) and - a light chain is conjugated or fused to both i) the polypeptide having at least 80% of identity with the amino acid sequence that ranges from the amino acid residue (K) at position 45 to the amino acid residue (I) at position 90 in SEQ ID NO:2 (“predicted epitope-rich peptide Niv(F) B ”) and ii) the polypeptide having at least 80% of identity with the amino acid sequence that ranges from the amino acid residue (I) at position 318 to the amino acid residue (L) at position 355 in SEQ ID NO:3 (“predicted epitope- rich peptide Niv(N) B ”).
  • the antibody of the present invention comprises: - a heavy chain of the antibody that is conjugated or fused to the polypeptide having at least 80% of identity with the amino acid sequence that ranges from the amino acid residue (Q) at position 71 to the amino acid residue (T) at position 602 in SEQ ID NO:1 (Niv(G)B ectodomain) and - a light chain is conjugated or fused to both a fusion protein wherein i) the polypeptide having at least 80% of identity with the amino acid sequence that ranges from the amino acid residue (I) at position 318 to the amino acid residue (L) at position 355 in SEQ ID NO:3 (“predicted epitope-rich peptide Niv(N) B ”) is fused to ii) the polypeptide having at least 80% of identity with the amino acid sequence that ranges from the amino acid residue (K) at position 45 to the amino acid residue (I) at position 90 in SEQ ID NO:2 (“predicted epitope-rich peptide Niv
  • the light chain is conjugated or fused to a fusion protein comprising the polypeptide having at least 80% of identity with the amino acid sequence that ranges from the amino acid residue (K) at position 45 to the amino acid residue (I) at position 90 in SEQ ID NO:2 (“predicted epitope-rich peptide Niv(F) B ”) fused via its C-terminal directly or via a linker to the N-terminal of the polypeptide having at least 80% of identity with the amino acid sequence that ranges from the amino acid residue (I) at position 318 to the amino acid residue (L) at position 355 in SEQ ID NO:3 (“predicted epitope-rich peptide Niv(N)B”).
  • the light chain of the antibody is conjugated or fused to the fusion protein via its C-terminal.
  • the polypeptide having at least 80% of identity with the amino acid sequence that ranges from the amino acid residue (I) at position 318 to the amino acid residue (L) at position 355 in SEQ ID NO:3 (“predicted epitope-rich peptide Niv(N)B”) is fused via a linker to the polypeptide having at least 80% of identity with the amino acid sequence that ranges from the amino acid residue (K) at position 45 to the amino acid residue (I) at position 90 in SEQ ID NO:2 (“predicted epitope-rich peptide Niv(F) B ”).
  • the linker consists of the amino acid sequence as set forth in SEQ ID NO:10.
  • SEQ ID NO: 10 AEAAAKEAAAKA
  • the antibody of the present invention comprises: - a heavy chain of the antibody that is conjugated or fused to the polypeptide having at least 80% of identity with the amino acid sequence that ranges from the amino acid residue (Q) at position 71 to the amino acid residue (T) at position 602 in SEQ ID NO:1 (Niv(G) B ectodomain) and - a light chain is conjugated or fused to both the fusion protein having at least 80% of identity with amino acid sequence as set forth in SEQ ID NO:11.
  • the antibody is an IgG antibody, preferably of an IgG1 or IgG4 antibody, or even more preferably of an IgG4 antibody.
  • the antibody is a chimeric antibody, in particular a chimeric mouse/human antibody.
  • the antibody is humanized antibody. Chimeric or humanized antibodies can be prepared based on the sequence of a murine monoclonal antibody prepared as described above.
  • DNA encoding the heavy and light chain immunoglobulins can be obtained from the murine hybridoma of interest and engineered to contain non-murine (e.g., human) immunoglobulin sequences using standard molecular biology techniques.
  • the murine variable regions can be linked to human constant regions using methods known in the art (see e.g., U.S. Patent No. 4,816,567 to Cabilly et al.).
