Anti-TREM1 antibody agents, compositions, and their uses

Abstract

This specification provides an antibody agent that specifically binds to TREM1, a nucleic acid encoding the antibody agent, a composition containing the antibody agent, and a method for preparing and using the antibody agent.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 461,130, filed on 21 April 2023, which is incorporated herein by reference in its entirety. [Background technology]

[0002] The incidence of immune-mediated inflammatory diseases (IMIDs) in Western civilization is reported to be in the range of 5-7%. While various treatment strategies have been explored, the failure rate remains high. [Overview of the Initiative] [Problems that the invention aims to solve]

[0003] (Summary) This disclosure provides, in particular, antibody agents (e.g., antibodies, antigen-binding moieties thereof, nucleic acids encoding these, and entities comprising these) that are especially useful for binding to induced receptor 1 (TREM1) expressed on myeloid cells.

[0004] This disclosure provides insight that the levels of a particular cell type and / or products produced by that particular cell type (e.g., proteins) in a particular subject (e.g., in a sample from such subject) may indicate potential responsiveness to anti-inflammatory therapies (e.g., anti-TREM1 antibodies or nucleic acids encoding them).

[0005] The inventors note that certain therapeutic strategies for addressing inflammation focus on specific targets other than TREM1 (e.g., TNFα) (see, e.g., Sakemi et al., Medicine 99:e23344, 2020). Certain patients may have a low or no response to such alternative therapies. For example, response rates to certain TNFα therapies have often been reported to be less than 50%. Without wishing to be bound by any particular theory, this disclosure provides the anti-TREM1 antibody agents described herein and the nucleic acids encoding them for use in the treatment of subjects having inflammatory diseases, injuries or conditions in which there is a relatively low likelihood of response to alternative therapies (e.g., therapies targeting TNFα), or ineffectiveness or reduced effectiveness of continuing such therapies, and / or a relatively high likelihood of response to different therapies (e.g., therapies targeting TREM1). [Means for solving the problem]

[0006] In at least one aspect, the present disclosure provides an antibody agent that binds to human induced receptor 1 (TREM1) expressed on myeloid cells, comprising: (a) a light chain having CDR1, CDR2, and CDR3 sequences that collectively have at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with the sequence found in SEQ ID NO: 18, and / or collectively include 1, 2, 3, 4, or 5 or fewer amino acid sequence differences compared to the sequence found in SEQ ID NO: 18; and / or (b) a heavy chain having CDR1, CDR2, and CDR3 sequences that collectively have at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with the sequence found in SEQ ID NO: 14, and / or collectively include 1, 2, 3, 4, or 5 or fewer amino acid sequence differences compared to the sequence found in SEQ ID NO: 14.

[0007] In some embodiments, the antibody agent of the present disclosure comprises a light chain (LC) having (i) the amino acid sequence of SEQ ID NO: 19, an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 19, or an amino acid sequence having one, two, three, four, or five or fewer amino acid sequence differences compared to SEQ ID NO: 19, or an amino acid sequence containing these; (ii) the amino acid sequence of GAS, or an amino acid sequence having one or two or fewer amino acid sequence differences compared to the amino acid sequence of GAS, or an amino acid sequence containing these; and (iii) the amino acid sequence of SEQ ID NO: 20, an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 20, or an amino acid sequence having one, two, three, four, or five or fewer amino acid sequence differences compared to SEQ ID NO: 20, or an amino acid sequence containing these.

[0008] In some embodiments, the antibody agent of the present disclosure is HC CDR1 having an amino acid sequence that is (i) the amino acid sequence of SEQ ID NO: 15, an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 15, or an amino acid sequence having 1, 2, 3, 4, or 5 or fewer amino acid sequences different from SEQ ID NO: 15, or an amino acid sequence containing these; (ii) the amino acid sequence of SEQ ID NO: 16, an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 16, or an amino acid sequence having 1, 2, 3, 4, or 5 or fewer amino acid sequences different from SEQ ID NO: 16, or an amino acid sequence containing these; CDR2; and (iii) a heavy chain (HC) containing HC CDR3, which is an amino acid sequence of the amino acid sequence of SEQ ID NO: 17, an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 17, or an amino acid sequence having 1, 2, 3, 4, or 5 or fewer amino acid sequences compared to SEQ ID NO: 17, or an amino acid sequence containing these.

[0009] In some embodiments, the antibody agent of the present disclosure comprises a light chain comprising a variable region (VL) comprising one, two, three, or four FR regions, which collectively has at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with the sequence found in SEQ ID NO: 18, and / or collectively comprises one, two, three, four, or five or fewer amino acid sequence differences compared to the sequence found in SEQ ID NO: 18. In some embodiments, the light chain includes a variable region (VL) containing one, two, three, or four FR regions, each independently having an amino acid sequence that is one of the amino acid sequences of SEQ ID NOs. 25, 26, 27, or 28, an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to one of SEQ ID NOs. 25, 26, 27, or 28, or an amino acid sequence that differs by one, two, three, four, or five or fewer amino acid sequences from one of SEQ ID NOs. 25, 26, 27, or 28.

[0010] In some embodiments, the antibody agent of the present disclosure is (i) an amino acid sequence which is the amino acid sequence of SEQ ID NO: 25, an amino acid sequence which is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 25, or an amino acid sequence which is one, two, three, four, or five or fewer amino acid sequences different from SEQ ID NO: 25, or an amino acid sequence which is (i) an amino acid sequence which is the amino acid sequence of SEQ ID NO: 26, an amino acid sequence which is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 26, or an amino acid sequence which is one, two, three, four, or five or fewer amino acid sequences different from SEQ ID NO: 26, or an amino acid sequence which is (ii) (iii) an amino acid sequence; and / or an amino acid sequence that is the amino acid sequence of SEQ ID NO. 27, an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO. 27, or an amino acid sequence having 1, 2, 3, 4, or 5 or fewer amino acid sequence differences compared to SEQ ID NO. 27, or including these; and / or (iv) an amino acid sequence that is the amino acid sequence of SEQ ID NO. 28, an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO. 28, or an amino acid sequence having 1, 2, 3, 4, or 5 or fewer amino acid sequence differences compared to SEQ ID NO. 28, or including these.

[0011] In some embodiments, the antibody agent of the Disclosure comprises a light chain containing a constant region (CL) sequence. In some embodiments, the light chain comprises kappa CL or lambda CL. In some embodiments, the light chain comprises kappa CL. In some embodiments, the light chain comprises the amino acid sequence of SEQ ID NO: 32, an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 32, or an amino acid sequence having 5, 10, or 20 or fewer amino acid sequences different from SEQ ID NO: 32, or an amino acid sequence containing these.

[0012] In some embodiments, the antibody agent of the present disclosure comprises a heavy chain comprising a variable region (VH) comprising one, two, three, or four FR regions, which collectively has at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with the sequence found in SEQ ID NO: 14, and / or collectively comprises one, two, three, four, or five or fewer amino acid sequence differences compared to the sequence found in SEQ ID NO: 14. In some embodiments, the heavy chain includes a variable region (VH) containing one, two, three, or four FR regions, each independently having an amino acid sequence that is one of the amino acid sequences of SEQ ID NOs. 21, 22, 23, or 24, an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to one of SEQ ID NOs. 21, 22, 23, or 24, or an amino acid sequence that differs by one, two, three, four, or five or fewer amino acid sequences from one of SEQ ID NOs. 21, 22, 23, or 24.

[0013] In some embodiments, the antibody agent of the present disclosure is (i) an amino acid sequence which is the amino acid sequence of SEQ ID NO: 21, an amino acid sequence which is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 21, or an amino acid sequence which is one, two, three, four, or five or fewer amino acid sequences different from SEQ ID NO: 21, or an amino acid sequence which is (i) an amino acid sequence which is the amino acid sequence of SEQ ID NO: 22, an amino acid sequence which is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 22, or an amino acid sequence which is one, two, three, four, or five or fewer amino acid sequences different from SEQ ID NO: 22, or an amino acid sequence which is (ii) (iii) an amino acid sequence; and / or an amino acid sequence that is the amino acid sequence of SEQ ID NO. 23, an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO. 23, or an amino acid sequence having 1, 2, 3, 4, or 5 or fewer amino acid sequence differences compared to SEQ ID NO. 23, or including these; and / or (iv) an amino acid sequence of SEQ ID NO. 24, an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO. 24, or an amino acid sequence having 1, 2, 3, 4, or 5 or fewer amino acid sequence differences compared to SEQ ID NO. 24, or including these.

[0014] In some embodiments, the antibody agent of this disclosure comprises a heavy chain region including a sequence of at least one constant region (CH). In some embodiments, the at least one constant region comprises an Fc domain. In some embodiments, the Fc domain comprises an Fc domain from mouse, rat, rabbit, primate, human, dog, pig, or cat. In some embodiments, the Fc domain is selected from Fc domains of immunoglobulin isotypes. In some embodiments, the immunoglobulin isotype comprises IgA, IgG, IgM, or IgE. In some embodiments, the Fc domain comprises an Fc domain of IgG. In some embodiments, the Fc domain comprises an Fc domain of human IgG. In some embodiments, IgG is or comprises IgG1, IgG2, IgG3, or IgG4. In some embodiments, the constant region of IgG comprises one or more modifications. In some embodiments, one or more modifications modulate one or more properties of the antibody agent. In some embodiments, one or more modifications comprises a PVAdelG mutation. In some embodiments, the heavy chain is the amino acid sequence of SEQ ID NO: 30, an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 30, or an amino acid sequence having 5, 10, or 20 or fewer amino acid sequences different from SEQ ID NO: 30, or includes an amino acid sequence containing these.

[0015] In some embodiments, the antibody agent of the present disclosure includes VL having an amino acid sequence of SEQ ID NO: 18, an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 18, or an amino acid sequence having 5, 10, or 20 or fewer amino acid sequences different from SEQ ID NO: 18, or an amino acid sequence containing these. In some embodiments, the antibody agent of the present disclosure includes VH having an amino acid sequence of SEQ ID NO: 14, an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 14, or an amino acid sequence having 5, 10, or 20 or fewer amino acid sequences different from SEQ ID NO: 14, or an amino acid sequence containing these.

[0016] In some embodiments, the antibody agent of the present disclosure includes a light chain (LC) having an amino acid sequence which is the amino acid sequence of SEQ ID NO: 33, an amino acid sequence which is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 33, or an amino acid sequence which is 5, 10, or 20 or fewer amino acid sequences different from SEQ ID NO: 33, or an amino acid sequence which includes these. In some embodiments, the antibody agent of the present disclosure includes a heavy chain (HC) having an amino acid sequence which is the amino acid sequence of SEQ ID NO: 31, an amino acid sequence which is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 31, or an amino acid sequence which is 5, 10, or 20 or fewer amino acid sequences different from SEQ ID NO: 31, or an amino acid sequence which includes these.

[0017] In at least one aspect of this disclosure, (i) the antibody agent does not bind to TREM2 or has minimal binding affinity; (ii) the antibody agent competes for binding with a reference antibody agent that binds to TREM1; and (iii) the antibody agent has a binding affinity of about 0.1 nM to about 0.3 nM (K D (iv) The antibody agent binds to the monomeric human TREM1-ECD protein with a binding affinity of approximately 1.4 nM to approximately 2.4 nM (K D (v) The antibody agent binds to the monomer cynoTREM1-ECD protein, and in the enriched human monocyte cell binding assay, it exhibits a binding affinity (K) of approximately 80 pM to approximately 95 pM. D (vi) The antibody agent binds to human TREM1 at a rate of approximately 185 pM to approximately 245 pM in the enriched human neutrophil cell binding assay. D (vii) The antibody agent binds to human TREM1 at a rate of approximately 90 pM to approximately 115 pM in a whole blood human monocyte binding assay. D (viii) The antibody agent binds to human TREM1 at a rate of approximately 110 pM to approximately 150 pM in a whole blood human neutrophil cell binding assay. D (ix) The antibody agent binds to human TREM1 at a rate of approximately 235 pM to approximately 370 pM in whole blood cynoneutrophil cell binding assays. DThe present invention provides an antibody agent characterized by one or more of the following: (x) binding to cynoTREM1; (x) inhibiting TREM1 activity with an IC50 of approximately 20 pM to approximately 40 pM in a human whole blood concentrated neutrophil or primary monocyte function assay; (xi) inhibiting TREM1 activity with an IC50 of approximately 4 pM to approximately 13 pM in a cyno whole blood primary monocyte function assay; (xii) being able to be produced at a concentration of approximately 4 g / L to approximately 7 g / L; (xiii) having a melting temperature of approximately 70°C to approximately 80°C; (xiv) being able to bind to inactivated and activated TREM1; (xv) not binding to the surface of cells that do not express TREM1; or (xvi) antagonizing TREM1-mediated inhibition of monocyte maturation to macrophage.

[0018] In some embodiments, the antibody agents of this disclosure are characterized by reducing TREM1 activity and / or cell surface levels compared to a comparer. In some embodiments, the comparer is (i) a sample that does not come into contact with the TREM1 antibody agent disclosed herein, or (ii) a sample that comes into contact with a reference TREM1 antibody agent, or (iii) a sample that comes into contact with an isotype control antibody agent, or includes these. In some embodiments, the antibody agent reduces the level of TREM1 present on the cell surface. In some embodiments, the cells are monocytes or neutrophils. In some embodiments, the antibody agent reduces the level of TREM1 present on the cell surface by internal migration and / or clipping of TREM1. In some embodiments, the antibody agent reduces (e.g., inhibits) TREM1 activity. In some embodiments, inhibition of TREM1 activity includes inhibiting the binding of TREM1 to a TREM1 ligand. In some embodiments, the TREM1 ligand is PGLYRP1. In some embodiments, the antibody agent reduces the activity and / or level of TREM1 by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%. In some embodiments, the antibody agent is characterized by reducing (e.g., inhibiting) the TREM1-mediated immune response. In some embodiments, the TREM1-mediated immune response is an amplified immune response and / or not an innate immune response (e.g., a TLR-mediated immune response). In some embodiments, the TREM1-mediated immune response is mediated by monocytes (e.g., inflammatory monocytes) and / or neutrophils (e.g., activated neutrophils). In some embodiments, the TREM1-mediated immune response is or includes one or more of the following: (i) secretion of one or more cytokines, (ii) secretion of one or more chemokines, (iii) modulation of T cells, B cells or other cells, (iv) secretion of one or more factors that reduce or impair epithelial barrier integrity, and (v) secretion of one or more proteolytic enzymes. In some embodiments, one or more cytokines are pro-inflammatory cytokines.In some embodiments, one or more cytokines are selected from the group consisting of IL-1α, IL-1β, IL-6, IL-8, IL-10, IL-23, GM-CSF, TNF-RII, and TNFα. In some embodiments, one or more chemokines are selected from the group consisting of CCL2, CCL3, CCL4, CCL8, CCL20, CCL22, CCL24, CXCL1, CXCL5, CXCL9, CXCL10, and CXCL13. In some embodiments, modulation of T cells, B cells, or other cells is performed by one or more of IL-1α, IL-1β, IL-6, IL-10, IL-23, APRIL, BAFF, CD30, M-CSF, TNF-RII, and TNFα. In some embodiments, one or more factors that reduce or impair epithelial barrier integrity are selected from the group consisting of IL-1α, IL-1β, IL-6, IL-8, IL-10, IL-23, GM-CSF, TRAIL, TWEAK, MMP-1, IL-20, TNFR-II, and TNFα. In some embodiments, one or more proteolytic enzymes are or comprise matrix metalloproteinases (MMPs). In some embodiments, the MMPs are MMP1 and / or MMP9.

[0019] In some embodiments, the antibody agents of this disclosure are characterized by preventing or reducing (e.g., inhibiting) epithelial barrier damage. In some embodiments, epithelial barrier damage is mediated by one or more cytokines. In some embodiments, one or more cytokines are pro-inflammatory cytokines. In some embodiments, one or more cytokines are selected from the group consisting of IL-1β, IL-6, IL-8, IL-23, and TNFα.

[0020] In some embodiments, the antibody agent of the Disclosure is or comprises (i) an intact IgA, IgG, IgD, IgE, or IgM antibody, (ii) an antibody fragment, (iii) a single-domain antibody, (iv) a single-chain Fv, or (v) a polypeptide fused to an Fc domain with antigen-binding specificity. In some embodiments, the antibody agent is an antibody-drug conjugate (ADC). In some embodiments, the antibody agent further comprises a second binding specificity. In some embodiments, the second binding specificity confers binding to antigens other than human TREM1. In some embodiments, the antibody agent is selected from heterodimers, Crossmab, DVD-Ig, two-in-one (2-in-1) IgG and IgG-sc-Fv, scFv-scFv, BiTE, DART, diabody, Fab-scFv fusion, Fab-Fab fusion, or tandem antibodies.

[0021] In some embodiments, the antibody agents of this disclosure are produced by bacterial cells, yeast cells, insect cells, and mammalian cells. In some embodiments, the antibody agents are produced by mammalian cells. In some embodiments, the mammalian cell line is or contains CHO cells. In some embodiments, the antibody agents are produced by a cell-free system.

[0022] In at least one aspect, the Disclosure relates to LC CDR1, LC CDR2 and LC CDR1, which (i) collectively have at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with the sequence found in SEQ ID NO: 18, and / or collectively include differences of 1, 2, 3, 4, or 5 amino acids or less compared to the sequence found in SEQ ID NO: 18. The present invention provides a polypeptide having an amino acid sequence which is (ii) the amino acid sequence of SEQ ID NO: 18, an amino acid sequence which is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 18, or an amino acid sequence which is 5, 10, or 20 or fewer amino acid sequences different from SEQ ID NO: 18, and / or (iii) the amino acid sequence of SEQ ID NO: 33, an amino acid sequence which is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 33, or an amino acid sequence which is 5, 10, or 20 or fewer amino acid sequences different from SEQ ID NO: 33, or an amino acid sequence which includes these.

[0023] In at least one aspect, the Disclosure relates to (i) HC CDR1, HC CDR2 and HC CDR1, which collectively have at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with the sequence found in SEQ ID NO: 14, and / or collectively include differences of 1, 2, 3, 4, or 5 amino acids or less compared to the sequence found in SEQ ID NO: 14. The present invention provides a polypeptide having an amino acid sequence which is (ii) the amino acid sequence of SEQ ID NO: 14, an amino acid sequence which is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 14, or an amino acid sequence which is 5, 10, or 20 or fewer amino acid sequences different from SEQ ID NO: 14, and / or (iii) the amino acid sequence of SEQ ID NO: 31, an amino acid sequence which is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 31, or an amino acid sequence which is 5, 10, or 20 or fewer amino acid sequences different from SEQ ID NO: 31, or an amino acid sequence which includes these.

[0024] In at least one aspect, the Disclosure provides a polypeptide having amino acid sequences that are (i) LC CDR1, LC CDR2, and LC CDR3 sequences which collectively have at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with the sequence found in SEQ ID NO: 18 and / or collectively include 1, 2, 3, 4, or 5 or fewer amino acid sequence differences compared to the sequence found in SEQ ID NO: 18, and (ii) HC CDR1, HC CDR2, and HC CDR3 sequences which collectively have at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with the sequence found in SEQ ID NO: 14 and / or collectively include 1, 2, 3, 4, or 5 or fewer amino acid sequence differences compared to the sequence found in SEQ ID NO: 14, or include amino acid sequences which include these.

[0025] In at least one embodiment, the Disclosure provides a nucleic acid having a nucleotide sequence encoding an antibody agent described herein. In some embodiments, the nucleic acid has a nucleotide sequence encoding a polypeptide described herein. In some embodiments, the nucleic acid has a nucleotide sequence encoding a variable light chain (VL), the nucleotide sequence being or comprising the nucleotide sequence of SEQ ID NO: 39 or a nucleotide sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 39. In some embodiments, the nucleic acid has a nucleotide sequence encoding a variable heavy chain (VH), the nucleotide sequence being or comprising the nucleotide sequence of SEQ ID NO: 38 or a nucleotide sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 38. In some embodiments, the nucleic acid has a nucleotide sequence encoding an antibody agent that binds to TREM1, (i) the nucleotide sequence includes a first portion encoding a variable light chain (VL), the first portion being or including the nucleotide sequence of SEQ ID NO: 39 or a nucleotide sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 39, and (ii) the nucleotide sequence includes a second portion encoding a variable heavy chain (VH), the second portion being or including the nucleotide sequence of SEQ ID NO: 38 or a nucleotide sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 38. In some embodiments, the antibody agent encoded by the nucleotide sequence further includes a light chain constant region (CL) and / or at least one heavy chain constant region.

[0026] In at least one aspect, the disclosure provides a vector comprising a nucleic acid as described herein.

[0027] In at least one embodiment, this disclosure provides host cells comprising the vectors described herein. In some embodiments, the host cells are yeast cells, bacterial cells, mammalian cells, or insect cells.

[0028] In at least one aspect, the present disclosure provides a method for producing an antibody agent that binds to TREM1, comprising culturing host cells as described herein under conditions in which the antibody agent described herein is expressed by the host cells.

[0029] In at least one embodiment, the present disclosure provides a composition comprising an antibody agent described herein. In some embodiments, the composition comprises a polypeptide described herein.

[0030] In at least one embodiment, the Disclosure provides a pharmaceutical composition comprising or delivering an antibody agent described herein. In some embodiments, the pharmaceutical composition comprises or delivers a polypeptide described herein. In some embodiments, the pharmaceutical composition further comprises excipients and / or pharmaceutically acceptable carriers. In some embodiments, the pharmaceutical composition is formulated in one or more unit dosage forms.

[0031] In at least one aspect, the Disclosure provides a method for preparing a pharmaceutical composition, comprising the step of combining an antibody agent described herein, a polypeptide described herein, or a nucleic acid encoding some or all of these with one or more pharmaceutically acceptable carriers.

[0032] In at least one embodiment, the Disclosure provides a method for treating a disease, disorder, or condition related to a TREM1-mediated immune response in a subject, the method comprising the step of administering a pharmaceutical composition described herein to the subject. In some embodiments, the pharmaceutical composition, when administered to the subject, is characterized by reducing the level and / or activity of TREM1 compared to a comparator. In some embodiments, the comparator includes a subject that is similar in that the pharmaceutical composition was not administered or a reference TREM1 inhibitor was administered.

[0033] In some embodiments, the disease, disorder, or condition is an inflammatory disease, disorder, or condition. In some embodiments, the inflammatory disease, disorder, or condition is selected from inflammatory bowel disease (IBD), sepsis, fibrous disease, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), COVID-19, Post-MI (ischemic reperfusion), atherosclerosis, acute stroke (ischemic reperfusion), stroke (hemorrhagic), renal ischemia-reperfusion injury, pancreatitis, renal fibrosis, hepatic fibrosis, NASH, sickle cell occlusive attack, Marfan syndrome, HIV infection, motor neurogenerative disorders, periodontitis / gingivitis, cancer, diabetic foot ulcer, gout, lupus, psoriasis, arthropathy (e.g., arthritis or synovitis), and Behçet's disease. In some embodiments, the disease, disorder, or condition is inflammatory bowel disease (IBD) (e.g., intestinal IBD or extraintestinal signs of IBD (EIM)). In some embodiments, IBD is Crohn's disease (CD) or ulcerative colitis (UC). In some embodiments, the disease, disorder, or condition is unresponsive to alternative therapy. In some embodiments, the alternative therapy is or includes anti-TNFα therapy.

[0034] In some embodiments, the subject has received or is receiving alternative therapy. In some embodiments, the alternative therapy is alternative IBD therapy. In some embodiments, the alternative therapy is anti-TNFα therapy (e.g., infliximab, adalimumab, golimumab, and certolizumab pegol); JAK inhibitor therapy (including selective and non-selective inhibitors) (e.g., upadacitinib, tofacitinib, and filgotinib); anti-integrin therapy (e.g., vedolizumab and natalizumab); anti-IL-23 therapy (e.g., guselkumab, mirikizumab, and brazicumab); anti-IL-12 / 23 therapy (e.g., ustekinumab); anti-IL-23A therapy (e.g., risankizumab); S1PR agonist or modulator therapy (e.g., ozanimod and etrasimodo); 5-aminosalicylate therapy (e.g., mesalamine, orsalazine, valsalazide, and sulfasalazine); Munomodulator therapy (e.g., azathioprine, 6-mercaptopurine, and methotrexate); corticosteroid therapy (e.g., prednisone, methylprednisolone, hydrocortisone, and budesonide); anti-TL1A therapy (e.g., PRA023 and RVT-3101); kinase inhibitor therapy (e.g., ritrecitinib); TYK2 inhibitor therapy (e.g., duclavacitinib); anti-IL-36 therapy (e.g., spesolimab); anti-IL-13 therapy (e.g., dupilumab); miR-124 upregulator therapy (e.g., obefazimod); TLR9 agonist therapy (e.g., cobitolimod); or combinations thereof or including these.

