Anti-TREM-1 antibodies

Abstract

The present invention relates to novel anti-TREM-1 (triggering receptor expressed on myeloid cells-1) antibodies and antigen-binding fragments thereof, fusion proteins comprising said antibodies and antigen-binding fragments thereof, and therapeutic uses thereof.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to the field of inflammation and discloses novel anti-human TREM-1 (Triggering Receptor Expressed on Myeloid cells-1) antibodies and antigen-binding fragments thereof. [Background technology]

[0002] 2. Background of the Invention TREM-1 (triggering receptor expressed on myeloid cells-1), sometimes also known as CD354, is an immune receptor expressed by the majority of innate immune cells such as monocytes, macrophages, neutrophils, platelets, and dendritic cells, as well as by endothelial cells. The human TREM gene cluster is located on chromosome 6p21.1 and encodes six distinct proteins, TREM1-5 and TLT-1 (TREM-like transcript-1). TREM-1 is a membrane-bound glycoprotein receptor belonging to the Ig superfamily that contains three separate domains: an Ig-like structure (mainly involved in ligand binding), a transmembrane portion, and a short cytoplasmic tail that binds to an adaptor protein called DNAX-activating protein 12 or DAP12. Upon binding of its ligand, TREM-1 thus activates downstream signaling pathways with the help of DAP12.

[0003] As described for example by Tammaro et al. (Pharmacol Ther. 2017 Sep;177:81-95), engagement of TREM-1 induces signaling pathways including ZAP70 (zeta chain-associated protein kinase 70) and SYK (spleen tyrosine kinase), the latter promoting the subsequent recruitment and tyrosine phosphorylation of adaptor molecules such as Cbl (Casitas B lineage lymphoma), SOS (son of sevenless), and GRB2 (growth factor receptor-bound protein-2), which results in downstream signaling via PI3K, PLC-γ (phospholipase-C-gamma), ERK-1, ERK-2, and p38 MAPK. Activation of these pathways leads to increased Ca 2+ It induces recruitment, reorganization of the actin cytoskeleton, and activation of transcription factors such as NF-kB. Ultimately, activation of TREM-1 specifically leads to rapid neutrophil degranulation and oxidative burst, as well as expression and secretion of proinflammatory cytokines and chemokines.

[0004] The function of TREM-1 is to enhance, rather than initiate, inflammation by synergizing with pathogen recognition receptors (PRRs) to induce a vigorous immune response. Engagement of PRRs, including Nod-like receptors (NLRs) and Toll-like receptors (TLRs), therefore induces the upregulation of TREM-1 expression and / or its recruitment and clustering at the cell membrane, which leads to its dimerization and multimerization. The NLRs and / or TLRs can be activated by DAMPs (Danger Associated Molecular Patterns) or PAMPs (Pathogen Associated Molecular Patterns). In particular, activation of the NLRs and TLRs can occur under sterile inflammatory conditions by interaction with DAMPs and / or alarmins, or under infectious conditions by interaction with PAMPs. TREM-1 therefore plays a role in enhancing inflammation, whether it is induced by infection (infectious inflammation) or not (sterile inflammation). Thus, TREM-1 and its signaling pathways play a role in inflammation or hyperinflammation caused by infections such as sepsis and septic shock, but also contribute to the pathology of several non-infectious acute and chronic inflammatory diseases, including atherosclerosis, ischemia-reperfusion-induced tissue injury, colitis, fibrosis and cancer.

[0005] Of note, because of its importance in enhancing rather than initiating inflammation, inhibition of TREM-1 is expected to block the TREM-1-dependent enhancing loop of innate immune responses and attenuate inflammation rather than completely abolishing the inflammatory response. Identifying molecules that can specifically bind and inhibit TREM-1 may be particularly relevant for the treatment of infectious inflammatory diseases as well as non-infectious acute and chronic inflammatory diseases. Several TREM-1 inhibitors have already been described, such as inhibitory peptides including the TLT-1 peptide LR12, which is currently in clinical trials (WO2011 / 124685). However, to date, no TREM-1 inhibitors have been approved for therapeutic use.

[0006] Thus, there remains a need for novel TREM-1 inhibitors that can be used to attenuate inflammation, whether infectious or sterile inflammation. Summary of the Invention

[0007] The present invention relates to novel anti-human TREM-1 antibodies and antigen-binding fragments thereof. As illustrated in the Examples section, the novel anti-human TREM-1 antibodies and antigen-binding fragments thereof described herein are capable of binding and inhibiting human TREM-1. In particular, they are capable of attenuating the inflammatory response induced in an animal model of endotoxemia. Notably, the novel anti-human TREM-1 antibodies and antigen-binding fragments thereof described herein are capable of inhibiting the TREM-1 signaling pathway, regardless of the stimulatory signal by which it is activated. They are therefore capable of inhibiting the TREM-1 signaling pathway, which is either directly activated by the TREM-1 ligand complex or indirectly activated via stimulation of various Toll-like receptors (TLRs), such as, for example, TLR2 by PGN or TLR4 by LPS.

[0008] overview The present invention relates to an isolated anti-TREM-1 (Triggering Receptor Expressed on Myeloid Cells-1) antibody or antigen-binding fragment thereof, a) The variable region (VH) of the heavy chain of the isolated anti-TREM-1 antibody or antigen-binding fragment thereof comprises the following three complementarity determining regions (CDRs): -V H - CDR1: NTYIH (SEQ ID NO: 1); -V H - CDR2: RIDPAX1GX2TKYX3PKVX4G (SEQ ID NO: 2), where X1 is Asn (N) or Gly (G), X2 is Asn (N) or Arg (R), X3 is Ala (A), Asp (D), or Ser (S), and X4 is Gln (Q) or Lys (K); and -V H - CDR3: HX5GX6TMDY (SEQ ID NO: 3), where X5 is Tyr (Y) or Arg (R) and X6 is Ser (S) or Gly (G). Includes; b) The variable region (VL) of the light chain of the isolated anti-TREM-1 antibody or antigen-binding fragment thereof comprises the following three CDRs: -V L - CDR1: RASX7SVX8NYGISFX9N (SEQ ID NO: 4), wherein X7 is Glu (E) or Gln (Q), X8 is Asp (D) or Ser (S), and X9 is Met (M) or Leu (L); -V L -CDR2:AAX 10 X 11 X 12 X 13 X 14 (SEQ ID NO:5), where X 10 is Ser(S) or Glu(E), and X 11 is Asn(N) or Tyr(Y), and X 12 is Gln(Q) or Arg(R), and X 13 is Gly (G), Ala (A), or Lys (K); 14 is Ser (S) or Arg (R); and -V L -CDR3:QQSX 15 X 16 X 17 PX 18 T (SEQ ID NO:6), where X 15 is Lys (K), Arg (R), or Ser (S); X 16 is Glu(E), His(H), or Asn(N), and X 17 is Val(V) or Phe(F), and X 18 is Trp (W) or Tyr (Y) Includes.

[0009] In one embodiment, the isolated anti-TREM-1 antibody or antigen-binding fragment thereof has the following CDRs: -V H - CDR1: NTYIH (SEQ ID NO: 1), V H - CDR2: RIDPAGGRTKYDPKVKG (SEQ ID NO: 7), V H -CDR3: HYGGTMDY (SEQ ID NO: 8), V L- CDR1: RASESVDNYGISFLN (SEQ ID NO: 9), V L - CDR2: AAEYRGR (SEQ ID NO: 10), and V L - CDR3: QQSRHVPYT (SEQ ID NO: 11); or -V H - CDR1: NTYIH (SEQ ID NO: 1), V H - CDR2: RIDPAGGRTKYSPKVQG (SEQ ID NO: 12), V H -CDR3: HRGGTMDY (SEQ ID NO: 13), V L - CDR1: RASQSVSNYGISFLN (SEQ ID NO: 14), V L - CDR2: AASYQKR (SEQ ID NO: 15), and V L - CDR3: QQSSNFPWT (SEQ ID NO: 16); or -V H - CDR1: NTYIH (SEQ ID NO: 1), V H - CDR2: RIDPAGGRTKYAPKVKG (SEQ ID NO: 17), V H -CDR3: HRGGTMDY (SEQ ID NO: 13), V L - CDR1: RASQSVSNYGISFLN (SEQ ID NO: 14), V L - CDR2: AAEYRGR (SEQ ID NO: 10), and V L - CDR3: QQSSNVPYT (SEQ ID NO: 18); or -V H - CDR1: NTYIH (SEQ ID NO: 1), V H -CDR2: RIDPAGGRTKYAPKVQG (SEQ ID NO: 19), V H -CDR3: HYGGTMDY (SEQ ID NO: 8), V L - CDR1: RASQSVSNYGISFLN (SEQ ID NO: 14), V L - CDR2: AAEYQGR (SEQ ID NO: 20), and V L - CDR3: QQSSNVPYT (SEQ ID NO: 18); or -V H - CDR1: NTYIH (SEQ ID NO: 1), V H - CDR2: RIDPAGGRTKYAPKVKG (SEQ ID NO: 17), V H -CDR3: HRGGTMDY (SEQ ID NO: 13), VL - CDR1: RASQSVSNYGISFLN (SEQ ID NO: 14), V L - CDR2: AAEYRAR (SEQ ID NO: 21), and V L - CDR3: QQSSNVPYT (SEQ ID NO: 18); or -V H - CDR1: NTYIH (SEQ ID NO: 1), V H -CDR2: RIDPANGNTKYAPKVQG (SEQ ID NO: 22), V H -CDR3: HYGSTMDY (SEQ ID NO: 23), V L - CDR1: RASESVDNYGISFMN (SEQ ID NO: 24), V L - CDR2: AASNQGS (SEQ ID NO: 25), and V L -CDR3: QQSKEVPWT (SEQ ID NO: 26) Includes.

[0010] In one embodiment, the isolated anti-TREM-1 antibody or antigen-binding fragment thereof comprises a variable region of a heavy chain (VH) having a sequence set forth in any one of SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, and SEQ ID NO:32, or a sequence having at least 80% identity to any one of SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, and SEQ ID NO:32.

[0011] In one embodiment, the isolated anti-TREM-1 antibody or antigen-binding fragment thereof comprises a variable region of a light chain (VL) having a sequence set forth in any one of SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, and SEQ ID NO:38, or a sequence having at least 80% identity to any one of SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, and SEQ ID NO:38.

[0012] In one embodiment, the isolated anti-TREM-1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) having the sequence set forth in SEQ ID NO:27, or a sequence having at least 80% identity to SEQ ID NO:27, and a light chain variable region (VL) having the sequence set forth in SEQ ID NO:33, or a sequence having at least 80% identity to SEQ ID NO:33.

[0013] In one embodiment, the isolated anti-TREM1 antibody is a monoclonal antibody. In one embodiment, the isolated anti-TREM1 antibody is a humanized or human antibody. In one embodiment, the isolated anti-TREM-1 antibody or antigen-binding fragment thereof is monovalent, preferably the antigen-binding fragment is a Fab, Fv, or scFv.

[0014] Another object of the present invention is a fusion protein comprising said anti-TREM-1 antibody or an antigen-binding fragment thereof.

[0015] Another object of the invention is a nucleic acid encoding said anti-TREM-1 antibody or antigen-binding fragment, or said fusion protein.

[0016] Another object of the invention is a pharmaceutical composition comprising said isolated anti-TREM-1 antibody or antigen-binding fragment thereof, or said fusion protein, and at least one pharma- ceutically acceptable excipient.

[0017] Another object of the invention is said isolated anti-TREM-1 antibody or antigen-binding fragment thereof, said fusion protein, or said pharmaceutical composition for use as a medicament.

[0018] Another object of the present invention is the above-mentioned isolated anti-TREM-1 antibody or antigen-binding fragment thereof, the above-mentioned fusion protein, or the above-mentioned pharmaceutical composition for use in the treatment of a disease selected from an inflammatory or autoimmune disease; a cardiovascular disease; cancer, particularly a solid cancer; and an infectious disease, particularly a bacterial or viral infection. In one embodiment, the inflammatory or autoimmune disease is selected from inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, irritable bowel syndrome, fibrosis, pulmonary fibrosis, liver fibrosis, nonalcoholic steatohepatitis (NASH), alcoholic hepatitis, rheumatoid arthritis, psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, vasculitis, systemic inflammatory response syndrome (SIRS), sepsis, septic shock, type I diabetes, Graves' disease, multiple sclerosis, autoimmune myocarditis, Kawasaki disease, coronary artery disease, chronic obstructive pulmonary disease, interstitial lung disease, autoimmune thyroiditis, scleroderma, systemic sclerosis, osteoarthritis, atopic dermatitis, vitiligo, graft versus host disease, Sjogren's syndrome, autoimmune nephritis, Goodpasture's syndrome, chronic inflammatory demyelinating polyneuropathy, allergy, and asthma. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] definition In the present invention, the following terms have the following meanings:

[0020] "Ab" refers to antibody (or antibodies) and "mAb" refers to monoclonal antibody (or monoclonal antibodies).

[0021] The word "about" before a number includes up to ±10% of the value of said number. It is to be understood that the value to which the term "about" refers is itself specifically and preferably disclosed.

[0022] "Affinity" is used to define the strength of an antibody-antigen complex. Affinity measures the strength of interaction between the epitope on the antibody and the antigen-binding site. It is defined as the affinity constant, K A or the dissociation constant K D It can be represented by:

[0023] As used herein, "antibody" and "immunoglobulin or Ig" may be used interchangeably and refer to a protein having a combination of two heavy chains (H chains) and two light chains (L chains), whether or not they have an associated specific immune reactivity. "Antibody" refers to such an aggregate having significant known specific immune reaction activity against an antigen of interest (e.g., human TREM-1). The term "anti-hTREM-1 antibody" is used herein to refer to an antibody that exhibits immunological specificity for human TREM-1 protein. As explained elsewhere herein, "specificity" for human TREM-1 (hTREM-1) does not exclude cross-reactivity with orthologs of hTREM-1, such as monkey TREM-1. As discussed above, antibodies and immunoglobulins comprise light and heavy chains, with or without interchain covalent bonds between them. Basic immunoglobulin structure in vertebrate systems is relatively well understood. The collective term "immunoglobulin" includes five separate biochemically distinct classes of immunoglobulins: IgG, IgM, IgA, IgD, and IgE. Although the disclosure herein is generally directed to the IgG class of immunoglobulins, all five classes are within the scope of the present invention. IgG immunoglobulins contain two identical light chains having a molecular weight of about 23 kDa and two identical heavy chains having a molecular weight of about 53-70 kDa. The four chains are joined by disulfide bonds in a "Y" configuration, with the light chains attached like arms to the heavy chains starting at the mouth of the "Y" and continuing through the variable region. The light chains of immunoglobulins are classified as either kappa (κ) or lambda (λ). Each heavy chain class can be associated with either a κ or λ light chain. Generally, the light and heavy chains are covalently linked to each other, and the "tail" regions of the two heavy chains are linked to each other by covalent disulfide bonds or non-covalent bonds when the immunoglobulin is produced by either a hybridoma, a B cell, or a genetically modified host cell. In the heavy chain, the amino acid sequence runs from the N-terminus at the forked end of the Y configuration to the C-terminus at the bottom of each chain. Those skilled in the art will understand that heavy chains are classified as gamma (γ), mu (μ), alpha (α), delta (δ), or epsilon (ε), with several subclasses within them (e.g., γ1-γ4).It is the nature of this chain that determines the "class" of the antibody as IgG, IgM, IgA, IgD or IgE, respectively. Immunoglobulin subclasses or "isotypes" (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, etc.) are well characterized and are known to confer functional specialization. Modified versions of each of these classes and isotypes will be readily recognized by the skilled artisan in view of the present disclosure and are therefore within the scope of the present invention. As set forth herein, the variable region of an antibody enables the antibody to selectively recognize and specifically bind to an epitope on an antigen. That is, the light chain variable region or domain (VL) and the heavy chain variable region or domain (VH) of an antibody combine to form a variable region that defines a three-dimensional antigen-binding site. This quaternary antibody structure forms the antigen-binding site present at the end of each arm of the "Y". More specifically, the antigen-binding site is defined by three complementarity determining regions (CDRs) on each VH and VL.

[0024] As used herein, the term "antibody fragment", including the term "antigen-binding fragment (of an antibody)", refers to at least a portion of an intact antibody, preferably the antigen-binding or variable region of an intact antibody, which retains the ability to specifically interact (e.g., by binding, steric hindrance, stabilization / destabilization, spatial distribution) with an epitope of an antigen. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, Fv fragments, scFv fragments, disulfide-linked Fv (sdFv), Fd fragments consisting of a VH domain and a CH1 domain, linear antibodies, single domain antibodies such as sdAb (either VL or VH), camelid VHH domains, multispecific antibodies formed from antibody fragments such as bivalent fragments comprising two Fab fragments linked by a disulfide bridge at the hinge region, and isolated CDR or other epitope-binding fragments of an antibody. Antigen-binding fragments can also be incorporated into single domain antibodies, maxibodies, minibodies, nanobodies, intrabodies, diabodies, triabodies, tetrabodies, v-NAR and bis-scFv. Antigen-binding fragments can be grafted into polypeptide-based scaffolds such as fibronectin type III. Papain digestion of an antibody produces two identical antigen-binding fragments, called "Fab" fragments, and a remaining "Fc" fragment, a designation that reflects the ability to crystallize. The Fab fragment consists of the entire L chain, together with the variable region of the H chain (VH) and the first constant domain of the H chain (CH1). Each Fab fragment is monovalent with respect to antigen binding, i.e., it has a single antigen-binding site. Pepsin treatment of an antibody produces a single large F(ab')2 fragment that roughly corresponds to two disulfide-linked Fab fragments with bivalent antigen-binding activity and is still capable of cross-linking antigen. Fab' fragments differ from Fab fragments by having additional few residues at the carboxy terminus of the CH1 domain including one or more cysteines from the antibody hinge region. Fab'-SH is the designation herein for Fab' in which the cysteine ​​residue(s) of the constant domains bear a free thiol group. F(ab')2 antibody fragments originally were produced as pairs of Fab' fragments which have hinge cysteines between them. Other chemical couplings of antibody fragments are also known.

[0025] "Antigen" or "Ag" refers to a molecule that elicits an immune response, which may include either antibody production and / or activation of specific immunologically competent cells.

[0026] As used herein, the term "binding fragment" and, in particular, the term "antigen-binding fragment" refers to a portion or region of an antibody according to the invention that comprises fewer amino acid residues than the whole antibody. A "binding fragment" binds antigen and / or competes for antigen binding with the whole antibody from which it was derived. Antibody-binding fragments include, but are not limited to, single chain antibodies, Fv, Fab, Fab', Fab'-SH, F(ab)'2, Fd, defucosylated antibodies, diabodies, triabodies and tetrabodies.

[0027] "CDR" or "complementarity determining region" refers to the non-contiguous antigen-binding sites found within the variable regions of both heavy and light chain polypeptides. The exact amino acid sequence boundaries of a given CDR can be determined using any of a number of well-known schemes, including those described by Kabat et al. (1991), "Sequences of Proteins of Immunological Interest," 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD ("Kabat" numbering scheme), Al-Lazikani et al., (1997) JMB 273, 927-948 ("Chothia" numbering scheme), or a combination thereof. More recently, a universal numbering system, the ImMunoGeneTics (IMGT) information system™ (Lefranc et al., Nucleic Acids Res. 27:209-212 1999), has been developed and widely adopted. IMGT is an integrated information system specializing in immunoglobulins (IG), T cell receptors (TR) and major histocompatibility complexes (MHC) for humans and other vertebrates. As used herein, CDRs are referred to in terms of both amino acid sequence and location within a light or heavy chain (e.g., VH -CDR1, VH -CDR2,VH -CDR3, VL -CDR1, VL -CDR2, VL -CDR3). Because the "location" of the CDRs within the structure of an immunoglobulin variable region (or variable domain) is conserved across species and resides in structures called loops, the CDR and framework residues can be readily identified by using a numbering system that aligns the variable region sequences according to structural features. This information can be used when grafting and substituting CDR residues from one immunoglobulin into an acceptor framework, typically from a human antibody. The correspondence between the Kabat numbering system and the IMGT specific numbering system is also well known to those skilled in the art (e.g., Lefranc et al., supra).

[0028] "Epitope" refers to a specific arrangement of amino acids located on a protein or proteins to which an antibody or antigen-binding fragment thereof binds. Epitopes often consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and have specific three-dimensional structural characteristics as well as specific charge characteristics. Epitopes can be linear (or contiguous) or structural, i.e., they can include two or more sequences of amino acids in different regions of the antigen, which may not necessarily be contiguous.

[0029] "Framework regions" or "FR regions" or "non-CDR regions" comprise amino acid residues that are part of the variable region but not part of the CDRs (e.g., using the Kabat definition of CDRs or the IMGT® numbering definition of CDRs). Thus, a variable region framework is about 100-120 amino acids in length, but includes only amino acids outside the CDRs. For specific examples of heavy chain variable regions (VH), and for CDRs as defined by Kabat or Chothia: - FR1 may correspond to the domain of the variable region encompassing amino acids 1 to 25 according to the Chothia / AbM definition, or the domain after 5 residues according to the Kabat definition; - FR2 may correspond to the domain of the variable region encompassing amino acids 36 to 49; - FR3 may correspond to a domain of the variable region encompassing amino acids 67 to 98; and -FR4 may correspond to the domain of the variable region from amino acids 104-110 to the end of the variable region. The framework regions of the light chain are similarly separated by each CDR of the light chain variable region (VL). In naturally occurring antibodies, the six CDRs present in each monomeric antibody are short, non-contiguous sequences of amino acids that are specifically positioned to form an antigen-binding site when the antibody assumes a three-dimensional structure in an aqueous environment. As mentioned above, the remainder of the heavy and light chain variable regions (or domains) show less inter-molecular variability in amino acid sequence and correspond to the framework regions. The framework regions mainly adopt a β-sheet structure, and the CDRs form loops that connect, and in some cases form part of, the β-sheet structure. These framework regions thus act to form a scaffold that provides for the positioning of the six CDRs in the correct orientation by non-covalent interactions between the chains. The antigen-binding site formed by the positioned CDRs defines a surface that is complementary to an epitope on the immunoreactive antigen. This complementary surface promotes non-covalent binding of the antibody to the immunoreactive antigen epitope. As mentioned above, the location of the CDRs can be easily identified by those skilled in the art.

[0030] "Fc domain," "Fc portion," and "Fc region" may be used interchangeably and refer to the C-terminal fragment of an antibody heavy chain, e.g., from about amino acid (aa) 230 to about aa 450 of a human gamma heavy chain, or the corresponding sequences in other types of antibody heavy chains (e.g., α, δ, ε, and μ for human antibodies), or naturally occurring allotypes thereof.

[0031] As used herein, "Fv" refers to the minimum antibody fragment that contains a complete antigen recognition and binding site. This fragment consists of a dimer of one VH and one VL in tight non-covalent association. The folding of these two domains results in six hypervariable loops (three loops each from the heavy and light chains) that contribute to antigen binding and confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv containing only three CDRs specific for an antigen) has the ability to recognize and bind antigen, albeit with a lower affinity than the entire binding site.

[0032] A "heavy chain region" comprises an amino acid sequence derived from a constant domain of an immunoglobulin heavy chain. A protein comprising a heavy chain region comprises at least one of a CH1 domain, a hinge region (e.g., an upper, middle, and / or lower hinge domain), a CH2 domain, a CH3 domain, or a variant or fragment thereof. In certain embodiments, an antibody or antigen-binding fragment thereof according to the invention may comprise an Fc region of an immunoglobulin heavy chain (e.g., a hinge portion, a CH2 domain, and a CH3 domain). In certain embodiments, an antibody or antigen-binding fragment thereof according to the invention lacks at least a region of a constant domain (e.g., all or a portion of a CH2 domain). In certain embodiments, at least one, preferably all, of the constant domains are derived from a human immunoglobulin heavy chain. For example, in one embodiment, the heavy chain region comprises a complete human hinge domain. In certain embodiments, the heavy chain region comprises a complete human Fc region (e.g., hinge, CH2 and CH3 domain sequences from a human immunoglobulin). In certain embodiments, the constant domains of the components of the heavy chain region are derived from different immunoglobulin molecules. For example, the heavy chain region of the protein may comprise a CH2 domain derived from an IgG1 molecule and a hinge region derived from an IgG3 or IgG4 molecule. In certain embodiments, the constant domains are chimeric domains comprising regions of different immunoglobulin molecules. For example, the hinge may comprise a first region derived from an IgG1 molecule and a second region derived from an IgG3 or IgG4 molecule. In certain embodiments, the constant domains of the heavy chain region may be modified such that they vary in amino acid sequence from a naturally occurring (wild-type) immunoglobulin molecule. That is, an antibody or antigen-binding fragment thereof according to the invention may comprise alterations or modifications to one or more of the heavy chain constant domains (CH1, hinge, CH2 or CH3) and / or to the light chain constant domain (CL). Exemplary modifications include addition, deletion or substitution of one or more amino acids in one or more domains.

[0033] The "hinge region" includes the region of the heavy chain molecule that connects the CH1 domain to the CH2 domain. This hinge region contains approximately 25 residues and is flexible, thereby allowing the two N-terminal antigen-binding regions to move independently. The hinge region can be subdivided into three separate domains: the upper, middle, and lower hinge domains (Roux et al., 1998. J Immunol. 161(8):4083-90).

[0034] "Identity" or "identical," as used herein in the context of the sequences of two or more polypeptides, refers to the degree of sequence relatedness between the polypeptides, as determined by the number of matches between strings of two or more amino acid residues. "Identity" measures the percentage of match between the smaller of two or more sequences, with gap alignments (if any) that are addressed by a particular mathematical model or computer program (i.e., an "algorithm"). The identity of related polypeptides can be readily calculated by known methods. Such methods include, but are not limited to, those described in Computational Molecular Biology, Lesk, AM, (ed.), Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, DW, (ed.), Academic Press, New York, 1993; Computer Analysis of Sequence Data, Part 1, Griffin, AM, and Griffin, HG, (eds.), Humana Press, New Jersey, 1994; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; Sequence Analysis Primers, Gribskov, M. and Devereux, J., (eds.), M. Stockton Press, New York, 1991; and Carillo et al., SIAM J. Applied Math. 48, 1073 (1988). Preferred methods to determine identity are designed to give the largest match between the sequences tested. Methods to determine identity are described in publicly available computer programs.Preferred computer program methods for determining identity between two sequences include the GCG program package, including GAP (Devereux et al., Nucl. Acid. Res.\2, 387 (1984); Genetics Computer Group, University of Wisconsin, Madison, Wis.), BLASTP, BLASTN, and FASTA (Altschul et al., J. MoI. Biol. 215, 403-410 (1990)). The BLASTX program is publicly available from the National Center for Biotechnology Information (NCBI) and other sources (BLAST Manual, Altschul et al. NCB / NLM / NIH Bethesda, Md. 20894; Altschul et al., J. MoI. Biol. 215, 403-410 (1990)). The well-known Smith-Waterman algorithm may also be used to determine identity.

[0035] "Monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies in the population are identical except for possible natural mutations that may be present in small amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. Moreover, 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. In addition to their specificity, monoclonal antibodies are advantageous in that they may be synthesized uncontaminated by other antibodies. The modifier "monoclonal" should not be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies or antigen-binding fragments thereof according to the invention may be prepared by the hybridoma method first described by Kohler et al., 1975. Nature. 256(5517):495-7, or may be made using recombinant DNA methods in bacterial, eukaryotic or plant cells (U.S. Patent No. 4,816,567). The "monoclonal antibodies" can also be isolated from phage antibody libraries using the techniques described in Clackson et al., 1991. Nature. 352(6336):624-8 and Marks et al., 1991. J Mol Biol. 222(3):581-97, for example.