  • the murine CDR regions can be inserted into a human framework using methods known in the art. See e.g., U.S. Patent No. 5,225,539 to Winter, and U.S. Patent Nos.
  • the antibody is a human antibody.
  • human antibodies can be identified using transgenic or transchromosomic mice carrying parts of the human immune system rather than the mouse system.
  • HuMAb mice ® (Medarex, Inc.) contains human immunoglobulin gene miniloci that encode un-rearranged human heavy ( ⁇ and ⁇ ) and ⁇ light chain immunoglobulin sequences, together with targeted mutations that inactivate the endogenous ⁇ and ⁇ chain loci (see e.g., Lonberg, et al., 1994 Nature 368(6474): 856-859).
  • human antibodies can be raised using a mouse that carries human immunoglobulin sequences on transgenes and transchomosomes such as a mouse that carries a human heavy chain transgene and a human light chain transchromosome.
  • KM mice a mouse that carries a human heavy chain transgene and a human light chain transchromosome.
  • the antibody is specific for a cell surface marker of a professional APC.
  • the antibody may be specific for a cell surface marker of another professional APC, such as a B cell or a macrophage.
  • the antibody is selected from an antibody that specifically binds to DC immunoreceptor (DCIR), MHC class I, MHC class II, CD1, CD2, CD3, CD4, CD8, CDl lb, CD14, CD15, CD16, CD19, CD20, CD29, CD31, CD40, CD43, CD44, CD45, CD54, CD56, CD57, CD58, CD83, CD86, CMRF-44, CMRF-56, DCIR, DC-ASPGR, CLEC-6, CD40, BDCA-2, MARCO, DEC-205, mannose receptor, Langerin, DECTIN-1, B7-1, B7-2, IFN- ⁇ receptor and IL-2 receptor, ICAM-1, Fey receptor, LOX-1, and ASPGR.
  • DCIR DC immunoreceptor
  • MHC class I MHC class II
  • CD1, CD2, CD3, CD4, CD8, CDl lb CD14, CD15, CD16, CD19, CD20, CD29, CD31, CD40, CD43, CD44
  • the antibody is specific for CD40.
  • the anti-CD40 antibody derives from the 12E12 antibody and comprises: - a heavy chain comprising the complementarity determining regions CDR1H, CDR2H and CDR3H, the CDR1H having the amino acid sequence GFTFSDYYMY (SEQ ID NO:12), the CDR2H having the amino acid sequence YINSGGGSTYYPDTVKG (SEQ ID NO:13), and the CDR3H having the amino acid sequence RGLPFHAMDY (SEQ ID NO:14), - and a light chain comprising the complementarity determining regions CDR1L, CDR2L and CDR3L, the CDR1L having the amino acid sequence SASQGISNYLN (SEQ ID NO:15) the CDR2L having the amino acid sequence YTSILHS (SEQ ID NO:16) and the CDR3L having the amino acid sequence QQFNKLPPT (SEQ ID NO:17).
  • the anti-CD40 antibody derives from the 11B6 antibody and comprises: - a heavy chain comprising the complementarity determining regions CDR1H, CDR2H and CDR3H, the CDR1H having the amino acid sequence GYSFTGYYMH (SEQ ID NO:18), the CDR2H having the amino acid sequence RINPYNGATSYNQNFKD (SEQ ID NO:19), and the CDR3H having the amino acid sequence EDYVY (SEQ ID NO:20), and - a light chain comprising the complementarity determining regions CDR1L, CDR2L and CDR3L, the CDR1L having the amino acid sequence RSSQSLVHSNGNTYLH (SEQ ID NO:21) the CDR2L having the amino acid sequence KVSNRFS (SEQ ID NO:22) and the CDR3L having the amino acid sequence SQSTHVPWT (SEQ ID NO:23).