[0035] In some embodiments, the subject is determined to express (i) a biomarker relating to or surrogating elevated neutrophil and / or monocyte (e.g., inflammatory monocyte) levels; (ii) a biomarker comprising one or more products of neutrophils and / or monocytes (e.g., inflammatory monocytes) that correlates with reactivity to the antibody agents described herein; and / or (iii) a biomarker indicating TREM1 levels and / or activity. In some embodiments, the biomarker relates to or surrogates elevated activated neutrophil levels. In some embodiments, the biomarker comprises one or more of (i) cell-based biomarkers, (ii) tissue biomarkers, (iii) products produced by activated neutrophils, (iv) products produced by inflammatory monocytes, (v) TREM1 ligands, and (vi) TREM1 gene activation signatures. In some embodiments, cell-based biomarkers are monocyte and / or neutrophil counts, TREM1 RNA present in monocytes and / or neutrophils, TREM1 present in monocytes and / or neutrophils, or TREM1 present on the cell surface of monocytes and / or neutrophils. In some embodiments, tissue biomarkers are mucosal ulcers, neutrophils in the lamina propria and / or epithelial cells, or lymphocytes, plasma cells and / or eosinophils in the lamina propria. In some embodiments, products produced by activated neutrophils are calprotectin, PGLYRP1, or soluble TREM1. In some embodiments, products produced by inflammatory monocytes are soluble TREM1. In some embodiments, the TREM1 ligand is bacterial peptidoglycan (PGN) and / or PGLYRP1. In some embodiments, biomarkers are detected in samples selected from the group consisting of blood, diseased tissue, feces, components or fractions thereof, and combinations thereof. In some embodiments, the biomarker is monocyte and / or neutrophil count, and the biomarker is detected in diseased tissue. In some embodiments, the biomarker is TREM1 RNA present in monocytes and / or neutrophils, and the biomarker is detected in diseased tissue.In some embodiments, the biomarker is TREM1 present on the cell surface of monocytes and / or neutrophils, and the biomarker is detected in diseased tissue. In some embodiments, the biomarker is a tissue biomarker, and the biomarker is detected in diseased tissue. In some embodiments, the biomarker is soluble TREM1, and the biomarker is detected in blood and / or feces. In some embodiments, the biomarker is calprotectin, and the biomarker is detected in blood and / or feces. In some embodiments, the biomarker is bacterial PGN, and the biomarker is detected in feces. In some embodiments, the biomarker is PGLYRP1, and the biomarker is detected in blood and / or feces. In some embodiments, the biomarker is a TREM1 gene activation signature, and the biomarker is detected in diseased tissue and / or blood.

[0036] In at least one embodiment, the Disclosure provides a method comprising the steps of determining whether a subject expresses (i) a biomarker relating to or surrogating elevated levels of neutrophils and / or monocytes (e.g., inflammatory monocytes); (ii) a biomarker comprising one or more products of neutrophils and / or monocytes (e.g., inflammatory monocytes) that correlates with reactivity to an antibody agent disclosed herein; and / or (iii) a biomarker indicating TREM1 levels and / or activity; and if it is determined that the subject expresses a biomarker, administering an antibody agent disclosed herein to the subject. In some embodiments, the biomarker relates to or surrogates elevated levels of activated neutrophils. In some embodiments, the biomarker is one or more of (i) a cell-based biomarker, (ii) a tissue biomarker, (iii) a product produced by activated neutrophils, (iv) a product produced by inflammatory monocytes, (v) a TREM1 ligand, and (vi) a TREM1 gene activation signature. In some embodiments, cell-based biomarkers are monocyte and / or neutrophil counts, TREM1 RNA present in monocytes and / or neutrophils, TREM1 present in monocytes and / or neutrophils, or TREM1 present on the cell surface of monocytes and / or neutrophils. In some embodiments, tissue biomarkers are mucosal ulcers, neutrophils in the lamina propria and / or epithelial cells, or lymphocytes, plasma cells and / or eosinophils in the lamina propria. In some embodiments, products produced by activated neutrophils are calprotectin, PGLYRP1, or soluble TREM1. In some embodiments, products produced by inflammatory monocytes are soluble TREM1. In some embodiments, the TREM1 ligand is bacterial peptidoglycan (PGN) and / or PGLYRP1. In some embodiments, the biomarker is detected in a sample selected from the group consisting of blood, diseased tissue, feces, components or fractions thereof, and combinations thereof. In some embodiments, the biomarker is the number of monocytes and / or neutrophils, and the biomarker is detected in diseased tissue.In some embodiments, the biomarker is TREM1 RNA present in monocytes and / or neutrophils, and the biomarker is detected in diseased tissue. In some embodiments, the biomarker is TREM1 present in monocytes and / or neutrophils, and the biomarker is detected in diseased tissue. In some embodiments, the biomarker is TREM1 present on the cell surface of monocytes and / or neutrophils, and the biomarker is detected in diseased tissue. In some embodiments, the biomarker is a tissue biomarker, and the biomarker is detected in diseased tissue. In some embodiments, the biomarker is soluble TREM1, and the biomarker is detected in blood and / or feces. In some embodiments, the biomarker is calprotectin, and the biomarker is detected in blood and / or feces. In some embodiments, the biomarker is bacterial PGN, and the biomarker is detected in feces. In some embodiments, the biomarker is PGLYRP1, and the biomarker is detected in blood and / or feces. In some embodiments, the biomarker is a TREM1 gene activation signature, and the biomarker is detected in diseased tissue and / or blood. In some embodiments, the antibody agent, when administered to a subject, reduces the level and / or activity of TREM1 compared to a comparator. In some embodiments, the comparator includes a subject that is similar in that it was not administered the antibody agent or was administered a reference TREM1 inhibitor.

[0037] In at least one embodiment, the Disclosure provides a method for inhibiting TREM1, comprising the step of contacting cells, tissues, or subjects with a pharmaceutical composition described herein, thereby inhibiting TREM1 in the cells, tissues, or subjects. In some embodiments, inhibition of TREM1 includes a reduction in the level and / or activity of TREM1. In some embodiments, inhibition of TREM1 is assessed in comparison to a comparator.

[0038] In at least one embodiment, the Disclosure provides a method for antagonizing TREM1-mediated inhibition of monocyte-to-macrophage maturation, comprising the step of contacting cells, tissues, or subjects with a pharmaceutical composition described herein to thereby antagonize TREM1-mediated inhibition of monocyte-to-macrophage maturation in the cells, tissues, or subjects. In some embodiments, the antagonization of TREM1-mediated inhibition of monocyte-to-macrophage maturation is assessed in comparison to a comparator. In some embodiments, the comparator includes cells, tissues, or subjects that are similar in all respects except that the pharmaceutical composition was not administered or a reference TREM1 inhibitor was administered. In some embodiments, the contacting step includes administering the pharmaceutical composition to the cells, tissues, or subjects. In some embodiments, the subjects are mammals. In some embodiments, the mammals are humans. In some embodiments, the humans are adults. In some embodiments, the humans are children. [Brief explanation of the drawing]