[0036] "Single-chain antibody," as used herein, refers to any antibody or fragment thereof that is a protein having a primary structure comprising or consisting of an uninterrupted sequence of contiguous amino acid residues, including, without limitation, (1) a single-chain Fv molecule (scFv); (2) a single-chain protein comprising only a light chain variable region, without an associated heavy chain portion, or a fragment thereof comprising the three CDRs of the light chain variable region (VL); and (3) a single-chain protein comprising only a heavy chain variable region (VH), without an associated light chain portion, or a fragment thereof comprising the three CDRs of the heavy chain variable region.

[0037] "Single-chain Fv", also abbreviated as "sFv" or "scFv", refers to an antibody fragment comprising a VH and a VL linked into a single amino acid chain. Preferably, the scFv amino acid sequence further comprises a peptide linker between the VH and VL which enables the scFv to form the desired structure for antigen binding.

[0038] "Subject" refers to a mammal, preferably a human. According to the present invention, the subject is a mammal, preferably a human.

[0039] A "therapeutically effective amount" or "therapeutically effective dose" refers to an amount or dosage or concentration of an anti-hTREM-1 antibody or antigen-binding fragment thereof described herein intended to prevent, reduce, alleviate or slow (alleviate) one or more symptoms or signs of a disease without causing significant negative or adverse side effects to the subject in need of treatment.

[0040] "Treatment" or "treatment" refers to therapeutic treatment, prophylactic (or preventative) treatment, or both therapeutic and prophylactic (or preventative) treatment, the purpose of which is to prevent, reduce, alleviate, and / or slow down (alleviate) one or more symptoms or signs of a disease.

[0041] "TREM-1" refers to "triggering receptor expressed on myeloid cell-1" and is sometimes known as CD354. As mentioned above, TREM-1 is a membrane-bound immunoreceptor that contains three separate domains: an Ig-like structure (mainly involved in ligand binding), a transmembrane portion, and a short cytoplasmic tail. Unless otherwise indicated, the human TREM-1 protein has the amino acid sequence set forth in SEQ ID NO: 43, which corresponds to UniProtKB / Swiss-Prot accession numbers Q9NP99-1, last modified on October 1, 2000, and UniProtKB accession number Q38L15-1, last modified on November 22, 2005. Several transcripts are known for human TREM-1. The transcript commonly referred to as TREM1-201 (transcript ID ensembl ENST00000244709.8) encodes the amino acid sequence set forth in SEQ ID NO: 43. The transcript commonly referred to as TREM1-202 is also known as TREM-1 isoform 2 (ensembl transcript ID ENST00000334475.10) and encodes the amino acid sequence set forth in SEQ ID NO: 44 (corresponding to UniProtKB / Swiss-Prot accession number Q9NP99-2). The transcript commonly referred to as TREM1-207 is also known as TREM-1 isoform 3 (ensembl transcript ID ENST00000591620.1) and encodes the amino acid sequence set forth in SEQ ID NO: 45 (UniProtKB / Swiss-Prot accession number Q9NP99-3). The transcript commonly referred to as TREM1-204 (ensembl transcript ID ENST00000589614.5) encodes the amino acid sequence set forth in SEQ ID NO: 46 (corresponding to UniProtKB / Swiss-Prot accession number K7EKM5-1, last modified on January 9, 2013).

[0042] "hTREM-1" refers to human TREM-1.

[0043] "Variable" refers to the fact that certain regions of VH and VL differ widely in sequence among antibodies and are used in the binding and specificity of each particular antibody for its target antigen. However, this variability is not evenly distributed throughout the variable domains of antibodies. It is concentrated in three segments called "hypervariable loops" in each of VL and VH that form part of the antigen-binding site. Each of the six hypervariable loops may comprise a portion of a "complementarity determining region" or "CDR", as defined herein above.

[0044] "VH" refers to the variable region (or domain) of an antibody heavy chain.

[0045] "VL" refers to the variable region (or domain) of the light chain of an antibody.

[0046] Detailed Description The present invention relates to isolated antibodies, or antigen-binding fragments thereof, that bind to Triggering Receptor Expressed on Myeloid cells-1 (human TREM-1 or hTREM-1). The present invention therefore relates to isolated anti-human TREM-1 (or anti-hTREM-1) antibodies, or antigen-binding fragments thereof.

[0047] According to one embodiment, the isolated antibody, or antigen-binding fragment thereof, specifically binds to hTREM-1. In other words, according to one embodiment, the isolated antibody, or antigen-binding fragment thereof, is specific for hTREM-1.

[0048] The antibody or antigen-binding fragment thereof is capable of binding to the antigen (e.g., TREM-1, particularly hTREM-1) at a detectable level, preferably at about 10 3 M -1 More than 5×10, preferably about 3 M -1 , 10 4 M -1 , 5×10 4 M -1 , or 10 5 M -1The affinity constant (k a ), an antibody is said to be "specific," "immunospecific," or "specifically binds" to an antigen. The affinity of an antibody or antigen-binding fragment thereof for its cognate antigen is also generally measured using the equilibrium dissociation constant (K D Therefore, the antibody or antigen-binding fragment thereof is preferably capable of binding to the antigen (e.g., TREM-1, particularly hTREM-1) at a detectable level, preferably at a level of 10 -6 M or less, preferably 10 -7 M, 5×10 -8 M, 10 -8 M, 5×10 -9 M, 10 -9 M, or 5 x 10 -10 K below M D , or lower K D If it does react with an antigen, it is said to be "immunospecific," "specific for," or "specifically binds" to the antigen.

[0049] The affinity of an antibody or antigen-binding fragment thereof can be readily determined using conventional techniques, such as those described by Scatchard, 1949. Ann NY Acad Sci. 51:660-672. The binding characteristics of an antibody or antigen-binding fragment thereof for an antigen, cell or tissue can generally be determined and evaluated using immunodetection methods including, for example, immunofluorescence-based assays such as ELISA, immunohistochemistry (IHC) and / or fluorescence activated cell sorting (FACS), or by surface plasmon resonance (SPR, e.g., using BIAcore®).

[0050] In one embodiment, the isolated anti-hTREM-1 antibody, or antigen-binding fragment thereof, is about 10×10 -9 M or less, preferably about 9×10 -9 M, 8×10 -9 M, 7×10 -9 M, 6×10 -9 M, 5×10 -9 M, 4×10 -9 M, 3×10 -9 M, 2×10 -9 M or 10 -9K for binding to hTREM-1 is less than or equal to M D In one embodiment, the isolated anti-hTREM-1 antibody, or antigen-binding fragment thereof, has a titer of about 10 -9 M or less, preferably about 9×10 -10 M, 8×10 -10 M, 7×10 -10 M, 6×10 -10 M, or 5 x 10 -10 K for binding to hTREM-1 is less than or equal to M D In one embodiment, the K of an isolated anti-hTREM-1 antibody, or antigen-binding fragment thereof, for binding to hTREM-1 is D is about 1.10 -10 M ~ approx. 10.10 -9 M, preferably about 3.10 -10 M ~ approx. 8.10 -9 The range is M.

[0051] According to one embodiment, the isolated antibody, or antigen-binding fragment thereof, comprises: - SEQ ID NO: 43, which corresponds to the UniProtKB / Swiss-Prot accession number Q9NP99-1, last modified on October 1, 2000, and to the UniProtKB accession number Q38L15-1, last modified on November 22, 2005; and corresponds to the amino acid sequence encoded by the transcript commonly referred to as TREM1-201 (transcript ID ensembl ENST00000244709.8); - SEQ ID NO: 44, which corresponds to the UniProtKB / Swiss-Prot accession number Q9NP99-2; and corresponds to the amino acid sequence encoded by the transcript also commonly referred to as TREM1-202 and known as TREM-1 isoform 2 (ensembl transcript ID ENST00000334475.10); - SEQ ID NO: 45, which corresponds to the UniProtKB / Swiss-Prot accession number Q9NP99-3; and corresponds to the amino acid sequence encoded by the transcript also commonly referred to as TREM1-207 and known as TREM-1 isoform 3 (ensembl transcript ID ENST00000591620.1); or - SEQ ID NO: 46, which corresponds to the UniProtKB / Swiss-Prot accession number K7EKM5-1, last modified on January 9, 2013; and also corresponds to the transcript commonly referred to as TREM1-204 (ensembl transcript ID ENST00000589614.5) The present invention binds human TREM-1 having an amino acid sequence as set forth in at least one of the above.

[0052] In one embodiment, the isolated antibody, or antigen-binding fragment thereof, binds hTREM-1 having the amino acid sequence set forth in SEQ ID NO: 43, hTREM-1 having the amino acid sequence set forth in SEQ ID NO: 44, hTREM-1 having the amino acid sequence set forth in SEQ ID NO: 45, and / or hTREM-1 having the amino acid sequence set forth in SEQ ID NO: 46. In one embodiment, the isolated antibody, or antigen-binding fragment thereof, binds hTREM-1 having the amino acid sequence set forth in SEQ ID NO: 43.

[0053] According to embodiments, the isolated anti-hTREM-1 antibody, or antigen-binding fragment thereof, is capable of inhibiting hTREM-1.

[0054] As used herein, "capable of inhibiting hTREM-1" means that the isolated anti-hTREM-1 antibody, or antigen-binding fragment thereof, is capable of inhibiting the function and / or activity of TREM-1, in particular hTREM-1. Thus, in one embodiment, the isolated anti-hTREM-1 antibody, or antigen-binding fragment thereof, is capable of inhibiting activation of the TREM-1 signaling pathway. In one embodiment, the isolated anti-hTREM-1 antibody, or antigen-binding fragment thereof, is capable of inhibiting clustering of TREM-1. In one embodiment, the isolated anti-hTREM-1 antibody, or antigen-binding fragment thereof, is capable of inhibiting dimerization of TREM-1. In one embodiment, the isolated anti-hTREM-1 antibody, or antigen-binding fragment thereof, is capable of inhibiting ligand binding on TREM-1.

[0055] In one embodiment, the isolated anti-hTREM-1 antibody, or antigen-binding fragment thereof, is capable of inhibiting the function and / or activity of TREM-1, particularly hTREM-1, regardless of the stimulatory signal by which TREM-1 is activated. In one embodiment, the isolated anti-hTREM-1 antibody, or antigen-binding fragment thereof, is capable of inhibiting the function and / or activity of TREM-1, particularly hTREM-1, activated in a ligand-dependent manner (e.g., using PGLYRP1) and / or in a ligand-independent manner (e.g., via a TLR). Stimulation methods for activating TREM-1, particularly hTREM-1, are well known in the art and include, for example, direct activation by incubation of cells expressing TREM-1 (such as neutrophils) with a TREM-1 ligand complex (e.g., PGLYRP1 (peptidoglycan recognition protein 1) complexed with peptidoglycan); and indirect activation by activation of Toll-like receptors (TLRs) (such as TLR2 and / or TLR4) by incubation of cells expressing TREM-1 (such as neutrophils) with peptidoglycan (PGN), lipopolysaccharide (LPS), or heat-killed or heat-inactivated bacteria (such as heat-killed E. coli or heat-killed Bacillus subtilis). Thus, in one embodiment, an isolated anti-hTREM-1 antibody, or antigen-binding fragment thereof, is capable of inhibiting the function and / or activity of TREM-1, particularly hTREM-1, following activation of TREM-1 either by a TREM-1 ligand complex (e.g., PGLYRP1 complexed with PGN), by PGN stimulation, by LPS stimulation, or by heat-killed or heat-inactivated bacteria (e.g., heat-killed E. coli or heat-killed Bacillus subtilis, etc.).

[0056] Methods for assessing TREM-1 inhibition are well known in the art and include, for example, the assays described in the Examples section herein below.

[0057] Assays for assessing TREM-1 inhibition include in vitro assessment of reactive oxygen species (ROS) generation by neutrophils stimulated to activate the TREM-1 signaling pathway, for example by incubation in the presence of lipopolysaccharide (LPS), or in the presence of peptidoglycan (PGN) alone, or in the presence of PGLYRP1 (peptidoglycan recognition protein 1) complexed with peptidoglycan (the so-called PPx or PP complex), or in the presence of heat-killed or heat-inactivated bacteria such as E. coli or Bacillus subtilis. In one embodiment, compounds capable of binding TREM-1 and inhibiting ROS generation by LPS-stimulated, PGN-stimulated, PP-stimulated, or heat-killed or heat-inactivated bacteria-stimulated neutrophils are therefore capable of inhibiting TREM-1.

[0058] Assays to assess TREM-1 inhibition also include assays to assess proinflammatory responses in primate or human cells or primary hTREM-1 knock-in mice cells (e.g., human or cynomolgus monkey or hTREM-1 knock-in mice neutrophil, monocyte, or whole blood samples) stimulated to activate the TREM-1 signaling pathway, for example, by incubation in the presence of LPS, or in the presence of PGN alone, or in the presence of PP complexes, or in the presence of heat-killed or heat-inactivated bacteria such as E. coli or B. subtilis. The present invention also includes in vitro assessment of expression and / or secretion of proinflammatory cytokines / chemokines, such as cytokine chemokine ligand 2 (CCL2), also known as monocyte chemoattractant protein 1 (MCP1), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), interferon gamma-inducible protein 10 (IP-10), also known as CXC motif chemokine ligand 10 (CXCL10), and tumor necrosis factor alpha (TNF-α or TNFa). In one embodiment, a compound capable of binding TREM-1 and inhibiting expression and / or secretion of proinflammatory cytokines / chemokines by LPS-stimulated, PGN-stimulated, PP-stimulated, or heat-killed or heat-inactivated bacteria-stimulated neutrophils or whole blood is therefore capable of inhibiting TREM-1.

[0059] Assays for assessing TREM-1 inhibition also include in vitro assessment of expression and / or secretion of proinflammatory cytokines / chemokines (such as CCL2, also known as MCP1, IL-1β, IL-6, IL-8, IP-10, also known as CXCL10, and TNF-α or TNFa) by human monocytic cell lines (e.g., THP-1 cell line) or human myelomonocytic cell lines (e.g., U937 cell line) stimulated to activate the TREM-1 signaling pathway, for example by incubation in the presence of LPS, or in the presence of PGN alone, or in the presence of PP complexes, or in the presence of heat-killed or heat-inactivated bacteria such as E. coli or Bacillus subtilis. In one embodiment, compounds capable of binding TREM-1 and inhibiting expression and / or secretion of proinflammatory cytokines / chemokines by LPS-stimulated, PGN-stimulated, PP-stimulated, or heat-killed or heat-inactivated bacteria-stimulated human monocytic cell lines or human myelomonocytic cell lines are therefore capable of inhibiting TREM-1.

[0060] Assays for evaluating TREM-1 inhibition also include in vivo evaluation of expression and / or secretion of proinflammatory cytokines / chemokines (such as CCL2 also known as MCP1, IL-1β, IL-6, IL-8, IP-10 also known as CXCL10, and TNF-α or TNFa) in mouse models. Examples of relevant mouse models include transgenic BRGSF mice with endotoxemia induced by LPS, hTREM-1 knock-in mice with endotoxemia induced by LPS, hTREM-1 knock-in mice with systemic inflammatory response induced by PGN, and hTREM-1 knock-in mice treated with, for example, LPS or PGN to induce a local inflammatory response. In one embodiment, compounds capable of binding TREM-1 and inhibiting expression and / or secretion of proinflammatory cytokines / chemokines in the above mouse models are therefore capable of inhibiting TREM-1.

[0061] In one embodiment, the anti-hTREM-1 antibodies, or antigen-binding fragments thereof, described herein are isolated antibodies, or antigen-binding fragments thereof.

[0062] As used herein, "isolated," as in "isolated antibody or antigen-binding fragment thereof," is intended to refer to an antibody, or antigen-binding fragment thereof, that is substantially free of other proteins or antibodies having different antigenic specificities (e.g., an isolated antibody, or antigen-binding fragment thereof, that specifically binds hTREM-1 and is substantially free of proteins or antibodies that specifically bind antigens other than hTREM-1). An isolated antibody, or antigen-binding fragment thereof, that specifically binds hTREM-1 may, however, have cross-reactivity to other related antigens, such as TREM-1 molecules from other genera or species. Furthermore, an isolated antibody, or antigen-binding fragment thereof, will be substantially free of other cellular material and / or chemicals, particularly those that would interfere with therapeutic use of the antibody or antigen-binding fragment thereof, including, but not limited to, enzymes, hormones, and other proteinaceous or non-proteinaceous components.

[0063] In one embodiment, the isolated antibody, or antigen-binding fragment thereof, is purified.

[0064] In one embodiment, an isolated antibody, or antigen-binding fragment thereof, is purified to obtain greater than 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 98%, or 99% purity by weight of the antibody or antigen-binding fragment, preferably greater than 90%, 96%, 97%, 98% or 99% purity by weight. In one embodiment, purity is determined by analytical size exclusion chromatography (SEC).

[0065] In one embodiment, the isolated antibody, or antigen-binding fragment thereof, is purified to obtain an endotoxin level of less than 0.5, 0.4, 0.3, 0.2, or 0.1 EU per mg of protein, preferably less than 0.1 EU per mg of protein.

[0066] In one embodiment, as described above, the isolated antibody, or antigen-binding fragment thereof, binds hTREM-1 and at least one orthologue of hTREM-1. Thus, in one embodiment, the isolated antibody, or antigen-binding fragment thereof, binds hTREM-1 and at least one TREM-1 from another genus or species. In other words, in one embodiment, the isolated antibody, or antigen-binding fragment thereof, is cross-reactive (cross-reacts) with other related antigens. In one embodiment, the isolated antibody, or antigen-binding fragment thereof, binds hTREM-1 and monkey TREM-1 (in particular, cynomolgus monkey TREM-1 or cynomolgus TREM-1 for short).

[0067] In one embodiment, the isolated anti-hTREM-1 antibody or antigen-binding fragment thereof is a molecule selected from the group consisting of or including a whole antibody, a humanized antibody, a single chain antibody, a dimeric single chain antibody, an Fv, a scFv, a Fab, a Fab', a Fab'-SH, a F(ab')2, an Fc-silent antibody or antigen-binding fragment (i.e., an antibody or antigen-binding fragment comprising an Fc-silent), an antibody or antigen-binding fragment having a modified Fc, such as a defucosylated Fc (defucosylated antibody), a bispecific antibody, a diabody, a triabody, and a tetrabody.

[0068] Antigen-binding fragments of antibodies can be obtained using standard methods. For example, Fab or F(ab')2 fragments can be generated by protease digestion of isolated antibodies according to conventional techniques. Alternatively, antigen-binding fragments of antibodies, such as Fab fragments, can be expressed as recombinant proteins.

[0069] In one embodiment, the isolated antibody, or antigen-binding fragment thereof, is monoclonal. In another embodiment, the isolated antibody, or antigen-binding fragment thereof, is polyclonal.

[0070] In one embodiment, the isolated antibody, or antigen-binding fragment thereof, is monovalent. In another embodiment, the isolated antibody, or antigen-binding fragment thereof, is bivalent.

[0071] Examples of monovalent antigen-binding antibody fragments include Fab fragments, scFv fragments, and Fv fragments. In one embodiment, the antigen-binding antibody fragment is thus a molecule selected from the group comprising or consisting of Fab, Fv, and scFv. In one embodiment, the isolated antibody, or antigen-binding fragment thereof, is a Fab.

[0072] In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises a fully human or substantially human heavy chain constant region (referred to herein as C H ) and / or a light chain constant region (abbreviated as C L In one embodiment, the constant region is of human origin.

[0073] The term "substantially human" in the context of the constant region of a humanized or chimeric antibody or antigen-binding fragment thereof, refers to a constant region having an amino acid sequence having at least 70% identity, preferably at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to the amino acid sequence of a human constant region.

[0074] In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, is an antibody that binds to an intact or substantially intact mouse C H and / or C. L In one embodiment, the constant region is of murine origin.

[0075] In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, is a murine antibody, or antigen-binding fragment thereof.

[0076] In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, is a chimeric antibody, or antigen-binding fragment thereof.

[0077] "Chimeric antibody," as used herein, refers to an antibody or antigen-binding fragment thereof that comprises a first amino acid sequence linked to a second amino acid sequence that is not naturally linked to it in nature. The amino acid sequences that are normally present in separate proteins that are combined in a chimeric (or fusion) protein, or that are normally present in the same protein, may be arranged in a new configuration in the chimeric (or fusion) protein. Chimeric proteins can be created, for example, by chemical synthesis, or by creating and translating a polynucleotide in which the peptide regions are encoded in the desired relationship. The term "chimeric antibody," as used herein, refers to an antibody or antigen-binding fragment thereof that comprises a first amino acid sequence linked to a second amino acid sequence that is not naturally linked to it in nature. (a) the constant region, or a portion thereof, is modified, substituted or exchanged such that the variable region is linked to a constant region of a different or altered class, effector function and / or species, or to an entirely different molecule, such as an enzyme, protein, toxin, hormone, growth factor, drug, etc., that confers new properties to the chimeric antibody; or (b) the variable region or a portion thereof is modified, substituted or exchanged with a variable region or portion thereof having a different or altered antigen specificity; or with a corresponding sequence from another species or another antibody class or subclass. It includes antibodies and antigen-binding fragments thereof.

[0078] In one embodiment, the antibody or antigen-binding fragment thereof according to the invention is a deimmunized antibody or antigen-binding fragment thereof.

[0079] Deimmunization aims to reduce the immunogenicity of an antibody or its antigen-binding fragment without interfering with its ability to bind and inhibit hTREM-1 as described herein. Methods for deimmunizing an antibody or its antigen-binding fragment are well known in the art. Such methods include in particular substituting key amino acids within human T-cell epitope sequences present in the amino acid sequence of an antibody or its antigen-binding fragment, thus preventing the binding of the antibody or its antigen-binding fragment to HLA (human leukocyte antigen) and the subsequent induction of a T-cell response.

[0080] In one embodiment, the antibody or antigen-binding fragment thereof according to the invention is a humanized antibody or antigen-binding fragment thereof.

[0081] "Humanized antibody" as used herein refers to a chimeric antibody or antigen-binding fragment thereof that contains minimal sequence derived from a non-human immunoglobulin. This includes antibodies made by non-human cells with variable and constant regions that have been altered to more resemble antibodies made by human cells, for example, by altering the non-human antibody amino acid sequence to incorporate amino acids found in human germline immunoglobulin sequences. Humanized antibodies or antigen-binding fragments thereof according to the invention may contain, for example, in the CDRs, amino acid residues that are not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). The term "humanized antibody" also includes antibodies and antigen-binding fragments thereof in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences. In other words, the term "humanized antibody" may refer to antibodies or antigen-binding fragments thereof in which the CDRs of a recipient human antibody are replaced with CDRs from a donor non-human antibody. A humanized antibody or antigen-binding fragment thereof may also comprise residues of donor origin in framework sequences. A humanized antibody or antigen-binding fragment thereof may also comprise at least a portion of a human immunoglobulin constant region. A humanized antibody or antigen-binding fragment thereof may also comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences.

[0082] A "humanized antibody" can retain the same antigen specificity as the original or donor antibody (such as the donor non-human antibody). However, using certain methods of humanization, the binding affinity and / or specificity of the antibody can be enhanced.

[0083] Methods for humanizing antibodies or antigen-binding fragments thereof according to the invention are well known in the art. For example, humanized antibodies and antigen-binding fragments thereof can be produced according to various techniques, such as by using for immunization transgenic animals engineered to express a human antibody repertoire (Jakobovitz et al., 1993. Nature. 362(6417):255-8) or by selecting an antibody repertoire using phage display methods. Such techniques are known to those skilled in the art and can be carried out starting from a monoclonal antibody or an antigen-binding fragment thereof, as disclosed herein.

[0084] In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, is from the IgG class.

[0085] In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, is derived from the human IgG1 subclass. In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, is therefore an IgG1 antibody, preferably a human IgG1 antibody or a chimeric human IgG1 antibody. In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, is derived from the human IgG4 subclass. In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, is therefore an IgG4 antibody, preferably a human IgG4 antibody or a chimeric human IgG4 antibody. In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, is therefore derived from the human IgG2 subclass. In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, is therefore an IgG2 antibody, preferably a human IgG2 antibody or a chimeric human IgG2 antibody. In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, is therefore derived from the human IgG3 subclass. In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, is therefore an IgG3 antibody, preferably a human IgG3 antibody or a chimeric human IgG3 antibody.

[0086] As used herein, with reference to a given sequence, the phrase "characterized as having an amino acid of [...] replaced by a different amino acid" refers to the occurrence, in said sequence, of a conservative amino acid modification.

[0087] As used herein, the phrase "conservative amino acid modifications" refers to modifications that do not significantly affect or alter the binding characteristics of an antibody or antigen-binding fragment thereof containing that amino acid sequence. Such conservative modifications include amino acid substitutions, additions, and deletions. Modifications can be introduced into an antibody or antigen-binding fragment thereof by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis.

[0088] Conservative amino acid substitutions are typically those in which an amino acid residue is replaced with an amino acid residue having a side chain with similar physicochemical properties. The designated variable region and CDR sequences may contain 1, 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, 31, 32, 33, 34, 35 or more amino acid insertions, deletions and / or substitutions. When substitutions are made, preferred substitutions are conservative modifications. Families of amino acid residues with similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Thus, one or more amino acid residues within the CDRs and / or variable regions of an antibody or antigen-binding fragment thereof according to the invention can be replaced with another amino acid residue from the same side chain family and the altered antibody can be tested for retained function (i.e., the properties described herein, such as binding to hTREM-1) using the assays described herein. In one embodiment, a series of amino acids within the CDRs and / or variable regions of an antibody or antigen-binding fragment thereof according to the invention may be replaced with a structurally similar series which differs in the order and / or composition of side chain family members.

[0089] In the present invention, unless otherwise specified, the positions of the complementarity determining regions (CDRs) are determined using the Kabat nomenclature.

[0090] According to one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises at least one, preferably at least two, and more preferably at least three of the following complementarity determining regions (CDRs): -V H - CDR1: NTYIH (SEQ ID NO: 1); -V H - CDR2: RIDPAX1GX2TKYX3PKVX4G (SEQ ID NO: 2), where X1 is N or G, X2 is N or R, X3 is A, D, or S, and X4 is Q or K; or RIDPAX1GX2TKYX3PKFX4G (SEQ ID NO: 39), where X1 is N or G, X2 is N or R, X3 is A, D, or S, and X4 is Q or K; and / or -V H - CDR3: HX5GX6TMDY (SEQ ID NO: 3), wherein X5 is Y or R and X6 is S or G The variable region of the heavy chain (also called heavy chain variable region or VH) comprises

[0091] According to one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises at least one, preferably at least two, and more preferably at least three of the following CDRs: -V H - CDR1: NTYIH (SEQ ID NO: 1); -V H - CDR2: RIDPAX1GX2TKYX3PKVX4G (SEQ ID NO: 2), where X1 is N or G, X2 is N or R, X3 is A, D or S, and X4 is Q or K; and / or -V H - CDR3: HX5GX6TMDY (SEQ ID NO: 3), wherein X5 is Y or R and X6 is S or G including VH.

[0092] According to one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises at least one, preferably at least two, and more preferably at least three of the following CDRs: -V H - CDR1: NTYIH (SEQ ID NO: 1); -VH - CDR2: RIDPAX1GX2TKYX3PKFX4G (SEQ ID NO: 39), wherein X1 is N or G, X2 is N or R, X3 is A, D or S, and X4 is Q or K; and / or -V H - CDR3: HX5GX6TMDY (SEQ ID NO: 3), wherein X5 is Y or R and X6 is S or G including VH.