  • the anti-CD40 antibody derives from the 12B4 antibody and comprises: - a heavy chain comprising the complementarity determining regions CDR1H, CDR2H and CDR3H, the CDR1H having the amino acid sequence GYTFTDYVLH (SEQ ID NO:24), the CDR2H having the amino acid sequence YINPYNDGTKYNEKFKG (SEQ ID NO:25), and the CDR3H having the amino acid sequence GYPAYSGYAMDY (SEQ ID NO:26), and - a light chain comprising the complementarity determining regions CDR1L, CDR2L and CDR3L, the CDR1L having the amino acid sequence RASQDISNYLN (SEQ ID NO:27) the CDR2L having the amino acid sequence YTSRLHS (SEQ ID NO:28) and the CDR3L having the amino acid sequence HHGNTLPWT (SEQ ID NO:29).
  • the anti-CD40 antibody is selected from the group consisting of selected mAb1, mAb2, mAb3, mAb4, mAb5 and mAb6 as described in Table A.
  • mAb1 [11B6 SEQ ID NO:30 SEQ ID NO:31 SEQ ID NO:30 (Amino acid sequence of variable heavy chain region (VH) (v2) of Humanized 11B6) EVQLVQSGAEVKKPGASVKISCKASGYSFTGYYMHWVKQAHGQGLEWIGRINPYNGATSYNQNFKDRAT LTVDKSTSTAYMELSSLRSEDTAVYYCAREDYVYWGQGTTVTVSSAS SEQ ID NO:31 (Amino acid sequence of variable light chain (VL) Vk (v2) of humanized 11B6 VL) DVVMTQSPLSLPVTLGQPASISCRSSQSLVHSNGNTYLHWYQQRPGQSPRLLIYKVSNRFSGVPDRFSG SGSGTDFTLKISR
  • the anti-CD40 antibody comprises: a heavy chain wherein the variable domain has the the amino acid sequence set forth as SEQ ID NO:32, and a light chain wherein the variable domain has a sequence set forth as SEQ ID NO:31. In some embodiments, the anti-CD40 antibody comprises: a heavy chain wherein the variable domain has the the amino acid sequence set forth as SEQ ID NO:33, and a light chain wherein the variable domain has a sequence set forth as SEQ ID NO:34. In some embodiments, the anti-CD40 antibody comprises: a heavy chain wherein the variable domain has the amino acid sequence set forth as SEQ ID NO:35, and a light chain wherein the variable domain has a sequence set forth as SEQ ID NO:36.
  • the anti-CD40 antibody comprises: a heavy chain wherein the variable domain has the the amino acid sequence set forth as SEQ ID NO:37, and a light chain wherein the variable domain has a sequence set forth as SEQ ID NO:38. In some embodiments, the anti-CD40 antibody comprises: a heavy chain wherein the variable domain has the the amino acid sequence set forth as SEQ ID NO:39, and a light chain wherein the variable domain has a sequence set forth as SEQ ID NO:40. In some embodiments, the anti-CD40 antibody is a CD40 agonist antibody. CD40 agonist antibodies are described in WO2010/009346, WO2010/104747 and WO2010/104749.
  • anti-CD40 agonist antibodies in development include CP-870,893 that is a fully human IgG2 CD40 agonist antibody developed by Pfizer. It binds CD40 with a KD of 3.48 ⁇ 10 ⁇ 10 M, but does not block binding of CD40L (see e.g., U.S. Pat. No. 7,338,660) and SGN-40 that is a humanized IgG1 antibody developed by Seattle Genetics from mouse antibody clone S2C6, which was generated using a human bladder carcinoma cell line as the immunogen.
  • the CD40 agonist antibody is selected from the group consisting of selected mAb1, mAb2, mAb3, mAb4, mAb5 and mAb6 as described in Table A.
  • the antibody is specific for Langerin.
  • the antibody derives from the antibody 15B10 having ATCC Accession No. PTA-9852.
  • the antibody derives from the antibody 2G3 having ATCC Accession No. PTA- 9853.
  • the antibody derives from the antibody 91E7, 37C1, or 4C7 as described in WO2011032161.