[0039] [Figure 1A] This is a t-distribution type stochastic neighbor embedding (tSNE) plot showing cell subpopulations identified from single-cell transcriptomics data from samples derived from IBD patients. The cell populations were further analyzed for differences in clinical aspects (e.g., anti-TNFα therapy responder status or inflammatory status). [Figure 1B] This is a tSNE plot showing the myeloid cell population from Figure 1A. [Figure 2] This is a tSNE plot of single-cell data from tissue samples from inflammatory bowel disease (IBD) patients. Cells are shaded based on the hypergeometric odds ratio of the likelihood of cell neighborhood enrichment in cells derived from inflammatory samples. Inflammatory monocyte cell populations are circled and are highly associated with inflammation. [Figure 3] This is a volcano plot showing the difference in cell type abundances in inflammatory samples compared to non-inflammatory samples from IBD patients. The x-axis represents the effect size (log2 (times of change)), and the y-axis represents significance (-log10 (p-value)). Inflammatory monocytes are the cell type most significantly associated with inflammatory samples. [Figure 4A]This is a tSNE plot of single-cell data from inflammatory tissue derived from IBD patients. Cells are shaded based on TREM1 expression levels. Inflammatory monocyte populations are circled. [Figure 4B] This is a tSNE plot of single-cell data from non-inflammatory tissue derived from IBD patients. Cells are shaded based on TREM1 expression levels. Inflammatory monocyte populations are circled. [Figure 4C] This is a tSNE plot of single-cell data from healthy tissue derived from non-IBD patients. Cells are shaded based on TREM1 expression levels. Inflammatory monocyte populations are circled. [Figure 5A] This is a tSNE plot of single-cell data from peripheral blood mononuclear cells (PBMCs) derived from IBD patients. Cells are shaded based on TREM1 expression levels. [Figure 5B] This is a tSNE plot of single-cell data from peripheral blood mononuclear cells (PBMCs) derived from healthy individuals. Cells are shaded based on TREM1 expression levels. [Figure 6A] This is a tSNE plot of single-cell data from IBD patient tissue samples. Cells are shaded based on the hypergeometric odds ratio of enrichment in post-treatment samples from non-responders (NR) to anti-TNFα therapy compared to responders (R). Inflammatory monocyte cell populations are circled. [Figure 6B] This is a tSNE plot of single-cell data from post-treatment IBD patient tissue samples derived from non-responders of anti-TNFα therapy. Cells are shaded based on TREM1 expression levels. Inflammatory monocyte populations are circled. [Figure 6C] This is a tSNE plot of single-cell data from pre- and post-treatment tissue samples from Crohn's disease (CD) patients who were unresponsive to anti-TNFα therapy. Cells are shaded based on TREM1 expression levels. Inflammatory monocyte populations are circled. [Figure 6D]This is a tSNE plot of single-cell data from pre- and post-treatment tissue samples from ulcerative colitis (UC) patients who were unresponsive to anti-TNFα therapy. Cells are shaded based on TREM1 expression levels. Inflammatory monocyte populations are circled. [Figure 7] This study shows the correlation between the enrichment of TREM1+ myeloid cells (primarily monocytes), assessed using single-cell transcriptomics of mucosal biopsies in inflammatory tissue from patients with active ulcerative colitis, and the level of neutrophil infiltration, assessed using the Nancy histopathology index of adjacent biopsies. A Nancy score of ≤1 means no neutrophil infiltration was observed ("none"), a score of 2 means mild neutrophil infiltration ("mild"), and a score of ≥3 means severe neutrophil infiltration ("severe"). [Figure 8A] The figure shows the binding of the anti-TREM1 antibody clone A to TREM1 on the cell surface of neutrophils present in whole blood from healthy human subjects, as analyzed using flow cytometry. The figure shows data from a single donor, which was considered representative of data from eight different donors. [Figure 8B] This shows geometric mean fluorescence intensity (MFI) data for binding of AlexaFluor® 647-labeled anti-TREM1 antibody clone A to enriched human primary neutrophils (CD45+ / CD66abce+) isolated from three healthy volunteer donors. The geometric MFI for anti-TREM1 antibody clone 1 is plotted against anti-TREM1 antibody clone 1 concentration (log scale). Error bars represent the mean ± SD from technical replicates. [Figure 8C] The figure shows the binding of the anti-TREM1 antibody clone A to TREM1 on the cell surface of all CD14+ monocytes present in whole blood from healthy human subjects, as analyzed using flow cytometry. The figure shows data from a single donor, which was considered representative of data from eight different donors. [Figure 8D]This shows geometric mean fluorescence intensity (MFI) data for binding of AlexaFluor® 647-labeled anti-TREM1 antibody clone A to enriched human primary monocytes (CD45+ / CD14+) isolated from four healthy volunteer donors. The geometric MFI for anti-TREM1 antibody clone 1 is plotted against anti-TREM1 antibody clone 1 concentration (log scale). Error bars represent the mean ± SD from technical replicates. [Figure 8E] The figure shows the lack of binding of anti-TREM1 antibody clone A to CD45+ Lin+ (CD3+ or CD7+ or CD20+) cells (e.g., T cells, NK cells, and B cells) present in whole blood derived from healthy human subjects, as analyzed using flow cytometry. The figure shows data from a single donor that was considered representative of data from eight different donors. [Figure 9] The figure shows the binding of anti-TREM1 antibody clone A to TREM1 on the cell surface of monocytes in response to bacterial PGN or LPS stimulation, as analyzed using flow cytometry. The figure shows data from a single donor, which was considered representative of the data from monocytes from eight different donors. [Figure 10A-10C] The figures show the culture medium concentrations of inflammatory cytokines and chemokines (CCL3 (Figure 10A), CCL4 (Figure 10B), IL-1β (Figure 10C), IL-6 (Figure 10D), IL-23 (Figure 10E), and TNFα (Figure 10F)) secreted by primary monocytes in response to stimulation with PGLYRP1 alone, PGN alone, or a combination of PGN and PGLYRP1. Unstimulated cells (culture medium) are used to show baseline cytokine levels. The mean and standard deviation of four replicates are shown. Statistical significance was determined by one-way ANOVA and Tukey's multiple comparison test: ns = not significant; ** = p < 0.01; *** = p < 0.001; **** = p < 0.0001. The figures show data from a single donor considered representative of data from 12 different donors. [Figure 10D-10F]The figures show the culture medium concentrations of inflammatory cytokines and chemokines (CCL3 (Figure 10A), CCL4 (Figure 10B), IL-1β (Figure 10C), IL-6 (Figure 10D), IL-23 (Figure 10E), and TNFα (Figure 10F)) secreted by primary monocytes in response to stimulation with PGLYRP1 alone, PGN alone, or a combination of PGN and PGLYRP1. Unstimulated cells (culture medium) are used to show baseline cytokine levels. The mean and standard deviation of four replicates are shown. Statistical significance was determined by one-way ANOVA and Tukey's multiple comparison test: ns = not significant; ** = p < 0.01; *** = p < 0.001; **** = p < 0.0001. The figures show data from a single donor considered representative of data from 12 different donors. [Figure 11] This figure shows the culture medium concentrations of inflammatory cytokines and chemokines (CCL3, CCL4, and IL-8) secreted by primary neutrophils in response to stimulation with PGLYRP1 alone, PGN alone, or a combination of PGN and PGLYRP1. Unstimulated cells (culture medium) are used to show baseline cytokine levels. The mean and standard deviation of 8 replicates are shown. Statistical significance was determined by one-way ANOVA and Tukey's multiple comparison test: ns = not significant; * = p < 0.05; ** = p < 0.01; *** = p < 0.001; **** = p < 0.0001. The figure shows data from a single donor considered representative of data from 19 different donors. [Figure 12] This shows the amino acid sequence alignment between the extracellular domain (ECD) of human TREM1 (amino acids 20-205 of UniProt accession number: Q9NP99) and the ECD of human TREM2 (amino acids 19-174 of UniProt accession number: Q9NZC2). [Figure 13] This image shows the maximum biolayer interferometry (BLI) response at the nanometer level for the binding of human TREM2-ECD (BioLegend, 786404 and R&D Systems, 1828-T2-050) to exemplary anti-TREM1 antibody agents. An anti-TREM2 antibody (R&D Systems, MAB17291) was used as a positive control. [Figure 14] The results from the multispecificity assay are shown. Binding of anti-TREM1 antibody agents to each of over 6,000 human membrane proteins expressed in HEK293 cells was measured. Anti-TREM1 antibody agent clone A showed high selectivity for binding to TREM1. [Figure 15] This shows the mean fluorescence intensity (MFI) of G401 cells that are TMEM178A-positive and TREM1-negative, stained with clone A of the anti-TREM1 antibody conjugated with Alexa Fluor 647 (AF647). The geometric mean (GeoMean) MFI of one dataset considered representative of three experiments is shown. An isotype control antibody conjugated with AF647 is used as a negative control. [Figure 16] The results of a differential scanning fluorescence quantitative assay to evaluate the thermal stability of anti-TREM1 antibody agents are shown. [Figure 17A-17C] The media concentrations of inflammatory cytokines and chemokines (CCL3 (Figure 17A), CCL4 (Figure 17B), IL-1β (Figure 17C), IL-6 (Figure 17D), IL-23 (Figure 17E), and TNFα (Figure 17F)) secreted by primary monocytes stimulated by a combination of PGN and PGLYRP1, and also treated with anti-TREM1 antibody clone A, isotype control, or untreated with the antibody are shown. Unstimulated cells (media) are used to show baseline cytokine levels. The mean and standard deviation of four replicates are shown. nd = not detected. Statistical significance was determined by one-way ANOVA and Tukey's multiple comparison test: ns = not significant; * = p < 0.05; *** = p < 0.001; **** = p < 0.0001. The figure shows data from a single donor considered representative of data from 12 different donors. [Figures 17D-17F]The media concentrations of inflammatory cytokines and chemokines (CCL3 (Figure 17A), CCL4 (Figure 17B), IL-1β (Figure 17C), IL-6 (Figure 17D), IL-23 (Figure 17E), and TNFα (Figure 17F)) secreted by primary monocytes stimulated by a combination of PGN and PGLYRP1, and also treated with anti-TREM1 antibody clone A, isotype control, or untreated with the antibody are shown. Unstimulated cells (media) are used to show baseline cytokine levels. The mean and standard deviation of four replicates are shown. nd = not detected. Statistical significance was determined by one-way ANOVA and Tukey's multiple comparison test: ns = not significant; * = p < 0.05; *** = p < 0.001; **** = p < 0.0001. The figure shows data from a single donor considered representative of data from 12 different donors. [Figure 18] This shows the culture medium concentrations of TNFα secreted by primary human monocytes from healthy volunteers stimulated with PGN, PGLYRP1, or a combination of PGN and PGLYRP1, in the presence of either anti-TREM1 antibody clone A or isotype control. Ten-point titration curves were performed for either anti-TREM1 antibody clone A or isotype control. Unstimulated cells (culture medium) are used to show baseline cytokine levels. The mean and standard deviation of four replicates are shown. The figure shows data from a single donor considered representative of data from 12 different donors. Nonlinear curve fits of log(antibody) vs. response (three parameters) of the data are shown. [Figures 19A-19C]This figure shows the culture medium concentrations of inflammatory cytokines and chemokines (CCL3 (Figure 19A), CCL4 (Figure 19B), and IL-8 (Figure 19C)) secreted by primary neutrophils stimulated by a combination of PGN and PGLYRP1, and also treated with anti-TREM1 antibody clone A, isotype control, or untreated with the antibody. Unstimulated cells (culture medium) are used to show baseline cytokine levels. The mean and standard deviation of 8 replicates are shown. nd = not detected. Statistical significance was determined by one-way ANOVA and Tukey's multiple comparison test: ns = not significant; **** = p < 0.0001. The figure shows data from a single donor considered representative of data from 17 different donors. [Figure 20] This shows the culture medium concentrations of CCL4 secreted by primary human neutrophils from healthy volunteers stimulated with PGN, PGLYRP1, or a combination of PGN and PGLYRP1 in the presence of either anti-TREM1 antibody clone A or isotype control. Ten-point titration curves were performed for either anti-TREM1 antibody clone A or isotype control. Unstimulated cells (culture medium) are used to show baseline cytokine levels. The figure shows data from a single donor considered representative of data from 10 different donors. Nonlinear curve fits of log(antibody) vs. response (three parameters) of the data are shown. [Figures 21A-21B] The results of transepithelial electrical resistance (TEER) assays of jejunal epithelial cells from two donors (jejunal donor 1 (Figure 21A) and jejunal donor 5 (Figure 21B)) treated with differentiation medium containing various concentrations of TNFα (15 ng / mL, 30 ng / mL, and 50 ng / mL) are shown. Differentiation medium alone (untreated) or treatment with differentiation medium containing a solvent (TNFα solvent) was used as a control. The mean and standard deviation of three replicates are shown. [Figures 22A-22D]The results of a TEER assay are shown for jejunal epithelial cells derived from four donors (Donor 1 (Figure 22A), Donor 2 (Figure 22B), Donor 5 (Figure 22C), and Donor 6 (Figure 22D)) treated with differentiation medium alone (untreated) or differentiation medium supplemented with 50% of either unstimulated human monocyte-conditioned medium or PGN and PGLYRP1-stimulated monocyte-conditioned medium. The mean and standard deviation of three replicates are shown. [Figures 23A-23D] The results of a TEER assay are shown, in which jejunal epithelial cells derived from four donors (Donor 1 (Figure 23A), Donor 2 (Figure 23B), Donor 5 (Figure 23C), and Donor 6 (Figure 23D)) were treated with conditioned medium produced by unstimulated cultured monocytes (conditioned medium), cultured monocytes stimulated with bacterial peptidoglycan (PGN) and PGLYRP1 (PGN:PGLYPR1), or cultured monocytes stimulated with PGN:PGLYPR1 in the presence of an anti-TREM1 antibody clone A or isotype control. Cells treated without conditioned medium were also included as a control. The conditioned medium was produced from four healthy volunteers (Donors 1, 2, 5, and 6). The conditioned medium produced by Donor 1 and 2 monocytes was tested with jejunal donor 1 cells, while the conditioned medium produced by Donor 5 and 6 monocytes was tested with jejunal donor 5 cells. The mean and standard deviation of three replicates are shown. Statistical significance was determined by one-way ANOVA and Tukey's multiple comparison test: ns = not significant; * = p < 0.05; ** = p < 0.01; *** = p < 0.001; **** = p < 0.0001. [Figure 24A]The results of the TEER assay are shown for epithelial cells treated with TREM1-conditioned medium generated by unstimulated monocytes (untreated monocytes), monocytes stimulated with bacterial peptidoglycan (PGN) and PGLYRP1 (TREM1-ligand), or monocytes stimulated with TREM1-ligand in the presence of an isotype control antibody, anti-TREM1 antibody clone A, or anti-TNFα antibody. Figure 24A shows the results from conditioned medium generated by donor monocytes that respond to anti-TREM1 antibody clone A but not to anti-TNFα antibody and exhibit low TNFα induction (approximately 400 pg / mL) upon stimulation with PGN and PGLYRP1. Figure 24B shows the results from conditioned medium generated by donor monocytes that respond to both anti-TREM1 antibody clone A and anti-TNFα antibody and exhibit high TNFα induction (approximately 1000 pg / mL) upon stimulation with PGN and PGLYRP1. [Figure 24B] The results of the TEER assay are shown for epithelial cells treated with TREM1-conditioned medium generated by unstimulated monocytes (untreated monocytes), monocytes stimulated with bacterial peptidoglycan (PGN) and PGLYRP1 (TREM1-ligand), or monocytes stimulated with TREM1-ligand in the presence of an isotype control antibody, anti-TREM1 antibody clone A, or anti-TNFα antibody. Figure 24A shows the results from conditioned medium generated by donor monocytes that respond to anti-TREM1 antibody clone A but not to anti-TNFα antibody and exhibit low TNFα induction (approximately 400 pg / mL) upon stimulation with PGN and PGLYRP1. Figure 24B shows the results from conditioned medium generated by donor monocytes that respond to both anti-TREM1 antibody clone A and anti-TNFα antibody and exhibit high TNFα induction (approximately 1000 pg / mL) upon stimulation with PGN and PGLYRP1. [Figure 25]Results from a biolayer interference assay used to evaluate the effect of anti-TREM1 antibody agents on blocking the interaction between TREM1 and its ligand, PGLYRP1, are presented. Recombinant hTREM1-chFc1 was immobilized on an Octet AHC biosensor, then incubated with an anti-TREM1 antibody agent clone A or isotype control, and subsequently incubated with PGLYRP1. Binding of PGLYRP1 to immobilized TREM1 correlates with the measured response. Data were fitted using a sigmoid (4-parameter) nonlinear regression equation. Fitting curves for isotype controls are not provided due to the absence of dose-dependent responses. Data are from a single experiment representative of three replicates. [Figure 26] This report presents results from a cell-based assay evaluating the effect of the anti-TREM1 antibody clone A on monocyte TREM1 cell surface levels. Human peripheral CD14+ monocytes isolated from healthy volunteers were treated with either the anti-TREM1 antibody clone A or an isotype control antibody. After 18 hours, cells were stained with different and non-competitive anti-TREM1 (clone TREM26) antibodies conjugated with a fluorescent dye, and total cell surface TREM1 levels (regardless of the anti-TREM1 antibody clone A binding status) were measured as fluorescence intensity using flow cytometry. Cell background staining is the background fluorescence intensity observed when cells are stained with an isotype control antibody conjugated with a fluorescent dye. The figure shows data from a single donor considered representative of data from seven different donors. [Figure 27]This report presents results from a cell-based assay evaluating the effect of the anti-TREM1 antibody clone A on neutrophil cell surface levels. Human peripheral neutrophils isolated from healthy volunteers were treated with either the anti-TREM1 antibody clone A or an isotype control antibody. After 19 hours, cells were stained with different and non-competitive anti-TREM1 (clone TREM26) antibodies conjugated with a fluorescent dye, and total cell surface TREM1 levels (regardless of the anti-TREM1 antibody clone A binding status) were measured as fluorescence intensity using flow cytometry. Cell background staining is the background fluorescence intensity observed when cells are stained with an isotype control antibody conjugated with a fluorescent dye. The figure shows data from a single donor considered representative of data from nine different donors. [Figure 28A]This report presents flow cytometry results from assays evaluating the effects of anti-TREM1 antibody activation and inhibition on the differentiation of inflammatory monocytes into macrophages. Isolated human peripheral monocytes were cultured for 6 days in the presence of GM-CSF (2.5 ng / mL), IL-23 (10 ng / mL), and IFN-γ (50 ng / mL) to generate inflammatory monocytes. The inflammatory monocytes were then cultured in differentiation medium containing TGF-β (1 ng / mL) and IL-10 (10 ng / mL) to induce differentiation into macrophages. In parallel, the inflammatory monocytes were cultured in differentiation medium containing TGF-β (1 ng / mL) and IL-10 (10 ng / mL) in the presence of PGN (1 μg / mL) and PGLYRP1 (250 nM) to activate TREM1. To investigate the effect of TREM1 inhibition on the differentiation of inflammatory monocytes into macrophages, anti-TREM1 antibody clone A (10 nM) or isotype control (10 nM) was further added. After 6 days in differentiation medium, the differentiation state was evaluated by staining for cell surface markers CD64 and MERTK and determining the percentage of cells in each condition that were inflammatory monocytes (CD64+MERTK-) or macrophages (CD64+MERTK+). Figures 28B-28E show results from cell-based assays to characterize the effect of anti-TREM1 antibody clone A on TREM-1 pathway-stimulated inflammatory cytokine release from cells derived from inflammatory monocytes. Figures 28B-28E show the production of TNFα (Figure 28B), IL-1β (Figure 28C), IL-6 (Figure 28D), and MDC (CCL22; Figure 28E) from inflammatory monocytes treated with TGFβ and IL-10 for 6 days in the presence of medium alone; peptidoglycan and PGLYRP1 (PGN+PGLYRP1); peptidoglycan, PGLYRP1, and anti-TREM1 antibody clone A (PGN+PGLYRP1+anti-TREM1 clone A); or peptidoglycan, PLYRP1, and isotype antibody control (PGN+PGLYRP1+isotype). [Figures 28B-28E]This report presents flow cytometry results from assays evaluating the effects of anti-TREM1 antibody activation and inhibition on the differentiation of inflammatory monocytes into macrophages. Isolated human peripheral monocytes were cultured for 6 days in the presence of GM-CSF (2.5 ng / mL), IL-23 (10 ng / mL), and IFN-γ (50 ng / mL) to generate inflammatory monocytes. The inflammatory monocytes were then cultured in differentiation medium containing TGF-β (1 ng / mL) and IL-10 (10 ng / mL) to induce differentiation into macrophages. In parallel, the inflammatory monocytes were cultured in differentiation medium containing TGF-β (1 ng / mL) and IL-10 (10 ng / mL) in the presence of PGN (1 μg / mL) and PGLYRP1 (250 nM) to activate TREM1. To investigate the effect of TREM1 inhibition on the differentiation of inflammatory monocytes into macrophages, anti-TREM1 antibody clone A (10 nM) or isotype control (10 nM) was further added. After 6 days in differentiation medium, the differentiation state was evaluated by staining for cell surface markers CD64 and MERTK and determining the percentage of cells in each condition that were inflammatory monocytes (CD64+MERTK-) or macrophages (CD64+MERTK+). Figures 28B-28E show results from cell-based assays to characterize the effect of anti-TREM1 antibody clone A on TREM-1 pathway-stimulated inflammatory cytokine release from cells derived from inflammatory monocytes. Figures 28B-28E show the production of TNFα (Figure 28B), IL-1β (Figure 28C), IL-6 (Figure 28D), and MDC (CCL22; Figure 28E) from inflammatory monocytes treated with TGFβ and IL-10 for 6 days in the presence of medium alone; peptidoglycan and PGLYRP1 (PGN+PGLYRP1); peptidoglycan, PGLYRP1, and anti-TREM1 antibody clone A (PGN+PGLYRP1+anti-TREM1 clone A); or peptidoglycan, PLYRP1, and isotype antibody control (PGN+PGLYRP1+isotype). [Figure 29A]Flow cytometry data from cell-based assays characterizing the potential for membrane TREM1 internalization by anti-TREM1 antibody clone A in monocytes are shown. Human monocytes isolated from healthy volunteers were treated with medium alone (Figure 29A) or stimulated with peptidoglycan (PGN; 1 μg / ml; Figure 29B). Cells were incubated with anti-TREM1 antibody clone A or isotype control and stained with Fab-labeled anti-hIgG1 using pH-sensitive dyes. [Figure 29B] Flow cytometry data from cell-based assays characterizing the potential for membrane TREM1 internalization by anti-TREM1 antibody clone A in monocytes are shown. Human monocytes isolated from healthy volunteers were treated with medium alone (Figure 29A) or stimulated with peptidoglycan (PGN; 1 μg / ml; Figure 29B). Cells were incubated with anti-TREM1 antibody clone A or isotype control and stained with Fab-labeled anti-hIgG1 using pH-sensitive dyes. [Figure 30] The results from a cell-based assay characterizing the effect of anti-TREM1 antibody clone A on soluble TREM1 (sTREM1) production levels from primary monocytes are shown. [Figure 31] We present results from a cell-based assay to characterize the effect of the anti-TREM1 antibody clone A on TREM1-stimulated TL1a production in primary monocytes. [Figures 32A-32C] The results from cell-based assays characterizing the effect of anti-TREM1 antibody clone A on TREM-1 pathway-stimulated inflammatory cytokine release from cells derived from ulcerative colitis (UC) patient samples are shown. Figures 32A–32C show TNFα (Figure 32A), IL-1β (Figure 32B), and IL-23 (Figure 32C) production from cells derived from UC patients treated with medium alone; peptidoglycan and PGLYRP1 (PGN+PGLYRP1); peptidoglycan, PGLYRP1, and anti-TREM1 antibody clone A (PGN+PGLYRP1+anti-TREM1 clone A); or peptidoglycan, PGLYRP1, and isotype antibody control (PGN+PGLYRP1+isotype). [Figure 33A] Results from cell-based assays to characterize the effect of anti-TREM1 antibody clone A on epithelial barrier permeability are shown. Donor-derived epithelial cells seeded in Transwell plate inserts were cultured until a corrected transepithelial electrical resistance (TEER) measurement of approximately 200 ohms·cm² was achieved, and then treated with medium alone; TREM1-conditioned medium + isotype control antibody; TREM1-conditioned medium + anti-TREM1 antibody clone A; or TREM1-conditioned medium + infliximab (Figure 33A). Figures 33B and 33C are bar graphs showing the relative permeability of jejunal epithelial cell monolayers from two representative donors classified as having high TNFα induction (Figure 33B) or low TNFα induction (Figure 33C) in the presence of medium alone, anti-TREM1 antibody clone A, infliximab, or isotype control antibody. [Figure 33B] Results from cell-based assays to characterize the effect of anti-TREM1 antibody clone A on epithelial barrier permeability are shown. Donor-derived epithelial cells seeded in Transwell plate inserts were cultured until a corrected transepithelial electrical resistance (TEER) measurement of approximately 200 ohms·cm² was achieved, and then treated with medium alone; TREM1-conditioned medium + isotype control antibody; TREM1-conditioned medium + anti-TREM1 antibody clone A; or TREM1-conditioned medium + infliximab (Figure 33A). Figures 33B and 33C are bar graphs showing the relative permeability of jejunal epithelial cell monolayers from two representative donors classified as having high TNFα induction (Figure 33B) or low TNFα induction (Figure 33C) in the presence of medium alone, anti-TREM1 antibody clone A, infliximab, or isotype control antibody. [Figure 33C]Results from cell-based assays to characterize the effect of anti-TREM1 antibody clone A on epithelial barrier permeability are shown. Donor-derived epithelial cells seeded in Transwell plate inserts were cultured until a corrected transepithelial electrical resistance (TEER) measurement of approximately 200 ohms·cm² was achieved, and then treated with medium alone; TREM1-conditioned medium + isotype control antibody; TREM1-conditioned medium + anti-TREM1 antibody clone A; or TREM1-conditioned medium + infliximab (Figure 33A). Figures 33B and 33C are bar graphs showing the relative permeability of jejunal epithelial cell monolayers from two representative donors classified as having high TNFα induction (Figure 33B) or low TNFα induction (Figure 33C) in the presence of medium alone, anti-TREM1 antibody clone A, infliximab, or isotype control antibody. [Figure 34] We present results from cell-based assays to characterize the effect of anti-TREM1 antibody clone A on TREM-1 pathway-stimulated IL-8 release from primary neutrophils derived from two donors, compared to the binding domain of anti-TREM1 antibody (mAb 0318 (described in WO2019195126A1 incorporated herein by reference)) and an antibody having the same Fc domain as anti-TREM1 antibody clone A. [Figure 35] The deuterium exchange heatmaps of TREM1 protein mixed with anti-TREM1 antibody clone A are shown after incubation times of 15 seconds, 60 seconds, 180 seconds, 600 seconds, 1800 seconds, and 7200 seconds. [Figures 36A-36C] Bar graphs show inflammatory cytokine / chemokine production in enriched neutrophils from healthy volunteer donors, cultured in medium alone, with 2 mM anti-TREM1 antibody clone A, 2 mM isotype control, 50 nM PGLRYP1, or peptidoglycan (PGN; 300 ng / mL). After 24 hours, tissue culture supernatant was collected and analyzed for quantification of CCL3 (Figure 36A), CCL4 (Figure 36B), and IL-8 (Figure 36C) proteins. Error bars represent the mean ± SD from 8 technical replicates. Significance was determined by one-way ANOVA, Tukey's multiple comparison test; ns = not significant, **** = p < 0.0001. [Figures 37A-37D] Bar graphs show inflammatory cytokine / chemokine production in enriched primary monocytes from healthy volunteer donors, cultured in medium alone, with 1.25 mM anti-TREM1 antibody clone A, 1.25 mM isotype control, 500 nM PGLRYP1, or peptidoglycan (PGN; 100 ng / mL). After 18–24 hours, tissue culture supernatant was collected and analyzed for quantification of CCL3 (Figure 37A), CCL4 (Figure 37B), IL-6 (Figure 37C), and TNFα (Figure 37D) proteins. Error bars represent the mean ± SD from four technical replicates. Significance was determined by one-way ANOVA, Tukey's multiple comparison test; ns = not significant, ** = p < 0.01, *** = p < 0.001, **** = p < 0.0001. [Figure 38A] Flow cytometry data of TREM1 receptor occupancy percentage using the saturated concentration of anti-TREM1 antibody clone A are shown. Enriched monocytes (2 × 10⁵ cells / well) isolated from healthy volunteer donors were activated with peptidoglycan (100 ng / mL) and PGLYRP1 (500 nM) in the presence of serial dilutions of anti-TREM1 antibody clone A or isotype control. After 24 hours, TREM1 levels on the surface of the monocytes were determined by flow cytometry. [Figure 38B] This shows the TREM1 receptor occupancy in primary monocytes plotted against normalized TNFα levels. TNFα levels were normalized against the maximum cytokine released within each donor. [Figures 39A-39D]The bar graphs show the production of inflammatory cytokines / chemokines in whole blood from healthy volunteer donors cultured with 1 μM anti-TREM1 antibody clone A, 1 μM isotype control, or 1 μg / ml LPS. After 18–24 hours, tissue culture supernatants were collected and analyzed for the quantification of IL-1β (Figure 39A), IL-2 (Figure 39B), IL-4 (Figure 39C), IL-6 (Figure 39D), IL-8 (Figure 39E), IL-10 (Figure 39F), IL-17A (Figure 39G), IFNγ (Figure 39H), GM-CSF (Figure 39I), TNFα (Figure 39J), CCL2 (Figure 39K), CCL3 (Figure 39L), and CCL4 (Figure 39M) proteins. Error bars represent the mean ± SD from three technical replicates. Significance was determined by one-way ANOVA and Tukey's multiple comparison test; ns = not significant, *** = p < 0.001, **** = p < 0.0001. [Figure 39E-39H] The bar graphs show the production of inflammatory cytokines / chemokines in whole blood from healthy volunteer donors cultured with 1 μM anti-TREM1 antibody clone A, 1 μM isotype control, or 1 μg / ml LPS. After 18–24 hours, tissue culture supernatants were collected and analyzed for the quantification of IL-1β (Figure 39A), IL-2 (Figure 39B), IL-4 (Figure 39C), IL-6 (Figure 39D), IL-8 (Figure 39E), IL-10 (Figure 39F), IL-17A (Figure 39G), IFNγ (Figure 39H), GM-CSF (Figure 39I), TNFα (Figure 39J), CCL2 (Figure 39K), CCL3 (Figure 39L), and CCL4 (Figure 39M) proteins. Error bars represent the mean ± SD from three technical replicates. Significance was determined by one-way ANOVA and Tukey's multiple comparison test; ns = not significant, *** = p < 0.001, **** = p < 0.0001. [Figures 39I-39L]The bar graphs show the production of inflammatory cytokines / chemokines in whole blood from healthy volunteer donors cultured with 1 μM anti-TREM1 antibody clone A, 1 μM isotype control, or 1 μg / ml LPS. After 18–24 hours, tissue culture supernatants were collected and analyzed for the quantification of IL-1β (Figure 39A), IL-2 (Figure 39B), IL-4 (Figure 39C), IL-6 (Figure 39D), IL-8 (Figure 39E), IL-10 (Figure 39F), IL-17A (Figure 39G), IFNγ (Figure 39H), GM-CSF (Figure 39I), TNFα (Figure 39J), CCL2 (Figure 39K), CCL3 (Figure 39L), and CCL4 (Figure 39M) proteins. Error bars represent the mean ± SD from three technical replicates. Significance was determined by one-way ANOVA and Tukey's multiple comparison test; ns = not significant, *** = p < 0.001, **** = p < 0.0001. [Figure 39M] The bar graphs show the production of inflammatory cytokines / chemokines in whole blood from healthy volunteer donors cultured with 1 μM anti-TREM1 antibody clone A, 1 μM isotype control, or 1 μg / ml LPS. After 18–24 hours, tissue culture supernatants were collected and analyzed for the quantification of IL-1β (Figure 39A), IL-2 (Figure 39B), IL-4 (Figure 39C), IL-6 (Figure 39D), IL-8 (Figure 39E), IL-10 (Figure 39F), IL-17A (Figure 39G), IFNγ (Figure 39H), GM-CSF (Figure 39I), TNFα (Figure 39J), CCL2 (Figure 39K), CCL3 (Figure 39L), and CCL4 (Figure 39M) proteins. Error bars represent the mean ± SD from three technical replicates. Significance was determined by one-way ANOVA and Tukey's multiple comparison test; ns = not significant, *** = p < 0.001, **** = p < 0.0001. [Figure 40A] The results of baseline percentage flow cytometry analysis of free TREM1 (Figure 40A) and total TREM1 (Figure 40B) in neutrophils, after subtracting isotype controls following weekly IV administration of the anti-TREM1 antibody clone A for 14 weeks in cynomolgus monkeys, are shown. [Figure 40B]The results of baseline percentage flow cytometry analysis of free TREM1 (Figure 40A) and total TREM1 (Figure 40B) in neutrophils, after subtracting isotype controls following weekly IV administration of the anti-TREM1 antibody clone A for 14 weeks in cynomolgus monkeys, are shown. [Figure 41] This graph shows the percentage (arithmetic mean (±SD)) of baseline free TREM1 receptor levels in neutrophils compared to time after a single 1-hour IV infusion of various concentrations of anti-TREM1 antibody clone A in human subjects. Day 0 = Start of infusion. [Figure 42] This graph shows the percentage (arithmetic mean (±SD)) of baseline free TREM1 receptor levels in monocytes compared to time after a single 1-hour IV infusion of various concentrations of anti-TREM1 antibody clone A in human subjects. Day 0 = Start of infusion. [Figure 43] This graph shows the percentage (arithmetic mean (±SD)) of baseline total TREM1 receptor levels in neutrophils compared to time after a single 1-hour IV infusion of various concentrations of anti-TREM1 antibody clone A in human subjects. Day 0 = Start of infusion. [Figure 44] This graph shows the individual arithmetic mean (±SD) of the percentage of TREM1 receptor occupancy in neutrophils, compared to time after a single 1-hour IV infusion of various concentrations of anti-TREM1 antibody clone A in human subjects. Day 0 = Start of infusion. [Figure 45] This graph shows the percentage (arithmetic mean (±SD)) of total TREM1 receptor levels in monocytes from baseline, compared to time after a single 1-hour IV infusion of various concentrations of anti-TREM1 antibody clone A in human subjects. Day 0 = Start of infusion. [Figure 46] This graph shows the individual arithmetic mean (±SD) of TREM1 receptor occupancy percentage in monocytes, compared to time after a single 1-hour IV infusion of various concentrations of anti-TREM1 antibody clone A in human subjects. Day 0 = Start of infusion. [Figure 47]Line graphs show the individual arithmetic mean (±SD) changes in total soluble TREM1 (sTREM1) from baseline, compared to time after a single 1-hour IV infusion of various concentrations of anti-TREM1 antibody clone A in human subjects. Day 0 = Start of infusion. [Figure 48A] This shows the stability of anti-TREM1 antibody clone A in human (Figure 48A) and cynomolgus monkey (Figure 48B) serum as determined by ELISA binding assay. [Figure 48B] This shows the stability of anti-TREM1 antibody clone A in human (Figure 48A) and cynomolgus monkey (Figure 48B) serum as determined by ELISA binding assay. [Modes for carrying out the invention]

[0040] definition In this application, unless otherwise clearly indicated in the context, (i) the term “a” is understood to mean “at least one”; (ii) the term “or” is understood to mean “and / or”; (iii) the terms “comprising” and “including” are understood to encompass an enumeration of components or steps presented by themselves or together with one or more additional components or steps; (iv) the terms “about” and “approximately” are understood to allow for standard variations that would be understood by those skilled in the art; and (v) the endpoints are included where a range is provided.

[0041] When the term “about” is used herein in reference to a value, it refers to a value that is similar to the reference value. Generally, a person skilled in the art familiar with the context will understand the relative degree of variation encompassed by “about” in this context. For example, in some embodiments, the term “about” may encompass a range of values ​​within or less of 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, and 1% of the reference value.

[0042] Administration: As used herein, the term “administration” typically refers to the administration of a composition to a subject or system to achieve the delivery of a drug that is, or is contained in, or otherwise delivered by the composition.

[0043] Adult: As used herein, the term “adult” refers to a person who is 18 years of age or older. In some embodiments, an adult person has a weight in the range of about 90 pounds to about 250 pounds.

[0044] Affinity: As is known in the art, "affinity" is a measure of the robustness with which two or more binding partners relate to each other. Those skilled in the art are aware of the various assays that can be used to assess affinity and, further, of appropriate controls for such assays. In some embodiments, affinity is assessed by quantitative assays. In some embodiments, affinity is assessed over multiple concentrations (e.g., one binding partner at a time). In some embodiments, affinity is assessed in the presence of one or more potential competing entities (e.g., relevant, which may be present in a physiological setting). In some embodiments, affinity is assessed against a reference (e.g., a known affinity above a certain threshold [see “positive control”] or a known affinity below a certain threshold [see “negative control”]). In some embodiments, affinity may be assessed against a contemporary reference, and in some embodiments, affinity may be assessed against a historical reference. Typically, when affinity is assessed against a reference, it is assessed under equivalent conditions.

[0045] Drug: As used herein, the term "drug" refers to an entity (e.g., lipids, metals, nucleic acids, polypeptides, polysaccharides, small molecules, etc., or complexes, combinations, mixtures, or systems thereof [e.g., cells, tissues, organisms]) or a phenomenon (e.g., heat, electric current or electric field, magnetic force or magnetic field, etc.).

[0046] Agonist: Those skilled in the art will understand that the term “agonist” may be used to refer to a drug, state, or event whose presence, level, degree, type, or form correlates with an increase in the level or activity of another drug (i.e., an agonist or target agent). Generally, an agonist may be or may include any chemical class of drugs, including, for example, small molecules, polypeptides, nucleic acids, carbohydrates, lipids, metals, and / or any other entities exhibiting related activation activity. In some embodiments, the agonist may be direct (in which case it directly affects its target), and in some embodiments, the agonist may be indirect (in which case it affects a change in the level or activity of its target, for example, by interacting with a regulator of the target, rather than by binding to the target).

[0047] Amino Acids: As used herein, the term “amino acid” refers to any compound and / or substance that can be incorporated into a polypeptide chain, for example, through the formation of one or more peptide bonds. In some embodiments, an amino acid has the general structure H2N-C(H)(R)-COOH. In some embodiments, an amino acid is a naturally occurring amino acid. In some embodiments, an amino acid is a non-natural amino acid, in some embodiments, an amino acid is a D amino acid, and in some embodiments, an amino acid is an L amino acid. As used herein, the term “standard amino acid” refers to any of the 20 L amino acids commonly found in naturally occurring peptides. “Non-standard amino acid” refers to any amino acid other than a standard amino acid, whether found in or potentially found in natural sources. In some embodiments, amino acids in a polypeptide, including carboxy-terminal and / or amino-terminal amino acids, may contain structural modifications compared to the general structure described above. For example, in some embodiments, an amino acid may be modified compared to its general structure by methylation, amidation, acetylation, pegylation, glycosylation, phosphorylation, and / or substitution (e.g., of an amino acid group, a carboxylic acid group, one or more protons, and / or hydroxyl groups). In some embodiments, such modifications may alter the stability or cyclic half-life of the modified amino acid-containing polypeptide compared to, for example, a polypeptide containing an otherwise identical unmodified amino acid. In some embodiments, such modifications do not significantly alter the relevant activity of the modified amino acid-containing polypeptide compared to a polypeptide containing an otherwise identical unmodified amino acid. As is evident from the context, in some embodiments, the term “amino acid” may be used to refer to a free amino acid, and in some embodiments, it may be used to refer to an amino acid residue of a polypeptide, for example, an amino acid residue within a polypeptide.

[0048] Antibody: As used herein, the term “antibody” refers to a polypeptide containing sufficient canonical immunoglobulin sequence elements to confer specific binding to a particular target antigen. As is known in the art, naturally produced intact antibodies are approximately 150 kD tetramers composed of two identical heavy-chain polypeptides (each about 50 kD) and two identical light-chain polypeptides (each about 25 kD), which relate to each other in what is commonly referred to as a “Y-shaped” structure. Each heavy chain consists of at least four domains (each about 110 amino acids long), with an amino acid-terminal variable (VH) domain (located at the tip of the Y structure) followed by three constant domains: CH1, CH2, and carboxy-terminal CH3 (located at the bottom of the Y base). A short region known as the “switch” connects the heavy-chain variable region to the constant domain. The “hinge” connects the CH2 and CH3 domains to the rest of the antibody. Two disulfide bonds in this hinge region connect the two heavy-chain polypeptides to each other in the intact antibody. Each light chain consists of two domains: an amino-terminal variable (VL) domain followed by a carboxy-terminal constant (CL) domain, separated from each other by another "switch." An intact antibody tetramer is composed of two heavy-chain-light-chain dimers, where the heavy and light chains are linked by a single disulfide bond, and two other disulfide bonds connect the heavy-chain hinge regions, thereby linking the dimers together to form a tetramer. Naturally produced antibodies are also typically glycosylated at the CH2 domain. Each domain in a natural antibody has a structure characterized by an "immunoglobulin fold," formed from two beta sheets (e.g., 3, 4, or 5-strand sheets) packed together in a compressed antiparallel beta barrel. Each variable domain contains three hypervariable loops known as "complement determining regions" (CDR1, CDR2, and CDR3), as well as four somewhat invariant "framework" regions (FR1, FR2, FR3, and FR4).When a natural antibody folds, the FR region forms a beta sheet that provides the structural framework of the domain, and the CDR loop regions from both the heavy and light chains are brought together in three-dimensional space to create a single hypervariable antigen-binding site located at the tip of the Y structure.