[0093] According to one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises the three following CDRs: -V H - CDR1: NTYIH (SEQ ID NO: 1); -V H - CDR2: RIDPAX1GX2TKYX3PKVX4G (SEQ ID NO: 2), wherein X1 is N or G, X2 is N or R, X3 is A, D, or S, and X4 is Q or K; or RIDPAX1GX2TKYX3PKFX4G (SEQ ID NO:39), wherein X1 is N or G, X2 is N or R, X3 is A, D, or S, and X4 is Q or K; and -V H - CDR3: HX5GX6TMDY (SEQ ID NO: 3), wherein X5 is Y or R and X6 is S or G including VH.

[0094] According to one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises the three following CDRs: -V H - CDR1: NTYIH (SEQ ID NO: 1); -V H - CDR2: RIDPAX1GX2TKYX3PKVX4G (SEQ ID NO: 2), where X1 is N or G, X2 is N or R, X3 is A, D, or S, and X4 is Q or K; and -V H - CDR3: HX5GX6TMDY (SEQ ID NO: 3), wherein X5 is Y or R and X6 is S or G including VH.

[0095] According to one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises the three following CDRs: -V H - CDR1: NTYIH (SEQ ID NO: 1); -V H - CDR2: RIDPAX1GX2TKYX3PKFX4G (SEQ ID NO: 39), where X1 is N or G, X2 is N or R, X3 is A, D, or S, and X4 is Q or K; and -V H - CDR3: HX5GX6TMDY (SEQ ID NO: 3), wherein X5 is Y or R and X6 is S or G including VH.

[0096] V having the sequence set forth in SEQ ID NO:2 H Examples of CDR2 include, but are not limited to, RIDPAGGRTKYDPKVKG (SEQ ID NO: 7), RIDPAGGRTKYSPKVQG (SEQ ID NO: 12), RIDPAGGRTKYAPKVKG (SEQ ID NO: 17), RIDPAGGRTKYAPKVQG (SEQ ID NO: 19), and RIDPANGNTKYAPKVQG (SEQ ID NO: 22). Thus, in one embodiment, the V H - CDR2 comprises or is selected from the group consisting of RIDPAGGRTKYDPKVKG (SEQ ID NO: 7), RIDPAGGRTKYSPKVQG (SEQ ID NO: 12), RIDPAGGRTKYAPKVKG (SEQ ID NO: 17), RIDPAGGRTKYAPKVQG (SEQ ID NO: 19), and RIDPANGNTKYAPKVQG (SEQ ID NO: 22).

[0097] V having the sequence set forth in SEQ ID NO:39 H Examples of CDR2 include, but are not limited to, RIDPANGNTKYAPKFQG (SEQ ID NO: 40). Thus, in one embodiment, a V having the sequence set forth in SEQ ID NO: 39 above is H - CDR2 is RIDPANGNTKYAPKFQG (SEQ ID NO: 40).

[0098] V having the sequence set forth in SEQ ID NO:3 H Examples of CDR3 include, but are not limited to, HYGGTMDY (SEQ ID NO: 8), HRGGTMDY (SEQ ID NO: 13), and HYGSTMDY (SEQ ID NO: 23). Thus, in one embodiment, the V H - CDR3 comprises or is selected from the group consisting of HYGGTMDY (SEQ ID NO: 8), HRGGTMDY (SEQ ID NO: 13), and HYGSTMDY (SEQ ID NO: 23).

[0099] In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises at least one (e.g., one, two or three) of the following CDRs, preferably all three of the following CDRs: -V H - CDR1: NTYIH (SEQ ID NO: 1); -V H - CDR2: RIDPAGGRTKYDPKVKG (SEQ ID NO: 7); and / or -V H -CDR3: HYGGTMDY (SEQ ID NO: 8) including VH.

[0100] In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises at least one (e.g., one, two or three) of the following CDRs, preferably all three of the following CDRs: -V H - CDR1: NTYIH (SEQ ID NO: 1); -V H - CDR2: RIDPAGGRTKYSPKVQG (SEQ ID NO: 12); and / or -V H -CDR3: HRGGTMDY (SEQ ID NO: 13) including VH.

[0101] In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises at least one (e.g., one, two or three) of the following CDRs, preferably all three of the following CDRs: -V H - CDR1: NTYIH (SEQ ID NO: 1); -V H - RIDPAGGRTKYAPKVKG (SEQ ID NO: 17); and / or -V H -CDR3: HRGGTMDY (SEQ ID NO: 13) including VH.

[0102] In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises at least one (e.g., one, two or three) of the following CDRs, preferably all three of the following CDRs: -V H - CDR1: NTYIH (SEQ ID NO: 1); -V H - RIDPAGGRTKYAPKVQG (SEQ ID NO: 19); and / or -V H -CDR3: HYGGTMDY (SEQ ID NO: 8) including VH.

[0103] In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises at least one (e.g., one, two or three) of the following CDRs, preferably all three of the following CDRs: -V H - CDR1: NTYIH (SEQ ID NO: 1); -V H -RIDPANGNTKYAPKVQG (SEQ ID NO: 22); and / or -V H -CDR3: HYGSTMDY (SEQ ID NO: 23) including VH.

[0104] In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises at least one (e.g., one, two or three) of the following CDRs, preferably the three following CDRs: -V H - CDR1: NTYIH (SEQ ID NO: 1); -V H -RIDPANGNTKYAPKFQG (SEQ ID NO: 40); and / or -V H -CDR3: HYGSTMDY (SEQ ID NO: 23) including VH.

[0105] In one embodiment, a V having an amino acid sequence as set forth in any one of SEQ ID NOs: 1 to 3, 7, 8, 12, 13, 17, 19, 22, 23, 39, and 40 as described hereinabove H -CDR1, V H -CDR2 and / or V H - Either of the CDR3 is composed of different amino acids In one embodiment, the V sequences having SEQ ID NOs: 1-3, 7, 8, 12, 13, 17, 19, 22, 23, 39, and 40 are characterized as having one, two, three, or more amino acid(s) substituted. H -CDR1, V H -CDR2 and / or V H - Any of the CDR3 may be characterized as having an amino acid sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with a particular CDR or set of CDRs listed in the corresponding SEQ ID NO. In other words, in one embodiment, any of the V H -CDR1, V H -CDR2 and / or V H - CDR3 has an amino acid sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or greater identity with the corresponding amino acid sequence set forth in any one of SEQ ID NOs: 1-3, 7, 8, 12, 13, 17, 19, 22, 23, 39 and 40.

[0106] According to one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises at least one, preferably at least two, and more preferably at least three of the following complementarity determining regions (CDRs): -V L - CDR1: RASX7SVX8NYGISFX9N (SEQ ID NO: 4), where X7 is E or G, X8 is D or S, and X9 is M or L; -V L -CDR2:AAX 10 X11 X 12 X 13 X 14 (SEQ ID NO:5), where X 10 is S or E, and X 11 is N or Y, and X 12 is Q or R, and X 13 is G, A, or K, and X 14 is S or R; and / or -V L -CDR3:QQSX 15 X 16 X 17 PX 18 T (SEQ ID NO: 6), where X 15 is K, R, or S; X 16 is E, H, or N, and X 17 is V or F, and X 18 is W or Y The variable region of the light chain (also referred to as light chain variable region or VL) comprises:

[0107] According to one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises the three following CDRs: -V L - CDR1: RASX7SVX8NYGISFX9N (SEQ ID NO: 4), where X7 is E or G, X8 is D or S, and X9 is M or L; -V L -CDR2:AAX 10 X 11 X 12 X 13 X 14 (SEQ ID NO:5), where X 10 is S or E, and X 11 is N or Y, and X 12 is Q or R, and X 13 is G, A, or K, and X 14 is S or R; and -V L -CDR3:QQSX 15 X 16 X 17 PX 18 T (SEQ ID NO: 6), where X 15 is K, R, or S; X 16is E, H, or N, and X 17 is V or F, and X 18 is W or Y Contains, contains VL

[0108] V having the sequence set forth in SEQ ID NO:4 herein above L Examples of CDR1 include, but are not limited to, RASESVDNYGISFLN (SEQ ID NO: 9), RASQSVSNYGISFLN (SEQ ID NO: 14), and RASESVDNYGISFMN (SEQ ID NO: 24). Thus, in one embodiment, the V L - CDR1 comprises or is selected from the group consisting of RASESVDNYGISFLN (SEQ ID NO: 9), RASQSVSNYGISFLN (SEQ ID NO: 14), and RASESVDNYGISFMN (SEQ ID NO: 24).

[0109] V having the sequence set forth in SEQ ID NO:5 herein above L Examples of CDR2 include, but are not limited to, AAEYRGR (SEQ ID NO: 10), AASYQKR (SEQ ID NO: 15), AAEYQGR (SEQ ID NO: 20), AAEYRAR (SEQ ID NO: 21), and AASNQGS (SEQ ID NO: 25). Thus, in one embodiment, a V L - CDR2 comprises or is selected from the group consisting of AAEYRGR (SEQ ID NO: 10), AASYQKR (SEQ ID NO: 15), AAEYQGR (SEQ ID NO: 20), AAEYRAR (SEQ ID NO: 21), and AASNQGS (SEQ ID NO: 25).

[0110] V having the sequence set forth in SEQ ID NO:6 hereinabove L Examples of CDR3 include, but are not limited to, QQSRHVPYT (SEQ ID NO: 11), QQSSNFPWT (SEQ ID NO: 16), QQSSNVPYT (SEQ ID NO: 18), and QQSKEVPWT (SEQ ID NO: 26). Thus, in one embodiment, a V L- CDR3 comprises or is selected from the group consisting of QQSRHVPYT (SEQ ID NO: 11), QQSSNFPWT (SEQ ID NO: 16), QQSSNVPYT (SEQ ID NO: 18), and QQSKEVPWT (SEQ ID NO: 26).

[0111] In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises at least one (e.g., one, two or three) of the following CDRs, preferably all three of the following CDRs: -V L - CDR1: RASESVDNYGISFLN (SEQ ID NO: 9); -V L - CDR2: AAEYRGR (SEQ ID NO: 10); and / or -V L - CDR3: QQSRHVPYT (SEQ ID NO: 11); Including, including VL.

[0112] In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises at least one (e.g., one, two or three) of the following CDRs, preferably all three of the following CDRs: -V L - CDR1: RASQSVSNYGISFLN (SEQ ID NO: 14); -V L - CDR2: AASYQKR (SEQ ID NO: 15) and / or -V L - CDR3: QQSSNFPWT (SEQ ID NO: 16); Including, including VL.

[0113] In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises at least one (e.g., one, two or three) of the following CDRs, preferably all three of the following CDRs: -V L - CDR1: RASQSVSNYGISFLN (SEQ ID NO: 14); -V L - CDR2: AAEYRGR (SEQ ID NO: 10); and / or -V L - CDR3: QQSSNVPYT (SEQ ID NO: 18); Including, including VL.

[0114] In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises at least one (e.g., one, two or three) of the following CDRs, preferably all three of the following CDRs: -V L - CDR1: RASQSVSNYGISFLN (SEQ ID NO: 14); -V L - CDR2: AAEYQGR (SEQ ID NO: 20); and / or -V L - CDR3: QQSSNVPYT (SEQ ID NO: 18); Including, including VL.

[0115] In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises at least one (e.g., one, two or three) of the following CDRs, preferably all three of the following CDRs: -V L - CDR1: RASQSVSNYGISFLN (SEQ ID NO: 14); -V L - CDR2: AAEYRAR (SEQ ID NO: 21); and / or -V L - CDR3: QQSSNVPYT (SEQ ID NO: 18); Including, including VL.

[0116] In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises at least one (e.g., one, two or three) of the following CDRs, preferably all three of the following CDRs: -V L - CDR1: RASESVDNYGISFMN (SEQ ID NO: 24); -V L - CDR2: AASNQGS (SEQ ID NO: 25); and / or -V L - CDR3: QQSKEVPWT (SEQ ID NO: 26); Including, including VL.

[0117] In one embodiment, a V having an amino acid sequence set forth in any one of SEQ ID NOs: 4 to 6, 9 to 11, 14 to 16, 18, 20, 21, and 24 to 25 described herein above. L -CDR1, V L -CDR2 and / or V L Any of the CDR3 may be characterized as having one, two, three or more amino acid(s) substituted with a different amino acid. In one embodiment, the V L -CDR1, V L -CDR2 and / or V L - Any of the CDR3 may be characterized as having an amino acid sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with a particular CDR or set of CDRs listed in the corresponding SEQ ID NO. In other words, in one embodiment, any of the V L -CDR1, V L -CDR2 and / or V L - CDR3 has an amino acid sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or greater identity with a corresponding amino acid sequence set forth in any one of SEQ ID NOs: 4 to 6, 9 to 11, 14 to 16, 18, 20, 21, and 24 to 25.

[0118] According to one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises: At least one, preferably at least two, more preferably three of the following CDRs: -V H - CDR1: NTYIH (SEQ ID NO: 1); -V H- CDR2: RIDPAX1GX2TKYX3PKVX4G (SEQ ID NO: 2), where X1 is N or G, X2 is N or R, X3 is A, D, or S, and X4 is Q or K; or RIDPAX1GX2TKYX3PKFX4G (SEQ ID NO: 39), where X1 is N or G, X2 is N or R, X3 is A, D, or S, and X4 is Q or K; and / or -V H - CDR3: HX5GX6TMDY (SEQ ID NO: 3), wherein X5 is Y or R and X6 is S or G A heavy chain variable region (VH) comprising: At least one, preferably at least two, more preferably three of the following CDRs: -V L - CDR1: RASX7SVX8NYGISFX9N (SEQ ID NO: 4), where X7 is E or G, X8 is D or S, and X9 is M or L; -V L -CDR2:AAX 10 X 11 X 12 X 13 X 14 (SEQ ID NO:5), where X 10 is S or E, and X 11 is N or Y, and X 12 is Q or R, and X 13 is G, A, or K, and X 14 is S or R; and / or -V L -CDR3:QQSX 15 X 16 X 17 PX 18 T (SEQ ID NO: 6), where X 15 is K, R, or S; X 16 is E, H, or N, and X 17 is V or F, and X 18 is W or Y The variable region of the light chain (VL), Includes.

[0119] In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, At least one, preferably at least two, more preferably three of the following CDRs: -V H - CDR1: NTYIH (SEQ ID NO: 1); -V H - CDR2: RIDPAX1GX2TKYX3PKVX4G (SEQ ID NO: 2), where X1 is N or G, X2 is N or R, X3 is A, D or S, and X4 is Q or K; and / or -V H - CDR3: HX5GX6TMDY (SEQ ID NO: 3), wherein X5 is Y or R and X6 is S or G VH; and At least one, preferably at least two, more preferably three of the following CDRs: -V L - CDR1: RASX7SVX8NYGISFX9N (SEQ ID NO: 4), where X7 is E or G, X8 is D or S, and X9 is M or L; -V L -CDR2:AAX 10 X 11 X 12 X 13 X 14 (SEQ ID NO:5), where X 10 is S or E, and X 11 is N or Y, and X 12 is Q or R, and X 13 is G, A, or K, and X 14 is S or R; and / or -V L -CDR3:QQSX 15 X 16 X 17 PX 18 T (SEQ ID NO:6), where X 15 is K, R, or S; X 16 is E, H, or N, and X 17 is V or F, and X 18 is W or Y Including, VL Includes.

[0120] In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, At least one, preferably at least two, more preferably three of the following CDRs: -V H - CDR1: NTYIH (SEQ ID NO: 1); -V H - CDR2: RIDPAX1GX2TKYX3PKFX4G (SEQ ID NO: 39), where X1 is N or G, X2 is N or R, X3 is A, D or S, and X4 is Q or K; and / or -V H - CDR3: HX5GX6TMDY (SEQ ID NO: 3), wherein X5 is Y or R and X6 is S or G VH; and At least one, preferably at least two, more preferably three of the following CDRs: -V L - CDR1: RASX7SVX8NYGISFX9N (SEQ ID NO: 4), where X7 is E or G, X8 is D or S, and X9 is M or L; -V L -CDR2:AAX 10 X 11 X 12 X 13 X 14 (SEQ ID NO:5), where X 10 is S or E, and X 11 is N or Y, and X 12 is Q or R, and X 13 is G, A, or K, and X 14 is S or R; and / or -V L -CDR3:QQSX 15 X 16 X 17 PX 18 T (SEQ ID NO:6), where X 15 is K, R, or S; X 16 is E, H, or N, and X 17 is V or F, and X 18 is W or Y Including, VL Includes.

[0121] According to one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises: The three following CDRs: -V H - CDR1: NTYIH (SEQ ID NO: 1); -V H -CDR2: RIDPAX1GX2TKYX3PKVX4G (SEQ ID NO: 2), where X1 is N or G, X2 is N or R, X3 is A, D, or S, and X4 is Q or K; or RIDPAX1GX2TKYX3PKFX4G (SEQ ID NO: 39), where X1 is N or G, X2 is N or R, X3 is A, D, or S, and X4 is Q or K; and -V H - CDR3: HX5GX6TMDY (SEQ ID NO: 3), wherein X5 is Y or R and X6 is S or G VH; and The three following CDRs: -V L - CDR1: RASX7SVX8NYGISFX9N (SEQ ID NO: 4), where X7 is E or G, X8 is D or S, and X9 is M or L; -V L -CDR2:AAX 10 X 11 X 12 X 13 X 14 (SEQ ID NO:5), where X 10 is S or E, and X 11 is N or Y, and X 12 is Q or R, and X 13 is G, A, or K, and X 14 is S or R; and -V L -CDR3:QQSX 15 X 16 X 17 PX 18 T (SEQ ID NO: 6), where X 15 is K, R, or S; X 16 is E, H, or N, and X 17 is V or F, and X 18 is W or Y Including, VL Includes.

[0122] According to one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises: The three following CDRs: -V H - CDR1: NTYIH (SEQ ID NO: 1); -V H - CDR2: RIDPAX1GX2TKYX3PKVX4G (SEQ ID NO: 2), where X1 is N or G, X2 is N or R, X3 is A, D, or S, and X4 is Q or K; and -V H - CDR3: HX5GX6TMDY (SEQ ID NO: 3), wherein X5 is Y or R and X6 is S or G VH; and The three following CDRs: -V L - CDR1: RASX7SVX8NYGISFX9N (SEQ ID NO: 4), where X7 is E or G, X8 is D or S, and X9 is M or L; -V L -CDR2:AAX 10 X 11 X 12 X 13 X 14 (SEQ ID NO:5), where X 10 is S or E, and X 11 is N or Y, and X 12 is Q or R, and X 13 is G, A, or K, and X 14 is S or R; and -V L -CDR3:QQSX 15 X 16 X 17 PX 18 T (SEQ ID NO:6), where X 15 is K, R, or S; X 16 is E, H, or N, and X 17 is V or F, and X 18 is W or Y Including, VL Includes.

[0123] According to one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises: The three following CDRs: -V H - CDR1: NTYIH (SEQ ID NO: 1); -V H - CDR2: RIDPAX1GX2TKYX3PKFX4G (SEQ ID NO: 39), where X1 is N or G, X2 is N or R, X3 is A, D, or S, and X4 is Q or K; and -V H - CDR3: HX5GX6TMDY (SEQ ID NO: 3), wherein X5 is Y or R and X6 is S or G VH; and The three following CDRs: -V L - CDR1: RASX7SVX8NYGISFX9N (SEQ ID NO: 4), where X7 is E or G, X8 is D or S, and X9 is M or L; -V L -CDR2:AAX 10 X 11 X 12 X 13 X 14 (SEQ ID NO:5), where X 10 is S or E, and X 11 is N or Y, and X 12 is Q or R, and X 13 is G, A, or K, and X 14 is S or R; and -V L -CDR3:QQSX 15 X 16 X 17 PX 18 T (SEQ ID NO: 6), where X 15 is K, R, or S; X 16 is E, H, or N, and X 17 is V or F, and X 18 is W or Y Including, VL Includes.

[0124] According to one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, has the following CDRs: -V H - CDR1: NTYIH (SEQ ID NO: 1), V H - CDR2: RIDPAGGRTKYDPKVKG (SEQ ID NO: 7), V H -CDR3: HYGGTMDY (SEQ ID NO: 8), V L - CDR1: RASESVDNYGISFLN (SEQ ID NO: 9), V L - CDR2: AAEYRGR (SEQ ID NO: 10), and V L - CDR3: QQSRHVPYT (SEQ ID NO: 11); or -V H - CDR1: NTYIH (SEQ ID NO: 1), V H - CDR2: RIDPAGGRTKYSPKVQG (SEQ ID NO: 12), V H -CDR3: HRGGTMDY (SEQ ID NO: 13), V L - CDR1: RASQSVSNYGISFLN (SEQ ID NO: 14), V L - CDR2: AASYQKR (SEQ ID NO: 15), and V L - CDR3: QQSSNFPWT (SEQ ID NO: 16); or -V H - CDR1: NTYIH (SEQ ID NO: 1), V H - CDR2: RIDPAGGRTKYAPKVKG (SEQ ID NO: 17), V H -CDR3: HRGGTMDY (SEQ ID NO: 13), V L - CDR1: RASQSVSNYGISFLN (SEQ ID NO: 14), V L - CDR2: AAEYRGR (SEQ ID NO: 10), and V L - CDR3: QQSSNVPYT (SEQ ID NO: 18); or -V H - CDR1: NTYIH (SEQ ID NO: 1), V H -CDR2: RIDPAGGRTKYAPKVQG (SEQ ID NO: 19), V H -CDR3: HYGGTMDY (SEQ ID NO: 8), V L - CDR1: RASQSVSNYGISFLN (SEQ ID NO: 14), V L- CDR2: AAEYQGR (SEQ ID NO: 20), and V L - CDR3: QQSSNVPYT (SEQ ID NO: 18); or -V H - CDR1: NTYIH (SEQ ID NO: 1), V H - CDR2: RIDPAGGRTKYAPKVKG (SEQ ID NO: 17), V H -CDR3: HRGGTMDY (SEQ ID NO: 13), V L - CDR1: RASQSVSNYGISFLN (SEQ ID NO: 14), V L - CDR2: AAEYRAR (SEQ ID NO: 21), and V L - CDR3: QQSSNVPYT (SEQ ID NO: 18); or -V H - CDR1: NTYIH (SEQ ID NO: 1), V H -CDR2: RIDPANGNTKYAPKVQG (SEQ ID NO: 22), V H -CDR3: HYGSTMDY (SEQ ID NO: 23), V L - CDR1: RASESVDNYGISFMN (SEQ ID NO: 24), V L - CDR2: AASNQGS (SEQ ID NO: 25), and V L - CDR3: QQSKEVPWT (SEQ ID NO: 26); or -V H - CDR1: NTYIH (SEQ ID NO: 1), V H -CDR2: RIDPANGNTKYAPKFQG (SEQ ID NO: 40), V H -CDR3: HYGSTMDY (SEQ ID NO: 23), V L - CDR1: RASESVDNYGISFMN (SEQ ID NO: 24), V L - CDR2: AASNQGS (SEQ ID NO: 25), and V L -CDR3: QQSKEVPWT (SEQ ID NO: 26) Includes.

[0125] According to one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, has the following CDRs: -V H - CDR1: NTYIH (SEQ ID NO: 1), V H- CDR2: RIDPAGGRTKYDPKVKG (SEQ ID NO: 7), V H -CDR3: HYGGTMDY (SEQ ID NO: 8), V L - CDR1: RASESVDNYGISFLN (SEQ ID NO: 9), V L - CDR2: AAEYRGR (SEQ ID NO: 10), and V L - CDR3: QQSRHVPYT (SEQ ID NO: 11); or -V H - CDR1: NTYIH (SEQ ID NO: 1), V H - CDR2: RIDPAGGRTKYSPKVQG (SEQ ID NO: 12), V H -CDR3: HRGGTMDY (SEQ ID NO: 13), V L - CDR1: RASQSVSNYGISFLN (SEQ ID NO: 14), V L - CDR2: AASYQKR (SEQ ID NO: 15), and V L - CDR3: QQSSNFPWT (SEQ ID NO: 16); or -V H - CDR1: NTYIH (SEQ ID NO: 1), V H - CDR2: RIDPAGGRTKYAPKVKG (SEQ ID NO: 17), V H -CDR3: HRGGTMDY (SEQ ID NO: 13), V L - CDR1: RASQSVSNYGISFLN (SEQ ID NO: 14), V L - CDR2: AAEYRGR (SEQ ID NO: 10), and V L - CDR3: QQSSNVPYT (SEQ ID NO: 18); or -V H - CDR1: NTYIH (SEQ ID NO: 1), V H -CDR2: RIDPAGGRTKYAPKVQG (SEQ ID NO: 19), V H -CDR3: HYGGTMDY (SEQ ID NO: 8), V L - CDR1: RASQSVSNYGISFLN (SEQ ID NO: 14), V L - CDR2: AAEYQGR (SEQ ID NO: 20), and V L - CDR3: QQSSNVPYT (SEQ ID NO: 18); or -V H - CDR1: NTYIH (SEQ ID NO: 1), VH - CDR2: RIDPAGGRTKYAPKVKG (SEQ ID NO: 17), V H -CDR3: HRGGTMDY (SEQ ID NO: 13), V L - CDR1: RASQSVSNYGISFLN (SEQ ID NO: 14), V L - CDR2: AAEYRAR (SEQ ID NO: 21), and V L - CDR3: QQSSNVPYT (SEQ ID NO: 18); or -V H - CDR1: NTYIH (SEQ ID NO: 1), V H -CDR2: RIDPANGNTKYAPKVQG (SEQ ID NO: 22), V H -CDR3: HYGSTMDY (SEQ ID NO: 23), V L - CDR1: RASESVDNYGISFMN (SEQ ID NO: 24), V L - CDR2: AASNQGS (SEQ ID NO: 25), and V L -CDR3: QQSKEVPWT (SEQ ID NO: 26) Includes.

[0126] In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, The three following CDRs: -V H - CDR1: NTYIH (SEQ ID NO: 1); -V H - CDR2: RIDPAGGRTKYDPKVKG (SEQ ID NO: 7); and -V H -CDR3: HYGGTMDY (SEQ ID NO: 8) VH, The three following CDRs: -V L - CDR1: RASESVDNYGISFLN (SEQ ID NO: 9); -V L - CDR2: AAEYRGR (SEQ ID NO: 10); and -V L -CDR3: QQSRHVPYT (SEQ ID NO: 11) Including, VL Includes.

[0127] In one embodiment, the V H -CDR1, V H -CDR2 and / or V H -V having any one of CDR3 and / or SEQ ID NOs: 9 to 11 L -CDR1, V L -CDR2 and / or V L - Any of the CDR3 may be characterized as having an amino acid sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with a particular CDR or set of CDRs listed in the corresponding SEQ ID NO. In other words, in one embodiment, any of the V H -CDR1, V H -CDR2, V H -CDR3, V L -CDR1, V L -CDR2 and / or V L - CDR3 has an amino acid sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or greater identity with the corresponding amino acid sequence set forth in SEQ ID NOs: 1, 7, 8 and 9-11.

[0128] V having SEQ ID NOs: 1, 7, 8 H -CDR1, V H -CDR2 and V H -VH comprising CDR3 and VH having SEQ ID NOs: 9 to 11 L -CDR1, V L -CDR2 and V L An example of an antibody comprising a VL having SEQ ID NOs: 1, 7, 8 is INO-10-3. H -CDR1, V H -CDR2 and V H -VH comprising CDR3 and VH having SEQ ID NOs: 9 to 11 L -CDR1, V L -CDR2 and V L An example of an antigen-binding antibody fragment comprising a VL comprising -CDR3 is the Fab fragment INO-10-F3 (or F3).