  • the anti-Langerin antibody comprises a heavy chain comprising the complementarity determining regions CDR1H, CDR2H and CDR3H of the 15B10 antibody and a light chain comprising the complementarity determining regions CDR1L, CDR2L and CDR3L of the 15B10 antibody.
  • the anti-Langerin antibody comprises a heavy chain comprising the complementarity determining regions CDR1H, CDR2H and CDR3H of the 2G3 antibody and a light chain comprising the complementarity determining regions CDR1L, CDR2L and CDR3L of the 2G3 antibody.
  • the anti-Langerin antibody comprises a heavy chain comprising the complementarity determining regions CDR1H, CDR2H and CDR3H of the 4C7 antibody and a light chain comprising the complementarity determining regions CDR1L, CDR2L and CDR3L of the 4C7 antibody.
  • the antibody is selected from the group consisting of selected mAb7, mAb8 and mAb9, as described in Table B.
  • mAb7 SEQ ID NO:41
  • SEQ ID NO:42 mAb9
  • SEQ ID NO:45 SEQ ID NO:46
  • SEQ ID NO:42 Amino acid sequence of variable light chain (VL) 15B10)
  • LGLYFCS SEQ ID NO:43 (Amino acid sequence of variable heavy chain region (VH) of
  • the anti-Langerin antibody comprises: a heavy chain wherein the variable domain has the the amino acid sequence set forth as SEQ ID NO:43, and a light chain wherein the variable domain has a sequence set forth as SEQ ID NO:44. In some embodiments, the anti-Langerin antibody comprises: a heavy chain having the the amino acid sequence set forth as SEQ ID NO:45, and a light chain having a sequence set forth as SEQ ID NO:46.
  • the antibodies of the invention may be produced by any technique known per se in the art, such as, without limitation, any chemical, biological, genetic or enzymatic technique, either alone or in combination.
  • the antibodies of the invention can be synthesized by recombinant DNA techniques as is now well-known in the art.
  • these fragments can be obtained as DNA expression products after incorporation of DNA sequences encoding the desired (poly) peptide into expression vectors and introduction of such vectors into suitable eukaryotic or prokaryotic hosts that will express the desired polypeptide, from which they can be later isolated using well-known techniques.
  • the amino acid sequence herein described comprise one or more sequences originating from the restriction cloning site(s) present in the polynucleotide encoding for said amino acid sequence. Typically, said sequences may consist of 2 amino acid residues and typically include AP, AS, AR, PR, SA, TR, and TS sequences. In some embodiments, the amino acid sequences herein described the sequence of a signal peptide. As used herein, the term "signal peptide" has its general meaning in the art and refers to a pre-peptide which is present as an N-terminal peptide on a precursor form of a protein.
  • the function of the signal peptide is to facilitate translocation of the expressed polypeptide to which it is attached into the endoplasmic reticulum.
  • the signal peptide is normally cleaved off in the course of this process.
  • the signal peptide may be heterologous or homologous to the organism used to produce the polypeptide.
  • the antibody of the present invention comprises: - a heavy chain having at least 80% of identity with the amino acid sequence as set forth in SEQ ID NO:47, and - a light chain having at least 80% of identity with amino acid sequence as set forth in SEQ ID NO:48.
  • a further object of the invention relates to a polynucleotide that encodes for a heavy chain and/or light chain of the antibody of the present invention.
  • said polynucleotide is a DNA or RNA molecule, which may be included in any suitable vector, such as a plasmid, cosmid, episome, artificial chromosome, phage or a viral vector.
  • a further object of the invention relates to a vector comprising a polynucleotide of the present invention.
  • Such vectors may comprise regulatory elements, such as a promoter, enhancer, terminator and the like, to cause or direct expression of said antibody upon administration to a subject.