[0049] The CDR of the antigen-binding site of an antibody can be determined by the methods described in Lefranc et al., Dev. Comp. Immunol. Vol. 27 (No. 1): pp. 55-77 (2003), Kabat et al., J. Biol. Chem. Vol. 252, pp. 6609-6616 (1977), Kabat et al., Sequences of protein of immunological interest. (1991), Chothia et al., J. Mol. Biol. Vol. 196: pp. 901-917 (1987), and MacCallum et al., J. Mol. Biol. Vol. 262: pp. 732-745 (1996). CDRs determined by these definitions typically contain duplicate or subset amino acid residues when compared to one another. In certain embodiments, the term "CDR" refers to the CDR as defined by MacCallum et al., J.Mol.Biol. 262:732-745 (1996) and Martin A., Protein Sequence and Structure Analysis of Antibody Variable Domains, in Antibody Engineering, Kontermann and Dubel eds., Chapter 31, pp. 422-439, Springer-Verlag, Berlin (2001). In certain embodiments, the term "CDR" refers to the CDR as defined by Kabat et al., J.Biol.Chem. 252:6609-6616 (1977) and Kabat et al., Sequences of protein of immunological interest. (1991). In certain embodiments, the term "CDR" refers to the CDR as defined by Lefranc et al., Dev.Comp.Immunol. 27(1):55-77 (2003). In certain embodiments, the heavy chain CDR and light chain CDR of an antibody are defined using different conventions. For example, in some embodiments, the heavy chain CDR is defined according to MacCallum (above), and the light chain CDR is defined according to Kabat (above).

[0050] The Fc region of naturally occurring antibodies binds to elements of the complement system, including, for example, receptors on effector cells, such as effector cells that mediate cytotoxicity. As is known in the art, the affinity and / or other binding properties of the Fc region to Fc receptors can be modulated via glycosylation or other modifications. In some embodiments, antibodies produced and / or utilized according to the present invention include a glycosylated Fc domain, and include an Fc domain having modified or altered glycosylation. For the purposes of the present invention, in certain embodiments, any polypeptide or polypeptide complex containing sufficient immunoglobulin domain sequences as found in naturally occurring antibodies may be referred to and / or used as an “antibody,” whether such polypeptides are produced naturally (e.g., by organisms reacting to an antigen) or by recombinant operations, chemical synthesis, or other artificial systems or methods. In some embodiments, the antibody is polyclonal, and in some embodiments, the antibody is monoclonal. In some embodiments, the antibody has a constant region sequence characteristic of mouse, rabbit, primate, or human antibodies. In some embodiments, antibody sequence elements are humanized, primatized, chimeric, etc., as is known in the art. Furthermore, as used herein, the term “antibody” may refer to any construct or format known or developed in the art that utilizes the structural and functional features of an antibody in an alternative presentation, in appropriate embodiments (unless otherwise specifically described or evident from the context).For example, in the embodiments, the antibodies used according to the present invention include intact IgA, IgG, IgE, or IgM antibodies; bipolar or polyspecific antibodies (e.g., Zybodies®); antibody fragments, e.g., Fab fragments, Fab' fragments, F(ab')2 fragments, Fd' fragments, Fd fragments, and isolated CDRs or sets thereof; single-chain Fv; polypeptide Fc fusions; single-domain antibodies (e.g., shark single-domain antibodies such as IgNAR or fragments thereof); camelid antibodies; masked antibodies (e.g., Probodies®); and small modular antibodies. The format is selected from, but is not limited to, ImmunoPharmaceuticals ("SMIPs"); single-chain or Tandem diabodies (TandAb)); VHH; Anticalins (registered trademark); Nanobodies (registered trademark) minibodies (minibody); BiTE (registered trademark); Ankyrin repeat proteins or DARPINs (registered trademark); Avimers (registered trademark); DART; TCR-like antibodies; Adnectins (registered trademark); Affilins (registered trademark); Trans-bodies (registered trademark); Affibodies (registered trademark); TrimerX (registered trademark); MicroProteins; Fynomers (registered trademark), Centyrins (registered trademark); and KALBITOR (registered trademark). In some embodiments, the antibody may lack covalent modifications (e.g., binding to glycans) that it would have if naturally produced. In some embodiments, the antibody may include covalent modifications (e.g., binding to glycans, payloads [e.g., detectable portion, therapeutic portion, catalytic portion, etc.] or other pendant groups [e.g., polyethylene glycol, etc.]).

[0051] Antibody Agent: As used herein, the term “antibody agent” refers to a drug that specifically binds to a particular antigen. In some embodiments, the term encompasses any polypeptide or polypeptide complex containing sufficient immunoglobulin structural elements to confer specific binding. Exemplary antibody agents include, but are not limited to, monoclonal or polyclonal antibodies. In some embodiments, an antibody agent may include one or more constant region sequences characteristic of canine, cat, mouse, rabbit, primate, or human antibodies. In some embodiments, an antibody agent may include one or more sequence elements that are human, humanized, primated, chimeric, etc., as known in the art. In some embodiments, an antibody agent may include one or more complementarity-determining regions that are human, and / or one or more constant region sequences that are characteristic of human antibodies. In many embodiments, the term “antibody agent” is used to refer to one or more constructs or formats known or developed in the art that utilize the structural and functional features of an antibody in an alternative presentation.For example, in some embodiments, the antibody agents used in accordance with this disclosure include: intact IgA, IgG, IgE, or IgM antibodies; bi- or polyspecific antibodies (e.g., Zybodies®); antibody fragments (e.g., Fab fragment, Fab' fragment, F(ab')2 fragment, Fd' fragment, Fd fragment and isolated CDRs or sets thereof); single-chain Fv; polypeptides containing antigen-binding specificity fused to Fc; single-domain antibodies (e.g., shark single-domain antibodies such as IgNAR or fragments thereof); camelid antibodies; masked antibodies (e.g., Probodies®); small modular The format may be selected from, but is not limited to, ImmunoPharmaceuticals ("SMIPs"); single-chain or Tandem diabodies (TandAb)); VHH; Anticalins; Nanobodies (minibodies); BiTE; Ankyrin repeat proteins or DARPINs; Avimers; DART; TCR-like antibodies; Adnectins; Affilins; Trans-bodies; Affibodies; TrimerX; MicroProteins; Fynomers; Centyrins; and KALBITOR (registered trademark). In some embodiments, the format may be selected from, but is not limited to, these. Antibodies may lack covalent modifications (e.g., binding to glycans) that they would have if naturally produced. In some embodiments, antibodies may include covalent modifications (e.g., binding to glycans, payloads [e.g., detectable portion, therapeutic portion, catalytic portion, etc.] or other pendant groups [e.g., polyethylene glycol, etc.]). In many embodiments, the antibody preparation is a polypeptide or includes such polypeptide, the amino acid sequence of which is recognized by those skilled in the art as a complementarity-determining region (CDR), and in some embodiments, the antibody preparation is a polypeptide or includes such polypeptide, the amino acid sequence of which is substantially identical to that found in a reference antibody, and includes at least one CDR (e.g., at least one heavy-chain CDR and / or at least one light-chain CDR).In some embodiments, the included CDR is substantially identical to the reference CDR in that its sequence is identical to that of the reference CDR or it contains 1 to 5 amino acid substitutions. In some embodiments, the included CDR is substantially identical to the reference CDR in that it exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the reference CDR. In some embodiments, the included CDR is substantially identical to the reference CDR in that it exhibits at least 96%, 97%, 98%, 99%, or 100% sequence identity with the reference CDR. In some embodiments, the included CDR has an amino acid sequence in which at least one amino acid in the included CDR is deleted, added, or substituted compared to the reference CDR, but the included CDR is otherwise identical to the reference CDR. In some embodiments, the included CDR is substantially identical to the reference CDR in that it has an amino acid sequence that is otherwise identical to the reference CDR, although 1 to 5 amino acids in the included CDR are deleted, added, or substituted compared to the reference CDR. In some embodiments, the included CDR is substantially identical to the reference CDR in that it has an amino acid sequence that is otherwise identical to the reference CDR, although at least 1 amino acid in the included CDR is substituted compared to the reference CDR. In some embodiments, the included CDR is substantially identical to the reference CDR in that it has an amino acid sequence that is otherwise identical to the reference CDR, although 1 to 5 amino acids in the included CDR are deleted, added, or substituted compared to the reference CDR. In some embodiments, the antibody agent is a polypeptide comprising or containing a structural element whose amino acid sequence is recognized as an immunoglobulin variable domain by those skilled in the art. In some embodiments, the antibody agent is a polypeptide protein having a binding domain that is homologous or substantially homologous to an immunoglobulin binding domain.

[0052] Antibody-dependent cell-mediated cytotoxicity: As used herein, the term “antibody-dependent cell-mediated cytotoxicity” or “ADCC” refers to the phenomenon in which antibody-bound target cells are killed by immune effector cells. While we do not wish to be bound to any particular theory, the inventors acknowledge that ADCC is typically understood to involve Fc receptor (FcR)-carrying effector cells that can recognize and subsequently kill antibody-coated target cells (e.g., cells expressing surface-specific antigens to which antibodies bind). Effector cells mediating ADCC may include, but are not limited to, one or more immune cells such as natural killer (NK) cells, macrophages, neutrophils, and eosinophils.

[0053] Antibody fragment: As used herein, “antibody fragment” refers to a portion of an antibody or antibody preparation described herein, typically a portion containing an antigen-binding moiety or its variable region. Antibody fragments can be produced by any means. For example, in some embodiments, antibody fragments can be produced enzymatically or chemically by fragmentation of an intact antibody or antibody preparation. Alternatively, in some embodiments, antibody fragments can be produced recombinantly (e.g., by the expression of a modified nucleic acid). In some embodiments, antibody fragments can be produced synthetically, in whole or in part. In some embodiments, antibody fragments (in particular antigen-binding antibody fragments) may have a length of at least about 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 amino acids or more, and in some embodiments, at least about 200 amino acids.

[0054] Antibody polypeptide: As used herein, the term “antibody polypeptide” means a polypeptide comprising characteristic sequence elements of an antibody (e.g., one or more CDRs or sets of CDRs, e.g., CDR1, 2, and 3, each found in a reference antibody chain, and / or one or more FR regions and / or sets of FR regions, e.g., the fully variable region of the heavy or light chain of a reference antibody), and in many embodiments, the antibody polypeptide contains sufficiently many sequence elements that bind to an epitope (e.g., an epitope bound to a reference antibody containing the characteristic sequence elements). In some embodiments, the antibody polypeptide is a full-length antibody or its heavy or light chain. In some embodiments, the antibody polypeptide is or comprises the fully variable region of the heavy and / or light chain of a reference antibody, and in some such embodiments, the antibody polypeptide contains sufficient characteristic antibody sequence elements to confer specific binding to the relevant epitope, i.e., the antibody polypeptide contains at least one binding site. In some embodiments, the "antibody polypeptide" may include a binding domain that is homologous or substantially homologous to the immunoglobulin-binding domain (e.g., exhibiting significant sequence homology and / or significant sequence identity in some embodiments). In some embodiments, the antibody polypeptide exhibits at least 99% identity to the immunoglobulin-binding domain. In some embodiments, the "antibody polypeptide" has a binding domain that exhibits at least 70%, 80%, 85%, 90%, or 95% identity to the immunoglobulin-binding domain, for example, to a reference immunoglobulin-binding domain. In some embodiments, the "antibody polypeptide" may have amino acid sequence identity to an antibody, chain, or variable regions (or combinations thereof) found in a natural source. In some embodiments, the antibody polypeptide may be prepared, for example, by isolation from a natural source or antibody library, recombinant production in or using a host system, chemical synthesis, or a combination thereof. In some embodiments, the antibody polypeptide is the antibody agent described herein.

[0055] Antigen: As used herein, the term “antigen” refers to an agent that induces an immune response and / or (ii) an agent that binds to a T cell receptor (e.g., when presented by an MHC molecule) or an antibody. In some embodiments, the antigen induces a humoral immune response (e.g., including the production of antigen-specific antibodies), and in some embodiments, the antigen induces a cellular response (e.g., involving T cells whose receptors specifically interact with the antigen). In some embodiments, the antigen may or may not bind to an antibody and induce a specific physiological response in an organism. Generally, the antigen may be or include any chemical entity, e.g., small molecules, nucleic acids, polypeptides, carbohydrates, lipids, polymers (except in some embodiments, biopolymers [e.g., except nucleic acid or amino acid polymers]), etc. In some embodiments, the antigen is or includes a polypeptide. In some embodiments, the antigen is or includes a glycan. Those skilled in the art will generally recognize that antigens may be provided in isolated or pure form, or alternatively, in crude form (for example, together with other materials, for example, in an extract such as a cell extract of an antigen-containing source or other relatively crude preparation). In some embodiments, the antigens used according to the present invention are provided in crude form. In some embodiments, the antigen is a recombinant antigen.

[0056] Approximately: As used herein, the terms “approximately” or “about” refer to a value that is similar to the stated reference value when applied to one or more values ​​of interest. In certain embodiments, unless otherwise specified or evident from the context, the terms “approximately” or “about” refer to a range of values ​​that fall within the range of 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) the stated reference value (except where such a number is greater than 100% of the possible value).

[0057] Related: Two events or entities are “related” to each other if, as the term is used herein, the presence, level, degree, type, and / or form of one correlates with the other. For example, a particular entity (e.g., polypeptide, gene signature, metabolite, microorganism, etc.) is considered related to a particular disease, disorder, or condition if its presence, level, and / or form correlates with the incidence and / or prevalence of a disease, disorder, or condition (e.g., in a relevant population). In some embodiments, two or more entities are physically “related” to each other if they interact directly or indirectly and are thereby physically close to and / or remain close to each other. In some embodiments, two or more entities that are physically related to each other are covalently linked, and in some embodiments, two or more entities that are physically related to each other are not covalently linked but are non-covalently related, for example, by hydrogen bonds, van der Waals interactions, hydrophobic interactions, magnetism, and combinations thereof.

[0058] Bonding: Those skilled in the art will understand that, as used herein, the term “bonding” typically refers to a non-covalent relationship between or in two entities. A “direct” bond involves physical contact between entities or parts, while an indirect bond involves physical interaction via physical contact with one or more intermediate entities. Bonding between two or more entities can be assessed in any of a variety of contexts, typically including when the interacting entities or parts are studied in isolation or in the context of a more complex system (e.g., covalently or otherwise related to a carrier entity and / or a biological system or cell).

[0059] Biological Sample: As used herein, the term “biological sample” typically refers to a sample obtained from or derived from the biological source of interest described herein (e.g., tissue, organism, or cell culture). In some embodiments, the source of interest includes an organism, such as an animal or a human. In some embodiments, the biological sample is or includes biological tissue or biological fluid. In some embodiments, the biological sample may be or include bone marrow; blood; blood cells; ascites; tissue or fine-needle biopsy specimens; cell-containing fluids; suspended nucleic acids; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph; gynecological fluid; skin swabs; vaginal swabs; oral swabs; nasal swabs; lavage or irrigation fluids, e.g., tubal irrigation fluid or bronchoalveolar irrigation fluid; aspirates; scrapings; bone marrow specimens; tissue biopsy specimens; surgical specimens; feces, other fluids, secretions and / or excretions; and / or cells thereof. In some embodiments, the biological sample is or includes cells obtained from an individual. In some embodiments, the obtained cells are or include cells from the individual from which the sample is obtained. In some embodiments, the sample is a “primary sample” obtained directly from the source of interest by any suitable method. For example, in some embodiments, the primary biological sample is obtained by a method selected from the group consisting of biopsy (e.g., fine-needle aspiration or tissue biopsy), surgery, collection of bodily fluids (e.g., blood, lymph, feces, etc.). In some embodiments, as is evident from the context, the term “sample” refers to a preparation obtained by processing the primary sample (e.g., removing one or more components from the primary sample and / or adding one or more agents to the primary sample). For example, by filtration using a semipermeable membrane. Such a “processed sample” may include, for example, nucleic acids or proteins extracted from the sample, or nucleic acids or proteins obtained by subjecting the primary sample to techniques such as mRNA amplification or reverse transcription, isolation and / or purification of certain components.

[0060] Carrier: As used herein, refers to a diluent, adjuvant, excipient, or vehicle through which the composition is administered. In some exemplary embodiments, the carrier may include a sterile solution, such as water and oil, and may include oils of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. In some embodiments, the carrier is or contains one or more solid components.

[0061] CDR: As used herein, refers to the complementarity-determining region within the antibody variable region. There are three CDRs in each of the heavy and light chain variable regions, which are named CDR1, CDR2, and CDR3 in each variable region. A “set of CDRs” or “CDR set” refers to a group of three or six CDRs occurring in either a single variable region capable of binding to an antigen or in a homologous heavy and light chain variable region capable of binding to an antigen. Certain systems have been established in the art to define CDR boundaries (e.g., IMGT, Kabat, Chothia, etc.), and those skilled in the art are aware of the differences between these systems and can understand CDR boundaries to the extent necessary to understand and practice the claimed invention.

[0062] Children: As used herein, the term “child” refers to a human being between 1 day and 18 years of age. In some embodiments, a child may be an infant (e.g., 12 months or younger, 11 months or younger, 10 months or younger, 9 months or younger, 8 months or younger, 7 months or younger, 6 months or younger, 5 months or younger, 4 months or younger, 3 months or younger, 2 months or younger, or 1 month or younger), and in some embodiments, a child may be older than an infant. In some embodiments, a child may be a toddler (e.g., 1 to 3 years), and in some embodiments, a child may be younger or older than a toddler. In some embodiments, a child may be a teenager (e.g., 12 to 18 years), and in some embodiments, a child may be younger than a teenager (and / or older or younger than a toddler, or older than an infant). Weight may vary considerably across age and a particular child, with a typical range being 4 pounds to 150 pounds.

[0063] Combination therapy: As used herein, the term “combination therapy” refers to a clinical intervention in which a subject is simultaneously exposed to two or more treatment regimens (e.g., two or more therapeutic agents). In some embodiments, two or more therapeutic regimens may be administered simultaneously. In some embodiments, two or more therapeutic regimens may be administered sequentially (e.g., the first regimen is administered before any dose of the second regimen). In some embodiments, two or more therapeutic regimens are administered in overlapping dosing regimens. In some embodiments, the administration of combination therapy may involve administering one or more therapeutic agents or modalities to a subject receiving other agents or modalities. In some embodiments, combination therapy does not necessarily require (or does not necessarily require) that the individual agents be administered together in a single composition. In some embodiments, the two or more therapeutic agents or modalities of combination therapy are administered separately to the subject in separate compositions, for example, via separate routes of administration (e.g., one agent is oral and the other is intravenous) and / or at different time points. In some embodiments, two or more therapeutic agents may be administered together via the same route of administration and / or at the same time by a combination composition or by a combination compound (e.g., as part of a single chemical complex or covalent entity).

[0064] Equivalent: As used herein, the term “equivalent” means two or more agents, entities, situations, states, etc., that are not identical to one another but are similar enough to allow for comparison, and that a person skilled in the art would understand that reasonable conclusions can be drawn based on observed differences or similarities. In some embodiments, equivalent sets of states, situations, individuals, or groups are characterized by several substantially identical features and one or a few different features. A person skilled in the art would understand, in context, what degree of identity is required for two or more agents, entities, situations, states, etc., to be considered equivalent in any given situation. For example, a person skilled in the art would understand that a set of situations, individuals, or groups are equivalent if they are characterized by a sufficient number and type of substantially identical features to justify a reasonable conclusion that differences in results or observed phenomena obtained by or between different sets of situations, individuals, or groups are caused by differences in these different features.

[0065] Corresponding: As used herein, the term “corresponding” refers to a relationship between two entities, events, or phenomena that share sufficient characteristics to be reasonably equivalent, such that the “corresponding” property is evident. For example, in some embodiments, the term may be used in reference to a compound or composition to specify the position and / or identity of a structural element in the compound or composition through comparison with a suitable reference compound or composition. For example, in some embodiments, a monomer residue in a polymer (e.g., an amino acid residue in a polypeptide or a nucleic acid residue in a nucleic acid) may be confirmed to “correspond” to a residue in a suitable reference polymer. For example, a person skilled in the art will understand that, for the sake of simplicity, residues in a polypeptide are often specified using a canonical numbering system based on a reference-related polypeptide, so that the amino acid “corresponding” to the residue at position 190 does not necessarily have to be, for example, the 190th amino acid in a particular amino acid chain, but rather corresponds to a residue found at position 190 in the reference polypeptide, and a person skilled in the art will readily understand how to confirm the “corresponding” amino acid. For example, those skilled in the art will recognize a variety of sequence alignment strategies, including, for example, software programs such as BLAST, CS-BLAST, CUSASW++, DIAMOND, FASTA, GGSEARCH / GLSEARCH, Genoogle, HMMER, HHpred / HHsearch, IDF, Infernal, KLAST, USEARCH, parasail, PSI-BLAST, PSI-Search, ScalaBLAST, Sequilab, SAM, SSEARCH, SWAPHI, SWAPHI-LS, SWIMM, or SWIPE, which can be used to identify the "corresponding" residues in polypeptides and / or nucleic acids as described herein.

[0066] Domain: The term “domain,” as used herein, refers to a segment or part of an entity. In some embodiments, a “domain” is associated with a particular structural and / or functional feature of an entity, thereby substantially or completely retaining that particular structural and / or functional feature if the domain is physically separated from the rest of its parent entity. Alternatively or additionally, a domain may be or include a part of an entity that, when separated from a (parent) entity and linked to a different (recipient) entity, substantially retains and / or imparts to the recipient entity one or more structural and / or functional features characteristic of the parent entity. In some embodiments, a domain is a segment or part of a molecule (e.g., a small molecule, carbohydrate, lipid, nucleic acid, or polypeptide). In some embodiments, a domain is a segment of a polypeptide, and in some such embodiments, a domain is characterized by a particular structural element (e.g., a particular amino acid sequence or sequence motif, α-helix features, β-sheet features, coiled-coil features, random-coil features, etc.) and / or a particular functional feature (e.g., binding activity, enzymatic activity, folding activity, signaling activity, etc.).

[0067] Dosing regimen: As used herein, the term “dosing regimen” refers to a set of unit doses (typically more than one) administered individually to a subject, typically at intervals of time. In some embodiments, a given therapeutic agent may have a recommended dosing regimen comprising one or more doses. In some embodiments, a dosing regimen comprises multiple doses, each time-separated from the other doses. In some embodiments, the individual doses are separated from each other by time intervals of the same length, and in some embodiments, a dosing regimen comprises multiple doses separated by at least two different time intervals. In some embodiments, all doses in a dosing regimen are unit doses of the same amount. In some embodiments, different doses in a dosing regimen are different amounts. In some embodiments, a dosing regimen comprises a first dose of a first amount, followed by one or more additional doses of a second amount different from the first dose. In some embodiments, a dosing regimen comprises a first dose of a first amount, followed by one or more additional doses of a second amount the same as the first dose. In some embodiments, the administration regimen correlates with the desired or beneficial outcome when administered to the relevant population (i.e., it is a therapeutic administration regimen).

[0068] Effector cells: As used herein, refer to immune system cells that express one or more Fc receptors and mediate one or more effector functions. In some embodiments, effector cells may include, but are not limited to, one or more monocytes, macrophages, neutrophils, dendritic cells, eosinophils, mast cells, platelets, large granular lymphocytes, Langerhans cells, natural killer (NK) cells, T lymphocytes, and B lymphocytes, and may come from any organism, including, but not limited to, humans, mice, rats, rabbits, and monkeys.