[0129] In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, The three following CDRs: -V H - CDR1: NTYIH (SEQ ID NO: 1); -V H - CDR2: RIDPAGGRTKYSPKVQG (SEQ ID NO: 12); and -V H -CDR3: HRGGTMDY (SEQ ID NO: 13) VH, The three following CDRs: -V L - CDR1: RASQSVSNYGISFLN (SEQ ID NO: 14); -V L - CDR2: AASYQKR (SEQ ID NO: 15) and -V L -CDR3: QQSSNFPWT (SEQ ID NO: 16) Including, VL Includes.

[0130] In one embodiment, the V H -CDR1, V H -CDR2 and / or V H -V having any one of CDR3 and / or SEQ ID NOs: 14 to 16 L -CDR1, V L -CDR2 and V L - Any of the CDR3 may be characterized as having an amino acid sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with a particular CDR or set of CDRs listed in the corresponding SEQ ID NO. In other words, in one embodiment, any of the V H -CDR1, V H -CDR2, V H -CDR3, V L -CDR1, V L -CDR2 and / or V L- CDR3 has an amino acid sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or greater identity with the corresponding amino acid sequence set forth in SEQ ID NOs: 1, 12, 13 and 14-16.

[0131] V having SEQ ID NO: 1, 12, 13 H -CDR1, V H -CDR2 and V H -VH having CDR3 and VH having SEQ ID NOs: 14 to 16 L -CDR1, V L -CDR2 and V L An example of an antibody comprising a VL having the CDR3 is INO-10-2. H -CDR1, V H -CDR2 and V H -VH having CDR3 and VH having SEQ ID NOs: 14 to 16 L -CDR1, V L -CDR2 and V L An example of an antigen-binding antibody fragment comprising a VL comprising -CDR3 is the Fab fragment INO-10-F2 (or F2).

[0132] In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, The three following CDRs: -V H - CDR1: NTYIH (SEQ ID NO: 1); -V H - CDR2: RIDPAGGRTKYAPKVKG (SEQ ID NO: 17); and -V H -CDR3: HRGGTMDY (SEQ ID NO: 13) VH, The three following CDRs: -V L - CDR1: RASQSVSNYGISFLN (SEQ ID NO: 14); -V L - CDR2: AAEYRGR (SEQ ID NO: 10); and -V L -CDR3: QQSSNVPYT (SEQ ID NO: 18) Including, VL Includes.

[0133] In one embodiment, the V H -CDR1, V H -CDR2 and / or V H - any of CDR3 and / or V having SEQ ID NO: 14, 10, 18 L -CDR1, V L -CDR2 and V L - Any of the CDR3 may be characterized as having an amino acid sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with a particular CDR or set of CDRs listed in the corresponding SEQ ID NO. In other words, in one embodiment, any of the V H -CDR1, V H -CDR2, V H -CDR3, V L -CDR1, V L -CDR2 and / or V L - CDR3 has an amino acid sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or greater identity with the corresponding amino acid sequence set forth in SEQ ID NOs: 1, 17, 13, 14, 10, and 18.

[0134] V having SEQ ID NOs: 1, 17, 13 H -CDR1, V H -CDR2 and V H - VH comprising CDR3 and VH having SEQ ID NO: 14, 10, 18 L -CDR1, V L -CDR2 and V L An example of an antibody comprising a VL having SEQ ID NOs: 1, 17, 13 is INO-10-4. H -CDR1, V H -CDR2 and V H - VH comprising CDR3 and VH having SEQ ID NO: 14, 10, 18 L -CDR1, V L -CDR2 and VL An example of an antigen-binding antibody fragment comprising a VL comprising -CDR3 is the Fab fragment INO-10-F4 (or F4).

[0135] In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, The three following CDRs: -V H - CDR1: NTYIH (SEQ ID NO: 1); -V H - CDR2: RIDPAGGRTKYAPKVQG (SEQ ID NO: 19); and -V H -CDR3: HYGGTMDY (SEQ ID NO: 8) VH, The three following CDRs: -V L - CDR1: RASQSVSNYGISFLN (SEQ ID NO: 14); -V L - CDR2: AAEYQGR (SEQ ID NO: 20); and -V L -CDR3: QQSSNVPYT (SEQ ID NO: 18) Including, VL Includes.

[0136] In one embodiment, the V H -CDR1, V H -CDR2 and / or V H - any of CDR3 and / or V having SEQ ID NO: 14, 20, 18 L -CDR1, V L -CDR2 and V L - Any of the CDR3 may be characterized as having an amino acid sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with a particular CDR or set of CDRs listed in the corresponding SEQ ID NO. In other words, in one embodiment, any of the V H -CDR1, V H -CDR2, V H -CDR3, V L -CDR1, VL -CDR2 and / or V L - CDR3 has an amino acid sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or greater identity with the corresponding amino acid sequence set forth in SEQ ID NOs: 1, 19, 8, 14, 20, and 18.

[0137] V having SEQ ID NOs: 1, 19, 8 H -CDR1, V H -CDR2 and V H - VH comprising CDR3 and VH having SEQ ID NO: 14, 20, 18 L -CDR1, V L -CDR2 and V L An example of an antibody comprising a VL having SEQ ID NOs: 1, 19, 8 is INO-10-5. H -CDR1, V H -CDR2 and V H - VH comprising CDR3 and VH having SEQ ID NO: 14, 20, 18 L -CDR1, V L -CDR2 and V L An example of an antigen-binding antibody fragment comprising a VL comprising -CDR3 is the Fab fragment INO-10-F5 (or F5).

[0138] In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, The three following CDRs: -V H - CDR1: NTYIH (SEQ ID NO: 1); -V H - CDR2: RIDPAGGRTKYAPKVKG (SEQ ID NO: 17); and -V H -CDR3: HRGGTMDY (SEQ ID NO: 13) VH, The three following CDRs: -V L - CDR1: RASQSVSNYGISFLN (SEQ ID NO: 14); -V L - CDR2: AAEYRAR (SEQ ID NO: 21); and -VL -CDR3: QQSSNVPYT (SEQ ID NO: 18) Including, VL Includes.

[0139] In one embodiment, the V H -CDR1, V H -CDR2 and / or V H - any of CDR3 and / or V having SEQ ID NO: 14, 21, 18 L -CDR1, V L -CDR2 and V L - Any of the CDR3 may be characterized as having an amino acid sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with a particular CDR or set of CDRs listed in the corresponding SEQ ID NO. In other words, in one embodiment, any of the V H -CDR1, V H -CDR2, V H -CDR3, V L -CDR1, V L -CDR2 and / or V L - CDR3 has an amino acid sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or greater identity with the corresponding amino acid sequence set forth in SEQ ID NOs: 1, 17, 13, 14, 21, and 18.

[0140] V having SEQ ID NOs: 1, 17, 13 H -CDR1, V H -CDR2 and V H - VH comprising CDR3 and VH having SEQ ID NO: 14, 21, 18 L -CDR1, V L -CDR2 and V L An example of an antibody comprising a VL having SEQ ID NOs: 1, 17, 13 is INO-10-6. H -CDR1, V H -CDR2 and V H - VH comprising CDR3 and VH having SEQ ID NO: 14, 21, 18 L-CDR1, V L -CDR2 and V L An example of an antigen-binding antibody fragment comprising a VL comprising -CDR3 is the Fab fragment INO-10-F6 (or F6).

[0141] In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, The three following CDRs: -V H - CDR1: NTYIH (SEQ ID NO: 1); -V H - CDR2: RIDPANGNTKYAPKVQG (SEQ ID NO: 22); and -V H -CDR3: HYGSTMDY (SEQ ID NO: 23) VH, The three following CDRs: -V L - CDR1: RASESVDNYGISFMN (SEQ ID NO: 24); -V L - CDR2: AASNQGS (SEQ ID NO: 25); and -V L -CDR3: QQSKEVPWT (SEQ ID NO: 26) Including, VL Includes.

[0142] In one embodiment, V having SEQ ID NO: 1, 22, 23 H -CDR1, V H -CDR2 and / or V H -V having any one of CDR3 and / or SEQ ID NOs: 24 to 26 L -CDR1, V L -CDR2 and V L - Any of the CDR3 may be characterized as having an amino acid sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with a particular CDR or set of CDRs listed in the corresponding SEQ ID NO. In other words, in one embodiment, any of the V H -CDR1, V H -CDR2, V H-CDR3, V L -CDR1, V L -CDR2 and / or V L - CDR3 has an amino acid sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or greater identity with the corresponding amino acid sequences set forth in SEQ ID NOs: 1, 22, 23 and 24-26.

[0143] V having SEQ ID NO: 1, 22, 23 H -CDR1, V H -CDR2 and V H -VH having CDR3 and VH having SEQ ID NOs: 24 to 26 L -CDR1, V L -CDR2 and V L An example of an antibody comprising a VL having SEQ ID NO: 1, 22, 23 is INO-10-1. H -CDR1, V H -CDR2 and V H -VH having CDR3 and VH having SEQ ID NOs: 24 to 26 L -CDR1, V L -CDR2 and V L An example of an antigen-binding antibody fragment comprising a VL comprising -CDR3 is the Fab fragment INO-10-F1 (or F1).

[0144] In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, The three following CDRs: -V H - CDR1: NTYIH (SEQ ID NO: 1); -V H - CDR2: RIDPANGNTKYAPKFQG (SEQ ID NO: 40); and -V H -CDR3: HYGSTMDY (SEQ ID NO: 23) VH, The three following CDRs: -V L - CDR1: RASESVDNYGISFMN (SEQ ID NO: 24); -V L- CDR2: AASNQGS (SEQ ID NO: 25); and -V L -CDR3: QQSKEVPWT (SEQ ID NO: 26) Including, VL Includes.

[0145] In one embodiment, V having SEQ ID NO: 1, 40, 23 H -CDR1, V H -CDR2 and / or V H -V having any one of CDR3 and / or SEQ ID NOs: 24 to 26 L -CDR1, V L -CDR2 and V L - Any of the CDR3 may be characterized as having an amino acid sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with a particular CDR or set of CDRs listed in the corresponding SEQ ID NO. In other words, in one embodiment, any of the V H -CDR1, V H -CDR2, V H -CDR3, V L -CDR1, V L -CDR2 and / or V L - CDR3 has an amino acid sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or greater identity with the corresponding amino acid sequences set forth in SEQ ID NOs: 1, 40, 23 and 24-26.

[0146] V having SEQ ID NO: 1, 40, 23 H -CDR1, V H -CDR2 and V H -VH having CDR3 and VH having SEQ ID NOs: 24 to 26 L -CDR1, V L -CDR2 and V L An example of an antibody comprising a VL having SEQ ID NO: 1, 40, 23 is INO-10. H -CDR1, V H -CDR2 and V H-VH having CDR3 and VH having SEQ ID NOs: 24 to 26 L -CDR1, V L -CDR2 and V L An example of an antigen-binding antibody fragment comprising a VL comprising -CDR3 is the Fab fragment INO-10-F.

[0147] According to one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises a variable region of the heavy chain (VH) comprising or consisting of a sequence selected from the group consisting of SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, and SEQ ID NO:41.

[0148] In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises a VH comprising or consisting of a sequence selected from the group comprising: SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:41, and a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or greater identity to SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, or SEQ ID NO:41.

[0149] In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises a VH comprising or consisting of a sequence selected from the group comprising or consisting of SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, and SEQ ID NO:41 with 1, 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, 31, 32, 33, 34, 35 or more amino acid(s) substituted by a different amino acid. In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises a VH comprising or consisting of a sequence selected from the group consisting of SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, and SEQ ID NO:41 with 1, 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, 31, 32, 33, 34, 35 or more amino acid(s) substituted with a different amino acid, wherein said amino acid substitution(s) do not occur in any of the three CDRs.

[0150] In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises a VH having an amino acid sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or greater identity with SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, and / or SEQ ID NO:41. In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises a VH having an amino acid sequence of framework regions that share at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or greater identity with the amino acid sequence of the framework regions (i.e., non-CDR regions) of SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, and / or SEQ ID NO:41.

[0151] According to one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises a VH comprising or consisting of a sequence selected from the group consisting of SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, and SEQ ID NO:32.

[0152] In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises a VH comprising or consisting of a sequence selected from the group comprising: SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, and a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or greater identity to SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, or SEQ ID NO:32.

[0153] In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises a VH comprising or consisting of a sequence selected from the group comprising or consisting of SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, and SEQ ID NO:32 with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 2, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or more amino acid(s) substituted by a different amino acid. In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises a VH comprising or consisting of a sequence selected from the group consisting of SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, and SEQ ID NO:32 with 1, 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, 31, 32, 33, 34, 35 or more amino acid(s) substituted with a different amino acid, wherein said amino acid substitution(s) do not occur in any of the three CDRs.

[0154] In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises a VH having an amino acid sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or greater identity with SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, and / or SEQ ID NO:32. In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises a VH having an amino acid sequence of framework regions that share at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or greater identity with the amino acid sequence of the framework regions (i.e., non-CDR regions) of SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, and / or SEQ ID NO:32.

[0155] According to one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises a variable region of the light chain (VL) comprising or consisting of a sequence selected from the group consisting of SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, and SEQ ID NO:42.

[0156] In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises a sequence comprising or selected from the group consisting of SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:42, and a VL comprising or consisting of a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or greater identity to SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, or SEQ ID NO:42.

[0157] In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises a VL comprising or consisting of a sequence selected from the group comprising or consisting of SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, and SEQ ID NO:42 with 1, 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, 31, 32, 33, 34, 35 or more amino acid(s) substituted by a different amino acid. In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises a VL comprising or consisting of a sequence selected from the group consisting of SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, and SEQ ID NO:42 with 1, 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, 31, 32, 33, 34, 35 or more amino acid(s) substituted by a different amino acid, wherein said amino acid substitution(s) do not occur in any of the three CDRs.

[0158] In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises a VL having an amino acid sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or greater identity with SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, and / or SEQ ID NO: 42. In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises a VL having an amino acid sequence of framework regions that share at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or greater identity with the amino acid sequence of the framework regions (i.e., non-CDR regions) of SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, and / or SEQ ID NO: 42.

[0159] According to one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises a VL comprising or consisting of a sequence selected from the group consisting of SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, and SEQ ID NO:38.

[0160] In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises a sequence comprising or selected from the group consisting of SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, and a VL comprising or consisting of a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or greater identity to SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, or SEQ ID NO:38.

[0161] In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises a VL comprising or consisting of a sequence selected from the group comprising or consisting of SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, and SEQ ID NO:38 with 1, 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, 31, 32, 33, 34, 35 or more amino acid(s) substituted by a different amino acid. In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises a VL comprising or consisting of a sequence selected from the group consisting of SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, and SEQ ID NO:38 with 1, 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, 31, 32, 33, 34, 35 or more amino acid(s) substituted by a different amino acid, wherein the amino acid substitution(s) do not occur in any of the three CDRs. In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises a VL having an amino acid sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or greater identity with SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, and / or SEQ ID NO: 38. In one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises a VL having an amino acid sequence of framework regions that share at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or greater identity with the amino acid sequence of the framework regions (i.e., non-CDR regions) of SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, and / or SEQ ID NO: 38.

[0162] According to one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises: - a variable region of the heavy chain (VH) comprising or consisting of a sequence selected from the group consisting of SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:41, and a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, or SEQ ID NO:41; and - a variable region of the light chain (VL) comprising or consisting of a sequence selected from the group consisting of SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:42, and a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, or SEQ ID NO:42; Includes.

[0163] According to one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises: - a VH comprising or consisting of a sequence selected from the group consisting of SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, and SEQ ID NO:41, or a VH having, comprising, or consisting of a sequence of framework regions sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the framework regions (i.e., non-CDR regions) of SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, or SEQ ID NO:41; and - a VL comprising or consisting of a sequence selected from the group comprising or consisting of SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, and SEQ ID NO:42, or a VL having, comprising or consisting of a sequence of framework regions that share at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the framework regions (i.e., non-CDR regions) of SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, or SEQ ID NO:42. Includes.

[0164] According to one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises: - a VH comprising or consisting of a sequence selected from the group comprising or consisting of SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, and a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, or SEQ ID NO:32; and - a VL comprising or consisting of a sequence selected from the group consisting of SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, and a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, or SEQ ID NO:38; Includes.

[0165] According to one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises: - a VH comprising or consisting of a sequence selected from the group consisting of SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, and SEQ ID NO:32, or a VH having, comprising, or consisting of a sequence of framework regions sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the framework regions (i.e., non-CDR regions) of SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, or SEQ ID NO:32; and - a VL comprising or consisting of a sequence comprising or consisting of SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, and SEQ ID NO:38, or a VL having, comprising or consisting of a sequence of framework regions sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the framework regions (i.e., non-CDR regions) of SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, or SEQ ID NO:38. Includes.

[0166] According to one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises: - a VH comprising or consisting of SEQ ID NO:27 or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to SEQ ID NO:27, or a VH having, comprising or consisting of a sequence of framework regions sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to the framework regions of SEQ ID NO:27; and - a VL comprising or consisting of a sequence selected from the group comprising or consisting of SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:42 and a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, or SEQ ID NO:42, or a VL having, comprising or consisting of a sequence of framework regions which share at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the framework regions of SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, or SEQ ID NO:42. Includes.

[0167] According to one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises: - a VH comprising or consisting of a sequence selected from the group comprising or consisting of SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, and SEQ ID NO:32, SEQ ID NO:41, and a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, and SEQ ID NO:32, or SEQ ID NO:41, or a VH having, comprising or consisting of a sequence of framework regions sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the framework regions of SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, or SEQ ID NO:41; and - a VL comprising or consisting of SEQ ID NO: 33 or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to SEQ ID NO: 33, or a VL having, comprising or consisting of a sequence of framework regions sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to the framework regions of SEQ ID NO: 33. Includes.

[0168] According to one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises: - a VH comprising or consisting of SEQ ID NO:27, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to SEQ ID NO:27, or a VH having a sequence of framework regions sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to the framework regions of SEQ ID NO:27; and a VL comprising or consisting of SEQ ID NO:33, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to SEQ ID NO:33, or a VL having a sequence of framework regions sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to the framework regions of SEQ ID NO:33; or - a VH comprising or consisting of SEQ ID NO:28, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to SEQ ID NO:28, or a VH having a sequence of framework regions sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to the framework regions of SEQ ID NO:28; and a VL comprising or consisting of SEQ ID NO:34, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to SEQ ID NO:34, or a VL having a sequence of framework regions sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to the framework regions of SEQ ID NO:34; or - a VH comprising or consisting of SEQ ID NO:29, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to SEQ ID NO:29, or a VH having a sequence of framework regions sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to the framework regions of SEQ ID NO:29; and a VL comprising or consisting of SEQ ID NO:35, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to SEQ ID NO:35, or a VL having a sequence of framework regions sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to the framework regions of SEQ ID NO:35; or - a VH comprising or consisting of SEQ ID NO: 30, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to SEQ ID NO: 30, or a VH having a sequence of framework regions sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to the framework regions of SEQ ID NO: 30; and a VL comprising or consisting of SEQ ID NO:36, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to SEQ ID NO:36, or a VL having a sequence of framework regions sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to the framework regions of SEQ ID NO:36; or - a VH comprising or consisting of SEQ ID NO: 31, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to SEQ ID NO: 31, or a VH having a sequence of framework regions sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to the framework regions of SEQ ID NO: 31; and a VL comprising or consisting of SEQ ID NO:37, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to SEQ ID NO:37, or a VL having a sequence of framework regions sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to the framework regions of SEQ ID NO:37; or - a VH comprising or consisting of SEQ ID NO: 32, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to SEQ ID NO: 32, or a VH having a sequence of framework regions sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to the framework regions of SEQ ID NO: 32; and a VL comprising or consisting of SEQ ID NO:38, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to SEQ ID NO:38, or a VL having a sequence of framework regions sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to the framework regions of SEQ ID NO:38; or - a VH comprising or consisting of SEQ ID NO: 41, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to SEQ ID NO: 41, or a VH having a sequence of framework regions sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to the framework regions of SEQ ID NO: 41; and a VL comprising or consisting of SEQ ID NO:42, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to SEQ ID NO:42, or a VL having a sequence of framework regions that share at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to the framework regions of SEQ ID NO:42. Includes.

[0169] According to one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises: - a VH comprising or consisting of SEQ ID NO:27 or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to SEQ ID NO:27, or a VH having, comprising or consisting of a sequence of framework regions sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to the framework regions of SEQ ID NO:27; and - a VL comprising or consisting of SEQ ID NO: 33 or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to SEQ ID NO: 33, or a VL having, comprising or consisting of a sequence of framework regions sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to the framework regions of SEQ ID NO: 33. Includes.

[0170] An example of such an antibody is INO-10-3 (or MAB3). An example of such an antigen-binding antibody fragment is the Fab fragment INO-10-F3 (or F3).

[0171] According to one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises: - a VH comprising or consisting of SEQ ID NO:28 or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to SEQ ID NO:28, or a VH having, comprising or consisting of a sequence of framework regions sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to the framework regions of SEQ ID NO:28; and - a VL comprising or consisting of SEQ ID NO: 34 or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to SEQ ID NO: 34, or a VL having, comprising or consisting of a sequence of framework regions sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to the framework regions of SEQ ID NO: 34. Includes.

[0172] An example of such an antibody is INO-10-2 (or MAB2). An example of such an antigen-binding antibody fragment is the Fab fragment INO-10-F2 (or F2).

[0173] According to one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises: - a VH comprising or consisting of SEQ ID NO:29 or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to SEQ ID NO:29, or a VH having, comprising or consisting of a sequence of framework regions sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to the framework regions of SEQ ID NO:29; and - a VL comprising or consisting of SEQ ID NO: 35 or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to SEQ ID NO: 35, or a VL having, comprising or consisting of a sequence of framework regions sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to the framework regions of SEQ ID NO: 35. Includes.

[0174] An example of such an antibody is INO-10-4 (or MAB4). An example of such an antigen-binding antibody fragment is the Fab fragment INO-10-F4 (or F4).

[0175] According to one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises: - a VH comprising or consisting of SEQ ID NO: 30, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to SEQ ID NO: 30, or a VH having, comprising or consisting of a sequence of framework regions sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to the framework regions of SEQ ID NO: 30; and - a VL comprising or consisting of SEQ ID NO: 36 or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to SEQ ID NO: 36, or a VL having, comprising or consisting of a sequence of framework regions sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to the framework regions of SEQ ID NO: 36. Includes.

[0176] An example of such an antibody is INO-10-5 (or MAB5). An example of such an antigen-binding antibody fragment is the Fab fragment INO-10-F5 (or F5).

[0177] According to one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises: - a VH comprising or consisting of SEQ ID NO: 31, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to SEQ ID NO: 31, or a VH having, comprising or consisting of a sequence of framework regions sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to the framework regions of SEQ ID NO: 31; and - a VL comprising or consisting of SEQ ID NO: 37 or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with SEQ ID NO: 37, or a VL having, comprising or consisting of a sequence of framework regions sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the framework regions of SEQ ID NO: 37. Includes.

[0178] An example of such an antibody is INO-10-6 (or MAB6). An example of such an antigen-binding antibody fragment is the Fab fragment INO-10-F6 (or F6).

[0179] According to one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises: - a VH comprising or consisting of SEQ ID NO: 32 or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to SEQ ID NO: 32, or a VH having, comprising or consisting of a sequence of framework regions sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to the framework regions of SEQ ID NO: 32; and - a VL comprising or consisting of SEQ ID NO: 38 or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with SEQ ID NO: 38, or a VL having, comprising or consisting of a sequence of framework regions sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the framework regions of SEQ ID NO: 38. Includes.

[0180] An example of such an antibody is INO-10-1 (or MAB1). An example of such an antigen-binding antibody fragment is the Fab fragment INO-10-F1 (or F1).

[0181] According to one embodiment, the anti-hTREM-1 antibody, or antigen-binding fragment thereof, comprises: - a VH comprising or consisting of SEQ ID NO: 41, or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to SEQ ID NO: 41, or a VH having, comprising or consisting of a sequence of framework regions sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to the framework regions of SEQ ID NO: 41; and - a VL comprising or consisting of SEQ ID NO: 42 or a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to SEQ ID NO: 42, or a VL having, comprising or consisting of a sequence of framework regions sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to the framework regions of SEQ ID NO: 42. Includes.

[0182] An example of such an antibody is INO-10. An example of such an antigen-binding antibody fragment is the Fab fragment INO-10-F.

[0183] The present invention further relates to fusion proteins comprising the antibodies or antigen-binding fragments thereof described herein. For example, the fusion protein may comprise a naturally occurring long half-life protein or protein domain (e.g., human serum albumin).

[0184] In one embodiment, the fusion protein comprises an antibody or antigen-binding fragment thereof described herein and HSA (human serum albumin). In one embodiment, the HSA comprises or consists of the sequence of SEQ ID NO: 59. In one embodiment, the HSA comprises or consists of the sequence of SEQ ID NO: 60. In one embodiment, the HSA is therefore fused (or conjugated), optionally via a linker, to an antibody or antigen-binding fragment thereof described herein.

[0185] In one embodiment, HSA is fused (or conjugated) to an antibody or antigen-binding fragment thereof described herein via a short linker, such as a linker of 5 or fewer amino acids (e.g., a linker of 3, 4, or 5 amino acids). In one embodiment, HSA is fused (or conjugated) to an antibody or antigen-binding fragment thereof described herein via a longer linker, such as a linker of 10 or more amino acids (e.g., a linker of 12, 13, 14, 15, or 16 amino acids).

[0186] In one embodiment, HSA is fused (or conjugated) to the heavy chain of the antibody or antigen-binding fragment thereof. In one embodiment, HSA is fused (or conjugated) to the CH1 domain of the truncated heavy chain of the antibody or antigen-binding fragment thereof. In one embodiment, HSA is fused (or conjugated) at the C-terminus of the heavy chain (or truncated heavy chain) of the antibody or antigen-binding fragment thereof. In one embodiment, HSA is fused (or conjugated) to the light chain of the antibody or antigen-binding fragment thereof. In one embodiment, HSA is fused (or conjugated) at the N-terminus of the light chain of the antibody or antigen-binding fragment thereof.

[0187] In one embodiment, the antibodies or antigen-binding fragments thereof described herein are modified, e.g., to increase their half-life in vivo, e.g., in serum. Methods for modifying antibodies are well known in the art and include, but are not limited to, conjugation to repeating chemical moieties, such as, for example, polyethylene glycol (PEG), conjugation to human serum albumin, etc.

[0188] Another object of the present invention is an isolated nucleic acid encoding an antibody or antigen-binding fragment thereof according to the present invention. Another object of the present invention is an isolated nucleic acid encoding a fusion protein as described herein.

[0189] As used herein, "isolated nucleic acid" is intended to refer to a nucleic acid that has been substantially separated from other nucleic acid sequences, particularly other genomic DNA sequences, and proteins or complexes, such as ribosomes and polymerases, that naturally accompany the native sequence. The term encompasses a nucleic acid sequence that has been removed from its natural environment, including recombinant or cloned DNA or RNA isolates, as well as chemically synthesized analogs or biologically synthesized analogs from heterologous systems. A substantially pure nucleic acid includes a nucleic acid in isolated form.

[0190] Of course, this refers to the nucleic acid in its originally isolated state, and does not exclude genes or sequences later added to the isolated nucleic acid by the hand of man.

[0191] In one embodiment, the isolated nucleic acid is purified.

[0192] In one embodiment, the isolated nucleic acid is purified to (i) 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95% or more, and most preferably 96%, 97%, 98% or 99% by weight of the nucleic acid as measured by absorbance or fluorescence methods (e.g., by measuring the ratio of absorbance at 260 and 280 nm (A260 / 280)); or (ii) homogeneity as shown by agarose gel electrophoresis and the use of an intercalating agent such as ethidium bromide, SYBR Green, GelGreen, and the like.