  • promoters and enhancers used in the expression vector for animal cell include early promoter and enhancer of SV40, LTR promoter and enhancer of Moloney mouse leukemia virus, promoter and enhancer of immunoglobulin H chain and the like. Any expression vector for animal cell can be used, so long as a gene encoding the human antibody C region can be inserted and expressed. Examples of suitable vectors include pAGE107, pAGE103, pHSG274, pKCR, pSG1 beta d2-4 and the like. Other examples of plasmids include replicating plasmids comprising an origin of replication, or integrative plasmids, such as for instance pUC, pcDNA, pBR, and the like.
  • a further object of the present invention relates to a host cell which has been transfected, infected or transformed by a polynucleotide and/or a vector according to the invention.
  • the polynucleotides of the invention may be used to produce an antibody of the present invention in a suitable expression system.
  • Common expression systems include E. coli host cells and plasmid vectors, insect host cells and Baculovirus vectors, and mammalian host cells and vectors.
  • Other examples of host cells include, without limitation, prokaryotic cells (such as bacteria) and eukaryotic cells (such as yeast cells, mammalian cells, insect cells, plant cells, etc.). Specific examples include E.coli, Kluyveromyces or Saccharomyces yeasts.
  • Mammalian host cells include Chinese Hamster Ovary (CHO cells) including dhfr- CHO cells (described in Urlaub and Chasin, 1980) used with a DHFR selectable marker, CHOK1 dhfr+ cell lines, NSO myeloma cells, COS cells and SP2 cells, for example GS CHO cell lines together with GS Xceed TM gene expression system (Lonza), or HEK cells.
  • CHO cells Chinese Hamster Ovary (CHO cells) including dhfr- CHO cells (described in Urlaub and Chasin, 1980) used with a DHFR selectable marker, CHOK1 dhfr+ cell lines, NSO myeloma cells, COS cells and SP2 cells, for example GS CHO cell lines together with GS Xceed TM gene expression system (Lonza), or HEK cells.
  • the present invention also relates to a method of producing a recombinant host cell expressing the antibody according to the invention, said method comprising the steps of: (i) introducing in vitro or ex vivo a recombinant polynucleotide or a vector as described above into a competent host cell, (ii) culturing in vitro or ex vivo the recombinant host cell obtained and (iii), optionally, selecting the cells which express and/or secrete said antibody.
  • Such recombinant host cells can be used for the production of antibodies of the present invention.
  • the host cell as disclosed herein are thus particularly suitable for producing the antibody of the present invention.
  • the polypeptides are produced by culturing the host cells for a period of time sufficient for expression of the antibody in the host cells and, optionally, secretion of the antibody into the culture medium in which the host cells are grown.
  • the antibodies can be recovered and purified for example from the culture medium after their secretion using standard protein purification methods.
  • Pharmaceutical and vaccine compositions The antibodies as described herein may be administered as part of one or more pharmaceutical compositions. Except insofar as any conventional carrier medium is incompatible with the antibodies of the present invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this invention.
  • materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatine; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil, sesame oil; olive oil; corn oil and soybean oil; glycols; such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as
  • the antibodies as described herein are particularly suitable for preparing vaccine composition.
  • a further object of the present invention relates to a vaccine composition comprising an antibody of the present invention.
  • the vaccine composition of the present invention comprises an adjuvant.
  • the adjuvant is alum.
  • the adjuvant is Incomplete Freund’s adjuvant (IFA) or other oil based adjuvant that is present between 30-70%, preferably between 40-60%, more preferably between 45-55% proportion weight by weight (w/w).
  • the adjuvant is Polyinosinic-polycytidylic acid (poly (I:C)) or Polyinosinic- Polycytidylic acid – poly-L-lysine carboxymethylcellulose (Poly-ICLC).
  • the vaccine composition of the present invention comprises at least one Toll- Like Receptor (TLR) agonist which is selected from the group consisting of TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, and TLR8 agonists.
  • TLR Toll- Like Receptor
  • Therapeutic methods The antibodies as well as the pharmaceutical or vaccine compositions as herein described are particularly suitable for inducing an immune response against Nipah virus and thus can be used for vaccine purposes.