[0069] Epitope: As used herein, includes any portion that is specifically recognized by an immunoglobulin (e.g., antibody or receptor) binding component. In some embodiments, the epitope consists of a plurality of chemical atoms or groups on the antigen. In some embodiments, such chemical atoms or groups are exposed on the surface if the antigen takes on a relevant three-dimensional structure. In some embodiments, if the antigen takes on such a structure, the chemical atoms or groups are physically close to each other in space. In some embodiments, if the antigen takes on an alternative structure (e.g., linearized), at least some of such chemical atoms or groups are physically separated from each other.

[0070] Excipients: As used herein, these refer to non-therapeutic agents that may be included in a pharmaceutical composition to provide or contribute to, for example, a desired consistency or stabilizing effect. Suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, corn syrup, rice, wheat, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol, and the like.

[0071] Framework or framework region: As used herein, this refers to the sequence of the variable region after subtracting the CDR. Since the CDR sequence can be determined by different systems, the framework sequence is similarly subject to corresponding different interpretations. Six CDRs divide the framework regions of the heavy and light chains into four sub-regions (FR1, FR2, FR3, and FR4) on each chain, where CDR1 is located between FR1 and FR2, CDR2 is located between FR2 and FR3, and CDR3 is located between FR3 and FR4. Without specifying a particular sub-region as FR1, FR2, FR3, or FR4, as referred to elsewhere, the framework region represents a combination of FRs within the variable region of a single naturally occurring immunoglobulin chain. As used herein, FR represents one of the four sub-regions; for example, FR1 represents the first framework region closest to the amino terminus and 5' of the variable region relative to CDR1, and FRs represents two or more sub-regions that constitute the framework region.

[0072] Functional: As used herein, a “functional” biomolecule is a biomolecule in a form that exhibits characteristic properties and / or activity.

[0073] Fragment: A “fragment” of a material or entity as described herein includes a portion separated from the whole, but has a structure lacking one or more parts found in the whole. In some embodiments, the fragment consists of such separated portions. In some embodiments, the fragment consists of or includes characteristic structural elements or parts found in the whole. In some embodiments, the polymer fragment comprises or consists of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500 or more monomer units (e.g., residues) found throughout the polymer. In some embodiments, polymer fragments contain or consist of at least about 5%, 10%, 15%, 20%, 25%, 30%, 25%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more monomer units (e.g., residues) found throughout the polymer. The whole material or entity may, in some embodiments, be referred to as the “parent” of the fragments.

[0074] High affinity binding: The term "high affinity binding," as used herein, refers to the high degree of rigidity with which a particular ligand binds to its partner. Affinity can be measured by any available method, including those known in the art. In some embodiments, binding is measured in a binding assay using K d High affinity is considered to be present when the affinity is approximately 500 pM or less (for example, approximately 400 pM, approximately 300 pM, approximately 200 pM, approximately 100 pM, approximately 90 pM, approximately 80 pM, approximately 70 pM, approximately 60 pM, approximately 50 pM, approximately 40 pM, approximately 30 pM, approximately 20 pM, approximately 10 pM, approximately 5 pM, approximately 4 pM, approximately 3 pM, approximately 2 pM, etc.). In some embodiments, binding is considered to be strong in the target polypeptide than in the selected reference polypeptide (for example, Kd is low. ) In the case, it is considered to have high affinity. In some embodiments, the binding is the K of the polypeptide of interest d and the K of the selected reference polypeptide d When the ratio with is 1:1 or less (for example, 0.9:1, 0.8:1, 0.7:1, 0.6:1, 0.5:1, 0.4:1, 0.3:1, 0.2:1, 0.1:1, 0.05:1, 0.01:1 or less), it is considered to have high affinity. In some embodiments, the binding is the K of the polypeptide of interest d is the K of the selected reference polypeptide d When it is about 100% or less (for example, about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, about 10%, about 5%, about 4%, about 3%, about 2%, about 1% or less), it is considered to have high affinity.

[0075] Homology: As used herein, the term "homology" refers to the overall relationship between polymer molecules, for example, between polypeptide molecules. In some embodiments, polymer molecules such as antibodies are considered to be "homologous" to each other when these sequences have at least 80%, 85%, 90%, 95% or 99% identity. In some embodiments, polymer molecules are considered to be "homologous" to each other when these sequences have at least 80%, 85%, 90%, 95% or 99% similarity.

[0076] Human: In some embodiments, a human is a fetus, infant, child, adolescent, young adult, adult or elderly person.

[0077] Humanized: As is known in the art, the term "humanized" is commonly used to refer to an antibody (or antibody component), and this amino acid sequence is the V of a reference antibody generated in a non-human species (for example, mouse) H and V LThe humanized antibody includes a region sequence and further modifications to the reference antibody for the purpose of making it "human-like," i.e., for further resemblance to the human germline variable sequence. In some embodiments, the "humanized" antibody (or antibody component) immunospecifically binds to the antigen of interest and has a framework (FR) region having substantially the same amino acid sequence as a human antibody and a complementation-determining region (CDR) having substantially the same amino acid sequence as a non-human antibody. The humanized antibody contains substantially all of at least one, typically two, variable domains (Fab, Fab', F(ab')2, FabC, Fv), where all or substantially all of the CDR region and all or substantially all of the framework region corresponding to a non-human immunoglobulin (i.e., donor immunoglobulin) are human immunoglobulin consensus sequences. In some embodiments, the humanized antibody also includes an immunoglobulin constant region (Fc), typically at least a portion of the human immunoglobulin constant region. In some embodiments, the humanized antibody contains both a light chain and at least the variable domains of the heavy chain. The antibody contains the C of the heavy chain constant region. H 1. Hinge, C H 2, C H 3, and optionally C H It may also include 4 regions. In some embodiments, the humanized antibody is humanized V L It contains only the region. In some embodiments, the humanized antibody is humanized V H It contains only the region. In some specific embodiments, the humanized antibody is humanized V H and V L It contains a region.

[0078] Identity: As used herein, the term “identity” refers to the overall relationship between polymer molecules, for example, between nucleic acid molecules (e.g., DNA molecules and / or RNA molecules) and / or between polypeptide molecules. In some embodiments, polymer molecules are considered “substantially identical” to one another if their sequences have at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identity. The calculation of identity percentage between two nucleic acid or polypeptide sequences can be carried out, for example, by aligning the two sequences for optimal comparison purposes (e.g., gaps can be introduced into one or both of the first and second sequences for optimal alignment, and non-identical sequences can be ignored for comparison purposes). In certain embodiments, the length of sequences aligned for comparison is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or substantially 100% of the length of the reference sequence. Nucleotides at corresponding positions are then compared. Molecules are identical at a position if the position in the first sequence is occupied by the same residue (e.g., a nucleotide or amino acid) as the corresponding position in the second sequence. The percentage of identity between two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps that need to be introduced for optimal alignment of the two sequences and the length of each gap. The comparison of sequences and the determination of the percentage of identity between two sequences can be achieved using mathematical algorithms. For example, the percentage of identity between two nucleotide sequences can be determined using the Meyers and Miller algorithm (CABIOS, 1989, 4:11-17), which is incorporated into the ALIGN program (version 2.0). In some exemplary embodiments, nucleic acid sequence comparisons generated by the ALIGN program use a PAM120 weighted residue table, a gap length penalty of 12, and a gap length penalty of 4.Alternatively, the percentage of identity between two nucleotide sequences can be determined using the GAP program in the GCG software package, which employs the NWSgapdna.CMP matrix.

[0079] Improved, increased, or reduced: As used herein, the terms “improved,” “increased,” or “reduced,” or grammatically equivalent comparative terms, refer to values ​​relating to equivalent reference measures. For example, in some embodiments, an assessed value achieved with the agent of interest may be “improved” compared to a value obtained with an equivalent reference agent. Alternatively or additionally, in some embodiments, an assessed value achieved with the subject or system of interest may be “improved” compared to a value obtained with the same subject or system under different conditions (e.g., before or after an event such as administration of the agent of interest), or with a different equivalent subject (e.g., with an equivalent subject or system different from the subject or system of interest, in the presence of one or more indicators of a particular disease, disorder, or condition, or before exposure to a condition or agent, etc.).

[0080] K D :As used herein, this refers to the dissociation constant of a binder (e.g., an antibody or its binding component) from a complex with a partner (e.g., an antibody or its binding component to which it binds).

[0081] Low affinity binding: The term “low affinity binding,” as used herein, refers to the low degree of rigidity with which a particular ligand binds to its partner. As used herein, affinity can be measured by any available method, including methods known in the art. In some embodiments, binding is K D If the affinity is approximately 501 pM or higher (e.g., greater than approximately 501 pM, 600 pM, 700 pM, 800 pM, 900 pM, 1 nM, 1.1 nM, 1.2 nM, 1.3 nM, 1.4 nM, 1.5 nM, etc.), it is considered to have low affinity. In some embodiments, the binding affinity is the same as or lower for the target polypeptide than for the selected reference polypeptide (e.g., K DIf the affinity is approximately the same or higher, it is considered to be low affinity. In some embodiments, the binding is to the K of the polypeptide of interest. D and the selected reference polypeptide K D If the ratio is 1:1 or greater (for example, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2:1, 3:1, 4:1, 5:1, 10:1 or greater), it is considered to have low affinity. In some embodiments, the binding is to the K of the target polypeptide. d However, the K of the selected reference polypeptide D If the percentage is 100% or more (for example, 100%, 105%, 110%, 115%, 120%, 125%, 130%, 135%, 140%, 145%, 150%, 155%, 160%, 165%, 170%, 175%, 180%, 185%, 190%, 195%, 200%, 300%, 400%, 500%, 1000%, or higher), it is considered to have low affinity.

[0082] Non-responder: As used herein, the term “non-responder” refers to a subject who, after receiving anti-inflammatory therapy (e.g., alternative anti-inflammatory therapy that does not directly target TREM1 (e.g., anti-TNFα therapy)) for a period of time, shows no improvement in clinical signs and symptoms. In some embodiments, a primary non-responder shows no improvement in clinical signs and symptoms after receiving anti-inflammatory therapy. In some embodiments, a secondary non-responder shows initial improvement in clinical signs or symptoms after receiving anti-inflammatory therapy, but shows a statistically significant decrease in such improvement over time. Those skilled in the art will understand that the medical community may establish appropriate durations for any particular disease or condition or for any particular patient or patient type. In some embodiments, for example, the duration may be at least 8 weeks. In some embodiments, the duration may be at least 12 weeks. In some embodiments, the duration may be at least 14 weeks.

[0083] Pharmaceutical composition: As used herein, the term “pharmaceutical composition” refers to an activator formulated with one or more pharmaceutically acceptable carriers. In some embodiments, the activator is presented in a unit dose appropriate for administration in a therapeutic regime of the subject in question (e.g., an amount demonstrated to have a statistically significant probability of achieving a predetermined therapeutic effect when administered), or in a unit dose appropriate for administration in a therapeutic regime of a different equivalent subject (e.g., an equivalent subject or system different from the subject or system of interest in the presence of one or more indicators of a particular disease, disorder, or condition, or prior to exposure to a condition or drug, etc.). In some embodiments, comparative terms refer to a statistically relevant difference (e.g., a range of prevalence and / or magnitude sufficient to achieve statistical significance). A person skilled in the art can recognize, or readily determine, the degree of difference and / or prevalence necessary or sufficient to achieve such statistical significance in a given context.

[0084] Pharmacologically acceptable: As used herein, the term “pharmaceutically acceptable” means a compound, material, composition and / or dosage form that, within the bounds of sound medical judgment, is suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reaction or other problems or complications that are balanced by a reasonable benefit / risk ratio.

[0085] Polypeptide: As used herein, refers to a polymer chain of amino acids. In some embodiments, the polypeptide has an amino acid sequence found in nature. In some embodiments, the polypeptide has an amino acid sequence not found in nature. In some embodiments, the polypeptide has an amino acid sequence that is modified in the sense that it is designed and / or produced by human hands. In some embodiments, the polypeptide may contain or consist of natural amino acids, non-natural amino acids, or both. In some embodiments, the polypeptide may contain or consist of only natural amino acids or only non-natural amino acids. In some embodiments, the polypeptide may contain D amino acids, L amino acids, or both. In some embodiments, the polypeptide may contain only D amino acids. In some embodiments, the polypeptide may contain only L amino acids. In some embodiments, the polypeptide may include one or more pendant groups or other modifications, e.g., modifications or attachments to one or more amino acid side chains at the N-terminus of the polypeptide, the C-terminus of the polypeptide, or any combination thereof. In some embodiments, such pendant groups or modifications may be selected from the group consisting of acetylation, amidation, lipidation, methylation, pegylation, etc., and may include combinations thereof. In some embodiments, the polypeptide may be cyclic and / or may contain a cyclic portion. In some embodiments, the polypeptide may not be cyclic and / or may not contain a cyclic portion at all. In some embodiments, the polypeptide may be linear. In some embodiments, the polypeptide may be a stapled polypeptide and / or may contain a stapled polypeptide. In some embodiments, the term “polypeptide” may be suffixed to the name of a reference polypeptide, activity, or structure, in which case it is used herein to refer to polypeptides that share the relevant activity or structure and may thus be considered members of the same class or family of polypeptides.In each of such classes, this specification provides exemplary polypeptides within the class whose amino acid sequence and / or function are known, and / or which are recognized by those skilled in the art, and in some embodiments such exemplary polypeptides are reference polypeptides of the polypeptide class or family. In some embodiments, members of the polypeptide class or family exhibit significant sequence homology or identity with the reference polypeptide of this class (in some embodiments, all polypeptides within this class), share common sequence motifs (e.g., characteristic sequence elements), and / or share common activity (in some embodiments, at equivalent levels or within a specified range). For example, in some embodiments, the member polypeptide includes at least about 30–40% and often more than or equal to about 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of overall sequence homology or identity with the reference polypeptide, and / or often more than 90% and even more than 95%, 96%, 97%, 98%, or 99% of sequence identity (a conserved region, for example, which may be or may include a characteristic sequence element in some embodiments). Such a conserved region typically comprises at least 3–4 amino acids, often more than 20, and in some embodiments, the conserved region comprises at least one stretch of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more consecutive amino acids. In some embodiments, the relevant polypeptide may include or be derived from fragments of the parent polypeptide. In some embodiments, the useful polypeptide may include or be derived from several fragments found in the same parent polypeptide in different spatial arrangements from those found in the polypeptide of interest (for example, a fragment directly linked to the parent may be spatially separated from the polypeptide of interest, and vice versa, and / or the fragments may be present in the polypeptide of interest in a different order from the parent), thereby the polypeptide of interest being a derivative of the parent polypeptide.

[0086] Reference: As used herein, the term “reference” refers to the standard or control on which the comparison is made. For example, in some embodiments, the drug, animal, individual, population, sample, sequence, or value of interest is compared to the drug, animal, individual, population, sample, sequence, or value of the reference or control. In some embodiments, the reference or control is tested and / or determined substantially concurrently with the test or determination of the object of interest. In some embodiments, the reference or control is a historical reference or control optionally contained in a tangible medium. Typically, as will be understood by those skilled in the art, the reference or control is determined or characterized under equivalent conditions or circumstances under which it is assessed. Those skilled in the art will understand that there is sufficient similarity to justify reliance on and / or comparison of certain possible references or controls.

[0087] Specific Binding: As used herein, the term “specific binding” refers to the ability to identify possible binding partners in the environment in which binding occurs. A binder that interacts with one particular target in the presence of other potential targets is said to “specifically bind” to the target with which it interacts. In some embodiments, specific binding is assessed by detecting or determining the degree of relationship between the binder and its partner; in some embodiments, specific binding is assessed by detecting or determining the degree of dissociation of the binder-partner complex; in some embodiments, specific binding is assessed by detecting or determining the ability of the binder to compete for alternative interactions between its partner and another entity. In some embodiments, specific binding is assessed by performing such detection or determination over a range of concentrations.

[0088] Specific: When the term “specific” is used herein in reference to an active drug, it will be understood by those skilled in the art that it means the drug identifies a potential target entity or appearance. For example, in some embodiments, a drug is said to bind “specifically” to a target if it preferentially binds to that target in the presence of one or more competing alternative targets. In many embodiments, specific interaction depends on the presence of specific structural features of the target entity (e.g., epitopes, cavities, binding sites). It should be understood that specificity does not have to be absolute. In some embodiments, specificity may be evaluated in comparison to one or more other potential target entities (e.g., competitors). In some embodiments, specificity is evaluated in comparison to a reference specific binder. In some embodiments, specificity is evaluated in comparison to a reference nonspecific binder. In some embodiments, the drug or entity does not detectably bind to competing alternative targets under conditions in which it binds to its target entity. In some embodiments, the binder binds to its target entity with a higher on-rate, lower off-rate, increased affinity, decreased dissociation, and / or increased stability compared to competing alternative targets.

[0089] Specificity: As is known in this field, "specificity" is a measure of a particular ligand's ability to distinguish its binding partner from other potential binding partners.

[0090] Subject: As used herein, the term “Subject” means a living organism, typically a mammal (e.g., a human, and in some embodiments, a prenatal human form). In some embodiments, the Subject has a relevant disease, disorder, or condition. In some embodiments, the Subject is susceptible to a disease, disorder, or condition. In some embodiments, the Subject exhibits one or more symptoms or characteristics of a disease, disorder, or condition. In some embodiments, the Subject does not exhibit any symptoms or characteristics of a disease, disorder, or condition. In some embodiments, the Subject is a person having one or more characteristics that are characteristic of susceptibility to or risk of a disease, disorder, or condition. In some embodiments, the Subject is a patient. In some embodiments, the Subject is a Subject to be administered and / or has been administered a diagnosis and / or treatment.

[0091] Substantial: As used herein, the term “substantial” refers to a quantitative state that exhibits a complete or near-complete range or degree of the desired feature or characteristic. Those skilled in the art of biology will understand that biological and chemical phenomena rarely progress toward completion and / or toward perfection, or achieve or avoid absolute results. Thus, the term “substantial” is used herein to capture the potential lack of perfection inherent in many biological and chemical phenomena.

[0092] Substantial identity: As used herein, refers to a comparison between sequences of amino acids or nucleic acids. As will be understood by those skilled in the art, two sequences are generally considered "substantial identity" if they contain identical residues at corresponding positions. As is known in the art, sequences of amino acids or nucleic acids can be compared using any of the algorithms available in commercially available computer programs, for example, BLASTN for nucleotide sequences and BLASTP, gapped BLAST, and PSI-BLAST for amino acid sequences. Exemplary programs of this nature are described in Altschul et al., Basic local alignment search tool, J.Mol.Biol., vol. 215(no. 3): pp. 403-410, 1990; Altschul et al., Methods in Enzymology; Altschul et al., Nucleic Acids Res., vol. 25: pp. 3389-3402, 1997; Baxevanis et al., Bioinformatics: A Practical Guide to the Analysis of Genes and Proteins, Wiley, 1998; and Misener et al. (eds.), Bioinformatics Methods and Protocols (Methods in Molecular Biology, vol. 132), Humana Press, 1999. In addition to confirming identical sequences, the programs described above typically provide an indicator of the degree of identity. In some embodiments, two sequences are considered substantially identical if at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more of their corresponding residues are identical across the relevant residue stretch. In some embodiments, the relevant stretch is the entire sequence.In some embodiments, the relevant stretch consists of at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500 or more residues. In the context of CDRs, the reference to “substantially identical” typically refers to a CDR having fewer than or equal to (e.g., 3, 2, or 1) amino acid sequence changes compared to a reference CDR. In some embodiments, a CDR that is substantially identical to a reference CDR differs from the reference CDR by one or more amino acid changes at the end of the reference CDR, and in some such embodiments, the relevant CDR is identical to the reference CDR except at one or both ends. As is known in the art, CDR elements typically have lengths ranging from a few amino acids (e.g., 3, 4, 5, 6, or 7) to about 20 or 30 amino acids (see, for example, Collis et al., J.Mol.Biol. 325:337, 2003, incorporated herein by reference), and thus, in some embodiments, a CDR may be considered substantially identical to a reference CDR if it shares at least about 80% (or less for shorter CDRs), at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100% identity with a reference CDR.

[0093] Substantial Sequence Homology: The term “substantial homology” is used herein to refer to a comparison between sequences of amino acids or nucleic acids. As will be understood by those skilled in the art, two sequences are generally considered “substantial homology” if they contain homologous residues at corresponding positions. Homologous residues may be identical residues. Alternatively, homologous residues may be non-identical residues having appropriately similar structural and / or functional characteristics. For example, as is well known to those skilled in the art, certain amino acids are typically classified by being “hydrophobic” or “hydrophilic” amino acids and / or having “polar” or “nonpolar” side chains. Substituting one amino acid with another amino acid of the same type can often be considered a “homologous” substitution. Typical amino acid classifications are summarized below.

[0094] [Table 1]

[0095] [Table 2]

[0096] As is well known in this field, amino acid or nucleic acid sequences can be compared using commercially available computer programs, for example, BLASTN for nucleotide sequences and various algorithms including BLASTP, gapped BLAST, and PSI-BLAST for amino acid sequences. Exemplary programs of this nature are described in Altschul et al., Basic local alignment search tool, J.Mol.Biol., vol. 215(no. 3): pp. 403-410, 1990; Altschul et al., Methods in Enzymology; Altschul et al., "Gapped BLAST and PSI-BLAST: a new generation of protein database search programs", Nucleic Acids Res., vol. 25: pp. 3389-3402, 1997; Baxevanis et al., Bioinformatics: A Practical Guide to the Analysis of Genes and Proteins, Wiley, 1998; and Misener et al. (eds.), Bioinformatics Methods and Protocols (Methods in Molecular Biology, vol. 132), Humana Press, 1999. In addition to confirming homologous sequences, the programs described above typically provide an indicator of the degree of homology. In some embodiments, two sequences are considered substantially homologous if at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or more of their corresponding residues are homologous across the relevant residue stretch. In some embodiments, the relevant stretch is the entire sequence.For some embodiments, the relevant stretch consists of at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, at least 95, at least 100, at least 125, at least 150, at least 175, at least 200, at least 225, at least 250, at least 275, at least 300, at least 325, at least 350, at least 375, at least 400, at least 425, at least 450, at least 475, at least 500 or more residues.

[0097] To treat: As used herein, the terms “treat,” “treatment,” or “treating” are used to mean one or more of the following: partial or complete reduction, improvement, mitigation, inhibition, prevention, delay of onset, reduction of severity, and / or reduction of frequency (e.g., incidence) of one or more symptoms or characteristics of a disease, disorder, and / or condition. In some embodiments, treatment may be prophylactic and may be administered, for example, to subjects who do not exhibit signs of a disease, disorder, and / or condition. In some embodiments, treatment may be administered to subjects who exhibit only early signs of a disease, disorder, and / or condition and may reduce the risk of developing a pathology associated with the disease, disorder, and / or condition, and / or delay the onset of one or more characteristics of a disease, disorder, and / or condition, and / or reduce the rate of onset or worsening.

[0098] Treatment: As used herein, the term “treatment” (similarly, “to treat” or “to treat”) refers to the administration of a treatment that partially or completely reduces, improves, alleviates, inhibits, delays the onset of, reduces the severity of, and / or reduces the incidence of one or more symptoms, characteristics and / or causes of a particular disease, disorder and / or condition. In some embodiments, such treatment may be for subjects that do not exhibit signs of the disease, disorder and / or condition in question, and / or for subjects that exhibit only initial signs of the disease, disorder and / or condition. Alternatively or additionally, such treatment may be for subjects that exhibit one or more signs of the disease, disorder and / or condition in question. In some embodiments, treatment may be for subjects that have been diagnosed with the disease, disorder and / or condition in question. In some embodiments, treatment may be for subjects that are known to have one or more susceptibility factors that are statistically correlated with an increased risk of developing the disease, disorder and / or condition in question. Thus, in some embodiments, treatment may be prophylactic, and in some embodiments, treatment may be therapeutic.

[0099] Therapeutic dose: As used herein, the term “therapeutic dose” refers to the amount of a substance (e.g., a therapeutic agent, composition, and / or formulation) administered as part of a therapeutic regimen that elicits a desired biological response. In some embodiments, the therapeutic dose of a substance is an amount sufficient to treat, diagnose, prevent, and / or delay the onset of a disease, disorder, and / or condition when administered to a subject suffering from or susceptible to the disease, disorder, and / or condition. As will be understood by those skilled in the art, the effective dose of a substance may vary depending on factors such as the desired biological endpoint, the substance being delivered, and the target cells or tissues. For example, the effective dose of a compound in a formulation for treating a disease, disorder, and / or condition is an amount that reduces, improves, alleviates, inhibits, delays the onset of, reduces the severity of, and / or reduces the incidence of one or more symptoms or characteristics of the disease, disorder, and / or condition. In some embodiments, the therapeutic dose is administered in a single dose, and in some embodiments, multiple unit doses are required to deliver the therapeutic dose.