[0193] In one embodiment, the nucleic acid encodes at least the heavy chain variable region (VH) and / or the light chain variable region (VL) of an antibody or antigen-binding fragment thereof according to the invention. In one embodiment, the nucleic acid may encode the variable and constant regions of an antibody or antigen-binding fragment thereof according to the invention. In one embodiment, the nucleic acid may encode the heavy and light chains of an antibody or antigen-binding fragment thereof according to the invention on separate nucleic acids or on the same nucleic acid molecule.

[0194] In one embodiment, the nucleic acid according to the invention comprises or consists of a sequence encoding the VH of an antibody or antigen-binding fragment thereof according to the invention.

[0195] In one embodiment, the nucleic acid according to the invention comprises or consists of a sequence encoding the VH of an antibody or antigen-binding fragment thereof according to the invention, said sequence comprising or selected from the group consisting of SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, and a sequence sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, or SEQ ID NO:52.

[0196] In one embodiment, the nucleic acid according to the invention comprises or consists of a sequence encoding the VL of an antibody or antigen-binding fragment thereof according to the invention.

[0197] In one embodiment, the nucleic acid according to the invention comprises or consists of a sequence encoding the VL of an antibody or antigen-binding fragment thereof according to the invention, said sequence comprising or selected from the group consisting of SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, and a sequence sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, or SEQ ID NO:58.

[0198] In one embodiment, the nucleic acid according to the present invention comprises - a sequence encoding the VH of an antibody or antigen-binding fragment thereof according to the invention; and - a sequence encoding the VL of an antibody or antigen-binding fragment thereof according to the invention It comprises or consists of:

[0199] In one embodiment, the nucleic acid according to the present invention comprises - a sequence selected from the group consisting of SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, and a sequence sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or greater identity with SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, or SEQ ID NO:52; and - a sequence selected from the group consisting of SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, and a sequence sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, or SEQ ID NO:58. It comprises or consists of:

[0200] In one embodiment, the nucleic acid according to the present invention comprises - a VH encoding sequence comprising or consisting of a nucleic acid sequence set forth in SEQ ID NO: 47 or a nucleic acid sequence sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or greater identity with SEQ ID NO: 47; and - a sequence encoding a VL comprising or consisting of a nucleic acid sequence set forth in SEQ ID NO: 53 or a nucleic acid sequence sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with SEQ ID NO: 53 In one embodiment, the nucleic acid encodes the VH and VL of the INO-10-3 antibody or the INO-10-F3 (or F3) Fab fragment.

[0201] In one embodiment, the nucleic acid according to the present invention comprises - a VH encoding sequence comprising or consisting of a nucleic acid sequence set forth in SEQ ID NO: 48 or a nucleic acid sequence sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with SEQ ID NO: 48; and - a sequence encoding a VL comprising or consisting of a nucleic acid sequence set forth in SEQ ID NO: 54 or a nucleic acid sequence sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with SEQ ID NO: 54 In one embodiment, the nucleic acid encodes the VH and VL of the INO-10-2 antibody or the INO-10-F2 (or F2) Fab fragment.

[0202] In one embodiment, the nucleic acid according to the present invention comprises - a VH encoding sequence comprising or consisting of a nucleic acid sequence set forth in SEQ ID NO: 49 or a nucleic acid sequence sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or greater identity with SEQ ID NO: 49; and - a sequence encoding a VL comprising or consisting of a nucleic acid sequence as set forth in SEQ ID NO: 55 or a nucleic acid sequence sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with SEQ ID NO: 55 In one embodiment, the nucleic acid encodes the VH and VL of the INO-10-4 antibody or the INO-10-F4 (or F4) Fab fragment.

[0203] In one embodiment, the nucleic acid according to the present invention comprises - a VH encoding sequence comprising or consisting of a nucleic acid sequence set forth in SEQ ID NO: 50 or a nucleic acid sequence sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with SEQ ID NO: 50; and - a sequence encoding a VL comprising or consisting of a nucleic acid sequence as set forth in SEQ ID NO: 56 or a nucleic acid sequence sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with SEQ ID NO: 56 In one embodiment, the nucleic acid encodes the VH and VL of the INO-10-5 antibody or the INO-10-F5 (or F5) Fab fragment.

[0204] In one embodiment, the nucleic acid according to the present invention comprises - a VH encoding sequence comprising or consisting of a nucleic acid sequence set forth in SEQ ID NO: 51, or a nucleic acid sequence sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or greater identity with SEQ ID NO: 51; and - a sequence encoding a VL comprising or consisting of a nucleic acid sequence set forth in SEQ ID NO: 57 or a nucleic acid sequence sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with SEQ ID NO: 57 In one embodiment, the nucleic acid encodes the VH and VL of the INO-10-6 antibody or the INO-10-F6 (or F6) Fab fragment.

[0205] In one embodiment, the nucleic acid according to the present invention comprises - a VH encoding sequence comprising or consisting of a nucleic acid sequence set forth in SEQ ID NO: 52, or a nucleic acid sequence sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or greater identity with SEQ ID NO: 52; and - a sequence encoding a VL comprising or consisting of a nucleic acid sequence as set forth in SEQ ID NO: 58 or a nucleic acid sequence sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with SEQ ID NO: 58 In one embodiment, the nucleic acid encodes the VH and VL of the INO-10-1 antibody or the INO-10-F1 (or F1) Fab fragment.

[0206] Typically, the nucleic acids according to the invention are DNA or RNA molecules, which may be comprised in any suitable vector, such as, for example, a plasmid, cosmid, episome, artificial chromosome, phage or viral vector.

[0207] Therefore, another object of the present invention is a vector, such as, for example, an expression vector, comprising a nucleic acid encoding an antibody or an antigen-binding fragment thereof according to the present invention. Another object of the present invention is a vector, such as, for example, an expression vector, comprising a nucleic acid encoding a fusion protein according to the present invention.

[0208] The terms "vector", "cloning vector" and "expression vector" refer to vehicles by which DNA or RNA sequences (e.g., foreign genes) can be introduced into a host cell to transform the host cell and promote expression (e.g., transcription and translation) of the introduced sequence encoding an antibody or antigen-binding fragment thereof. Such vectors may contain regulatory elements, such as promoters, enhancers, terminators, etc., to cause or direct expression of the antibody or antigen-binding fragment thereof upon administration to a subject. Examples of promoters and enhancers used in expression vectors for animal cells include, but are not limited to, SV40 early promoter and enhancer, Moloney murine leukemia virus LTR promoter and enhancer, immunoglobulin H chain promoter and enhancer, etc. Any expression vector for animal cells may be used as long as a gene encoding an anti-hTREM-1 antibody or antigen-binding fragment thereof described herein is inserted and expressed. Examples of suitable vectors include pAGE107, pAGE103, pHSG274, pKCR, pSG1 beta d2-4, etc. Other examples of plasmids include replicative plasmids that contain an origin of replication, or integrative plasmids, such as pUC, pcDNA, pBR, etc. Other examples of viral vectors include adenovirus, retrovirus, herpes virus, and AAV vectors. Such recombinant viruses can be produced by techniques known in the art, such as by transfecting packaging cells, or by transient transfection with helper plasmids or viruses. Typical examples of viral packaging cells include PA317 cells, PsiCRIP cells, GPenv+ cells, 293 cells.

[0209] In one embodiment, a vector or expression vector according to the invention comprises a sequence encoding the heavy chain variable domain of an antibody or antigen-binding fragment thereof according to the invention operably linked to a regulatory element. In one embodiment, a vector or expression vector according to the invention comprises a sequence encoding the light chain variable domain of an antibody or antigen-binding fragment thereof according to the invention operably linked to a regulatory element.

[0210] In one embodiment, the expression vector according to the present invention is monocistronic. "Monocistronic" means that a single nucleic acid is expressed in a single expression vector. In one embodiment, the expression vector according to the present invention is polycistronic. "Polycistronic" means that at least two or more nucleic acids are expressed in a single expression vector.

[0211] Another object of the invention is an isolated host cell comprising the above-described vector, which may be used for the recombinant production of the anti-hTREM-1 antibodies or antigen-binding fragments thereof described herein.

[0212] In embodiments, the host cell can be a prokaryotic cell, or a eukaryotic cell, such as a yeast or mammalian cell. Examples of mammalian cells include monkey kidney CV1 line transformed by SV40 (COS-7, ATCC CRL 1651); human embryonic kidney lines (293 or 293T cell sublines); baby hamster kidney cells (BHK, ATCC CCL 10); Chinese hamster ovary cells / -DHFR (CHO); mouse Sertoli cells (TM4); mouse myeloma cells SP2 / 0-AG14 (ATCC CRL 1581; ATCC CRL 8287) or NSO (HPA culture collection number 85110503); monkey kidney cells (CV1 ATCC CCL 70); African green monkey kidney cells (VERO-76, ATCC CRL-1587); human cervical carcinoma cells (HELA, ATCC CCL 2); canine kidney cells (MDCK, ATCC CCL 34); buffalo rat hepatocytes (BRL 3A, ATCC CRL 1442); human lung cells (W138, ATCC CCL 75); human hepatocytes (Hep G2, HB 8065); mouse mammary tumor (MMT 060562, ATCC CCL51); TRI cells; MRC5 cells; FS4 cells; and DSM's PERC-6 cell line. Suitable expression vectors for use in each of these host cells are also generally known in the art.

[0213] It should be noted that the term "host cell" generally refers to a cultured cell line. A whole human into which a vector encoding an anti-hTREM-1 antibody or antigen-binding fragment thereof according to the invention or an expression vector has been introduced is expressly excluded from the definition of a "host cell."

[0214] Another object of the present invention is a method for producing and purifying the isolated anti-hTREM-1 antibodies or antigen-binding fragments thereof described herein.

[0215] In one embodiment, the method comprises: - introducing said recombinant nucleic acid or vector into a competent host cell in vitro or ex vivo; - culturing in vitro or ex vivo a host cell transformed with a nucleic acid or an expression vector according to the invention under conditions suitable for the expression of the anti-hTREM-1 antibody or antigen-binding fragment thereof; - optionally selecting cells that express and / or secrete said anti-hTREM-1 antibody or antigen-binding fragment thereof; and - recovering the expressed anti-hTREM-1 antibody or antigen-binding fragment thereof. Includes.

[0216] This recombinant process is well known in the art and can be used for the large-scale production of antibodies or antigen-binding fragments thereof, including monoclonal antibodies intended for in vitro, ex vivo and / or in vivo therapeutic uses.

[0217] In embodiments, the expressed antibody or antigen-binding fragment thereof is further purified. Methods for purifying antibodies or antigen-binding fragments thereof according to the invention are well known in the art and include, but are not limited to, the use of anti-CH1 antibodies, protein A-sepharose, gel electrophoresis, chromatography, particularly affinity chromatography.

[0218] Another object of the present invention is a composition comprising, consisting essentially of, or consisting of an antibody or antigen-binding fragment thereof according to the invention.

[0219] Another object of the present invention is a composition comprising, consisting essentially of or consisting of at least one fusion protein according to the invention.

[0220] A further object of the present invention is a composition comprising, consisting essentially of, or consisting of at least one nucleic acid encoding an antibody or antigen-binding fragment thereof, or a fusion protein according to the invention, or at least one vector containing such a nucleic acid.

[0221] Another object of the present invention is a pharmaceutical composition comprising, consisting essentially of, or consisting of at least one antibody or antigen-binding fragment thereof according to the invention and at least one pharma- ceutically acceptable excipient.

[0222] Another object of the present invention is a pharmaceutical composition comprising, consisting essentially of or consisting of at least one fusion protein according to the invention and at least one pharma- ceutically acceptable excipient.

[0223] A further object of the present invention is a pharmaceutical composition comprising, consisting essentially of, or consisting of at least one nucleic acid encoding an anti-hTREM-1 antibody or antigen-binding fragment thereof, or a fusion protein according to the present invention, or at least one vector comprising such a nucleic acid, and at least one pharma- ceutical acceptable excipient.

[0224] As used herein, "consisting essentially of" with respect to a composition or pharmaceutical composition means that at least one antibody or antigen-binding fragment thereof, fusion protein, nucleic acid, or vector is the only biologically active therapeutic or pharmaceutical agent within said composition or pharmaceutical composition.

[0225] The term "pharmaceutical acceptable excipient" or "pharmaceutical acceptable carrier" includes any and all solvents, dispersion media, coating agents, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. The excipient or carrier does not produce adverse, allergic or other undesired reactions when administered to a subject, preferably a human. A pharmaceutical acceptable excipient or carrier refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or any kind of formulation auxiliary. For human administration, the preparation must meet the sterility, pyrogenicity, and general safety and purity standards required by regulatory authorities, such as the FDA (US Food and Drug Administration) or EMA (European Medicines Agency).

[0226] Pharmaceutically acceptable excipients or carriers that may be used in the composition or pharmaceutical composition include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances (e.g. sodium carboxymethylcellulose), polyethylene glycol, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0227] In one embodiment, the pharmaceutical composition according to the invention comprises a pharma- ceutically acceptable vehicle for a formulation adapted for injection into a subject, which is in particular an isotonic, sterile saline solution (such as mono- or di-sodium phosphate, sodium chloride, potassium chloride, calcium chloride or magnesium chloride, or a mixture of such salts), or a dried, in particular lyophilized, composition, which, upon addition of sterile water or saline, as the case may be, allows the constitution of an injectable solution.

[0228] Another object of the present invention is a medicament comprising, consisting essentially of or consisting of at least one antibody or antigen-binding fragment thereof according to the invention.

[0229] Another object of the present invention is a medicament comprising, consisting essentially of or consisting of at least one fusion protein according to the invention.

[0230] A further object of the present invention is a medicament comprising, consisting essentially of or consisting of at least one nucleic acid encoding an antibody or or an antigen-binding fragment thereof, or a fusion protein according to the invention, or at least one vector comprising such a nucleic acid.

[0231] Another object of the present invention is a kit comprising at least one antibody, or an antigen-binding fragment thereof, or a fusion protein according to the invention, and, optionally, instructions for use.

[0232] By "kit" is intended any article of manufacture (e.g., package or container) that includes at least one antibody, or antigen-binding fragment thereof, or fusion protein according to the invention. The kit may be advertised, distributed, or sold as a unit for performing the methods described herein.

[0233] Another object of the invention is an antibody or an antigen-binding fragment thereof according to the invention for use as a medicament.

[0234] Another object of the invention is a fusion protein according to the invention for use as a medicament.

[0235] A further object of the present invention is a nucleic acid encoding an antibody or an antigen-binding fragment thereof, or a fusion protein according to the invention, or a vector comprising such a nucleic acid, for use as a medicament.

[0236] A further object of the present invention is a composition, pharmaceutical composition or medicament as described herein for use as a medicament.

[0237] For use in a subject in need thereof, the composition, pharmaceutical composition or medicament will be formulated for administration to the subject. The composition, pharmaceutical composition or medicament according to the present invention may be administered parenterally, by injection, by infusion, by inhalation spray, orally, rectally, nasally, topically, or via an implanted reservoir. The term administration as used herein therefore includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques.

[0238] Examples of forms suitable for injection include, but are not limited to, liquid solutions, such as sterile aqueous solutions, gels, dispersions, emulsions, suspensions, solid forms suitable for use in preparing solutions or suspensions upon addition of a liquid prior to use, such as powders, liposomal forms, etc.

[0239] In one embodiment, the antibody or antigen-binding fragment thereof, fusion protein, nucleic acid, vector, composition, pharmaceutical composition or medicament according to the invention is for administration to a subject in need thereof in a therapeutically effective amount or therapeutically effective dose.

[0240] It will be understood that the total daily use of the antibody or antigen-binding fragment thereof, fusion protein, nucleic acid, expression vector, composition, pharmaceutical composition or medicament according to the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective amount or therapeutically effective dose for any particular subject will vary depending on a variety of factors, including factors well known in the medical arts, such as the disease and severity of the disease being treated; the activity of the antibody or antigen-binding fragment thereof, fusion protein, nucleic acid, vector, composition, pharmaceutical composition or medicament employed; the age, weight, general health, sex and diet of the subject; the time of administration, route of administration and rate of excretion of the specific antibody or antigen-binding fragment thereof, fusion protein, nucleic acid, expression vector, composition, pharmaceutical composition or medicament employed; the duration of treatment; drugs used in combination or simultaneously with the specific antibody or antigen-binding fragment thereof, fusion protein, nucleic acid, vector, composition, pharmaceutical composition or medicament employed. For example, it is well within the scope of one of ordinary skill in the art to start administering a therapeutic agent at a level lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. The total dose required for each treatment may be administered in multiple doses or in a single dose.

[0241] In one embodiment, the dosing regimen or dosage used for the administration of the antibody, its antigen-binding fragment, or fusion protein may be adapted as a function of various parameters, in particular as a function of the mode of administration used, the pathology involved, or the duration of the desired treatment. For example, it is well within the scope of the skilled artisan to start the administration of the antibody, its antigen-binding fragment, or fusion protein at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved. The daily dosage of the antibody, antigen-binding fragment, or fusion protein may vary over a wide range from 0.01 to 1000 mg per adult per day. The composition, pharmaceutical composition, or medicament may 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 therapeutic agent for symptomatic adjustment of the dosage to the subject to be treated. A composition, pharmaceutical composition, or medicament may typically contain, for example, about 0.01 mg to about 500 mg of a therapeutic agent. A therapeutically effective amount of a therapeutic agent may be provided, for example, at a dosage level of 0.0002 mg / kg to about 20 mg / kg body weight per day. For example, an antibody, antigen-binding fragment thereof, or fusion protein present in a composition, pharmaceutical composition, or medicament described herein above may be provided at a concentration ranging from 1 mg / mL to about 100 mg / mL, such as, for example, at a concentration of 1 mg / mL, 5 mg / mL, 10 mg / mL, 50 mg / mL, or 100 mg / mL. In one embodiment, an antibody, antigen-binding fragment thereof, or fusion protein is provided at a concentration of about 10 mg / mL in either a 100 mg (10 mL) or 500 mg (50 mL) single-use vial. It will be understood that these dosages are exemplary, and that optimal dosages may be adapted taking into account the affinity and tolerability of the particular antibody, antigen-binding fragment thereof, or fusion protein in the composition, pharmaceutical composition, or medicament, which must be determined in clinical trials.

[0242] The present invention relates to an antibody, or antigen-binding fragment thereof, or fusion protein as described herein for treating (or for use in treating or for use in treating) a disease selected from an inflammatory or autoimmune disease; a cardiovascular disease; cancer, particularly a solid cancer; and an infectious disease, particularly a bacterial or viral infection, in a subject in need thereof.

[0243] The invention also relates to a nucleic acid encoding an antibody, or antigen-binding fragment thereof, or a fusion protein as described herein, or a vector comprising said nucleic acid as described herein, for treating (or for use in treating or in the treatment of) a disease selected from an inflammatory or autoimmune disease; a cardiovascular disease; cancer, particularly a solid cancer; and an infectious disease, particularly a bacterial or viral infection, in a subject in need thereof.

[0244] The present invention relates to a composition, pharmaceutical composition, or medicament as described herein for treating (or for use in treating or for use in treating) a disease selected from an inflammatory or autoimmune disease; a cardiovascular disease; cancer, particularly a solid cancer; and an infectious disease, particularly a bacterial or viral infection, in a subject in need thereof.

[0245] The present invention relates to a method for treating a disease selected from an inflammatory or autoimmune disease; a cardiovascular disease; cancer, particularly a solid cancer; and an infectious disease, particularly a bacterial or viral infection, in a subject in need thereof, said method comprising administering to the subject at least one isolated antibody, or antigen-binding fragment thereof, or fusion protein as described herein.

[0246] The present invention relates to a method for treating a disease selected from an inflammatory or autoimmune disease; a cardiovascular disease; cancer, particularly a solid cancer; and an infectious disease, particularly a bacterial or viral infection, in a subject in need thereof, said method comprising administering to the subject at least one nucleic acid encoding an antibody, or an antigen-binding fragment thereof, or a fusion protein as described herein, or at least one vector comprising said nucleic acid as described herein.

[0247] The present invention relates to a method for treating a disease selected from an inflammatory or autoimmune disease; a cardiovascular disease; cancer, particularly a solid cancer; and an infectious disease, particularly a bacterial or viral infection, in a subject in need thereof, said method comprising administering to the subject a composition, pharmaceutical composition or medicament as described herein.

[0248] The present invention relates to a pharmaceutical composition for treating (or for use in treating) a disease selected from an inflammatory or autoimmune disease; a cardiovascular disease; cancer, particularly a solid cancer; and an infectious disease, particularly a bacterial or viral infection, in a subject in need thereof, said pharmaceutical composition comprising: - an antibody or antigen-binding fragment thereof as described herein; - a fusion protein as described herein; a nucleic acid encoding an antibody, or antigen-binding fragment thereof, or a fusion protein described herein; or - a vector containing such a nucleic acid; and optionally at least one pharma- ceutically acceptable excipient. Includes at least one of the following.

[0249] The invention further relates to the use of an antibody, or antigen-binding fragment thereof, or a fusion protein as described herein for the manufacture of a medicament for treating a disease selected from an inflammatory or autoimmune disease; a cardiovascular disease; cancer, particularly a solid cancer; and an infection, particularly a bacterial or viral infection, in a subject in need thereof.

[0250] The invention further relates to the use of a nucleic acid encoding an antibody, or an antigen-binding fragment thereof, or a fusion protein as described herein, or a vector comprising such a nucleic acid, for the manufacture of a medicament for treating a disease selected from an inflammatory or autoimmune disease; a cardiovascular disease; cancer, particularly a solid cancer; and an infectious disease, particularly a bacterial or viral infection, in a subject in need thereof.

[0251] In one embodiment, the disease to be treated is an inflammatory disease. As used herein, the term "inflammatory disease" refers to disorders and conditions characterized by the presence of inflammation. Symptoms of inflammation may include chronic pain, swelling, redness, joint and muscle stiffness, loss of function and movement of the affected area. Examples of inflammatory diseases include inflammatory bowel disease (IBD), Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, vasculitis, sepsis, systemic inflammatory response syndrome (SIRS), multiple sclerosis, coronary artery disease, chronic obstructive pulmonary disease, interstitial lung disease, chronic inflammatory demyelinating polyneuropathy, and asthma. In one embodiment, the inflammatory disease is a connective tissue disease or disorder. Examples of inflammatory connective tissue diseases or disorders include rheumatoid arthritis, scleroderma, and lupus.

[0252] In one embodiment, the disease to be treated is an autoimmune disease. Examples of autoimmune diseases include inflammatory bowel disease (IBD), rheumatoid arthritis, psoriasis, systemic lupus erythematosus, vasculitis, type I diabetes, Graves' disease, multiple sclerosis, and autoimmune myocarditis.

[0253] In one embodiment, the disease to be treated is an inflammatory disease or an autoimmune disease.

[0254] In one embodiment, the inflammatory disease or autoimmune disease is inflammatory bowel disease (IBD) (including ALPI-associated IBD, monogenic very early onset IBD), Crohn's disease, ulcerative colitis, irritable bowel syndrome, fibrosis such as pulmonary fibrosis or hepatic fibrosis, rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, vasculitis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic hepatitis, systemic inflammatory response syndrome (SIRS), inflammatory bowel disease (IGD), or inflammatory bowel disease (IGD). Inflammatory bowel disease (IBD) is selected from the group consisting of inflammatory bowel disease, septic shock, type I diabetes, Graves' disease, multiple sclerosis, autoimmune myocarditis, Kawasaki disease, coronary artery disease, chronic obstructive pulmonary disease, interstitial lung disease, autoimmune thyroiditis, scleroderma, systemic sclerosis, osteoarthritis, spondylitis, ankylosing spondylitis, atopic dermatitis, vitiligo, macular degeneration, retinal degeneration, uveitis, hidradenitis suppurativa, gingival inflammation and disease, graft versus host disease, Sjogren's syndrome, autoimmune nephritis, Goodpasture's syndrome, chronic inflammatory demyelinating polyneuropathy, allergy, and asthma. As used herein, "inflammatory bowel disease (IBD)" encompasses monogenic polygenic IBD, monogenic IBD, very early onset IBD, early onset IBD, and treatment-resistant IBD.

[0255] In one embodiment, the inflammatory or autoimmune disease is selected from inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, irritable bowel syndrome, fibrosis, pulmonary fibrosis, liver fibrosis, nonalcoholic steatohepatitis (NASH), alcoholic hepatitis, rheumatoid arthritis, psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, vasculitis, systemic inflammatory response syndrome (SIRS), sepsis, septic shock, type I diabetes, Graves' disease, multiple sclerosis, autoimmune myocarditis, Kawasaki disease, coronary artery disease, chronic obstructive pulmonary disease, interstitial lung disease, autoimmune thyroiditis, scleroderma, systemic sclerosis, osteoarthritis, atopic dermatitis, vitiligo, graft versus host disease, Sjogren's syndrome, autoimmune nephritis, Goodpasture's syndrome, chronic inflammatory demyelinating polyneuropathy, allergy, and asthma.

[0256] In one embodiment, the inflammatory or autoimmune disease is selected from inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, vasculitis, systemic inflammatory response syndrome (SIRS), sepsis, septic shock, type I diabetes, Graves' disease, multiple sclerosis, autoimmune myocarditis, Kawasaki disease, coronary artery disease, chronic obstructive pulmonary disease, interstitial lung disease, autoimmune thyroiditis, scleroderma, systemic sclerosis, osteoarthritis, atopic dermatitis, vitiligo, graft versus host disease, Sjogren's syndrome, autoimmune nephritis, Goodpasture's syndrome, chronic inflammatory demyelinating polyneuropathy, allergy, and asthma.

[0257] In one embodiment, the disease to be treated is cardiovascular disease.Examples of cardiovascular disease include myocardial infarction, acute myocardial infarction, cerebral infarction, ischemia, coronary heart disease, acute coronary syndrome, stroke, aneurysm, stable angina, exertional angina, cardiomyopathy, hypertensive heart disease, chronic heart failure, acute heart failure, pulmonary heart failure, cardiac arrhythmia, inflammatory heart disease (such as endocarditis and myocarditis), vasculitis, peripheral arterial disease, SIRS-related myocardial and vascular dysfunction, and atherosclerosis.

[0258] In one embodiment, the disease to be treated is cancer. As used herein, the term "cancer" generally refers to diseases caused by uncontrolled division of abnormal cells. The term "cancer" specifically refers to any disease associated with tumor formation. The term "cancer" encompasses solid and hematological cancers, including both primary and metastatic cancers. Examples of cancer include carcinoma, adenocarcinoma, soft tissue cancer, sarcoma, teratoma, melanoma, leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, and brain cancer. In one embodiment, the cancer is immunoevasive. In one embodiment, the cancer is immunoresponsive. In one embodiment, the cancer is melanoma, renal or kidney cancer, hepatobiliary cancer, head and neck squamous cell carcinoma (HNSC), pancreatic cancer, colon cancer, bladder cancer, urothelial cancer, glioblastoma cancer, prostate cancer, lung cancer, breast (mammary) cancer, ovarian cancer, gastric cancer, esophageal cancer, endometrial cancer, cervical cancer, testicular cancer, leukemia, lymphoma, or mesothelioma. In one embodiment, the cancer is colon cancer, pancreatic cancer, or breast cancer.

[0259] In one embodiment, the disease to be treated is an infectious disease. As used herein, the term "infectious disease" refers to a pathological condition or disorder resulting from an infection. Examples of infectious diseases include bacterial disease (or bacterial infection), viral disease (or viral infection), fungal disease (or fungal infection), and parasitic disease (or parasitic infection), which are infectious diseases caused by bacteria, viruses, fungi, and parasites, respectively. Examples of bacterial diseases include E. coli infection.