  • a further object of the present invention relates to a method for vaccinating a subject in need thereof against Nipah virus comprising administering a therapeutically effective amount of the antibody of the present invention.
  • the antibodies as well as the pharmaceutical or vaccine compositions as herein described are particularly suitable for the treatment of Nipah virus infection.
  • the subject can be human or any other animal (e.g., birds and mammals) susceptible to Nipah virus infection (e.g., domestic animals such as cats and dogs; livestock and farm animals such as horses, cows, pigs, chickens, etc.).
  • the subject can be symptomatic or asymptomatic.
  • the active ingredient of the present invention i.e., the antibodies and the pharmaceutical or vaccine compositions as herein described
  • the specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed, the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific polypeptide employed; and like factors well known in the medical arts.
  • the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult per day.
  • compositions contain 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 mg of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated.
  • a medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, in particular from 1 mg to about 100 mg of the active ingredient.
  • An effective amount of the drug is ordinarily supplied at a dosage level from 0.0002 mg/kg to about 20 mg/kg of body weight per day, especially from about 0.001 mg/kg to 7 mg/kg of body weight per day.
  • the antibodies and the pharmaceutical or vaccine compositions as herein described may be administered to the subject by any route of administration and in particular by oral, nasal, rectal, topical, buccal (e.g., sub-lingual), parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) and transdermal administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the particular active agent which is being used.
  • the invention will be further illustrated by the following figures and examples. However, these examples and figures should not be interpreted in any way as limiting the scope of the present invention.
  • FIGURES Figure 1. Epitope mapping of NiV G antigen associated to the CD40 mAb.
  • FIG. 1 Schematic representation of Generation 1 (Gen-1) and Generation 2 (Gen-2) vaccines.
  • Figure 4 Gen-1, Gen-2 and IgG4 control vaccine SDS PAGE profiles in non-reduced (NR) versus reduced (R) conditions.
  • Figure 5 The G antigen fused to Gen-1 vaccine was confirmed by Western-Blot, using sera from Niv(G)-immunized mice and testing the in-house produced G protein as positive control. Molecular weight (kDa) markers are shown in the left lane. Arrows indicate the heavy chain (HC) and light chain (LC) of the vaccine constructions at the expected size, respectively.
  • Figure 6 Size exclusion chromatography (SEC) of Gen-1 and Gen-2 vaccines with standard proteins size markers. Recombinant mAb are indicated by arrows.
  • Figure 7 Binding assay of CD40.NiV vaccines to mouse cells expressing the human CD40 receptor.
  • Mouse splenocytes from hCD40 My/Hu Tg mice were incubated with 10nM of CD40.Niv Gen-1 mAbs and subsequently labeled for T-, B and DC cell markers, respectively. Untreated and splenocytes treated with the non-targeting IgG4.Niv were used as negative controls.
  • Figure 8 Binding assay of CD40.NiV vaccines to AGM PBMCs. Same method as Fig-7, using PBMCs from na ⁇ ve AGM.
  • Niv(G)-specific B cells are considered double positive for the two anti-Biotin mAbs.
  • Figure 13 Gen-1 and -2 CD40.NiV vaccines induced cellular immune responses in hCD40 Hy/Mu transgenic mice.
  • IFN-g T cells responses to the G, F and N overlapping pools of peptides were assessed by ELISpot, one week post boost.
  • Bottom right Percentages of G, F and N-specific responses, at 10 and 30ug of vaccine, respectively. Plain circle, with Poly-ICLC, open circles, without Poly-ICLC.
  • Figure 15 As in Figure 10, neutralization activity of AGM sera was measured by indirect inhibition assay
  • Figure 16 In vitro neutralization of NiV-B by sera from vaccinated AGM.
  • Figure 17 As in Fig-13, total specific IFN- ⁇ responses to the G, F and N antigens were measured in AGM circulating PBMCs collected at day 21 and 35 post-immunization. Number of spots are reported per million of PBMC. Pointed line represents threshold for positivity defined by the mean responses (+3SD) of the non-vaccinated AGM group. (right) Percentage (%) of specific T cell response to each vaccine antigen (mean ⁇ SD).