[0100] Variant: As used herein, the term “variant” refers to an entity that exhibits significant structural identity with a reference entity but is structurally different from the reference entity by the presence or level of one or more chemical parts. In many embodiments, a variant is also functionally different from its reference entity. Generally, whether a particular entity is considered precisely a “variant” of a reference entity depends on the degree of structural identity with the reference entity. As will be understood by those skilled in the art, any biological or chemical reference entity has certain characteristic structural elements. A variant is, by definition, a unique chemical entity that shares one or more such characteristic structural elements. For example, a small molecule may have a characteristic core structural element (e.g., a macrocyclic molecular core) and / or one or more characteristic pendant portions, thereby a variant of the small molecule sharing the core structural element and characteristic pendant portions but having different other pendant portions and / or different types of bonds present within the core (single-to-double, E-to-Z, etc.); a polypeptide may have a characteristic sequence element consisting of multiple amino acids having designated positions in a linear or three-dimensional space and / or contributing to a specific biological function; and a nucleic acid may have a characteristic sequence element consisting of multiple nucleotide residues having designated positions in a linear or three-dimensional space. For example, a variant polypeptide may differ from a reference polypeptide as a result of one or more differences in the amino acid sequence and / or one or more differences in the chemical portion (e.g., carbohydrates, lipids, etc.) covalently bonded to the polypeptide backbone. In some embodiments, the variant polypeptide exhibits overall sequence identity with the reference polypeptide, which is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, or 99%. Alternatively or additionally, in some embodiments, the variant polypeptide does not share at least one characteristic sequence element with the reference polypeptide. In some embodiments, the reference polypeptide has one or more biological activities. In some embodiments, the variant polypeptide shares one or more biological activities with the reference polypeptide.In some embodiments, the variant polypeptide lacks one or more biological activities of the reference polypeptide. In some embodiments, the variant polypeptide exhibits a reduced level of one or more biological activities compared to the reference polypeptide. In many embodiments, the polypeptide of interest is considered a “variant” of the parent or reference polypeptide if it has the same amino acid sequence as the parent but has a few sequence changes at specific positions. Typically, less than 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, or 2% of residues in the variant are substituted compared to the parent. In some embodiments, the variant has 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 substituted residue compared to the parent. Often, the variant has a very small number (e.g., less than 5, 4, 3, 2, or 1) substituted functional residues (i.e., residues that participate in specific biological activities). Furthermore, the variant typically has 5, 4, 3, 2, or 1 or fewer additions or deletions, and often has no additions or deletions compared to the parent. Furthermore, any additions or deletions are typically less than 25, 20, 19, 18, 17, 16, 15, 14, 13, 10, 9, 8, 7, or 6 residues, and generally less than 5, 4, 3, or 2 residues. In some embodiments, the parent or reference polypeptide is one found in nature.

[0101] Vector: As used herein, vector refers to a carrier for polynucleotides (i.e., DNA or RNA molecules) that can be used to introduce polynucleotides into cells. “Expression vector” is a vector containing a protein-coding sequence and essential regulatory regions required for the expression of the sequence in cells. In some embodiments, the protein-coding sequence is operably ligated to another sequence in the vector. The term “operably ligated” means that the regulatory regions required for the expression of the protein-coding sequence are positioned on the polynucleotide at the appropriate location for the sequence to produce protein expression.

[0102] This disclosure provides, in particular, TREM1 inhibitors, which are anti-TREM1 antibody agents or include anti-TREM1 antibody agents. This disclosure further provides pharmaceutical compositions comprising such TREM1 inhibitors, and methods of using them in the treatment of diseases, disorders or conditions.

[0103] Where described herein, this disclosure further provides the insight that neutrophil levels and / or monocyte levels may indicate responsiveness to certain anti-inflammatory therapies (e.g., TREM1 antibody agents described herein). This disclosure further demonstrates that certain neutrophils (e.g., activated neutrophils) may, in some embodiments, be particularly useful indicators of responsiveness to certain anti-inflammatory therapies (e.g., TREM1 antibody agents described herein). This disclosure provides a variety of biomarkers presented and / or acting as surrogates for neutrophil levels (e.g., activated neutrophil levels) and / or monocyte levels (e.g., inflammatory monocyte levels), and describes the use of such biomarkers in anti-inflammatory therapies (e.g., using TREM1 antibody agents described herein). In some embodiments, such biomarkers are, or include, neutrophil products and / or inflammatory monocyte products.

[0104] In particular, this disclosure provides the insight that subjects having elevated levels of activated neutrophils and / or elevated levels of inflammatory monocytes may be good candidates for TREM1-targeted therapies (e.g., using TREM1 antibody agents as described herein). Alternatively or additionally, in some embodiments, such subjects may be less favorable candidates for alternative therapies (e.g., TNFα-targeted therapies).

[0105] TREM1 Myeloid cell-expressed provocative receptor 1 (TREM1 or TREM-1) is a member of the Ig-like immunomodulatory receptor family found on the surface of certain myeloid cells, specifically neutrophils and monocyte subsets. These receptors are part of the innate immune system and have been described as "amplifiers" of inflammation. See, for example, Bouchon et al., J.Immunol. 164:4991 (2000); Dantas et al., Intl. Rev.Immunol. 39(4):188-202 (2020).

[0106] TREM1 polypeptide sequences have been reported from various organisms, each assigned a UniProt accession number, and are described in Table 1 below.

[0107] [Table 3] TIFF2026514609000005.tif224170TIFF2026514609000006.tif42170

[0108] The membrane-bound form of TREM1 includes (i) an outer domain containing a single Ig V-type domain, (ii) a transmembrane region, and (iii) a cytoplasmic tail that recruits DNAX-Activation Protein 12 (DAP12) for signal transduction. The soluble form (sTREM1) has also been described and is thought to be produced by proteolytic cleavage of TREM1 (potentially after activation; see, for example, Gomez-Pina et al., J.Immunol. 179 (No. 6): pp. 4065-4073 (2007); Gingras et al., Mol.Immunol. 38: p. 817 (2002); Bostanci et al., J.Dent.Res. 92 (No. 2): pp. 161-165 (2013); Jolly et al., Cell Mol.Immunol. 18 (No. 8): pp. 2054-2056 (2021)) or alternative splicing of TREM1 mRNA (see, for example, Baruach et al., J.Immunol. 195 (No. 12): pp. 5725-5731 (2015)). sTREM1 has been reported to compete with TREM1 for binding to at least some ligands. See Gibot et al., Intensive Care Med. 32:185, 2006. This binding activity may allow sTREM1 to act as a "decoy" receptor for TREM1 ligands, reducing TREM1 activation (see, for example, International Publication 2022 / 258979).

[0109] It has also been reported that the monomer TREM1 is inactive and that polymerization may be necessary for activity. See Carrasco et al., Cell Mol. Immunol. Vol. 16: p. 460, 2019.

[0110] Various potential ligands have been proposed for TREM1, including PGLYRP1, actin, HMGB1, Hsp70, extracellular cryoinducible RNA-binding protein (eCIRP), and / or one or more infectious pathogen-associated antigens (e.g., zymosan, HIV envelope glycoprotein and / or Marburg virus, Schistosoma mansoni egg antigen, etc.). See, for example, Fu et al., Front. Immunol. 8:917 (2017) and Singh et al., Expert Opin. Ther. Pat. 31(6):549-561 (2021).

[0111] TREM1 has been reported to be upregulated in response to, for example, hypoxia (in dendritic cells), vitamin D3, oxidized low-density lipoprotein, tumor necrosis factor alpha (TNFα), interleukin-1 beta (IL-1β), GM-CSF, PGE2, cAMP, and various microbial compounds, such as peptidoglycan (PGN), LPS, and lipoteichoic acid (LTA). See, for example, Rai and Agarwal, Reports Vol. 4 (No. 2): p. 17 (2021).

[0112] Activated TREM1 leads to phosphorylation of DAP12 by Src kinase, triggering a phosphorylation cascade that ultimately results in the activation of various transcription factors involved in the production of inflammatory mediators (e.g., IL-6, IL-8, IL-1β, and TNFα). See, for example, Dower et al., J.Immunol., Vol. 180 (No. 5): pp. 3520-2534 (2008). TREM1 activation also inhibits apoptosis-promoting agents such as BID, BAD, and BAX, and inhibits mitochondrial release of cytochrome C. See, for example, Campbell et al., mBio, Vol. 10 (No. 6); e02638-19 (2019); Yuan et al., J. Biol. Chem. Vol. 289 (No. 21): pp. 15118-15129 (2013); and Yuan et al., Am. J. Physiol. Lung Cell. Mol. Physiol., Vol. 310 (No. 5): L426-38 (2016).

[0113] TREM1 expression is downregulated by PU.1 and by anti-inflammatory cytokines such as IL-10 and TGF-beta, see, for example, Zeng et al., Eur. J. Immunol, vol. 37 (no. 8): pp. 2300-2388 (2007) and Schenk et al., J. Immunol., vol. 174 (no. 1): pp. 517-524 (2005). Certain other inhibitors of LPS-induced activation have also been reported to reduce TREM1 activity, see, for example, Owens et al., Front. Cell. Neurosci., vol. 11: p. 56 (2017).

[0114] anti-inflammatory therapy In general, inflammation can be caused by a variety of mechanisms, including but not limited to immune responses to injury and infection. Chronic inflammation is a characteristic feature of certain diseases (e.g., autoimmune diseases, cancer, inflammatory diseases, etc.) and can lead to tissue damage and / or tissue death over time. Anti-inflammatory therapy can inhibit inflammation and / or reduce the symptoms and / or markers of inflammation.

[0115] In some embodiments, anti-inflammatory therapy may reduce the levels of one or more inflammatory markers in a subject. In some embodiments, anti-inflammatory therapy may reduce the levels of one or more downstream signaling molecules (e.g., proteins, cytokines, chemokines, etc.) that trigger an inflammatory response. In some embodiments, anti-inflammatory therapy may bind to a target of interest (e.g., a protein, enzyme, etc.) associated with the inflammatory response. In some embodiments, anti-inflammatory therapy may inhibit the function of a target of interest (e.g., a protein, enzyme, etc.) associated with the inflammatory response. In some embodiments, anti-inflammatory therapy may prevent an inflammatory response by inhibiting the function of a target of interest (e.g., a protein, enzyme, etc.). In some embodiments, anti-inflammatory therapy may prevent the release / production of downstream signaling molecules (e.g., cytokines, chemokines, etc.) that trigger an inflammatory response by inhibiting the function of a target of interest (e.g., a protein, enzyme, etc.). In some embodiments, anti-inflammatory therapy may inhibit the production, processing, secretion, and / or binding of one or more cytokines, including but not limited to IL-1α, IL-1β, IL-2, IL-6, IL-4, IL-8, IL-10, IL-12, IL-17, IL-22, IL-23, TNFα, GM-CSF, TNF-RII, and IFNγ. In some embodiments, anti-inflammatory therapy may inhibit the production, processing, secretion, and / or binding of chemokines, including but not limited to CCL2, CCL3, CCL4, CCL8, CCL19, CCL20, CCL22, CCL24, CXCL1, CXCL5, CXCL9, and CXCL13. In some embodiments, anti-inflammatory therapy may inhibit the production, processing, secretion, and / or binding of activators of B cells, T cells, and / or other cells, including but not limited to IL-1α, IL-1β, IL-6, IL-10, IL-23, APRIL, BAFF, CD30, M-CSF, TNF-RII, and TNFα. In some embodiments, anti-inflammatory therapy may inhibit the production, processing, secretion, and / or binding of factors associated with reducing or impairing epithelial barrier integrity, including but not limited to IL-1α, IL-1β, IL-6, IL-8, IL-10, IL-23, GM-CSF, TRAIL, TWEAK, MMP-1, IL-20, TNFR-II, and TNFα.In some embodiments, anti-inflammatory therapy may prevent or reduce (e.g., inhibit) epithelial barrier damage. In some embodiments, anti-inflammatory therapy may inhibit the production, processing, secretion, and / or binding of granular proteins, including but not limited to S100A and antimicrobial peptides. In some embodiments, anti-inflammatory therapy may inhibit the production, processing, secretion, and / or binding of neutrophil products, including but not limited to myeloperoxidase (MPO), elastase, PR3, MMP8, MMP9, prolyl endopeptidase, lipocalin, and Lamp-2; see, for example, Herrero-Cervera et al., Cell Mol Immunol. 19: pp. 177-191 (2022).

[0116] In many embodiments, anti-inflammatory therapy involves the administration of one or more compositions that deliver anti-inflammatory agents (i.e., agents that inhibit, for example, a relevant target by reducing its level and / or activity). Those skilled in the art will be familiar with various such agents and / or compositions (e.g., those described herein). For completeness, the inventors note that the teachings of this disclosure may be applicable to various chemical classes of agents (e.g., small molecules, nucleic acids, polypeptides, etc.), and those skilled in the art will recognize appropriate modes for the delivery of such different classes. For example, in some embodiments, small molecule agents may be delivered by the administration of a composition containing the small molecule agent or a prodrug thereof (e.g., a prodrug that can be metabolized upon administration or otherwise converted to a small molecule agent). In some embodiments, nucleic acid agents may be delivered by the administration of a composition containing the nucleic acid agent or its complement, or a nucleic acid that otherwise encodes the nucleic acid agent (e.g., the nucleic acid agent can be generated in the subject to which the composition is administered). In some embodiments, polypeptide agents (e.g., peptide agents, antibody agents, etc.) may be delivered by administration of a composition comprising a polypeptide agent, a precursor of a polypeptide agent (e.g., thereby generating the polypeptide agent through processing in the subject to which the composition is administered), or a nucleic acid encoding a polypeptide agent (e.g., thereby generating the polypeptide agent in the body to which the composition is administered).

[0117] In some embodiments, the target of anti-inflammatory therapy may be or may include TREM1. In some embodiments, the target of anti-inflammatory therapy may be or may include an alternative target (e.g., TNFα). In some embodiments, anti-inflammatory therapy targeting an alternative target (i.e., a target other than TREM1), such as a TNFα inhibitor, may be referred to as an alternative therapy (e.g., an alternative anti-inflammatory therapy). Certain TREM1 inhibitors and inhibitors of alternative targets (e.g., TNFα inhibitors) are known, as described below, and in some cases, clinical formulations and protocols have been developed. In some embodiments of this disclosure, the anti-inflammatory therapy is an established therapy administered, for example, according to an established protocol (e.g., approved by the relevant regulatory authority, such as the U.S. Food and Drug Administration or the European Medicines Agency). In some embodiments, the anti-inflammatory therapy is or includes an anti-TREM1 antibody agent, nucleic acid encoding it, or a composition thereof, as described herein.

[0118] TREM1 inhibitors In some embodiments, inflammatory diseases, disorders, or conditions may be treated by inhibiting TREM1, particularly by administering TREM1 inhibitors (i.e., by TREM inhibitor therapy). In some embodiments, the TREM1 inhibitor is an anti-TREM1 agent or comprises an anti-TREM1 agent. Various TREM1 inhibitors are known in the art; see, for example, Siskind et al., Front Immunol, Vol. 13: pp. 907387 (2022); Sigalov, Front Immunol, Vol. 11: pp. 173 (2020); and Brynjolfsson et al., Inflamm Bowel Dis, Vol. 22 (No. 8): pp. 1803-11 (2016).

[0119] In some embodiments, the TREM1 inhibitor is or comprises a TREM1 decoy receptor. While we do not wish to be bound by any particular theory, the TREM1 decoy receptor binds to the TREM1 ligand, thereby preventing the binding of the TREM1 ligand to TREM1 and subsequent TREM1 activation. In some embodiments, the TREM1 decoy receptor is or comprises soluble TREM1 (sTREM1) or a TREM1 Fc fusion protein.

[0120] In some embodiments, the TREM1 inhibitor is soluble TREM1 (sTREM1) or contains soluble TREM1 (sTREM1). In some embodiments, sTREM1 is the cleaved extracellular domain of TREM1. While we do not wish to be bound to any particular theory, sTREM1 is thought to act as a decoy receptor for TREM1 by binding to the TREM1 ligand and reducing TREM1 activation and subsequent inflammatory responses (e.g., release of pro-inflammatory cytokines).

[0121] In some embodiments, the TREM1 inhibitor is or comprises a TREM1 Fc fusion protein. In some embodiments, the TREM1 Fc fusion protein comprises the extracellular domain of TREM1 (e.g., mouse TREM1) and the Fc domain (e.g., the Fc portion of human IgG1). While we do not wish to be bound by any particular theory, it is thought that the TREM1 Fc fusion protein acts by (i) acting as a TREM1 decoy receptor and (ii) promoting the clearance of the TREM1 ligand via Fc receptor-mediated endocytosis.

[0122] In some embodiments, the TREM1 inhibitor is or comprises a TREM1 decoy peptide. In some embodiments, the TREM1 decoy peptide is a peptide derived from a portion of the TREM1 extracellular domain. In some embodiments, the TREM1 decoy peptide is a peptide derived from a portion of the TREM1 ligand. While we do not wish to be bound to any particular theory, it is thought that the TREM1 decoy peptide (i) binds to TREM1 and acts as a competitive inhibitor preventing the TREM1 ligand from binding to TREM1, and / or (ii) binds to the TREM1 ligand, thereby preventing the TREM1 ligand from binding to TREM1 and subsequent activation of TREM1. In some embodiments, the TREM1 decoy peptide is or comprises the LP17 peptide having the amino acid sequence LQVTDSGLYRCVIYHPP (SEQ ID NO: 7). In some embodiments, the TREM1 decoy peptide is or comprises the M3 peptide having the amino acid sequence RGFFRGG (SEQ ID NO: 8). In some embodiments, the TREM1 decoy peptide is an N1 peptide having ARNVQHYHMK in an amino acid sequence corresponding to amino acid positions 77-86 of PGLYRP1 (SEQ ID NO: 9), or includes this N1 peptide.

[0123] In some embodiments, the TREM1 inhibitor is an inhibitor of the interaction of TREM1 with DAP12, or includes this inhibitor. While we do not wish to be bound by any particular theory, it is believed that TREM1-mediated signaling occurs through the interaction of TREM1 and DAP12. In some embodiments, the inhibitor of the interaction of TREM1 with DAP12 is a peptide derived from a portion of the TREM1 transmembrane domain, or includes this peptide. In some embodiments, the inhibitor of the interaction of TREM1 with DAP12 is a GF9 peptide having the amino acid sequence GLLSKSLVF (SEQ ID NO: 10), or includes this GF9 peptide. In some embodiments, the inhibitor of the interaction of TREM1 with DAP12 is a TREM1 sneaking ligand construct (SLC-TREM1), or includes this construct. In some embodiments, SLC-TREM1 comprises an E-selecting targeting domain, Pseudomonas aeruginosa exotoxin A, and a polypeptide derived from the transmembrane domain of TREM1 having the amino acid sequence LSKSLVF (SEQ ID NO: 11).

[0124] In some embodiments, the TREM1 inhibitor is a peptide derived from or comprising TREM1-like transcript 1 (TLT-1). In some embodiments, the peptide derived from TLT-1 is an LR17 peptide having the amino acid sequence LQEEDAGEYGCMVDGAR (SEQ ID NO: 12), or comprising the LR17 peptide. In some embodiments, the peptide derived from TLT-1 is an LR12 peptide having the amino acid sequence LQEEDAGEYGCM (SEQ ID NO: 13), or comprising the LR12 peptide. In some embodiments, the LR12 peptide may be referred to as nangibotide.

[0125] TREM1 antibody agent A TREM1 antibody agent that binds to TREM1 with high affinity (e.g., specifically) is disclosed herein.

[0126] A particular TREM1 antibody agent provided is characterized by its ability to inhibit TREM1 activation. In some embodiments, the provided TREM1 antibody agent directly binds to and inhibits TREM1. In some embodiments, the provided TREM1 antibody agent is characterized by its ability to reduce the cell surface expression of TREM1 (e.g., reducing TREM1 expression, intracellular translocation of TREM1, clipping of TREM1 to release sTREM1, etc.). In some embodiments, the provided TREM1 antibody agent is characterized by its ability to both inhibit TREM1 activation and reduce the cell surface expression of TREM1 (e.g., reducing TREM1 expression, intracellular translocation of TREM1, clipping of TREM1 to release sTREM1, etc.). While we do not wish to be bound by any particular theory, in some embodiments, the provided TREM1 antibody agent is characterized by its ability to both inhibit TREM1 activation and translocate TREM1.

[0127] In some embodiments, the provided TREM1 antibody agent is characterized by its ability to inhibit TREM1 activation and / or reduce the production of TREM1-driven inflammatory mediators (e.g., cytokines, other cells, chemokines, etc.) by one or more immune cells compared to a reference (e.g., healthy cells, untreated cells, etc.). In some embodiments, the provided TREM1 antibody agent is characterized by its ability to inhibit TREM1 activation and / or reduce the production of TREM1-driven inflammatory mediators (e.g., cytokines, chemokines, etc.) by one or more cells (e.g., neutrophils, myeloid cells (including monocytes), etc.) compared to a reference (e.g., healthy cells, untreated cells, etc.). In some embodiments, the provided TREM1 antibody agent is characterized by its ability to inhibit TREM1 activation and / or reduce the production of certain inflammatory cytokines (e.g., IL-1β, IL-6, IL-8, IL-23, TNFα, and / or combinations thereof) compared to a reference (e.g., healthy cells, untreated cells, etc.). In some embodiments, the provided TREM1 antibody agent is characterized by its ability to inhibit TREM1 activation and reduce the production of certain inflammatory mediators (e.g., APRIL, BAFF, CD30, M-CSF, TRAIL, TWEAK, MMP-1, IL-20, TNFR-II, etc.) compared to a reference (e.g., healthy cells, untreated cells, etc.). In some embodiments, the provided TREM1 antibody agent is characterized by its ability to inhibit TREM1 activation and reduce the production of certain inflammatory chemokines (e.g., CCL2, CCL3, CCL4, CCL8, CCL20, CCL22, CCL24, CXCL1, CXCL5, CXCL9, CXCL13, etc.) compared to a reference (e.g., healthy cells, untreated cells, etc.). In some embodiments, the provided TREM1 antibody agent is characterized by its ability to reduce the production of multiple pro-inflammatory mediators (e.g., cytokines, chemokines, etc.). In some embodiments, the provided TREM1 antibody agent is characterized by its ability to reduce the production of multiple pro-inflammatory mediators (e.g., cytokines, chemokines, etc.) while simultaneously maintaining the innate antimicrobial response.In some embodiments, the provided TREM1 antibody agent is characterized by its ability to reduce the production of multiple pro-inflammatory mediators (e.g., cytokines, chemokines, etc.) while simultaneously preventing further epithelial barrier damage caused by these pro-inflammatory mediators.

[0128] In some embodiments, the TREM1 antibody agents of the Disclosure are characterized by their ability to interfere with (i.e., reduce or block) the binding of TREM1 to one or more of its homologous ligands. For example, in some embodiments, the TREM1 antibody agents of the Disclosure interfere with (i.e., reduce or block) the binding of TREM1 to actin, PGLYRP1, HMGB1, Hsp70, extracellular cryoinducible RNA-binding protein (eCIRP), and / or one or more infectious pathogen-associated antigens (e.g., zymosan, HIV envelope glycoprotein, and / or Marburg virus, Skistosoma mansoni egg antigen, etc.). By interfering with the binding of TREM1 to one or more of its ligands, the TREM1 antibody agents of the Disclosure can inhibit downstream TREM1 signaling (e.g., via DAP12), thereby reducing or preventing the activation of immune cells (e.g., neutrophils, monocytes, etc.). In some embodiments, the TREM1 antibody agent of this disclosure interferes with (i.e., reduces or blocks) the binding of TREM1 to PGLYRP1.