[0260] In one embodiment, the disease to be treated comprises or is selected from the group consisting of aneurysm, Still's disease (particularly adult-onset Still's disease or AOSD), burns, cytokine release syndrome (CRS) following CAR-T cell therapy, immune effector cell-associated neurotoxicity syndrome (ICANS) following CAR-T cell therapy, cystic fibrosis, endometritis, familial Mediterranean fever, gout, hepatic granulomas, idiopathic granulomatous mastitis, kidney disease (including sterile chronic kidney injury, nephropathy), liver disease (non-alcoholic steatohepatitis) (NASH), alcoholic hepatitis), lung disease (acute respiratory distress syndrome (ARDS), sarcoidosis), obesity (and related diseases), pancreatitis, Alzheimer's disease, Parkinson's disease, stroke, trauma, and cardiovascular disease (CVD).

[0261] In one embodiment, the disease to be treated is inflammatory bowel disease (IBD), ALPI-associated IBD, monogenic very early onset IBD, Crohn's disease, or ulcerative colitis.

[0262] In one embodiment, the antibody, antigen-binding fragment thereof, fusion protein, nucleic acid, vector, composition, pharmaceutical composition or medicament described herein is to be administered or adapted for administration together with at least one additional therapeutically active agent or treatment. The antibody, antigen-binding fragment thereof, fusion protein, nucleic acid, vector, composition, pharmaceutical composition or medicament described herein may be administered simultaneously, separately or sequentially with said at least one additional therapeutically active agent or treatment. In one embodiment, the antibody, antigen-binding fragment thereof, fusion protein, nucleic acid, vector medicament described herein is to be administered or adapted for administration in combination with at least one additional therapeutically active agent or treatment, such as in a combined preparation, composition, pharmaceutical composition or medicament.

[0263] Examples of therapeutically active agents that may be used in conjunction with an antibody, antigen-binding fragment thereof, fusion protein, nucleic acid, vector, composition, pharmaceutical composition or medicament described herein include anti-TNFα (e.g., adalimumab, etanercept, infliximab, or certolizumab), anti-interleukin (IL)-12 / 23 (e.g., ustekinumab), anti-integrin (e.g., vedolizumab or natalizumab), JAK inhibitors (e.g., tofacitinib, baricitinib, or filgotinib), anti-PD-1 antibodies (e.g., pembrolizumab, nivolumab, cemiplimab), anti-PD-L1 antibodies (e.g., durvalumab, avelumab, atezolizumab), anti-PD-L2 antibodies, and anti-CTLA-4 antibodies (e.g., ipilimumab).

[0264] Examples of therapies that may be used in conjunction with an antibody, antigen-binding fragment thereof, fusion protein, nucleic acid, vector, composition, pharmaceutical composition or medicament described herein include PD-1 / PD-L1 / PD-L2 blockade therapy, CTLA4 blockade therapy, systemic checkpoint blockade therapy in which inhibitory molecules on T cells are blocked, adoptive T cell therapy, CAR-T cell therapy, cell therapy, such as dendritic cell therapy, and chemotherapy.

[0265] In one embodiment, the disease to be treated is an inflammatory disease as described above, such as inflammatory bowel disease (IBD) or rheumatoid arthritis as described above, and the antibody, antigen-binding fragment thereof, fusion protein, nucleic acid, vector, composition, pharmaceutical composition or medicament described herein is administered or adapted for administration together with at least one further therapeutically active agent comprising or selected from the group consisting of anti-TNFα, anti-IL-12 / 23, anti-integrin, and JAK inhibitors.

[0266] In one embodiment, the disease to be treated is a cancer as described above and the antibody, antigen-binding fragment thereof, fusion protein, nucleic acid, vector, composition, pharmaceutical composition or medicament as described herein is to be administered or adapted for administration together with at least one further therapeutically active agent or therapy selected from the group comprising or consisting of PD-1 / PD-L1 / PD-L2 blockade therapy, anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-PD-L2 antibodies, CTLA4 blockade therapy, anti-CTLA4 antibodies, systemic checkpoint blockade therapy in which inhibitory molecules on T cells are blocked, adoptive T cell therapy, CAR-T cell therapy, cell therapy such as dendritic cell therapy, and chemotherapy.

[0267] In one embodiment, a subject in need of treatment is identified or selected following measurement of his / her levels of TREM-1, in particular soluble TREM-1 (sTREM-1), in a biological sample.

[0268] In one embodiment, a subject in need of treatment is monitored through measuring his / her levels of TREM-1, particularly sTREM-1, in a biological sample. Such monitoring may include monitoring the progression of disease in the subject, monitoring the subject's response to treatment (i.e., response to an antibody, antigen-binding fragment thereof, fusion protein, nucleic acid, vector, composition, pharmaceutical composition or medicament described herein), and / or monitoring the effectiveness of treatment in the subject (i.e., effectiveness of an antibody, antigen-binding fragment thereof, fusion protein, nucleic acid, vector, composition, pharmaceutical composition or medicament described herein).

[0269] As used herein, "sTREM-1" as "soluble triggering receptor expressed on myeloid cell-1" refers to a soluble form of TREM-1 lacking the transmembrane and intracellular domains of TREM-1. In one embodiment, sTREM-1 therefore corresponds to a soluble form of the extracellular domain of TREM-1. In one embodiment, sTREM-1 corresponds to a truncated TREM-1 that is shed from the membrane of myeloid cells, particularly from activated myeloid cells. In one embodiment, sTREM-1 has an amino acid sequence corresponding to amino acids 21-205 of SEQ ID NO: 43. In one embodiment, sTREM-1 has an amino acid sequence corresponding to amino acids 31-205 of SEQ ID NO: 43. In one embodiment, sTREM-1 comprises an amino acid sequence corresponding to amino acids 31-137 of SEQ ID NO: 43 and is 200 amino acids or less in length, preferably 185 amino acids or less in length.

[0270] As used herein, a "biological sample" refers to a biological sample isolated, collected, or harvested from a subject, and may include bodily fluids, cell samples, and / or tissue extracts, such as homogenates or solubilized tissues, obtained from a subject. In one embodiment, the present invention does not involve obtaining a biological sample from a subject. Thus, in one embodiment, the biological sample from a subject is a biological sample previously obtained from the subject. The biological sample may be stored in an appropriate condition before use, as described herein. In one embodiment, the biological sample from a subject is a bodily fluid sample. Examples of bodily fluids include blood, plasma, serum, lymph, saliva, urine, bronchioloalveolar lavage fluid, cerebrospinal fluid, sweat, or any other bodily secretion or derivative thereof.

[0271] As used herein, the term "measuring" is interchangeable with the terms "measurement" or "detection" and means evaluating the presence, absence, content, or amount (which may be an effective amount) of a given substance, i.e., TREM-1 or sTREM-1, in a biological sample from a subject. As used herein, "measuring" includes derivation of a qualitative or quantitative concentration (e.g., blood or plasma concentration) of said substance, i.e., TREM-1 or sTREM-1, in the biological sample and in the subject. As used herein, the term "level" in "TREM-1 level", particularly "sTREM-1 level", refers to the content, amount, or concentration of TREM-1, particularly sTREM-1.

[0272] The level of TREM-1, in particular sTREM-1, may be measured by any method known in the art. Methods for measuring expression levels, such as transcription or translation levels, are well known to those skilled in the art.

[0273] Methods for measuring the transcription levels of TREM-1, particularly sTREM-1 (i.e., the levels of TREM-1 mRNA or cDNA, particularly the levels of sTREM-1 mRNA or cDNA) in the biological samples described herein above are well known to those skilled in the art and include, but are not limited to, PCR, qPCR, RT-PCR, RT-qPCR, Northern blots, hybridization techniques such as the use of microarrays, and combinations thereof, including, but not limited to, hybridization of amplicons obtained by RT-PCR, sequencing, such as next-generation DNA sequencing (NGS) or RNA-seq (also known as "whole transcriptome shotgun sequencing").

[0274] Methods for measuring the translational levels of TREM-1, particularly sTREM-1 (i.e., the levels of TREM-1 protein or sTREM-1 protein) are well known to those of skill in the art and include, but are not limited to, immunohistochemistry, multiplex methods (e.g., Luminex®), immunoassays, Western blots, enzyme-linked immunosorbent assays (ELISAs), sandwich ELISAs, multiplex ELISAs, capillary-based ELISAs (e.g., the ELLA® platform), electrochemiluminescence (ECL), also called electrogenerated chemiluminescence, or electrochemiluminescence immunoassays (ECLIA), enzyme-linked fluorescence assays (ELFAs), fluorescence-linked immunosorbent assays (FLISAs), enzyme immunoassays (EIAs), radioimmunoassays (RIAs), flow cytometry (FACS), surface plasmon resonance (SPR), biolayer interferometry (BLI), immunochromatographic assays (ICAs) (e.g., NEXUS® platform), and the like. IB10, Sphingotech) and mass spectrometry-based approaches.

[0275] The following sequences are listed herein: - SEQ ID NO:1: NTYIH; SEQ ID NO: 2: RIDPAX1GX2TKYX3PKVX4G, where X1 is N or G, X2 is N or R, X3 is A, D or S and X4 is Q or K; SEQ ID NO: 3: HX5GX6TMDY, where X5 is Y or R and X6 is S or G; - SEQ ID NO: 4: RASX7SVX8NYGISFX9N, where X7 is E or G, X8 is D or S and X9 is M or L; -SEQ ID NO:5: AAX 10 X 11 X 12 X 13 X 14 , where X 10 is S or E, and X 11 is N or Y, and X 12 is Q or R, and X13 is G, A, or K, and X 14 is S or R; SEQ ID NO: 6: QQSX 15 X 16 X 17 PX 18 T, where X 15 is K, R, or S; X 16 is E, H, or N, and X 17 is V or F, and X 18 is W or Y; - SEQ ID NO: 7: RIDPAGGRTKYDPKVKG; - SEQ ID NO: 8: HYGGTMDY; - SEQ ID NO: 9: RASESVDNYGISFLN; - SEQ ID NO: 10: AAEYRGR; - SEQ ID NO: 11: QQSRHVPYT; - SEQ ID NO: 12: RIDPAGGRTKYSPKVQG; - SEQ ID NO: 13: HRGGTMDY; - SEQ ID NO: 14: RASQSVSNYGISFLN; - SEQ ID NO: 15: AASYQKR; - SEQ ID NO: 16: QQSSNFPWT; - SEQ ID NO: 17: RIDPAGGRTKYAPKVKG; - SEQ ID NO: 18: QQSSNVPYT; - SEQ ID NO: 19: RIDPAGGRTKYAPKVQG; - SEQ ID NO: 20: AAEYQGR; - SEQ ID NO: 21: AAEYRAR; - SEQ ID NO: 22: RIDPANGNTKYAPKVQG; - SEQ ID NO: 23: HYGSTMDY; - SEQ ID NO:24: RASESVDNYGISFMN; - SEQ ID NO: 25: AASNQGS; - SEQ ID NO: 26: QQSKEVPWT; - SEQ ID NO:27: EVQLVESGGALVKPGGSLRLSCAASGFNIDNTYIHWVRQAPGKGLEWIGRIDPAGGRTKYDPKVKGRFTISADTSKNTAYLQMNSLKTEDTAVYYCTGHYGGTMDYWGQGTLVTVSS; -SEQ ID NO:28: EVQLVESGGALVKPGGSLRLSCAASGFNIGNTYIHWVRQAPGKGLEWIGRIDPAGGRTKYSPKVQGRFTISAPTSKNTAYLQMNSLKTEDTAVYYCTGHRGGTMDYWGQGTLVTVSS; -SEQ ID NO:29:EVQLVESGGALVKPGGSLRLSCAASGFNIGNTYIHWVRQAPGKGLEWVGRIDPAGGRTKYAPKVKGRFTISADDSKNTAYLQMNSLKTEDTAVYYCTGHRGGTMDYWGQGTLVTVSS; -SEQ ID NO:30:EVQLVESGGALVKPGGSLRLSCAASGFNIGNTYIHWVRQAPGKGLEWIGRIDPAGGRTKYAPKVQGRFTISADTSKNTAYLQMNSLKTEDTAVYYCTGHYGGTMDYWGQGTLVTVSS; -SEQ ID NO:31:EVQLVESGGALVKPGGSLRLSCAASGFNIGNTYIHWVRQAPGKGLEWVGRIDPAGGRTKYAPKVKGRFTISADDSKNTLYLQMNSLKTEDTAVYYCTGHRGGTMDYWGQGTLVTVSS; - SEQ ID NO:32: EVQLVESGGALVKPGGSLRLSCAASGFNIKNTYIHWVRQAPGKGLEWIGRIDPANGNTKYAPKVQGRFTISADTSKNTAYLQMNSLKTEDTAVYYCTGHYGSTMDYWGQGTLVTVSS; -SEQ ID NO:33: EIVLTQSPATLSLSPGERATLSCRASESVDNYGISFLNWYQQKPGQAPRLLIYAAEYRGRGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSRHVPYTFGQGTKVEIK; -SEQ ID NO:34: EIVLTQSPATLSLSPGERATLSCRASQSVSNYGISFLNWYQQKPGQAPRLLIYAASYQKRGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNFPWTFGQGTKVEIK; -SEQ ID NO:35: EIVLTQSPATLSLSPGERATLSCRASQSVSNYGISFLNWYQQKPGQAPRLLIYAAEYRGRGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNVPYTFGQGTKVEIK; -SEQ ID NO:36: EIVLTQSPATLSLSPGERATLSCRASQSVSNYGISFLNWYQQKPGQAPRLLIYAAEYQGRGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNVPYTFGQGTKLEIK; -SEQ ID NO:37: EIVLTQSPATLSLSPGERATLSCRASQSVSNYGISFLNWYQQKPGQAPRLLIYAAEYRARGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNVPYTFGQGTKVEIK; -SEQ ID NO:38: EIVLTQSPATLSLSPGERATLSCRASESVDNYGISFMNWFQQKPGQAPRLLIYAASNQGSGIPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSKEVPWTFGQGTKVEIK; - SEQ ID NO: 39: RIDPAX1GX2TKYX3PKFX4G, where X1 is N or G, X2 is N or R, X3 is A, D or S, and X4 is Q or K; - SEQ ID NO: 40: RIDPANGNTKYAPKFQG; - SEQ ID NO: 41: AVQLQQSVAALVRPGASVKLSCTASGFNIKNTYIHWVKQRPEQGLEWIGRIDPANGNTKYAPKFQGKATITADTSSDTAYLQLSSLTSDDTAIYYCTGHYGSTMDYWGQGTSVTVSS; - SEQ ID NO: 42: EIVLTQSPASLAVSLGQRATISCRASESVDNYGISFMNWFQQKPGQTPKLLIYAASNQGSGVPARFSGSGSGTDFSLNIHPMEDDDTAMYFCQQSKEVPWTFGGGTKLEIK; -SEQ ID NO: 43: MRKTRLWGLLWMLFVSELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKGFSGTPGSNENSTQNVYKIPPTTTKALCPLYTSPRTVTQAPPKSTADVSTPDSEINLTNVTDIIRVPVFNIVILLAGGFLSKSLVFSVLFAVTLRSFVP; -SEQ ID NO:44: MRKTRLWGLLWMLFVSELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKGFRCSTLSFSWLVDS; -SEQ ID NO: 45: MRKTRLWGLLWMLFVSELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKGFSGTPGSNENSTQNVYKIPPTTTKALCPLYTSPRTVTQAPPKSTADVSTPDSEINLTNVTDIIRYSFQVPGPLVWTLSPLFPSLCAERM; - அக்குக்க்குக்கு46:MRKTRLWGLLWMLFVSELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKE PHMLFDRIRLVVTKGFSGTPGSNENSTQNVYKIPPTTTKALCPLYTSPRTVTQAPPKSTADVSTPDSEINLTNVTDIIREKSMTFGIRRLDVESHPLPPLHTGHFRISQFFSQAGTQSLHSCYKGKPTP; -Sequence number 47:GAGGTGCAGCTGGTGGAGTCTGGAGTCTGGAGGCGCTCTCGTGGAAGCCTGGCGGCTCTCCTGCAGACTCTCTTGCGCTCCGGCTTCCAACATCGACAACACCTACATCCACTGGGTGCGGCAGGCTCCTGGAAAGGGACTCGAGTGGATCGGAAAGGAATCGACCCTGCTGGGAGGGAACCAAGTACGACCCCCGGTTCACCATCTCTGCGACACCTCCAAGAACCCGCCTACCTGCAGATGAACAGCCTCAAGACCGAGGACACCGCTGTCTACTACTGCACCGGGCACTACGGAGGACAATGGATTACTGGGGGACAGGGACACTCGTCACCGTCTCTAGC; -Sequence number 48:GAGGTGCAGCTGGTGGAGTCTGGAGGCGCTCTCGTGAAGCCTGGCGGCTCTCTCAGACTCTCTTGCGCTGCCTCCGGCTTCAACATCGGAAACACCTACATCCAGCTACTGGGTGCGGCAGGCTCCTGGAAAGGGACTCGAGTGGATCGGAAAGAATCGACCCTGCTGGAGGGAACCAAGTACTCCCCAAAGGTCCAGGGCGGTTCACCATCTCTGCCCTACCTCCAAGAACACCGCCTACCTGCAGATGAACAGCCTCAAGACCGAGGCACCGCTGTCTACTACTGTACCGGGCACAGGGGAGGACAATGGATTACTGGGACAGGGGACACTCGTCACCGTCTCTAGC; -Sequence number 49:GAGGTGCAGCTGGTGGAGTCTGGGAGGCGCTCTGGTGAAGCCTGGCGGGCTCTCGGAGACTGTCTTGCGCTCCTGGGCTCCGGCTTCAACATCGGCAACACCTACATCCACTGGGTGCGGCAGGCTCCTGGAAAGGGACTGGAGTGGGTGGGCAGAATCGATCCTGCTGGCGGAGAAACCAAGTACGCCCCAAAGGTGAAGGGACGGTTCACCATCTCTGCCGACGACTCCAAGAACCCGCCTACCTCCAGATGAACTCCCTCAAGACCGAGGACCCGCTGTGTACTACTGTACCGGGACACCGGGAGAGACAATGGATTACTGGGGCAGGGACAACTCGTGACCGTGTCTTCC; -Sequence number 50:GAGGTGCAGCTGGTGGAGTCTGGGAGGCGCTCTGGTGGAAGCCTGGCGGCTCTCTGAGACTGTCTTGCGCTGCCTCCGGCTTCAACATCGGCAACACCTACATCCACTGGGTGCGGCAGGCTCCTGGAAAGGGACTGGAGTGGATCGGCAGAATCGACCCTGCTGGCGGAAGAACCAAGTACGCCCCAAAGGTGCAGGACGGTTCACCATCTCTGCCACACCTCCAAGAACACCCGCCTACCTCCAGATGAACTCCCTCAAGACCGAGGACCCGCGTGTACTACTGCACCGGACACTACGGAGGACAATGGATTACTGGGGGACAGGGACACTCGTGACCGTGTCTTCC; -Sequence number 51:GAGGTGCAGCTGGTGGAGTCTGGGAGTCGCTCTGGTGAAGCCTGGCGGCTCTCTCAGACTCTCTTGCGCTGCCTCCGGCTTCAACATCGGAAACACCTACATCCACTGGGTGCGGCAGGCTCCTGGAAAGGGACTCGAGTGGGTCGGAGAAATCGATCCTGCTGGGAGGGAACCAAGTACCCCCAAAGGTCAAGGGCGGTTCACCATCTCTGCCGACGACTCCAAGAACACCCTGTACCTCCAGATGAACAGCCTCAAGACCGAGGACACCGCTGTACTACTGTACCGGGCACAGGGGAGGACAATGGGATTACTGGGGCAGGGGACACTCGTCACCGTCTCTAGC; -Sequence number 52:GAGGTGCAGCTGGTGGAGTCTGGGAGGCGCTCTGGTGAAGCCTGGCGGCTGGCCTCCGGCTTCAACATCAAGAACACCTACATCCAAGGTGCGGCAGCTCCTGGAAAGGGACTGGAGTGGATCGGCCGGATCGACCCTGCTAACGGCAACACCAAGTACGCCCCAAAGGTGCAGGACGGTTCACCATCTCTGCCACACCTCCAAGAAACACCGCCTACCTCCAGATGAACTCCCTCAAGACCGAGGACCCGCGTGTACTACTGCACCGGACACTACGGATCCACCATGGACTACTGGGGACAGGGGACACTCGTGACCGTGTCTTCC; -Sequence number 53:GAGATCGTCCTGACCCAGTCTCCTGCCACCCTGTCTCTTCTCCCGGCGAAAGAGCCACCCCTCTCTTGCAGAGCCCTCCGAGTCCGTGGACAACTACGGCATCTCCTTCCTCAACTGGTACCAACAGAAGCCTGGACAGGCCCCTAGGCTCCTCATCTACGCTGCTGAGTACAGGGGAAGGGGAATCCCGCTAGGTTCTCTGGGAGTGGGTCTGGGACCGACTTCACCCTCACCATCTCCTCCCTCGAGCCCGAGGACTTCGCTGTACTACTGCCAGCAGTCCCGGCACGTGCCTTACACCTTCGGGAGGGACCAAGGTGGAGATCAAG; -Sequence number 54:GAGATCGTCCTGACCCAGTCTCCTGCCACCCTGTCTCTGCCCGGCGAGAGACCACCCTGTCTTGCAGAGCCCTCCCAGTCCGTGTCCAACTACGGCATCTCCTTCCTGAACTGTACCAACACAGAAGCCTGGCCAGGCCCCTAGACTCCTCATCTACGCGCGCTCTTACCAGAAGCGGGGCATCCCCCGCCAGATTCTCTGGATCTGGATCTGGAACCGACTTCACCCTCACCATCTCCTCCCTCGAGCCCGAGGACTTCGCAGTGTACTACTGCCAGCAGTCCTCCAACTTCCCCTGGACCTTCGGACAGGGGACCAAGGTGGAGATCAAG; -Sequence number 55:GAGATCGTCCTGACCCAGTCTCCTGCCACCCTGTCTCTGCCCGGCGAGAGACCACCCTGTCTTGCAGAGCCCTCCCAGTCCGTGTCCAACTACGGCATCTCCTTCCTGAACTAGCCAGAGCCTGGCCAGGCCCCTAGACTCCTCATCTACGCCGCCGAGTACAGAGGCAGAGGCATCCCCCGCCAGATTCTCTGGATCTGGATCTGGGATCTGGAACCGACTTCACCCTCACCATCTCCTCCCTGGAGCCCGAGGACTTCGCAGTGTACTACTGCCAGCAGTCTCTCCAACGTGCCCTACACCTTCGGCCAGGGGACCAAGGTGGAGATCAAG; -Sequence number 56:GAGATCGTCCTGACCCAGTCTCCTGCCACCCTGTCTCTGCCCGGCGAGAGAGCCACCCTGTCTTGCAGAGCCTCCCAGTCCGTGTCCAACTACGGCATCTCCTTCCTGAACTAGCCTGTCCTGAACTGGTCCTGAACTGGTCTCCGAGTACCAGGGCAGAGGCATCCCTGCCAGATTCTCTGGATCTGGATCTGGGAACCGACTTCACCCTCACCATCTCCTCCCTGGAGCCCGAGGACTTCGCAGTGTACTACTGCCAGCAGTCTCTCCAACGTGCCCTACACCTTCGGCCAGGGACCAAGCTCGAGATCAAG; -Sequence number 57:GAGATCGTCCTGACCCAGTCTCCTGCCACCCTGTCTCTTCTCCCCGGCGAAAGAGCCACCCTCTCTTGCAGAGCCCTCCCAGTCCGTGTCCAACTACGGAATCTCCTTCCTCAACTGGTACCAACAGAAGCCTGGACAGGCCCCTAGGCTCCTCATCTACGCAGCTGAGTCACAGGGCTAGGGAATCCCCGTAGGTTCTCTGGATCTGGGAGTGGGACCGACTTCACCCTCACCATCTCCTCCCTGGAGCCCGAGGACTTCGCTGTGTACTACTGCCAGCAGTCTCTCCAACGTGCCTTACACCTTCGGGGCAGGGGACCAAGGTGGGAGATCAAG; -Sequence number 58:GAGATCGTCCTGACCCAGTCTCCTGCCACCCTGTCTCTGCCAGCAGAGCCACCTGTCTTGTCTCCCGGCGAGAGGCCCTCCGAGTCCGTGGACAACTACGGCATCTCCTTCATGAACTGGTTCCAACAGAAGCCTGGCCAGGCCCCTAGACTGCTCATCTACGCCGCCTCTAACCAGGGGCTCGCCCGCAGATTCTCTGGATCTGGATCTGGGAACCGACTTCACCCTCACCATCTCCTCCCTGGAGCCCGAGGACTTCGCAGTGTACTTCTGCCAGCAGCTCCAAGGAGGTCCTTGGACCTTTGGGAGGGACCAAGGTGGAGATCAAG; - குற்றுக்க்குக்கு 59:; -SEQ ID NO: 60:; -Sequence number 61: LQEEDAGEYGCM. [Brief description of the drawings]