  • Figure 19 Protection assay in AGM. Survival curve. Nine AGM were immunized twice with CD40.NiV (Gen-2) and challenged with 10 2 Pfu NiV-B (intratracheal route). Height na ⁇ ve animals were used as controls. Gehan-Breslow-Wilcoxon test, ****, p ⁇ 0.0001.
  • Figure 20 Clinical scores and temperatures of na ⁇ ve (black circle) and vaccinated AGMs (white circle). Dotted line score threshold for ethical considerations (left panel); dotted line: median temperature at day 0 (right panel).
  • Figure 21 Viral dissemination post-challenge.
  • A (left) Amount of viral NiV RNA quantified by RT-PCR (N gene) in PBLs. Values were normalized against those of the GADPH housekeeping gene. Genomic RNA was measured by RT-qPCR in nasal (middle) and pharyngeal (right) swabs.
  • Gen1 vaccine was assessed by western blot ( Figure 5), using sera from C57BL/6 mice immunized by the in-house produced G protein (+CpG). The H-chain fused with the G protein was revealed by the mouse sera. Binding assay: Gen-1 antibodies and same 12E12/VH3 clone without any antigen were marked by a fluorochrome. The clone 11B6 was also tested in parallel as positive control. Mouse splenocytes from hCD40 Tg mice ( Figure 7) and PBMCs from AGM ( Figure 8) were incubated with fluorescent vaccine in vitro. Cells were phenotyped and analyzed by FACS.
  • Gen-2 vaccine is also associated with in silico down selected peptides from the F and N proteins, and that are predicted to be enriched in T- and B-cells epitopes ( Figures 1 to 8).
  • the NiV surface glycoprotein (G) is a gold-standard antigen for inducing protective humoral responses.
  • Other cellular effectors, such as helper and effector T-cells, may also participate in host defense.
  • NiV F and NiV N (aa 318-355) down-selected peptides contain 356 and 266 predicted T- cell epitopes and three and linear B-cell epitopes, respectively. Globally, these amino acid sequences were screened for homology with other Henipaviruses, obtaining 100% homology between different Nipah strains for the F and N peptides and more than 98% for NiV G ECD.
  • hCD40Tg mice were immunized with two subcutaneous (SC) injections of CD40.NiV (Gen-1 or Gen-2) vaccine (10 ⁇ g) or an equivalent amount of NiV G protein, both with poly-ICLC (50 ⁇ g) on days 0 and 21.
  • Antibody-mediated immune responses were first evaluated by Luminex assay.
  • Our results showed a significant G-specific IgG titer with both vaccines (Figure 9).
  • Three weeks post- prime, mice immunized with the CD40-targeted NiV G protein showed significantly higher anti-NiV G IgG levels (P ⁇ 0.01), highlighting the benefit conferred by the DC-targeting system.
  • the CD40.NiV vaccine induces early and robust humoral and T-cell responses in AGMs
  • AGM African Green Monkey
  • Twelve animals have been imported and housed at the Bioprim animal center (Toulouse).
  • Two groups of animals have been immunized in a prime-boost homologous regimen, as follow: 3 AGM with Poly-ICLC alone versus 9 AGM with 200ug of Gen-2 vaccine + Poly-ICLC.
  • Vaccination elicited a neutralization potential of NiV G-specific IgG by day 10 post-prime, reaching significance two weeks post-boost (mean neutralization titer 3.2 ( ⁇ 0.2), P ⁇ 0.001), and remained high until day 56 ( Figures 15, 16 and 18).
  • the neutralizing capacity of specific antibodies was confirmed post-prime and post-boost using the Luminex-based surrogate inhibition assay (P ⁇ 0.001) (data not shown).
  • Enzyme activity levels (aspartate aminotransferase, AST; creatine kinase, CK) reflecting hepatic disorders were above normal values during the critical disease period for controls but not the vaccinated animals.