[0129] In some embodiments, the TREM1 antibody agents of this disclosure are characterized by their ability to reduce TREM1 expression on the cell surface of immune cells (e.g., neutrophils, monocytes, etc.). In some embodiments, the TREM1 antibody agents of this disclosure are characterized by their ability to promote the internal translocation of TREM1 into immune cells (e.g., neutrophils, monocytes, etc.) that express surface TREM1. In some embodiments, such immune cells are neutrophils or monocytes. In some embodiments, such immune cells are dendritic cells. Internal translocation of TREM1 can reduce or eliminate downstream TREM1 signaling (e.g., via DAP12), which can further reduce or prevent the activation of immune cells (e.g., neutrophils, monocytes, etc.). In some embodiments, TREM1 antibody agents can promote the internal translocation of TREM1 to varying degrees, at various time points and pharmacokinetics. While we do not wish to be bound by any particular theory, we propose that differences in the ability of TREM1 antibody agents to promote the internal translocation of TREM1 may affect one or more pharmacokinetic properties of the TREM1 antibody agent.

[0130] In some embodiments, the TREM1 antibody agents of the Disclosure are characterized by their ability to promote the proteolytic cleavage of TREM1. In some embodiments, the proteolytic cleavage of TREM1 results in the production of sTREM1. For example, in some embodiments, the TREM1 antibody agents of the Disclosure promote the proteolytic degradation of TREM1 by matrix metalloproteinases (MMPs, e.g., MMP1 or MMP9). By promoting the proteolytic cleavage of TREM1, the TREM1 antibody agents of the Disclosure can reduce or eliminate downstream TREM1 signaling (e.g., via DAP12), which can further reduce or prevent the activation of immune cells (e.g., neutrophils, monocytes, etc.).

[0131] In some embodiments, the TREM1 antibody agents of the Disclosure are characterized by their ability to inhibit TREM1-mediated immune responses. For example, in some embodiments, the TREM1 antibody agents of the Disclosure inhibit amplified immune responses that are not innate immune responses (e.g., TLR-mediated immune responses). In some embodiments, the immune response is mediated by monocytes (e.g., inflammatory monocytes) and / or neutrophils (e.g., activated neutrophils). In some embodiments, the immune response is mediated by dendritic cells.

[0132] In some embodiments, the provided TREM1 antibody agent has a binding affinity (K) of approximately 5 nM or less. D ) are characterized by binding to human TREM1 at a rate of approximately 5, 4, 3, 2, 1.5, 1, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.24, 0.23, 0.22, 0.21, 0.2, 0.19, 0.18, 0.17, 0.16, 0.15, 0.14, 0.13, 0.12, 0.11, 0.1, 0.09 or 0.08 nM or less. D It is characterized by binding to human TREM1 at a binding affinity (K). In some embodiments, the provided TREM1 antibody agent has a binding affinity of about 0.21 nM (K). D It is characterized by binding to human TREM1. In some embodiments, human TREM1 is the monomeric human TREM1 extracellular domain (ECD). In some embodiments, binding affinity is measured using a bio-layer interferometry (BLI) assay.

[0133] In some embodiments, the provided TREM1 antibody agent has a binding affinity (K) of approximately 5 nM or less. D ) are characterized by binding to cynoTREM1. In some embodiments, the provided TREM1 antibody agents have a binding affinity (K) of approximately 5, 4, 3, 2.5, 2.4, 2.3, 2.2, 2.1, 2, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15 or less. DIt is characterized by binding to cynoTREM1 at a binding affinity (K). In some embodiments, the provided TREM1 antibody agent has a binding affinity of about 1.9 nM (K). D It is characterized by binding to cynoTREM1. In some embodiments, cynoTREM1 is the monomer cynoTREM1 extracellular domain (ECD). In some embodiments, binding affinity is measured using a biolayer interference (BLI) assay.

[0134] In some embodiments, the provided TREM1 antibody agent has a binding affinity of 1 nM or less (K) in cell binding assays. D The binding affinity (K) of TREM1 is characterized by binding to TREM1 at approximately 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02 or 0.01 nM or less in cell binding assays. D The provided TREM1 antibody agents are characterized by binding affinity (K) of approximately 400, 390, 380, 370, 360, 350, 340, 330, 320, 310, 300, 290, 280, 270, 260, 250, 245, 240, 235, 230, 225, 220, 215, 210, 205, 200, 195, 190, 185, 180, 175, 170, 165, 160, 155, 150, 145, 140, 135, 130, 125, 120, 115, 110, 105, 100, 95, 90, 85, 80, 75 pM or less in cell binding assays. D Characterized by binding to TREM1 at ) . In some embodiments, the provided TREM1 antibody agent has a binding affinity of approximately 87 pM (K) in cell binding assays. D ) is characterized by binding to TREM1. In some embodiments, the provided TREM1 antibody agent has a binding affinity of approximately 213 pM (K) in cell binding assays. D) is characterized by binding to TREM1. In some embodiments, the provided TREM1 antibody agent has a binding affinity of approximately 103 pM (K) in cell binding assays. D Characterized by binding to TREM1 at ) . In some embodiments, the provided TREM1 antibody agent has a binding affinity of approximately 132 pM (K) in cell binding assays. D ) is characterized by binding to TREM1. In some embodiments, the provided TREM1 antibody agent has a binding affinity of approximately 251 pM (K) in cell binding assays. D ) are characterized by binding to TREM1. In some embodiments, the provided TREM1 antibody agent has a binding affinity (K) of approximately 23 pM to approximately 37 pM in cell binding assays. D ) are characterized by binding to TREM1. In some embodiments, the provided TREM1 antibody agent has a binding affinity of about 4 pM to about 13 pM (K) in cell binding assays. D Characterized by binding to TREM1. In some embodiments, the cell binding assay measures the binding of the provided TREM1 antibody agent to human TREM1. In some embodiments, the cell binding assay measures the binding of the provided TREM1 antibody agent to cynoTREM1. In some embodiments, the cell binding assay measures the binding of the provided TREM1 antibody agent to human TREM1 present on enriched human monocytes. In some embodiments, the cell binding assay measures the binding of the provided TREM1 antibody agent to human TREM1 present on enriched human neutrophils. In some embodiments, the cell binding assay measures the binding of the provided TREM1 antibody agent to human TREM1 present on whole blood human monocytes. In some embodiments, the cell binding assay measures the binding of the provided TREM1 antibody agent to human TREM1 present on whole blood human neutrophils. In some embodiments, the cell binding assay measures the binding of the provided TREM1 antibody agent to cynoTREM1 present on whole blood cyno monocytes. In some embodiments, the cell binding assay measures the binding of the provided TREM1 antibody agent to cynoTREM1 present on whole blood cynoneutrophils.

[0135] In some embodiments, the provided TREM1 antibody agent is characterized by inhibiting TREM1 activity in primary cell function assays with an IC50 of approximately 50 pM, 48 pM, 46 pM, 44 pM, 42 pM, 40 pM, 38 pM, 36 pM, 34 pM, 32 pM, 30 pM, 28 pM, 26 pM, 24 pM, 22 pM, 20 pM, 18 pM, 16 pM, 15 pM, 14 pM, 13 pM, 12 pM, 11 pM, 10 pM, 9 pM, 8 pM, 7 pM, 6 pM, 5 pM, 4 pM, 3 pM, or 2 pM. In some embodiments, such primary cell function assays measure inhibition of cytokine or chemokine production by activated neutrophils or monocytes. In some embodiments, the primary cell function assay measures inhibition of CCL3, CCL4, or IL-8 production by activated neutrophils. In some embodiments, inhibition of CCL3, CCL4, or IL-8 production reduces CCL3, CCL4, or IL-8 levels by at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% compared to CCL3, CCL4, or IL-8 levels produced by activated neutrophils not treated with the TREM1 antibody. In some embodiments, the primary cell function assay measures inhibition of CCL3, CCL4, TNFα, IL-1β, IL-6, or IL-23 production by monocytes.In some embodiments, inhibition of CCL3, CCL4, TNFα, IL-1β, IL-6, or IL-23 production is a reduction of at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% of CCL3, CCL4, TNFα, IL-1β, IL-6, or IL-23 levels compared to levels produced by monocytes not treated with the TREM1 antibody. In some embodiments, the primary cell function assay is a human whole blood concentrated neutrophil or monocyte primary cell function assay. In some embodiments, the primary cell function assay is a cyno-whole blood primary cell function assay.

[0136] In some embodiments, the provided TREM1 antibody agent is characterized by having a melting temperature of about 60°C or higher. In some embodiments, the provided TREM1 antibody agent is characterized by having a melting temperature of about 60, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, about 80, about 85, or about 90°C or higher. In some embodiments, the provided TREM1 antibody agent is characterized by having a melting temperature of about 74°C. In some embodiments, the melting temperature of the antibody agent is assessed using differential scanning fluorescence quantification.

[0137] In some embodiments, the provided TREM1 antibody agent is characterized by its ability to antagonize TREM1-mediated inhibition of monocyte-to-macrophage maturation.

[0138] In some embodiments, the provided TREM1 antibody agent is characterized by its ability to bind to inactivated TREM1. In some embodiments, the provided TREM1 antibody agent is characterized by its ability to bind to activated TREM1 (e.g., TREM1 activated by exposure to bacterial peptidoglycan and PGLYRP1). In some embodiments, the provided TREM1 antibody agent is characterized by its ability to bind to both inactivated and activated TREM1. While we do not wish to be bound by any particular theory, TREM1 activation is thought to result in a change in the conformation of TREM1. In some embodiments, the provided TREM1 antibody agent is characterized by its ability to bind to TREM1 in a multi-conformation mode.

[0139] In some embodiments, the provided TREM1 antibody agent is characterized by not binding to the surface of cells that do not express TREM1. In some embodiments, such cells may be human cells or cynomolgus monkey cells. While we do not wish to be bound to any particular theory, cells that do not typically express TREM1 may include, but are not limited to, B cells, T cells, and NK cells. In some embodiments, the provided TREM1 antibody agent is characterized by not binding to the cell surface of B cells. In some embodiments, the provided TREM1 antibody agent is characterized by not binding to the cell surface of T cells. In some embodiments, the provided TREM1 antibody agent is characterized by not binding to the cell surface of NK cells.

[0140] In some embodiments, the TREM1 antibody agent provided is characterized by its ability to inhibit epithelial barrier damage caused by TREM1 and / or one or more TREM1 inflammatory mediators. For example, in some embodiments, the TREM1 antibody agent of the Disclosure inhibits epithelial barrier damage caused by one or more cytokines (e.g., TNFα, IL-6, IL-8, and IL-1β) amplified by TREM1. In some embodiments, the TREM1 antibody agent provided is characterized by its ability to inhibit epithelial barrier damage caused by TREM1 soluble factors (e.g., TWEAK and TRAIL) associated with epithelial apoptosis.

[0141] In some embodiments, the provided TREM1 antibody agent is a human antibody. In some embodiments, the provided TREM1 antibody agent is a humanized antibody. In some embodiments, the provided TREM1 antibody agent is human IgG or contains human IgG. In some embodiments, the provided TREM1 antibody agent is human IgG1k or contains human IgG1k. In some embodiments, the provided TREM1 antibody agent contains a mutant Fc skeleton. In some embodiments, the provided TREM1 antibody agent contains a mutant Fc skeleton having reduced binding to the Fc receptor. In some embodiments, the TREM1 inhibitor is an anti-TREM1 chimeric antibody or contains an anti-TREM1 chimeric antibody.

[0142] In some embodiments, the TREM1 antibody agents disclosed herein compete with reference TREM1 antibody agents for binding to TREM1. In some embodiments, such reference TREM1 antibody agents are or include the anti-TREM1 antibody described in any of the following International Publications: 2013 / 120553, 2016 / 009086, 2017 / 152102, 2019 / 195126, 2020 / 0163564, 2021 / 011681, 2021 / 011678, 2022 / 233764, 2022 / 253991, and 2022 / 272018.

[0143] In some embodiments, the TREM1 antibody agent of the Disclosure may be an immunoglobulin (e.g., IgG1, IgG2, IgG3, or IgG4), a heterodimer, a Crossmab, DVD-Ig, two-in-one IgG, IgG-sc-Fv, scFv-scFv, BiTE, DART, diabody, Fab-scFv fusion, Fab-Fab fusion, or a tandem antibody. In some embodiments, the TREM1 antibody agent of the Disclosure may be an intact IgA, IgG, IgD, IgE, or IgM antibody; an antibody fragment; a single-domain antibody; a single-chain Fv; or a polypeptide having antigen-binding specificity fused to an Fc domain.

[0144] In some embodiments, the TREM1 antibody agents of this disclosure include a second binding specificity to antigens other than human TREM1. For example, the second binding specificity may be to another pro-inflammatory mediator or to a protein expressed on the surface of an immune cell.

[0145] In various embodiments, the provided TREM1 antibody agent is characterized by CDR sequences found in the heavy and / or light chain polypeptide variable region sequences contained in SEQ ID NOs: 14 and 18, respectively, as herein. In many embodiments, the provided antibody agent comprises all three CDRs from a single chain (i.e., heavy chain CDR1, 2, and 3 or light chain CDR1, 2, and 3 or both). Those skilled in the art will understand that different systems for defining CDR sequences have been described, such as those described in Lefranc et al., Dev. Comp. Immunol. Vol. 27 (No. 1): pp. 55-77 (2003), Kabat et al., J. Biol. Chem. Vol. 252, pp. 6609-6616 (1977), Kabat et al., Sequences of protein of immunological interest. (1991), Chothia et al., J. Mol. Biol. Vol. 196: pp. 901-917 (1987), and MacCallum et al., J. Mol. Biol. Vol. 262: pp. 732-745 (1996). Furthermore, those skilled in the art can easily define and utilize the sequences constituting the CDRs in sequences 14 and 18.

[0146] This disclosure provides antibody heavy chains and their binding portions (e.g., variable domains or CDRs), and also provides antibody light chains and their binding portions (e.g., variable domains or CDRs). In some embodiments, the provided heavy chains or their binding portions may be used together with the provided light chains or their binding portions. Alternatively or additionally, in some embodiments, the provided heavy chains or their binding portions may be used together with different light chains or their binding portions, and / or the provided light chains or their binding portions may be used together with different heavy chains or their binding portions.

[0147] In many embodiments, the provided antibody heavy chain or its binding portion (e.g., a variable domain or CDR) is used together with the provided antibody light chain or its binding portion (e.g., a variable domain or CDR). In some embodiments, the provided antibody heavy chain and light chain CDR are incorporated into one or more alternative framework regions.

[0148] In some embodiments, the TREM1 antibody agent of the Disclosure provided comprises heavy chain CDR1, CDR2, and CDR3 sequences that are at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical to SEQ ID NOs. 15, 16, and 17, respectively. In some embodiments, the TREM1 antibody agent of the Disclosure provided comprises light chain CDR1 and CDR3 sequences that are at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical to SEQ ID NOs. 19 and 20, respectively, and comprises the light chain CDR2 sequence of GAS. In some embodiments, the TREM1 antibody agent of the Disclosure provided comprises heavy chain CDR1, CDR2, and CDR3 sequences that are 100% identical to SEQ ID NOs. 15, 16, and 17, respectively. In some embodiments, the TREM1 antibody agent of the present disclosure provided comprises light chain CDR1 and CDR3 sequences which are 100% identical to SEQ ID NOs. 19 and 20, respectively, and comprises the light chain CDR2 sequence of GAS.

[0149] In some embodiments, the provided TREM1 antibody agent includes a heavy chain variable domain sequence having at least 60% sequence identity with SEQ ID NO: 14 or a portion thereof. In some embodiments, the provided TREM1 antibody agent includes a heavy chain variable domain sequence having at least 70% sequence identity with SEQ ID NO: 14 or a portion thereof. In some embodiments, the provided TREM1 antibody agent includes a heavy chain variable domain sequence having at least 80% sequence identity with SEQ ID NO: 14 or a portion thereof. In some embodiments, the provided TREM1 antibody agent includes a heavy chain variable domain sequence having at least 90% sequence identity with SEQ ID NO: 14 or a portion thereof. In some embodiments, the provided TREM1 antibody agent includes a heavy chain variable domain having at least 95% sequence identity with SEQ ID NO: 14 or a portion thereof. In some embodiments, the provided TREM1 antibody agent includes a heavy chain variable domain sequence having at least 99% sequence identity with SEQ ID NO: 14 or a portion thereof. In some embodiments, the provided TREM1 antibody agent includes a heavy chain variable domain sequence identical to SEQ ID NO: 14 or a portion thereof.

[0150] In some embodiments, the provided TREM1 antibody agent includes a light chain variable domain sequence having at least 60% sequence identity with SEQ ID NO: 18 or a portion thereof. In some embodiments, the provided TREM1 antibody agent includes a light chain variable domain sequence having at least 70% sequence identity with SEQ ID NO: 18 or a portion thereof. In some embodiments, the provided TREM1 antibody agent includes a light chain variable domain sequence having at least 80% sequence identity with SEQ ID NO: 18 or a portion thereof. In some embodiments, the provided TREM1 antibody agent includes a light chain variable domain sequence having at least 90% sequence identity with SEQ ID NO: 18 or a portion thereof. In some embodiments, the provided TREM1 antibody agent includes a light chain variable domain having at least 95% sequence identity with SEQ ID NO: 18 or a portion thereof. In some embodiments, the provided TREM1 antibody agent includes a light chain variable domain sequence having at least 99% sequence identity with SEQ ID NO: 18 or a portion thereof. In some embodiments, the provided TREM1 antibody agent includes a light chain variable domain sequence identical to SEQ ID NO: 18 or a portion thereof.

[0151] In some embodiments, the provided TREM1 antibody agent includes a heavy chain variable domain sequence having at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 14 and a light chain variable domain sequence having at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 18. In some embodiments, the provided TREM1 antibody agent includes a heavy chain variable domain sequence having 100% sequence identity with SEQ ID NO: 14 and a light chain variable domain sequence having 100% sequence identity with SEQ ID NO: 18.

[0152] In some embodiments, the provided TREM1 antibody agent is a single-chain antibody (e.g., scFv) comprising a heavy chain variable domain sequence having at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 14 and a light chain variable domain sequence having at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 18. In some embodiments, the provided TREM1 antibody agent is an scFv antibody containing a heavy chain variable domain sequence having 100% sequence identity with SEQ ID NO: 14 and a light chain variable domain sequence having 100% sequence identity with SEQ ID NO: 18.

[0153] In some embodiments, the heavy and / or light chains of the TREM1 antibody agent of this disclosure may have a difference of 1, 2, 3, 4, or 5 or fewer amino acid sequences compared to SEQ ID NO: 14 and / or SEQ ID NO: 18, respectively.

[0154] In some embodiments, the heavy chain of the TREM1 antibody agent of this disclosure may include one, two, three, or four framework regions (FR regions) that collectively have at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with the sequence found in SEQ ID NO: 14, and / or collectively include differences of one, two, three, four, or five or fewer amino acids compared to the sequence found in SEQ ID NO: 14. In some embodiments, the heavy chain of the TREM1 antibody agent of this disclosure may include a variable region (VH) containing one, two, three, or four FR regions, each independently having an amino acid sequence that is one of SEQ ID NOs: 21, 22, 23, or 24, an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to one of SEQ ID NOs: 21, 22, 23, or 24, or an amino acid sequence that differs by one, two, three, four, or five or fewer amino acid sequences from one of SEQ ID NOs: 21, 22, 23, or 24.

[0155] In some embodiments, the light chain of the TREM1 antibody agent of the present disclosure may include one, two, three, or four framework regions (FR regions) that collectively have at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with the sequence found in SEQ ID NO: 18, and / or collectively include differences of one, two, three, four, or five or fewer amino acids compared to the sequence found in SEQ ID NO: 18.

[0156] In some embodiments, the light chain of the TREM1 antibody agent of the present disclosure may include one, two, three, or four framework regions (FR regions) that collectively have at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with the sequence found in SEQ ID NO: 18, and / or collectively include differences of one, two, three, four, or five or fewer amino acids compared to the sequence found in SEQ ID NO: 18. In some embodiments, the light chain of the TREM1 antibody agent of this disclosure may include variable regions (VLs) each independently having one, two, three, or four FR regions, each containing an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to one of SEQ ID NOs: 25, 26, 27, or 28, or an amino acid sequence that differs from one of SEQ ID NOs: 25, 26, 27, or 28 by one, two, three, four, or five or fewer amino acid sequences, or an amino acid sequence containing these.

[0157] In some embodiments, the provided TREM1 antibody agent comprises at least one constant region (CH) (e.g., CH1, CH2, and / or CH3 regions). In some embodiments, the provided TREM1 antibody agent comprises the CH2 and CH3 regions, e.g., an Fc domain. In some embodiments, the Fc domain is a mouse, rat, rabbit, primate, human, dog, pig, or cat Fc domain. In some embodiments, the provided TREM1 antibody agent comprises an Fc domain selected from an immunoglobulin isotype (e.g., IgA, IgG, IgM, or IgE). In some embodiments, the provided TREM1 antibody agent comprises an IgG1, IgG2, IgG2, or IgG4 Fc domain. For example, in some embodiments, the provided TREM1 antibody agent of this disclosure comprises an IgG1 Fc domain. In some embodiments, the IgG1 Fc domain includes a polypeptide having a sequence with at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity in sequence number 29 or a portion thereof.

[0158] [ka]

[0159] In some embodiments, the Fc domain is a wild-type Fc domain, for example, a wild-type human Fc domain. In some embodiments, the Fc domain includes a variant, for example, the Fc domain includes the addition, substitution, or deletion of at least one amino acid residue in the Fc region, which results in, for example, reduced or decreased affinity to the Fc receptor.

[0160] The Fc domain of antibodies interacts with numerous receptors or ligands, including Fc receptors (e.g., FcγRI, FcγRIIA, FcγRIIIA), complement protein Clq, and other molecules such as proteins A and G. These interactions are essential for various effector functions and downstream signaling events, including antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell phagocytosis (ADCP), and complement-dependent cell-mediated cytotoxicity (CDC).

[0161] In some embodiments, the provided TREM1 antibody agent comprises a variant Fc domain having one or more of the following properties: (1) reduced effector function (e.g., reduced ADCC, ADCP, and / or CDC), (2) reduced binding to one or more Fc receptors, and / or (3) reduced binding to Clq complement. In some embodiments, the reduction of one or all of properties (1) to (3) is compared to an antibody having a wild-type Fc region that is otherwise similar. In some embodiments, the TREM1 antibody agent containing the variant Fc region has reduced affinity to human Fc receptors, e.g., FcγRI, FcγRII, and / or FcγRIII, or complement components, e.g., Clq. Exemplary Fc region variants are known in the art.

[0162] In some embodiments, the provided TREM1 antibody agent comprises a variant IgG1 Fc domain having one or more amino acid additions, substitutions, or deletions. In some embodiments, the provided TREM1 antibody agent comprises an IgG1 Fc domain having one or more amino acid substitutions and / or deletions at positions 233, 234, 235 and / or 236 (according to the EU numbering scheme). In some embodiments, the provided TREM1 antibody agent comprises an IgG1 Fc domain in which the ELLG residues at amino acid positions 233, 234, 235 and 236 (according to the EU numbering scheme) are replaced with PVA ("PVAdelG"). In some embodiments, the provided TREM1 antibody agent includes an IgG1 Fc domain sequence having at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with sequence number 30 or a portion thereof. In some embodiments, the provided TREM1 antibody agent includes an IgG1 Fc domain sequence identical to SEQ ID NO: 30 or a portion thereof.

[0163] [ka]

[0164] In some embodiments, the provided TREM1 antibody agent includes a heavy chain having at least 60% sequence identity with SEQ ID NO: 31 or a portion thereof. In some embodiments, the provided TREM1 antibody agent includes a heavy chain having at least 70% sequence identity with SEQ ID NO: 31 or a portion thereof. In some embodiments, the provided TREM1 antibody agent includes a heavy chain having at least 80% sequence identity with SEQ ID NO: 31 or a portion thereof. In some embodiments, the provided TREM1 antibody agent includes a heavy chain having at least 90% sequence identity with SEQ ID NO: 31 or a portion thereof. In some embodiments, the provided TREM1 antibody agent includes a heavy chain having at least 95% sequence identity with SEQ ID NO: 31 or a portion thereof. In some embodiments, the provided TREM1 antibody agent includes a heavy chain having at least 99% sequence identity with SEQ ID NO: 31 or a portion thereof. In some embodiments, the provided TREM1 antibody agent includes a heavy chain identical to SEQ ID NO: 31 or a portion thereof.