[0276] [Figure 1] Figure 1 is a histogram showing the effect of anti-TREM-1 antibody (INO-10 hIgG1) or Fab (INO-10 Fab) on intracellular reactive oxygen species (ROS) generation in neutrophils. Human primary neutrophils were incubated for 2 h under resting conditions (NS) or stimulated with LPS (100 ng / mL) in the presence or absence of the indicated concentrations of INO-10 IgG1 or INO-10 Fab. *p<0.05, **p<0.01, ***p<0.001 versus LPS alone as determined by parametric t-test. [Diagram 2]FIG. 2 is a graph showing expression of TREM-1 (assessed by flow cytometry) on U937 cells and on U937 cells pretreated with vitamin D3 to induce upregulation of TREM-1 (U937-vitD3). [Diagram 3] FIG. 3 is a graph showing binding (assessed by flow cytometry) of anti-TREM-1 Fab INO-10F and negative control INO-10F-0 (0.01-10 μg / mL) on U937 cells pretreated with vitamin D3 to induce upregulation of TREM-1. [Figure 4] Figures 4A-C are a set of graphs showing the effect of anti-TREM-1 Fab INO-10F on the production of cytokines (IL-6, IL-10 and IL-1β) by U937 cells pretreated with vitamin D3 (U937-vitD3). The concentrations of IL-6 (Figure 4A), IL-10 (Figure 4B) and IL-1β (Figure 4C) in the supernatants were measured after 24 h stimulation of U937-vitD3 cells in resting conditions or in the PP-activated condition (stimulation with the PP complex corresponding to PGLYRP1 complexed to peptidoglycan) in the presence of INO-10F or control (Ctrl) (INO-10F-0-Ctrl). *p<0.05, **p<0.01, ***p<0.001 versus PP alone as determined by parametric t-test. [Diagram 5] 5A-C are a set of graphs showing TREM-1 (FIG. 5A), CD14 (FIG. 5B) and TLR4 (FIG. 5C) expression on THP-1 cells and THP-1 cells pretreated with vitamin D3 to induce upregulation of TREM-1. TREM-1, CD14 and TLR4 expression was assessed by flow cytometry and compared to isotype controls. [Figure 6] FIG. 6 is a graph showing binding of anti-TREM-1 Fab INO-10F (0.01-10 μg / mL) on THP-1 cells and THP-1 cells pretreated with vitamin D3 (THP-1-vitD3), as assessed by flow cytometry. [Figure 7]Figures 7A-B show the effect of anti-TREM-1 Fab INO-10F on NF-κB activation in THP-1 Blue cells and THP-1-vitD3 Blue cells (i.e., THP-1 Blue cells pretreated with Vitamin D3 to induce upregulation of TREM-1). Figure 7A shows histograms showing NF-κB activation in THP-1 Blue cells and THP-1-vitD3 Blue cells, assessed by measuring the activity of SEAP (measured at 650 nm) either in the presence of INO-10F at the indicated concentrations (0.1-10 μg / mL) for 6 h (resting+INO-10F) or in the presence of INO-10F and LPS at the indicated concentrations (0.1-10 μg / mL) for 6 h (LPS+INO-10F). *p<0.05, **p<0.01 versus LPS alone as determined by metric t-test. Figure 7B is a graph showing the kinetics of NF-κB activation upon LPS priming (100 ng / mL) in the presence of the indicated concentrations (0.1-10 μg / mL) of INO-10F. *p<0.05, **p<0.01 versus LPS alone as determined by two-way ANOVA test. [Figure 8] Figure 8 is a histogram showing the effect of anti-TREM-1 Fab INO-10F on IL-8 production by THP-1 cells pretreated with vitamin D3 to induce upregulation of TREM-1 (THP-1-vitD3). IL-8 concentrations in the supernatant were assessed after 24 h stimulation of THP-1-vitD3 cells with LPS or no stimulation (NS) in the presence of INO-10F at the indicated concentrations (0, 0.1 or 10 μg / mL). *p<0.05, **p<0.01, ***p<0.001 versus LPS alone as determined by parametric t-test. [Figure 9] Figure 9 is a graph showing TREM-1 expression on neutrophils (assessed by flow cytometry) at the indicated times. Human primary neutrophils were cultured unstimulated, stimulated with LPS for 3 hours, or stimulated with LPS for 24 hours. TREM-1 expression is compared to an isotype control. [Figure 10]Figure 10 is a graph showing binding of INO-10F (assessed by flow cytometry) to freshly isolated human primary neutrophils at different concentrations (0.000001-10 µg / mL). [Figure 11] FIG. 11 is a graph showing reactive oxygen species (ROS) release by human primary neutrophils upon incubation for 2 h in the presence of the indicated concentrations (10-11 to 101 μg / mL) of INO-10F either with LPS (black squares) or in the unstimulated state (grey circles). [Figure 12] Figures 12A-B show the effect of anti-TREM-1 Fab INO-10F on reactive oxygen species (ROS) release by neutrophils. Figure 12A is a histogram showing ROS release by human primary neutrophils upon 2 h incubation with the indicated concentrations (0-10 μg / mL) of INO-10F either unstimulated (NS) or stimulated with a PP complex corresponding to PGLYRP1 complexed to peptidoglycan (PP). Figure 12B is a graph showing the binding rate of INO-10F at the indicated concentrations (0-10 μg / mL) on human primary neutrophils (black circles) and the rate of ROS release by human primary neutrophils after PP stimulation in the presence of the indicated concentrations (0-10 μg / mL) of INO-10F (gray squares). [Figure 13] 13 is a graph showing the effect of anti-TREM-1 Fab INO-10F on IL-6 production by neutrophils. IL-6 concentrations in neutrophil supernatants were assessed after 6 and 24 hours of stimulation with the indicated concentrations (0, 0.1, or 10 μg / mL) of INO-10F, either with LPS or in the unstimulated state. [Figure 14]Figures 14A-E are a set of histograms showing the effect of anti-TREM-1 Fab INO-10F on cytokine plasma concentrations after a 24-hour whole blood stimulation assay. INO-10F was added at the indicated concentrations (0-10 μg / mL) either in the non-stimulated state (NS) or together with LPS. As a positive control, stimulation with a known TREM-1 inhibitor (peptide LR12) was performed together with LPS. After 24 hours, expression of the following cytokines was assessed: IL-1β (Figure 14A), IL-10 (Figure 14B), TNFα (Figure 14C), IL-6 (Figure 14D), and IL-8 (Figure 14E). *p<0.05, **p<0.01, ***p<0.001 versus LPS alone as determined by parametric t-test. [Figure 15] Figure 15 is a box plot showing IL-8 plasma concentrations after a 24-hour whole blood stimulation assay. INO-10F was added at the indicated concentrations (0-10 μg / mL) to whole blood of 14 healthy volunteers either under resting conditions (NS) or together with LPS. As a positive control, stimulation with a known TREM-1 inhibitor (peptide LR12) was performed together with LPS. After 24 hours, plasma concentrations of IL-8 were assessed. *p<0.05, **p<0.01, ***p<0.001 versus LPS alone as determined by paired non-parametric t-test. [Figure 16]Figures 16A-G are a set of box plots showing the effect of anti-TREM-1 Fab INO-10F and HSA-INO-10F on plasma concentrations of human cytokines in transgenic BRGSF-his (humanized immune system) mice suffering from LPS-induced endotoxemia. BRGSF-his mice were administered either PBS (control (CTRL)) or LPS by intraperitoneal injection. BRGSF-his mice receiving LPS were first pretreated (30 min before LPS) with either vehicle (LPS), INO-10F (LPS+10F-10 μg / mL), or a fusion protein of HSA and INO-10F (LPS+HSA-10F-10 μg / mL) by intraperitoneal injection. Blood samples were collected 8 hours after LPS injection to assess plasma concentrations of the following human cytokines / chemokines: CCL2 (Figure 16A), IL-1β (Figure 16B), IL-10 (Figure 16C), IL-6 (Figure 16D), and IL-8 (Figure 16E), IP-10 (Figure 16F), and TNFα (Figure 16G). p values ​​between the indicated conditions relative to LPS alone were calculated according to non-parametric t-tests. [Figure 17] 17A-B are a set of graphs showing binding (assessed by flow cytometry) of anti-TREM-1 Fab INO-10F and anti-TREM-1 Fab variants INO-10F-0 (F0), INO-10F-1 (F1), INO-10F-2 (F2), INO-10F-3 (F3), INO-10F-4 (F4), INO-10F-5 (F5), and INO-10F-6 (F6) on U937 cells (FIG. 17A) and U937-vitD3 cells, i.e., U937 cells pretreated with vitamin D3 to induce upregulation of TREM-1 (FIG. 17B). [Figure 18]FIG. 18 is a histogram showing the effect of anti-TREM-1 Fab variants INO-10F-0 (F0), INO-10F-1 (F1), INO-10F-2 (F2), INO-10F-3 (F3), INO-10F-4 (F4), INO-10F-5 (F5), and INO-10F-6 (F6) on IL-6 production by U937 cells pretreated with vitamin D3. The concentration of IL-6 was determined in the supernatant after 24 h stimulation of U937-vitD3 cells in the presence of the indicated concentrations (0-10 μg / mL) of anti-TREM-1 Fab variants in the non-stimulated state (NS) or in the PP-activated state (stimulation with the PP complex corresponding to PGLYRP1 complexed with peptidoglycan). As a positive control, stimulation with a known TREM-1 inhibitor (peptide LR12) was performed in the PP-activated state (LR12). *p<0.05, **p<0.01, ***p<0.001, ****p<0.001 versus PP alone. [Figure 19] FIG. 19 is a graph comparing binding (assessed by flow cytometry) of the anti-TREM-1 Fab variants INO-10F-3 (F3) and INO-10F-O (F0) at the indicated concentrations (0.001-10 μg / mL) to freshly isolated primary neutrophils. [Figure 20] FIG. 20 is a histogram showing the effect of anti-TREM-1 Fab variants INO-10F-0 (F0), INO-10F-1 (F1), INO-10F-2 (F2), INO-10F-3 (F3), INO-10F-4 (F4), INO-10F-5 (F5), and INO-10F-6 (F6) on IL-8 production by human primary neutrophils. The concentration of IL-8 was determined in the supernatant after 24 h stimulation of neutrophils in the presence of the indicated concentrations (0-10 μg / mL) of the anti-TREM-1 Fab variants in the non-stimulated (NS) or LPS-activated state. As a positive control, stimulation with a known TREM-1 inhibitor (peptide LR12) was performed in the LPS-activated state (LR12). *p<0.05, **p<0.01, ***p<0.001, ****p<0.001 versus LPS alone. [Figure 21]Figures 21A-H are a set of graphs showing the effect of anti-TREM-1 Fab INO-10F and anti-TREM-1 Fab variants on intracellular reactive oxygen species (ROS) generation in neutrophils. Human primary neutrophils were stimulated with LPS (100 ng / mL) for 2 hours in the presence of the indicated concentrations (0.001-10 μg / mL) of INO-10 Fab (Figure 21A) or anti-TREM-1 Fab variants INO-10F-0 or F0 (Figure 21B), INO-10F-1 or F1 (Figure 21C), INO-10F-2 or F2 (Figure 21D), INO-10F-3 or F3 (Figure 21E), INO-10F-4 or F4 (Figure 21F), INO-10F-5 or F5 (Figure 21G), and INO-10F-6 or F6 (Figure 21H). [Figure 22] Figures 22A-C are a set of graphs showing the effect of anti-TREM-1 Fab variants (INO-10F-3 conjugated with HSA or F3-HSA) on intracellular reactive oxygen species (ROS) generation in neutrophils. Human primary neutrophils were stimulated for 2 h with LPS (100 ng / mL) (Figure 22A) or PP complexes (PP) corresponding to PGLYRP1 (5 μg / mL) complexed with peptidoglycan corresponding to PGN (10 μg / mL) (Figure 22B) or peptidoglycan (PGN-10 μg / mL) alone (Figure 22C) in the presence of the indicated concentrations (0.02-20 μg / mL) of F3-HSA. *p<0.05, **p<0.01, ***p<0.001 versus LPS alone (Figure 22A), PP alone (Figure 22B), or PGN alone (Figure 22C) as determined by parametric ANOVA test. [Diagram 23]Figures 23A-B are a set of box plots showing the effect of anti-TREM-1 Fab variants (INO-10F-3 conjugated with HSA or F3-HSA) on cytokine plasma concentrations after a 24-hour whole blood stimulation assay following lysis of red blood cells from five healthy donors. F3-HSA or isotype control (CTLR) was added at the indicated concentrations (0-20 μg / mL) in either non-stimulated conditions (NS) or in PP complexes (PP) corresponding to PGLYRP1 (5 μg / mL) complexed with peptidoglycan corresponding to PGN (10 μg / mL) or peptidoglycan alone (PGN-10 μg / mL). After 24 hours, expression of the following cytokines was assessed: IL-8 (Figure 23A) and TNFα (Figure 23B). *p<0.05, **p<0.01, ***p<0.001 versus PP alone or PGN alone as determined by non-parametric t-test. [Figure 24] Figures 24A-C are a set of histograms showing the effect of anti-TREM-1 Fab variants (INO-10F-3 conjugated with HSA or F3-HSA) on cytokine plasma concentrations following a 24-hour cynomolgus monkey whole blood stimulation assay following red blood cell lysis. F3-HSA or isotype control (CTRL) was added at the indicated concentrations (0-20 μg / mL) with either PP complexes (PP) corresponding to PGLYRP1 (5 μg / mL) complexed with peptidoglycan corresponding to PGN (10 μg / mL) or peptidoglycan alone (PGN-20 μg / mL). After 24 hours, expression of the following cytokines was assessed: IL-8 (Figure 24A), TNFα (Figure 24B) and IL-6 (Figure 24C). *p<0.05, **p<0.01, ***p<0.001 versus PGN alone as determined by non-parametric t-test. EXAMPLES

[0277] The present invention is further illustrated by the following examples.

[0278] Working Example: Materials and Methods Generation of anti-hTREM-1 antibodies / Fab fragments Novel anti-human TREM-1 (anti-hTREM1) mouse antibodies were obtained by immunizing mice with recombinant hTREM-1 protein. The sequences of the anti-hTREM-1 mouse antibodies and Fab fragments were obtained by hybridoma sequencing and sequence analysis (Diaclone, France). Recombinant chimeric anti-hTREM-1 antibodies (human IgG1 or hIgG1) and Fab fragments were then generated. Sequences from the variable regions were subcloned into the pQMCF-1.2 expression vector and the coding regions were verified by sequencing. CHOEBNALT85 1E9 cells (Icosagen) were then transfected with the pQMCF-1.2 expression vector in CHO TF medium (Xell AG) for 96 hours using R007 transfection reagent (Icosagen). Transfection was verified by PCR. Expression was confirmed by Coomassie staining and secretion was confirmed by end-point Coomassie staining to estimate productivity. Purification steps were then performed using capture with HiTrap MabSelect SuRe for hIgG1 or HisTrap Excel for Fab fragments (both GE Healthcare). Finally, gel filtration was performed with Superdex 200 Increase10 / 300GL (GE Healthcare) and the recovered proteins were filtered through 0.22 μm (Ultra Capsule GF, Merck Millipore). At the end of the process, the chimeric hIgG1 or Fab fragments must meet the following acceptance criteria: concentration 1 mg / mL, purity >90%, and endotoxin level <0.1 EU per mg of protein. The purified hIgG1 and Fab fragments were stored in the following buffer: Histidine-Tween buffer [20 mM histidine, 150 mM NaCl, 0.02% Tween 80, pH 6.0].

[0279] Cell isolation, culture and stimulation U937 cells: Cells of the human myelomonocytic cell line U937 (Culture Collections, Public Health England N° 85011440) were cultured in RPMI 1640 medium containing GlutaMAX and supplemented with 10% fetal calf serum or FCS (Thermo Fisher Scientific), 25 mM HEPES, 100 U / mL penicillin and streptomycin (all Thermo Fisher Scientific). In some experiments, where indicated, U937 cells were cultured in the same conditions supplemented with 100 nM 1,25-dihydroxyvitamin D3, also called vitamin D3 or vitD3 (Sigma-Aldrich, USA), to induce upregulation of TREM-1.

[0280] THP-1 Blue Cells: The human THP1-Blue cell line was derived from the human THP-1 monocytic cell line by stable transfection of an NF-κB-inducible SEAP (secreted embryonic alkaline phosphatase) reporter construct (InvivoGen, France). Indeed, these cells report activation of the NF-κB transcription factor. THP1 Blue cells were cultured in RPMI 1640 medium supplemented with 10% heat-inactivated FBS (fetal bovine serum), 2 mM L-glutamine, 25 mM HEPES, 100 μg / mL normocin, and 100 U / mL penicillin and streptomycin. In some experiments, where indicated, THP1 Blue cells were cultured in the same conditions supplemented with 100 nM 1,25-dihydroxyvitamin D3 (vitD3) to induce upregulation of TREM-1.

[0281] The expression of TREM-1, TLR4, and CD14 in U937 cells, THP1 cells, or human primary neutrophils was evaluated by flow cytometry. Cells were incubated with anti-TREM1-APC, anti-CD14-PE, or anti-TLR4-FITC antibodies, or the corresponding isotype controls (Miltenyi-Biotec, Germany) in the dark for 10 min at 4°C, then washed, and data were collected by flow cytometry (C6 Accuri, BD, USA). Flow cytometry data were analyzed using FlowJo software (TreeStar, USA).

[0282] Primary cells: Primary human neutrophils were isolated from peripheral blood of healthy donors by immunomagnetic negative cell sorting using the EasySep™ Human Monocyte / Neutrophil Isolation Kit (StemCell, Canada) according to the manufacturer's instructions. Purity was assessed by flow cytometry. Cells were suspended in RPMI 1640 medium containing GlutaMAX and supplemented with 10% FCS, 25 mM HEPES, 100 U / mL penicillin and streptomycin (all Thermo Fisher Scientific) prior to stimulation. Human primary neutrophils were incubated with or without anti-TREM-1 modulators (hIgG1 or Fab) for the indicated times and concentrations, under resting conditions (also called non-stimulating conditions or NS), with 100 ng / mL LPS from E. coli serotype 0127:B8 (Sigma-Aldrich), with PP complexes, also called PPx (corresponding to 5 μg / mL PGLYRP1 (peptidoglycan recognition protein 1) complexed to 10 μg / mL peptidoglycan, from Invivogen, France and Biotechne, UK, respectively), or with peptidoglycan (PGN) alone (10 μg / mL). Where indicated, neutrophils were incubated with 100 μg / mL of the clinical-stage TREM-1 inhibitor peptide LR12 (TLT-1 peptide with amino acids set forth in SEQ ID NO: 61-LQEEDAGEYGCM).

[0283] Binding to human and cynomolgus monkey TREM-1 Cells: U937 cells or primary neutrophils were centrifuged at 300 g for 5 min and the pellet was diluted with 1×10 6 The cells were resuspended to 1000 cells / mL. The molecules to be tested (hIgG1 or Fab) were diluted in FACS buffer (1x PBS, 0.5% BSA, 2.5 mM EDTA) at different concentrations (0.0001-20 μg / mL). The cells were incubated in the presence of the molecules to be tested (hIgG1 or Fab) for 30 min at 4°C and then centrifuged at 300 g for 5 min. The supernatant was removed and a 1x PBS wash was performed. The cells were washed again and centrifuged at 300 g for 5 min and the pellet was collected in FACS buffer. Secondary antibody (1:200, Allophycocyanin (APC) AffiniPure F(ab')2 Fragment Goat Anti-Human IgG (H+L) (Jackson ImmunoResearch, USA) was then added to the cell suspension. After 30 min of incubation at 4°C, the cells were washed with 1x PBS and centrifuged at 300g for 5 min. Finally, the cells were resuspended in FACS buffer and analyzed by flow cytometry (C6 Accuri, BD, USA) to quantify the binding of the tested molecules (hIgG1 or Fab) to the cells. Finally, the flow cytometry data were analyzed using FlowJo software.

[0284] Surface Plasmon Resonance (SPR): To evaluate the interaction kinetics of TREM-1 antibodies or Fabs with hTREM-1 (human TREM-1) and cTREM-1 (cynomolgus TREM-1), surface plasmon resonance (SPR) assays were performed (Biacore™ T200, GE Healthcare Biosciences). Anti-human Fc antibodies (Cytiva) were immobilized on a CM5 sensor chip to evaluate IgG1 affinity, and Fabs were immobilized directly on the chip. Immobilization experiments were performed at 25° C. using HBS-EP+1× running buffer (10 mM HEPES, 150 mM NaCl, 3 mM EDTA, 0.05% surfactant P20, pH 7.4). Anti-human Fc antibodies or Fabs were diluted in 10 mM sodium acetate at acidic pH before the immobilization procedure using amine coupling on the dextran matrix of the sensor chip. The surface was activated using a solution of 100 mM 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride or EDC and 400 mM N-hydroxysulfosuccinimide or NHS (EDC / NHS) (Liu Y, Wilson WD. Methods Mol Biol. 2010;613:1-23). ​​After these injections, ethanolamine was injected to deactivate the surface. Using the immobilization wizard, several thousand immobilized RU (resonance units) were obtained. The immobilization level was selected to adequately cover the surface of the sensor chip. Preliminary manual runs were performed to optimize the capture conditions and to obtain similar capture levels for all human antibodies. Binding of hTREM-1 or cTREM-1 protein was performed by injecting the sample into all flow cells. Human and cynomolgus TREM-1 proteins were diluted in running buffer (HBS-EP+1X) at concentrations of 0.1 nM, 0.5 nM, 2.5 nM, 10 nM and 40 nM, or 0.5 nM, 2 nM, 10 nM, 40 nM and 200 nM, respectively. Concentrations were assessed using a single cycle kinetic method. This approach consisted of successive injections of increasing concentrations of analyte, with one regeneration step at the end of the cycle using magnesium chloride buffer (Cytiva).The binding affinity of a TREM-1 antibody or Fab to hTREM-1 or cTREM-1 was determined by measuring the rates of complex formation and dissociation, using the equilibrium dissociation constant (K. D ) was determined. a (association rate) and k d The rate constants corresponding to the association and dissociation of monovalent complexes, such as (dissociation rate), were obtained by fitting the data to a 1:1 Langmuir model using the Biacore T200 evaluation software, version 3.1 (GE Healthcare). D is the formula K D =k d / k a By k a and k d Regarding.

[0285] Generation of reactive oxygen species (ROS) Quantification of intracellular ROS generation was assessed using cell-permeable DCFDA (2',7'-dichlorofluorescein diacetate) (Thermo Fisher Scientific), a chemically reduced form of fluorescein used as an indicator of the presence of ROS in cells. Upon cleavage of the acetate group by intracellular esterases and oxidation, non-fluorescent DCFDA is converted to highly fluorescent 2',7'-dichlorofluorescein (DCF). For example, human primary neutrophils were incubated for 2 h at 37 °C in 5% CO2 with 5 μM DCFDA in the presence of the molecule to be tested (hIgG1 or Fab) with or without 100 ng / mL LPS, or PP complexes (corresponding to 5 μg / mL PGLYRP1 (peptidoglycan recognition protein 1) complexed to 10 μg / mL peptidoglycan, from Invivogen, France and Biotechne, UK, respectively), or peptidoglycan (PGN) alone (10 μg / mL). Data were acquired using flow cytometry (C6 Accuri, BD, USA) or a fluorometer (Varioskan Lux, ThermoScientific). Results are expressed as mean fluorescence intensity (MFI) or relative fluorescence units (RFU).

[0286] THP-1 QuantiBlue Assay: NF-κB Cell Line Reporter The QUANTI Blue assay (InvivoGen) is a colorimetric enzymatic test for determining the activity of SEAP. The test is used in THP1 Blue cells containing a SEAP reporter gene inducible by NF-κB. Using this test, activation of NF-κB can be assessed by determining the activity of SEAP (measured at 650 nm). The Quanti Blue assay was performed after 48 hours of incubation of THP-1 Blue cells with 100 nM 1,25-dihydroxyvitamin D3 (vitD3). Cells (1×10 5 Cells / well) were incubated for 1-10 h at 37 °C, 5% CO2 in the presence or absence of the molecules to be tested (hIgG1 or Fab) at the indicated concentrations (0.1-1-10 μg / mL) and LPS (0.1 μg / mL). Subsequently, cells were centrifuged at 300 g for 5 min and the supernatants were collected. In a new clear 96-well microplate, the cell supernatants were mixed with Quanti Blue reagent (1:10) and incubated for 30 min at 37 °C, 5% CO2. Finally, the optical density was measured at 650 nm using a microplate reader (Varioskan Lux, ThermoScientific).

[0287] Whole Blood Testing Proinflammatory cytokine levels (IL-1β, TNFα, IL-6, IL-8, and IL-10) were assessed using a stimulation assay of whole blood obtained from healthy human donors. The molecules to be tested (hIgG1 or Fab) were first diluted to different concentrations (0.1-1-10 μg / mL or as indicated) and added to wells of a 12-well plate in the presence or absence of LPS (0.1 μg / mL, InvivoGen, France), or in the presence of PP complexes (corresponding to 5 μg / mL PGLYRP1 complexed to 10 μg / mL peptidoglycan, Invivogen, France and Biotechne, UK, respectively), or with peptidoglycan, also called PGN (Invivogen, France) alone. Subsequently, whole blood (after lysis of red blood cells with ammonium chloride (Stemcell, France)) was added to the wells and incubated for 24 hours at 37° C. and 5% CO2. Samples were then centrifuged at 300g for 10 min to collect plasma in which IL-8 levels were assessed using the Quantikine ELISA human IL-8 / CXCL8 kit (R&D Systems) according to the manufacturer's instructions or using Ella technology (Protein Simple, UK), an automated immunoassay system. Samples were added to singleplex or multiplex cartridges (Protein Simple, UK) to assess levels of five cytokines (IL-1β, TNFα, IL-6, IL-8, and IL-10) in a single assay.

[0288] Alternatively, whole blood from cynomolgus monkeys was used. Proinflammatory cytokine levels (IL-8, TNFα, IL-6) were assessed using a stimulation assay of whole blood obtained from healthy cynomolgus donors (Macaca fascicularis). The molecules to be tested (hIgG1 or Fab) were first diluted to different concentrations (0.2-2-20 μg / mL) and added to wells of a 24-well plate in the presence of PP complexes (or PPx) (corresponding to 5 μg / mL PGLYRP1 complexed to 10 μg / mL peptidoglycan, Invivogen, France and Biotechne, UK, respectively) or with peptidoglycan, also called PGN (Invivogen, France) alone. Subsequently, whole blood (after lysis of red blood cells with ammonium chloride (Stemcell, France)) was added to the wells and incubated for 24 hours at 37° C. and 5% CO2. Samples were then centrifuged at 300g for 10 min to collect plasma in which TNFα, IL-6 and IL-8 levels were assessed using Ella technology (Protein Simple, UK), an automated immunoassay system. Samples were added to singleplex or multiplex cartridges (Protein Simple, UK) to assess levels of three cytokines (TNFα, IL-6 and IL-8) in one assay.

[0289] U937-VitD3 stimulation U937 cells were cultured in RPMI 1640 GlutaMAX medium supplemented with 10% FCS, 25 mM HEPES, 100 U / ml penicillin and streptomycin in the presence of 100 nM 1,25-dihydroxyvitamin D3 (vitD3) for 48 h to induce upregulation of TREM-1. Cells were then harvested and seeded (1 × 10 cells) in the presence or absence of the indicated concentrations (0.1-1-10 μg / mL) of the tested molecule (hIgG1 or Fab) and LPS (0.1 μg / mL) for 24 h at 37 °C, 5% CO2. 5Cells were then centrifuged at 300g for 5 min and the supernatants were collected. Finally, the concentration of inflammatory cytokine levels (IL-1β, IL-6 and IL-10) in the supernatants was assessed using Ella technology (Protein Simple, UK).

[0290] neutrophil stimulation Primary human neutrophils were isolated from the blood of healthy donors as previously described and cultured at 1 × 10 6 Cells were then incubated for 24 h at 37 °C, 5% CO2 in the presence or absence of the molecules to be tested (hIgG1 or Fab) at the indicated concentrations (0.1-10 μg / mL) and LPS (0.1 μg / mL). Subsequently, cells were centrifuged at 300 g for 5 min and the supernatants were collected. Finally, the concentration of IL-6 or IL-8 in the supernatants was assessed using Quantikine ELISA human IL-6 or IL-8 kits (R&D Systems, France) or Ella technology (Protein Simple, UK) according to the manufacturer's instructions.

[0291] Humanized immune system (his-) mice BRGSF mice from GenOway (France) are BALB / c mice that exhibit the Rag2- / -Il2rg- / -SirpaNODFlk2+ / - genotype. His (humanized immune system) mice were generated as follows: Briefly, newborn mice (up to 5 days old) were injected with approximately 1 × 10 6 humanized IgG1-derived umbilical cord IgG1-derived IgG2-derived ...1-derived IgG2-derived IgG1-derived IgG1-derived IgG1-derived IgG2-derived IgG1-derived IgG1-derived IgG1-derived IgG2-derived IgG1-derived IgG1-derived IgG1-derived IgG2-derived IgG1-derived IgG1-derived IgG1-derived IgG2-derived IgG1-derived IgG1-derived IgG1-derived IgG2-derived IgG1-derived IgG1-derived IgG1-derived IgG2-derived IgG1-derived IgG1-derived IgG1-derived IgG2-derived IgG1-derived IgG1-derived IgG1-derived IgG1 5 Human hematopoietic progenitor cells (hHPC) CD34 + To boost the bone marrow immune system, all mice received four intraperitoneal (ip) injections of 10 μg of recombinant human hFLT3-L / Fc every two days before the experiment.

[0292] Experimental endotoxemia in humans His mice were subjected to LPS challenge to evaluate the in vivo immunomodulatory effect of anti-TREM-1 INO-10 Fab fragment (INO-10F). Briefly, the day after Flt3 ligand (FLT3L) boost, his mice received a single intraperitoneal (ip) dose of 10 mg / kg of either PBS, INO-10F, or a fusion protein with extended half-life comprising INO-10F conjugated to human serum albumin, also known as HSA (INO-10F-HSA), followed 30 min later by an ip injection of 8 mg / kg LPS (lipopolysaccharide; Escherichia coli serotype O127:B8, batch L3129, Sigma Chemical, St Louis, France). The concentration was adjusted to inject the same amount in each group of mice. After 8 h, blood samples were taken by intracardiac puncture and collected in EDTA tubes. Plasma was obtained by centrifugation of whole blood (300 g, 10 min) and stored at −80° C. Plasma levels of cytokines (CCL-2, IL-1β, IL-10, IL-6, IL-8, IP-10, and TNFα) were determined using SimplePlex cartridges implemented with Ella technology (Protein Simple, UK).