  • NiV viremia Plasma and tissue viral loads in challenged AGMs
  • NiV-B replication in nasal and nasopharyngeal swabs, fluids, including broncho-alveolar lavages (BALs), sera, urine, and thoracic exudates, and organs (lung, spleen, and neurological tissue) was undetectable in immunized AGMs, whereas it was detected at high levels in controls ( Figure 21B). This strong antiviral effect was confirmed by the lack of expression of the NiV N protein in tissues of the lungs and spleen, as assessed by histo-immunofluorescence (data not shown).
  • Viral syncytia were detected in the lungs of non-immunized animals. Of note, NiV-B infection of the brain could not be confirmed by histo-immunofluorescence. Overall, CD40.NiV (Gen-2) vaccination led to sterilizing immunity that limited viral propagation, as well as viral shedding, in AGMs. Immunological and cytokine features of challenged animals We further characterized the post-challenge immune responses by immunological phenotyping of the cell populations from 0 to 22 dpc. The succumbing animals showed profound and significant defects in the lymphoid populations (CD20+ B- and CD3+ T-cells) (data not shown).
  • the DC-targeting strategy allowed us to design a subunit construct containing immunogenic and cross-reactive epitopes from the F and N NiV proteins, in addition to the NiV G ECD, in contrast to most other NiV vaccine platforms (Bossart et al., 2012; Foster et al., 2022; Geisbert et al., 2021; 287 Loomis et al., 2020; Mohammed et al., 2020; Woolsey et al., 2023; Yoneda et al., 2013).
  • the CD40.NiV vaccine induced both IgG and IgA antibodies as early as 10 days post-prime in AGMs. We also show that neutralizing responses can be maintained, with a stable estimated mean log titer of approximately 2.2 ( ⁇ 0.1) 100 days after the peak of the Ab response. Responses were showed to cross-neutralize multiple strains of NiV, but also HeV. Although detectable at a lower level, we found that the CD40.NiV vaccine elicited a T-cell response against the NiV G ECD and down-selected F and N peptides in two preclinical models.

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Abstract

Le virus Nipah (NiV) est un paramyxovirus zoonotique récemment émergent, hautement pathogène. Les inventeurs ont maintenant conçu un mAb anti-CD40 associé soit à la protéine d'ectodomaine de Niv G (vaccin de 1e génération), soit à la protéine d'ectodomaine de Niv G et à des épitopes sélectionnés à partir des protéines de Niv F et N (vaccin de 2e génération). Des contrôles de qualité ont été effectués sur des lots de vaccins. L'immunogénicité des deux vaccins a été testée sur des souris hCD40Tg. Une réponse des lymphocytes T IFNg dépendant de la dose envers l'antigène a été observée. Trois semaines après amplification, un IgG spécifique a été détecté dans des groupes immunisés avec 10 ug de vaccin. Les réponses des cellules B ont été nettement améliorées 1 semaine après amplification. Tous les échantillons ont montré une neutralisation avec un titre moyen à 1 : 500 à la 4e semaine. Les inventeurs ont également démontré la puissance d'un vaccin candidat ciblant DC innovant pour prévenir une infection de NiV-B dans des expériences de provocation dans un modèle AGM. Des réponses ont été présentées pour neutraliser de manière croisée de multiples souches de NiV, et également de HeV. Le ciblage d'antigènes du virus Nipah à des APC professionnels peut être efficacement utilisé en tant que moyen prophylactique contre un défi du virus Nipah à une dose létale. Par conséquent, la présente invention concerne des anticorps qui sont dirigés contre un antigène de surface d'une cellule présentatrice d'antigène, la chaîne lourde et/ou la chaîne légère étant conjuguées ou fusionnées aux polypeptides antigéniques du virus Nipah.
EP23783875.0A 2022-10-05 2023-10-04 Vaccin ciblant dc dirigé contre une infection par le virus nipah Pending EP4598953A1 (fr)

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