[0293] result INO-10-F efficiently blocks TREM-1 activation in primary human neutrophils A total of 51 unique sequences of anti-hTREM-1 were obtained and generated as human IgG1 chimeric antibodies (hIgG1) and corresponding Fab fragments (or Fab for short). These constructs were screened for their ability to bind to human TREM-1. After validation of their interaction with human TREM-1, all constructs were screened for their ability to reduce the release of reactive oxygen species (ROS) by human primary neutrophils following activation of neutrophils by lipopolysaccharide (LPS). Indeed, activation of TREM-1 in neutrophils (which express TREM-1 on their surface) by their incubation with LPS significantly leads to ROS generation by neutrophils. The ability of the tested constructs to reduce ROS generation by LPS-activated neutrophils therefore reflects their ability to inhibit TREM-1. One lead, an anti-hTREM-1 Fab fragment, called INO-10F, was identified. As shown in Figure 1, INO-10F could significantly reduce ROS release by neutrophils at 1 μg / mL and 10 μg / mL. INO-10F could therefore inhibit the activation of TREM-1. Based on the data obtained from functional screening, INO-10F was identified as the best lead compound.

[0294] INO-10F binding to human TREM-1 as determined by flow cytometry and inhibition of TREM-1 activation in U937-vitD3 cells Incubation of U937 cells with vitamin D3 (1,25-dihydroxyvitamin D3) was associated with an increase in TREM-1 expression at the membrane compared to that of untreated U937 control cells (Figure 2). Using flow cytometry, it was shown that INO-10F binds to human TREM-1 in U937-vitD3 cells (i.e., U937 cells pretreated with vitamin D3) in a dose-dependent manner, reaching 50% binding at approximately 0.2 μg / mL (Figure 3). As expected, the negative control INO-10F-0 showed no binding to human TREM-1 on U937-vitD3 cells (Figure 3). Interestingly, INO-10F was also shown to inhibit TREM-1 activation in a dose-dependent manner. For example, activation of TREM-1 in myeloid cells (which express TREM-1 on their surface) via induction of an inflammatory response by PGLYRP-1:PGN complexes (or PP) significantly results in the expression and secretion of cytokines / chemokines by said cells. As shown in Figure 4, incubation of U937-vitD3 cells with increasing concentrations of INO-10F was associated with a decrease in the release of interleukin-6, also known as IL-6 (Figure 4A), interleukin-10, also known as IL-10 (Figure 4B), and interleukin-1β, also known as IL-1β (Figure 4C) induced by stimulation of U937-vitD3 cells with PGLYRP-1:PGN complexes (PPx or PP) for 24 h. In this assay, the maximal effect of INO-10F was achieved at 1-10 μg / mL, and 50% inhibition was reached at approximately 0.1 μg / mL.

[0295] INO-10F binding to human TREM-1 as determined by flow cytometry and inhibition of TREM-1 activation in THP-1 Blue vitD3 cells Incubation of THP-1 cells with vitamin D3 was associated with an increase in TREM-1 expression (Figure 5A), and an increase in human CD14, or hCD14 (Figure 5B) and a decrease in human Toll-like receptor 4, or hTLR4 (Figure 5C) compared to TREM-1 expression in the membrane of untreated THP-1 cells. Using flow cytometry, we showed that INO-10F bound to human TREM-1 expressed in THP-1-vitD3 cells (THP-1 cells pretreated with vitamin D3) in a dose-dependent manner, reaching 50% binding at 0.014 μg / mL (Figure 6). As expected, there was little binding of INO-10F to untreated THP-1 control cells (Figure 6).

[0296] To assess the activity of INO-10F, untreated THP-1 blue cells or THP-1 blue cells pretreated with vitamin D3 for 48 h were incubated with increasing doses of INO-10F in the presence or absence of LPS (100 ng / mL). Activation of TREM-1 in myeloid cells, such as monocytes (which express TREM-1 on their surface), via induction of an inflammatory response, e.g., by LPS, significantly leads to NF-κB activation in said cells. After 6 h, NF-κB activation was assessed using Quanti Blue reagent. As reflected by the inhibition of NF-κB activation shown in Figure 7A, INO-10F was able to inhibit TREM-1 only in cells overexpressing TREM-1 and was effective at 0.1-10 μg / mL. INO-10F had no effect on LPS-activated naïve THP-1 blue cells (i.e., THP-1 blue cells not pretreated with vitamin D3). A second experiment further confirmed that INO-10F was able to limit LPS-induced NF-κB activation in a time- and dose-dependent manner in vitamin D3-pretreated THP-1 Blue cells. INO-10F inhibited NF-κB activation for 6–10 h, with a maximal effect at 10 h, depending on the dose (Figure 7B).

[0297] IL-8 production of THP-1 blue cells was then evaluated after their pretreatment with vitamin D3 and their stimulation for 24 h with LPS (100 ng / mL) in the presence of increasing concentrations (0, 0.1 and 10 μg / mL) of INO-10F. INO-10F concentration-dependently reduced the release of IL-8 induced by LPS stimulation, reaching a maximal effect at 10 μg / mL (FIG. 8). This result confirms that INO-10F can inhibit TREM-1 in THP-1 blue cells pretreated with vitamin D3.

[0298] INO-10F binding to human TREM-1 as determined by flow cytometry and inhibition of TREM-1 activation in primary neutrophils and whole blood Human primary neutrophils express high levels of TREM-1 in the membrane under physiological conditions and do not upregulate its expression upon LPS stimulation. Indeed, as shown in Figure 9, the expression of TREM-1 in the membrane of human primary neutrophils is similar in the unstimulated state and after stimulation with LPS for either 3 or 24 hours. INO-10F was able to bind human TREM-1 in a concentration-dependent manner on freshly isolated human neutrophils, reaching 50% binding at approximately 0.023 μg / mL at 0.01-0.1 μg / mL (Figure 10). The ability of INO-10F to inhibit TREM-1 activation on neutrophils was then evaluated through the assessment of their release of ROS upon LPS stimulation. As expected, INO-10F alone did not induce any activation of TREM-1, as observed by the absence of ROS generation in the unstimulated state (Figure 11). ROS were generated by human primary neutrophils upon LPS stimulation, and INO-10F reduced this ROS generation by 50% at a concentration of approximately 4.6 μg / mL, confirming its ability to inhibit TREM-1 (FIG. 11). Similar experiments were performed using PGLYRP-1:PGN complexes (PPx or PP) to induce ROS generation in human primary neutrophils by direct activation of TREM-1. INO-10F also reduced ROS generation by neutrophils, reaching a maximal effect at 1 μg / mL (FIG. 12A), corresponding to the maximal binding concentration to human TREM-1 on human primary neutrophils (FIG. 12B).

[0299] Finally, IL-6 secretion by human primary neutrophils was assessed after incubation of neutrophils for 0, 6, and 24 h in the presence of INO-10F (0.1 or 10 μg / mL) either with LPS (100 mg / mL) or in the unstimulated state. As shown in Figure 13, INO-10F reduced LPS-induced IL-6 release in a dose- and time-dependent manner.

[0300] To further confirm the immunomodulatory properties of INO-10F through its inhibition of TREM-1, the effect of INO-10F was evaluated in a human whole blood cytokine assay stimulation. As detailed above, whole blood obtained from healthy human donors was incubated for 24 hours at 37°C and 5% CO2 in the presence of LPS (100 ng / mL) and either INO-10F or a positive control (i.e., peptide LR12, known to inhibit TREM-1). Plasma was collected and plasma levels of several cytokines were measured. As shown in Figure 14, in this assay, INO-10F reduced the release of several cytokines in a dose-dependent manner. Indeed, INO-10F limited the LPS-induced release of IL-1β (Figure 14A), IL-10 (Figure 14B), TNFα (Figure 14C), IL-6 (Figure 14D), and IL-8 (Figure 14E). The effect of INO-10F on IL-8 plasma concentrations was also evaluated in vitro after LPS stimulation of whole blood samples taken from 14 healthy volunteers. As shown in Figure 15, INO-10F induced a dose-dependent decrease (0.01-10 μg / mL) in IL-8 plasma concentrations. A decrease in LPS-induced IL-8 production was also observed using peptide LR12 (positive control). In whole blood assays, INO-10F did not induce any significant production of IL-8 or other studied cytokines in unstimulated conditions (i.e., in the absence of LPS).

[0301] Blockade of human TREM-1 reduces immune-inflammatory responses in the BRGS-F mouse endotoxemia model The immunomodulatory effect of INO-10F was evaluated in vivo in transgenic BRGSF mice with a humanized immune system in which endotoxemia was induced by intraperitoneal (ip) administration of LPS (8 mg / kg). Mice were randomly divided into four treatment groups to receive either ip PBS (control) alone or LPS together with either vehicle, INO-10F, or a fusion protein containing INO-10F. Indeed, among the mice administered LPS, the "LPS" group received vehicle as treatment, the "LPS+10F" group received ip administration of 10 μg / mL INO-10F, and the "LPS+HSA-10F" group received ip administration of 10 μg / mL INO-10F format with extended half-life consisting of a fusion protein of human serum albumin (HSA) and INO-10F (10F). Mice were pretreated with vehicle, INO-10F or HSA-INO-10F (HSA-10F) for 30 min, then LPS was administered to induce endotoxemia. Blood samples were collected 8 h after LPS injection, and human cytokine / chemokine concentrations were quantified in plasma (CCL-2, IL-1β, IL-10, IL-6, IL-8, IP-10, and TNFα). LPS significantly increased the release of human inflammatory cytokines / chemokines compared to the control group (CTRL). Interestingly, as shown in FIG. 16, both INO-10F and INO-10F-HSA could regulate the secretion of circulating human inflammatory cytokine chemokine ligand 2 (CCL2), also known as monocyte chemoattractant protein 1 or MCP1 (FIG. 16A), interleukin-1β or IL-1β (FIG. 16B), interleukin-10 or IL-10 (FIG. 16C), interleukin-6 or IL-6 (FIG. 16D), interleukin-8 or IL-8 (FIG. 16E), interferon gamma-inducible protein 10 (IP-10), also known as C-X-C motif chemokine ligand 10 or CXCL10 (FIG. 16F), and tumor necrosis factor alpha or TNFα or TNFa (FIG. 16G), with the effect being more pronounced for the HSA-INO-10F fusion protein with extended half-life.These results support the immunomodulatory effect of the anti-TREM-1 INO-10F Fab fragment in vivo.

[0302] Binding of optimized INO-10F mutants to TREM-1 To improve INO-10F binding properties and activity, humanized variants of the anti-TREM-1 INO-10 antibody and corresponding humanized variants of the anti-TREM-1 INO-10F Fab fragment were generated. The humanized variants of the anti-TREM-1 INO-10 antibody were named INO-10-2, INO-10-3, INO-10-4, INO-10-5, and INO-10-6, and the humanized variants of the anti-TREM-1 INO-10F Fab fragment were named INO-10F-2 (F2), INO-10F-3 (F3), INO-10F-4 (F4), INO-10F-5 (F5), and INO-10F-6 (F6). Two additional humanized variants were used as controls: INO-10F-0 (F0), which has the most similar CDRs to INO-10F (CDRs are V H - INO-10F-1 (F1), a humanized anti-TREM-1 Fab fragment (identical except for one amino acid difference in CDR2). First, the binding affinity constant, association rate and dissociation rate were determined using a surface plasmon resonance (SPR) assay. The Fab fragments were immobilized on the surface of a CM5 sensor chip, and then increasing concentrations of recombinant human TREM-1 or cynomolgus TREM-1 were injected. The results are shown in Table 1 below. No binding to TREM-1 (either hTREM-1 or cTREM-1) was observed with Fab fragment INO-10F-0 (F0). Fab fragment INO-10F-1 (F1) was only able to bind hTREM-1, with an affinity similar to that of Fab fragment INO-10F. Fab fragments INO-10F-2 to INO-10F-6 (F2 to F6) showed higher affinity than Fab fragment INO-10F. Table 1: Binding constants k for the interaction of different anti-TREM-1 monoclonal antibody Fab fragments with human and cynomolgus TREM-1. a or k on( association velocity), k d or k off (dissociation rate) and K D(equilibrium dissociation constant) [Table 1]

[0303] The optimized INO-10F mutant can inhibit TREM-1 in U937 and primary cells The binding of the optimized anti-TREM-1 Fab fragments to human TREM-1 expressed on U937 pretreated with vitamin D3 (U937-vitD3 cells) and on untreated control U937 cells was then evaluated. As expected, no binding was observed on U937 cells (Figure 17A). As shown in Figure 17B, on U937-vitD3 cells, INO-10F-F0 showed weak binding at 10 μg / mL, and INO-10F showed a similar binding profile to that previously obtained (see Figure 3). A clear shift towards better affinity was observed for the optimized variants INO-10F-1 to INO-10F-6, corroborating the SPR data (Figure 17B).

[0304] According to the results obtained with INO-10F, INO-10F-1 (V H- the humanized Fab fragment most similar to INO-10F, with identical CDRs except for one amino acid difference in CDR2, was able to reduce the release of IL-6 by U937-vitD3 cells induced by stimulation with the PGLYRP-1:PGN complex (PP complex), achieving approximately 50% inhibition (IC50) at 0.5 μg / mL. INO-10F-0 showed a reduced affinity for TREM-1 compared to INO-10F, associated with a limited reduction in IL-6 release observed only at 10 μg / mL. The improved affinity of INO-10F-2 (F2) to INO-10F-6 (F6) to TREM-1 led to a shift towards a reduction in the dose required to induce 50% inhibition (IC50) of IL-6 release. In particular, INO-10F-3 (F3) showed an IC50 of approximately 0.05 μg / mL. Peptide LR12, a known inhibitor of TREM-1, was used as a positive control (Figure 18). Binding of INO-10F-3 (F3) was confirmed on TREM-1 expressed by freshly isolated human neutrophils, reaching 50% binding at approximately 0.03 μg / mL (Figure 19).

[0305] Next, a neutrophil LPS stimulation assay was performed to evaluate the ability of the optimized anti-TREM-1 Fab fragments to reduce the release of IL-8 by human primary neutrophils after 24 h of stimulation with LPS. As shown in Figure 20, INO-10F-2 (F2) and INO-10F-3 (F3) showed good and significant inhibitory properties at 0.1-10 μg / mL. INO-10F-4 (F4) and INO-10F-6 (F6) were also able to significantly reduce IL-8 release when added at 1 μg / mL or 10 μg / mL. INO-10F-1 (F1) and INO-10F-5 (F5) were only able to significantly reduce IL-8 release when added at 10 μg / mL. Finally, a neutrophil LPS stimulation assay was also performed to evaluate the ability of the optimized anti-TREM-1 Fab fragments to reduce ROS generation induced after 24 h of LPS stimulation of human primary neutrophils. As shown in Figure 21A-H, INO-10F-2 (F2) and INO-10F-3 (F3) showed the best inhibition profile of ROS generation by LPS-activated neutrophils. Indeed, INO-10F-2 (F2) was able to inhibit ROS generation by 28% at 0.01 μg / mL to 44% at 10 μg / mL (Figure 21D), and INO-10F-3 (F3) was able to inhibit ROS release by 21% at 0.01 μg / mL to 52% at 10 μg / ml (Figure 21E). INO-10F-4 (F4) and INO-10F-6 (F6) were also able to inhibit ROS generation by LPS-activated neutrophils when added at 1 or 10 μg / mL. INO-10F-1 (F1) and INO-10F-5 (F5) were able to inhibit ROS generation by LPS-activated neutrophils only when added at 10 μg / mL. As expected, INO-10F-0 (F0) did not inhibit ROS generation by LPS-activated neutrophils.

[0306] INO-10F mutants bound to HSA can inhibit TREM-1 in primary cell and whole blood assays A fusion protein consisting of the optimized Fab fragment INO-10F-3 (or F3) conjugated with human serum albumin, also known as HSA, was generated. The inhibitory effect of the above fusion protein, called F3-HSA, on ROS generation by human primary neutrophils was evaluated (Figure 22). Human primary neutrophils were therefore stimulated for 2 h with LPS (100 ng / mL), or with the PP complex (PP) corresponding to PGLYRP1 (5 μg / mL) complexed with peptidoglycan (10 μg / mL), or with peptidoglycan alone (PGN-10 μg / mL) in the presence of the indicated concentrations (0-20 μg / mL) of F3-HSA. F3-HSA was able to inhibit ROS release after stimulation of neutrophils with LPS (approximately 50% reduction at approximately 1 μg / mL - see FIG. 22A), with PP complexes (approximately 85% reduction at approximately 1 μg / mL - FIG. 22B), or with PGN alone (approximately 75% reduction at approximately 1 μg / mL - FIG. 22C).

[0307] Next, the effect of F3-HSA was evaluated on cytokine plasma concentrations after a 24-h whole blood stimulation assay after lysis of red blood cells. F3-HSA or an isotype control (CTLR) was added to whole blood at the indicated concentrations (0-20 μg / mL) in the unstimulated state, or in the presence of a PP complex corresponding to PGLYRP1 (5 μg / mL) complexed with PGN (10 μg / mL), or in the presence of PGN alone (10 μg / mL). After 24 hours, the expression of the following cytokines was evaluated: IL-8 and TNFα. As shown in Figure 23, in this assay, F3-HSA reduced the release of both IL-8 and TNFα in a dose-dependent manner compared to the control, which did not reduce cytokine release. Indeed, F3-HSA reduced the release of IL-8 after stimulation with either PP or PGN alone (Figure 23A) and reduced the release of TNFα after stimulation with either PP or PGN alone (Figure 23B).

[0308] A similar assay was then performed with cynomolgus monkey whole blood. F3-HSA or an isotype control (CTLR) was therefore added at the indicated concentrations (0-20 μg / mL) to whole blood obtained from healthy cynomolgus donors (Macaca fascicularis) in the unstimulated state, or in the presence of a PP complex corresponding to PGLYRP1 (5 μg / mL) complexed with PGN (10 μg / mL), or in the presence of PGN alone (20 μg / mL). After 24 hours, the expression of the following cytokines was evaluated: IL-8, TNFα, and IL-6. As shown in FIG. 24, in this assay, F3-HSA dose-dependently reduced the release of IL-8, TNFα, and IL-6 compared to the control, which did not reduce cytokine release. Indeed, F3-HSA reduced the release of IL-8 after stimulation with PGN alone or PP (Figure 24A), reduced the release of TNFα after stimulation with PGN alone or PP (Figure 24B), and reduced the release of IL-6 after stimulation with either PGN alone or PP (Figure 24C).

Claims

**Claim 1** An isolated anti-TREM-1 (Triggering Receptor Expressed on Myeloid cells-1) antibody or antigen-binding fragment thereof, wherein a) the variable region of the heavy chain (VH) of the isolated anti-TREM-1 antibody or antigen-binding fragment thereof comprises the following three complementarity-determining regions (CDRs): V Ｈ -CDR1: NTYIH (SEQ ID NO: 1); V Ｈ -CDR2: RIDPAX １ GX ２ TKYX ３ PKVX ４ G (SEQ ID NO: 2) (where X １ is Asn (N) or Gly (G), X ２ is Asn (N) or Arg (R), X ３ is Ala (A), Asp (D), or Ser (S), X ４ is Gln (Q) or Lys (K)); and V Ｈ -CDR3: HX ５ GX ６ TMDY (SEQ ID NO: 3) (where X ５ is Tyr (Y) or Arg (R), and X ６ is Ser (S) or Gly (G)); comprising b) the variable region of the light chain (VL) of the isolated anti-TREM-1 antibody or antigen-binding fragment thereof comprises the following three CDRs: V Ｌ -CDR1: RASX ７ SVX ８ NYGISFX ９ N (SEQ ID NO: 4) (where X ７ is Glu (E) or Gln (Q), and X ８ is Asp (D) or Ser (S), and X ９ is Met (M) or Leu (L)); V Ｌ -CDR2: AAX １０ X １１ X １２ X １３ X １４ (SEQ ID NO: 5) (where X １０ is Ser (S) or Glu (E), X １１ is Asn (N) or Tyr (Y), X １２ is Gln (Q) or Arg (R), X １３ is Gly (G), Ala (A), or Lys (K), X １４ is Ser (S) or Arg (R)); and V Ｌ -CDR3: QQSX １５ X １６ X １７ PX １８ T (SEQ ID NO: 6) (where X １５ is Lys (K), Arg (R), or Ser (S), X １６ is Glu (E), His (H), or Asn (N), X １７ is Val (V) or Phe (F), X １８ is Trp (W) or Tyr (Y)); comprising An isolated anti-TREM-1 antibody or antigen-binding fragment thereof. **Claim 2** The following CDRs: V Ｈ -CDR1: NTYIH (SEQ ID NO: 1), V Ｈ -CDR2: RIDPAGGRRTKYDPKVKG (SEQ ID NO: 7), V Ｈ -CDR3: HYGGTMDY (SEQ ID NO: 8), V Ｌ -CDR1: RASESVDNYGISFLN (SEQ ID NO: 9), V Ｌ -CDR2: AAEYRRGR (SEQ ID NO: 10), and V Ｌ -CDR3: QQSRHVPYT (SEQ ID NO: 11); or V Ｈ -CDR1: NTYIH (SEQ ID NO: 1), V Ｈ -CDR2: RIDPAGGRTSKYSPKVQG (SEQ ID NO: 12), V Ｈ -CDR3: HRGGTMDY (SEQ ID NO: 13), V Ｌ -CDR1: RASQSVSNYGISFLN (SEQ ID NO: 14), V Ｌ -CDR2: AASYQKR (SEQ ID NO: 15), and V Ｌ -CDR3: QQSSNFPT (SEQ ID NO: 16); or V Ｈ -CDR1: NTYIH (SEQ ID NO: 1), V Ｈ -CDR2: RIDPAGGRRTKYAPKVKG (SEQ ID NO: 17), V Ｈ -CDR3: HRGGTDY (SEQ ID NO: 13), V Ｌ -CDR1: RASQSVSNYGISFLN (SEQ ID NO: 14), V Ｌ -CDR2: AAEYRGGR (SEQ ID NO: 10), and V Ｌ -CDR3: QQSSNVPYT (SEQ ID NO: 18); or V Ｈ -CDR1: NTYIH (SEQ ID NO: 1), V Ｈ -CDR2: RIDPAGGRRTKYAPKVQG (SEQ ID NO: 19), V Ｈ -CDR3: HYGGTMDY (SEQ ID NO: 8), V Ｌ -CDR1: RASQSVSYGISFLN (SEQ ID NO: 14), V Ｌ -CDR2: AAEYQGR (SEQ ID NO: 20), and V Ｌ -CDR3: QQSSNVPYT (SEQ ID NO: 18); or V Ｈ -CDR1: NTYIH (SEQ ID NO: 1), V Ｈ -CDR2: RIDPAGGRRTKYAPKVKG (SEQ ID NO: 17), V Ｈ -CDR3: HRGGTMDY (SEQ ID NO: 13), V Ｌ -CDR1: RASQSVSNYGISFLN (SEQ ID NO: 14), V Ｌ -CDR2: AAEYRAAR (SEQ ID NO: 21), and V Ｌ -CDR3: QQSSNVPYT (SEQ ID NO: 18); or V Ｈ -CDR1: NTYIH (SEQ ID NO: 1), V Ｈ -CDR2: RIDPANGNTKYAPKVQG (SEQ ID NO: 22), V Ｈ -CDR3: HYGSYMDY (SEQ ID NO: 23), V Ｌ -CDR1: RASESVDNYGISFMN (SEQ ID NO: 24), V Ｌ -CDR2: AASNQGS (SEQ ID NO: 25), and V Ｌ -CDR3: QQSKKEVPWT (SEQ ID NO: 26) The isolated anti-TREM-1 antibody or antigen-binding fragment thereof according to claim 1, comprising **Claim 3** The isolated anti-TREM-1 antibody or antigen-binding fragment thereof according to claim 1, comprising a variable region of the heavy chain (VH) having a sequence set forth in any one of SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, and SEQ ID NO: 32, or a sequence having at least 80% identity to any one of SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, and SEQ ID NO:

32. **Claim 4** The isolated anti-TREM-1 antibody or antigen-binding fragment thereof according to claim 1, comprising a variable region of the light chain (VL) having a sequence set forth in any one of SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, and SEQ ID NO: 38, or a sequence having at least 80% identity to any one of SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, and SEQ ID NO:

38. **Claim 5** The isolated anti-TREM-1 antibody or antigen-binding fragment thereof according to claim 1, comprising a variable region of the heavy chain (VH) having a sequence set forth in SEQ ID NO: 27, or a sequence having at least 80% identity to SEQ ID NO: 27, and a variable region of the light chain (VL) having a sequence set forth in SEQ ID NO: 33, or a sequence having at least 80% identity to SEQ ID NO:

33. **Claim 6** The isolated anti-TREM-1 antibody or antigen-binding fragment thereof according to claim 1, wherein the antibody is a monoclonal antibody. **Claim 7** The isolated anti-TREM-1 antibody or antigen-binding fragment thereof according to claim 1, wherein the antibody is a humanized antibody or a human antibody. **Claim 8** The isolated anti-TREM-1 antibody or antigen-binding fragment thereof according to claim 1, which is monovalent.

9. The isolated anti-TREM-1 antibody or antigen-binding fragment thereof according to claim 1, wherein the antigen-binding fragment is Fab, Fv, or scFv.

10. A fusion protein comprising the anti-TREM-1 antibody or antigen-binding fragment thereof according to any one of claims 1 to 9.

11. A nucleic acid encoding the anti-TREM-1 antibody or antigen-binding fragment thereof according to any one of claims 1 to 9, or the fusion protein comprising the anti-TREM-1 antibody or antigen-binding fragment thereof.

12. The isolated anti-TREM-1 antibody or antigen-binding fragment thereof according to any one of claims 1 to 9, or the fusion protein comprising the anti-TREM-1 antibody or antigen-binding fragment thereof; and At least one pharmaceutically acceptable excipient; A pharmaceutical composition comprising the same.

13. A medicament comprising the isolated anti-TREM-1 antibody or antigen-binding fragment thereof according to any one of claims 1 to 9, or the fusion protein comprising the anti-TREM-1 antibody or antigen-binding fragment thereof.

14. The pharmaceutical composition according to claim 12, for use in the treatment of a disease selected from inflammatory diseases or autoimmune diseases, cardiovascular diseases, cancer, and infectious diseases.

15. The inflammatory disease or autoimmune disease is selected from inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, irritable bowel syndrome, fibrosis, pulmonary fibrosis, liver fibrosis, non-alcoholic steatohepatitis (NASH), alcoholic hepatitis, rheumatoid arthritis, psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, vasculitis, systemic inflammatory response syndrome (SIRS), sepsis, septic shock, type I diabetes, Graves' disease, multiple sclerosis, autoimmune myocarditis, Kawasaki disease, coronary artery disease, chronic obstructive pulmonary disease, interstitial lung disease, autoimmune thyroiditis, scleroderma, systemic sclerosis, osteoarthritis, atopic dermatitis, vitiligo, graft-versus-host disease, Sjögren's syndrome, autoimmune nephritis, Goodpasture's syndrome, chronic inflammatory demyelinating polyneuropathy, allergy, and asthma. The pharmaceutical composition according to claim 14.

Images