[0165] In some embodiments, the TREM1 antibody agent includes a light chain constant region (CL). For example, such a light chain CL may include kappa CL or lambda CL. In some embodiments, the kappa CL is an amino acid sequence of SEQ ID NO: 32, an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 32, or an amino acid sequence having 5, 10, or 20 or fewer amino acid sequences different from SEQ ID NO: 32, or an amino acid sequence containing these.

[0166] [ka]

[0167] In some embodiments, the provided TREM1 antibody agent includes a light chain sequence having at least 60% sequence identity with SEQ ID NO: 33 or a portion thereof. In some embodiments, the provided TREM1 antibody agent includes a light chain having at least 70% sequence identity with SEQ ID NO: 33 or a portion thereof. In some embodiments, the provided TREM1 antibody agent includes a light chain having at least 80% sequence identity with SEQ ID NO: 33 or a portion thereof. In some embodiments, the provided TREM1 antibody agent includes a light chain having at least 90% sequence identity with SEQ ID NO: 33 or a portion thereof. In some embodiments, the provided TREM1 antibody agent includes a light chain having at least 95% sequence identity with SEQ ID NO: 33 or a portion thereof. In some embodiments, the provided TREM1 antibody agent includes a light chain having at least 99% sequence identity with SEQ ID NO: 33 or a portion thereof. In some embodiments, the provided TREM1 antibody agent includes a light chain identical to SEQ ID NO: 33 or a portion thereof.

[0168] In some embodiments, the provided TREM1 antibody agent includes a heavy chain sequence having at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 31 and a light chain sequence having at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 33. In some embodiments, the provided TREM1 antibody agent includes a heavy chain sequence having 100% sequence identity to SEQ ID NO: 31 and a light chain sequence having 100% sequence identity to SEQ ID NO: 33.

[0169] In some embodiments, the provided TREM1 antibody agent comprises two heavy chains, each having a sequence that is at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 31, and two light chains, each having a sequence that is at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 33. In some embodiments, the provided TREM1 antibody agent comprises two heavy chains having sequences identical to 100% of SEQ ID NO: 31 and two light chains having sequences identical to 100% of SEQ ID NO: 33.

[0170] In some embodiments, the provided TREM1 antibody agent comprises the heavy chain of SEQ ID NO: 31 and the light chain of SEQ ID NO: 33 or humanized variants thereof.

[0171] In some embodiments, the heavy and / or light chains of the TREM1 antibody agent of this disclosure may have a difference of 1, 2, 3, 4, or 5 or fewer amino acids in their sequence compared to SEQ ID NO: 31 and / or SEQ ID NO: 33, respectively.

[0172] Table 2 below provides exemplary TREM1 antibody agent sequences of the present disclosure.

[0173] [Table 4] TIFF2026514609000011.tif114168

[0174] TREM1 combination therapy In some embodiments, inflammatory diseases, disorders, or conditions may be treated with a combination of a TREM1 antibody and another anti-inflammatory drug. For example, in some embodiments, a TREM1 antibody may be used in combination with one or more alternative anti-inflammatory therapies that do not target TREM1 to treat inflammatory diseases, disorders, or conditions. Such alternative anti-inflammatory therapies may include, but are not limited to, anti-TNFα agents, α4 integrin targeters (e.g., natalizumab), α4β7 integrin targeters (e.g., vedolizumab), Janus kinase (JAK) inhibitors (e.g., tofacitinib), anti-IL-12 / IL-23 agents (e.g., ustekinumab), anti-TL1A agents (e.g., PRA023 and RVT-3101), and sphingosine-1-phosphate receptor (S1PR) agonists (e.g., ozanimod and etrasimodo).

[0175] In some embodiments, inflammatory diseases, disorders, or conditions may be treated by a combination of a TREM1 antibody and the administration of integrin inhibition, particularly integrin inhibitors (i.e., by integrin inhibitor therapy). In some embodiments, the integrin inhibitor is an antiintegrin agent or comprises an antiintegrin agent. In some embodiments, the antiintegrin agent is an α4 integrin targeter (e.g., natalizumab) or comprises an α4 integrin targeter (e.g., natalizumab). In some embodiments, the antiintegrin agent is an α4β7 integrin targeter (e.g., vedolizumabub) or comprises an α4β7 integrin targeter (e.g., vedolizumabub).

[0176] In some embodiments, inflammatory diseases, disorders, or conditions may be treated by a combination of a TREM1 antibody and the administration of sphingosine monophosphate receptor (S1PR) activation, particularly an S1PR agonist. In some embodiments, the S1PR agonist is or comprises ozanimod. In some embodiments, the S1PR agonist is or comprises etrasimodo.

[0177] In some embodiments, inflammatory diseases, disorders, or conditions may be treated by a combination of TREM1 antibody agents and TNFα inhibition, particularly by the administration of TNFα inhibitors (i.e., by TNFα inhibitory therapy). In some embodiments, the TNFα inhibitor is an anti-TNFα agent or comprises an anti-TNFα agent. Examples of anti-TNFα agents approved for use in the United States include monoclonal antibodies, e.g., adalimumab (Humira®), certolizumab pegol (Cimiza®), golimumab (Simponi®), infliximab (Remicade®), and decoy circulating receptor fusion proteins, e.g., etanercept (Enbrel®). These drugs are currently approved for use in the treatment of indications such as juvenile idiopathic arthritis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, Crohn's disease in adults, Crohn's disease in children, ulcerative colitis, psoriasis vulgaris, hidradenitis suppurativa, and uveitis. In some embodiments, the anti-TNFα agents are biosimilars of approved anti-TNFα agents.

[0178] In some embodiments, a TNFα inhibitor inhibits TNFα. In some embodiments, a TNF inhibitor specifically and / or selectively inhibits TNFα. In some embodiments, a TNFα inhibitor is or comprises an anti-TNFα antibody. In some embodiments, a TNFα inhibitor is or comprises an anti-TNFα antibody. In some embodiments, a TNFα inhibitor is or comprises an anti-TNFα monoclonal antibody. In some embodiments, a TNFα inhibitor is or comprises an anti-TNFα humanized antibody. In some embodiments, a TNFα inhibitor is or comprises an anti-TNFα chimeric antibody.

[0179] This disclosure also provides immunoconjugates comprising the TREM1 antibody agents described herein or a portion thereof, conjugated to anti-inflammatory agents, cytotoxic agents (e.g., chemotherapeutic agents), toxins (e.g., enzyme-active toxins of bacterial, fungal, plant, or animal origin, or fragments thereof), and / or diagnostic agents (e.g., radioisotopes, etc.).

[0180] nucleic acid This disclosure provides, in particular, nucleic acids encoding the TREM1 antibody agents described herein or polypeptides provided herein (e.g., LC polypeptides and / or HC polypeptides). This disclosure comprises polynucleotides encoding one or more of the following: a heavy chain, a VH domain, a heavy chain FR, a heavy chain CDR, a heavy chain constant domain, a light chain, a VL domain, a light chain FR, a light chain CDR, a light chain constant domain, or other immunoglobulin-like sequences disclosed herein, an antibody, or an antigen-binding fragment thereof. Such nucleic acids may be present in a vector. Such nucleic acids may be present in the genome of a cell, for example, in a cell of a target requiring treatment, or in a cell for antibody production, for example, a mammalian cell for the production of the antibody agents described herein or polypeptides provided herein (e.g., LC polypeptides and / or HC polypeptides).

[0181] The nucleic acids encoding the antibody agent or polypeptides provided herein (e.g., LC polypeptides and / or HC polypeptides) may be modified to include codons optimized for expression in a particular cell type or organism. The codon-optimized sequence is a synthetic sequence and preferably encodes the same polypeptide as the polypeptide encoded by the non-codon-optimized reference nucleic acid (or a bioactive fragment of a full-length polypeptide having substantially the same activity as the full-length polypeptide). Codon optimization may be carried out by commercial antibody development companies (e.g., Sanyou Bio, Aragen, Viva Biotech, Sino Biological, WuXi Biologics, etc.). In some embodiments, the coding region of the nucleic acid encoding the antibody agent or polypeptides provided herein (e.g., LC polypeptides and / or HC polypeptides) may, in whole or in part, include modified sequences that optimize codon use in a particular cell type (e.g., eukaryotic or prokaryotic cells). For example, the coding sequence of the humanized heavy (or light) chain variable region described herein may be optimized for expression in bacterial cells. Alternatively, the coding sequence may be optimized for expression in mammalian cells (e.g., CHO cells). Such sequences can be described as codon-optimized sequences.

[0182] In some embodiments, the Disclosure provides a single nucleic acid (e.g., DNA or RNA) encoding a TREM1 antibody heavy chain variable domain and a light chain variable domain. In some embodiments, the Disclosure provides a single nucleic acid encoding a heavy chain variable domain having a sequence that is at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 14, and a light chain variable domain having a sequence that is at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 18. In some embodiments, the nucleic acid has a nucleotide sequence that is at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 38 and / or SEQ ID NO: 39, or comprises such a nucleotide sequence.

[0183] In some embodiments, the Disclosure provides a single nucleic acid (e.g., DNA or RNA) encoding a TREM1 antibody heavy chain and a light chain. In some embodiments, the Disclosure provides a single polynucleotide encoding a heavy chain having a sequence that is at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 31, and a light chain having a sequence that is at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 33. In some embodiments, such nucleic acids have a nucleotide sequence that is at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 42 and / or SEQ ID NO: 43, or comprises such a nucleotide sequence.

[0184] In some embodiments, the Disclosure provides a composition comprising two or more nucleic acids (e.g., DNA or RNA), one nucleic acid encoding the TREM1 antibody heavy chain variable domain, and another nucleic acid encoding the TREM1 antibody light chain variable domain. In some embodiments, such a composition comprises a nucleic acid encoding a heavy chain variable domain having a sequence that is at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 14, and another nucleic acid encoding a light chain variable domain having a sequence that is at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 18. In some embodiments, the nucleic acid encoding the TREM1 antibody heavy chain variable domain has a nucleotide sequence that is at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to or containing such a nucleotide sequence. In some embodiments, the nucleic acid encoding the TREM1 antibody light chain variable domain has a nucleotide sequence that is at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to or containing such a nucleotide sequence.

[0185] In some embodiments, the Disclosure provides a composition comprising two or more nucleic acids (e.g., DNA or RNA), one nucleic acid encoding a TREM1 antibody heavy chain and another nucleic acid encoding a TREM1 antibody light chain. In some embodiments, such a composition comprises a nucleic acid encoding a heavy chain having a sequence that is at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 31, and another nucleic acid encoding a light chain having a sequence that is at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 33. In some embodiments, the nucleic acid encoding the TREM1 antibody heavy chain has a nucleotide sequence that is at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to or containing such a nucleotide sequence. In some embodiments, the nucleic acid encoding the TREM1 antibody heavy chain has a nucleotide sequence that is at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to or containing such a nucleotide sequence.

[0186] In some embodiments, the Disclosure provides two or more compositions, one of which comprises a nucleic acid encoding a TREM1 antibody heavy chain variable domain, and another comprising a nucleic acid encoding a TREM1 antibody light chain variable domain. In some embodiments, one composition comprises a nucleic acid encoding a heavy chain variable domain having a sequence that is at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 14, and another composition comprises a nucleic acid encoding a light chain variable domain having a sequence that is at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 18. In some embodiments, the nucleic acid encoding the TREM1 antibody heavy chain variable domain has a nucleotide sequence that is at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to or containing such a nucleotide sequence. In some embodiments, the nucleic acid encoding the TREM1 antibody light chain variable domain has a nucleotide sequence that is at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to or containing such a nucleotide sequence.

[0187] In some embodiments, the Disclosure provides two or more compositions, one of which comprises a nucleic acid encoding a TREM1 antibody heavy chain, and another comprising a nucleic acid encoding a TREM1 antibody light chain. In some embodiments, one composition comprises a nucleic acid encoding a heavy chain having a sequence that is at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 31, and another composition comprises a nucleic acid encoding a light chain having a sequence that is at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 33. In some embodiments, the nucleic acid encoding the TREM1 antibody heavy chain has a nucleotide sequence that is at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to or containing such a nucleotide sequence. In some embodiments, the nucleic acid encoding the TREM1 antibody heavy chain has a nucleotide sequence that is at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to or containing such a nucleotide sequence.

[0188] Table 3 provides exemplary polynucleotide sequences encoding the heavy chain and / or light chain of the TREM1 antibody agent of this disclosure.

[0189] [Table 5] TIFF2026514609000013.tif224168TIFF2026514609000014.tif124168

[0190] In some embodiments, the sequence of one or more nucleic acids encoding the TREM1 antibody agent of this disclosure or a portion thereof (e.g., heavy chain, light chain, heavy chain variable domain, or light chain variable domain) is a codon optimized for expression in a target, e.g., human. The sequence of one or more nucleic acids may also be a codon optimized for a specific organ.

[0191] In short, codon optimization refers to the process of modifying a nucleotide sequence to enhance expression in a target host cell by replacing at least one codon in the native sequence (e.g., approximately 1, 2, 3, 4, 5, 10, 15, 20, 25, 50, 75, 100 or more codons) with a codon more frequently used in the host cell's gene, while simultaneously maintaining the native amino acid sequence. Different species exhibit a particular bias towards certain codons of specific amino acids. Codon bias (differences in codon use between organisms) often correlates with the translation efficiency of messenger RNA (mRNA), and this correlation depends, at least in part, on the characteristics of the codon being translated and the availability of a particular transfer RNA (tRNA) molecule. The dominance of selected tRNAs in a cell is a general reflection of the codons most frequently used in peptide synthesis. Thus, genes can be tailored for optimal gene expression in a given organism based on codon optimization. Codon usage tables are readily available, such as the "Codon Usage Database" at www.kazusa.or.jp / codon / , and these tables can be adapted in numerous ways. See, for example, Nakamura, Y. et al., "Codon usage tabulated from the international DNA sequence databases: status for the year 2000," Nucl. Acids Res. Vol. 28: p. 292 (2000). Computer algorithms for codon-optimizing specific sequences for expression in specific host cells are also available, such as Gene Forge (Aptagen: Jacobus, Pa).

[0192] composition This disclosure provides, in particular, compositions comprising or for delivering antibody agents, conjugates, combinations and / or nucleic acids as described herein. In some embodiments, the composition is a pharmaceutical composition comprising one or more antibody agents (e.g., TREM1 antibody agents) and one or more pharmaceutical excipients as disclosed herein.

[0193] Polymer composition In particular, this disclosure provides a composition comprising a TREM1 antibody agent or a part thereof (e.g., a heavy chain, a light chain, a heavy chain variable domain, or a light chain variable domain) or one or more nucleic acids encoding a TREM1 antibody agent or a part thereof, and one or more polymers that form particles such as microspheres, microparticles, nanoparticles, nanospheres, or liposomes. Suitable polymers include, but are not limited to, natural or synthetic copolymers or polymers such as gelatin agar, starch, arabinogalactan, albumin, collagen, polyglycolic acid, polybutyric acid (polylactic acid, glycolide-L(-)lactide), poly(epsilon-caprolactone), poly(epsilon-caprolactone-CO-lactic acid), poly(epsilon-caprolactone-CO-glycolic acid), poly(B-hydroxybutyric acid), polyethylene oxide, polyethylene, poly(alkyl-2-cyanoacrylate), poly(hydroxyethyl methacrylate), polyamide, poly(amino acid), poly(2-hydroxyethyl DL-aspartamide), poly(ester urea), poly(L-phenylalanine / ethylene glycol / 1,6-diisocyanatohexane), or poly(methyl methacrylate).

[0194] In particular, this disclosure provides compositions comprising microspheres, microparticles, nanoparticles, nanospheres, or liposomes encapsulating nucleic acids encoding the heavy chain and light chain variable domains of a TREM1 antibody agent.

[0195] In particular, the present disclosure provides a composition comprising microspheres, microparticles, nanoparticles, nanospheres or liposomes encapsulating at least two nucleic acids, wherein one nucleic acid encodes the heavy chain variable domain of a TREM1 antibody agent and another nucleic acid encodes the light chain variable domain of the TREM1 antibody agent. In particular, the present disclosure provides a composition comprising microspheres, microparticles, nanoparticles, nanospheres or liposomes encapsulating at least two nucleic acids, wherein one nucleic acid encodes the heavy chain of a TREM1 antibody agent and another nucleic acid encodes the light chain of the TREM1 antibody agent.

[0196] In particular, the present disclosure provides at least two compositions, one composition comprising microspheres, microparticles, nanoparticles, nanospheres or liposomes encapsulating a nucleic acid encoding the heavy chain variable domain of a TREM1 antibody agent, and another composition comprising microspheres, microparticles, nanoparticles, nanospheres or liposomes encapsulating a nucleic acid encoding the light chain variable domain of the TREM1 antibody agent. In particular, the present disclosure provides at least two compositions, one composition comprising microspheres, microparticles, nanoparticles, nanospheres or liposomes encapsulating a nucleic acid encoding the heavy chain of a TREM1 antibody agent, and another composition comprising microspheres, microparticles, nanoparticles, nanospheres or liposomes encapsulating a nucleic acid encoding the light chain of the TREM1 antibody agent. In particular, the at least two compositions are delivered to cells simultaneously. In particular, the at least two compositions are delivered to cells at different time points.

[0197] Viral composition This disclosure, in particular, describes how to encode one or more nucleic acids encoding a TREM1 antibody or a portion thereof (e.g., heavy chain, light chain, heavy chain variable domain, or light chain variable domain) using a viral vector-based platform, including, but not limited to, lentiviruses of any generation designed to target specific cell types or receptors, such as vaccinia, fowlpox, self-replicating alphavirus, marabavirus, adenovirus (see, e.g., Tatsis et al., Adenoviruses, Molecular Therapy (2004), Vol. 10, pp. 616-629), second, third, or hybrid second / third generation lentiviruses, and recombinant lentiviruses of any generation designed to target specific cell types or receptors (e.g., Hu et al., Immunization Delivered by Lentiviral Vectors for Cancer and Infectious Diseases, Immunol Rev. (2011), Vol. 239 (No. 1): pp. 45-61, Sakuma et al., Lentiviral vectors: basic to translational, Biochem See J. (2012) Vol. 443 (No. 3): pp. 603-618, Cooper et al., Rescue of splicing-mediated intron loss maximizes expression in lentiviral vectors containing the human ubiquitin C promoter, Nucl. Acids Res. (2015) Vol. 43 (No. 1): pp. 682-690, Zufferey et al., Self-Inactivating Lentivirus Vector for Safe and Efficient In Vivo Gene Delivery, J. Virol. (1998) Vol. 72 (No. 12): pp. 9873-9880), or adeno-associated virus ("AAV") vector (US Patent No. 5,173,414; Tratschin et al., Mol. Cell. Biol. Vol. 5: pp. 3251-3260 (1985); Tratschin et al., Mol. Cell. Biol.(described in more detail in Volume 4: pp. 2072-2081 (1984); Hermonat and Muzyczka, PNAS Vol. 81: pp. 6466-6470 (1984); and Samuiski et al., J. Virol. 63: pp. 03822-3828 (1989)). Provided are compositions for delivery using, as will be well understood by those skilled in the art, viral delivery of one or more nucleic acids encoding an antibody agent or a portion thereof to facilitate expression of the antibody agent or a portion thereof by a cell, which may be accompanied by genome editing, such as the use of nuclease-based genome editing systems (e.g., genome editing systems based on Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR), transcription activator-like effector nucleases (TALEN), zinc finger nucleases (ZFN), and homing endonucleases (HE), or derivatives thereof).

[0198] Pharmaceutical composition The present disclosure provides, inter alia, a pharmaceutical composition for delivering, typically comprising, an active agent (e.g., an antibody agent or a portion thereof, or a nucleic acid encoding such an antibody agent or a portion thereof), one or more pharmaceutically or physiologically acceptable carriers, diluents or excipients. Non-limiting examples and methods for preparing such pharmaceutical compositions are well known in the art, such as, but not limited to, Gennaro, Remington’s Pharmaceutical Sciences, 18th Edition, Mack Publishing Co. (Easton, Pa.) 1990.

[0199] When a “therapeutically effective amount” or “immunologically effective amount” is indicated, the exact amount of a pharmaceutical composition comprising or delivering a TREM1 antibody agent described herein will be determined by a physician, taking into account, for example, individual differences in age, body weight, immune response, and the condition of the patient (subject).

[0200] In some embodiments, the pharmaceutical compositions described herein may include a pharmaceutically acceptable carrier selected to suit the administration method, solubility, and / or stability of the TREM1 antibody agent or a portion thereof (e.g., heavy chain, light chain, heavy chain variable domain, or light chain variable domain) and / or the nucleic acid encoding the TREM1 antibody agent or a portion thereof.

[0201] In some embodiments, the pharmaceutical compositions described herein may contain, but are not limited to, excipients and additives comprising, 1 to 99.99% by weight or volume, proteins, peptides, amino acids, lipids, and carbohydrates (e.g., monosaccharides, di, tri, tetra and oligosaccharides, derivatized sugars such as alditol, aldonic acid, esterified sugars, and polysaccharides or sugar polymers) individually or in combination, and which may be present individually or in combination. Exemplary protein excipients include serum albumin, e.g., human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, etc. Representative amino acid / antibody components that can also function in buffering capacity include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, etc. Suitable carbohydrate excipients for use in the compositions of this disclosure include, for example, monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, and sorbose; disaccharides such as lactose, sucrose, trehalose, and cellobiose; polysaccharides such as raffinose, melezitose, maltodextrin, dextran, and starch; and algitols such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol), and myo-inositol. In some embodiments, the excipients or additives are polymer excipients or additives, including, but not limited to, polyvinylpyrrolidone, ficol (polymer sugar), dextran (e.g., cyclodextrins such as 2-hydroxypropyl-3-cyclodextrin), polyethylene glycol, flavoring agents, antimicrobial agents, sweeteners, antioxidants, antistatic agents, surfactants (e.g., polysorbates such as "TWEEN® 20" and "TWEEN® 80"), lipids (e.g., phospholipids, fatty acids), steroids (e.g., cholesterol), and chelating agents (e.g., EDTA).

[0202] In some embodiments, the pharmaceutical compositions described herein may include buffers, such as neutral buffered saline or phosphate-buffered saline (PBS); carbohydrates, such as glucose, mannose, sucrose, dextran, or mannitol; proteins, polypeptides, or amino acids (e.g., glycine); antioxidants; chelating agents, such as EDTA or glutathione; adjuvants (e.g., aluminum hydroxide); and preservatives. In some embodiments, the buffer is a salt prepared from an organic acid or base. Exemplary buffers include, but are not limited to, organic acid salts (e.g., salts of citric acid, ascorbic acid, gluconic acid, carboxylic acids, tartaric acid, succinic acid, acetic acid, and phthalic acid), Tris, tromethamine hydrochloride, and phosphate buffers. In some embodiments, the pharmaceutical compositions are substantially free of impurities, for example, free from detectable levels of impurities (e.g., endotoxins).

[0203] In some embodiments, the pharmaceutical compositions described herein may be administered in an appropriate manner to the disease, disorder, or condition to be treated or prevented. In some embodiments, the dose and / or frequency of administration may be determined by factors such as the patient's condition and / or the type and / or severity of the patient's disease, disorder, or condition, but the appropriate dose may be determined by clinical trials.

[0204] In some embodiments, the pharmaceutical compositions provided by this disclosure may be in forms such as liquid, semi-solid, and solid dosage forms, e.g., liquids (e.g., liquids for injection and infusion), dispersants or suspensions, liposomes, and suppositories. Typically, the pharmaceutical compositions comprising or delivering antibody agents are liquids for injection or infusion, and in some such embodiments, such compositions may be formulated for intravenous, subcutaneous, intradermal, intratumoral, intranodal, intramedullary, intramuscular, transarterial, sublingual, intranasal, topical, or intraperitoneal administration. In some embodiments, the pharmaceutical compositions provided are formulated for intravenous administration. In some embodiments, the pharmaceutical compositions provided are formulated for subcutaneous administration.

[0205] The pharmaceutical compositions described herein may be formulated for administration using infusion techniques commonly known in the art (see, for example, Rosenberg et al., New Eng. J. of Med. 319:1676, 1988, which is incorporated herein by reference in its entirety).

[0206] In some embodiments, the pharmaceutical compositions described herein are administered in combination with (for example, before, concurrently with, or following) additional therapies for symptoms, diseases, or disorders, such as standard treatments for symptoms, diseases, or disorders. In some embodiments, the pharmaceutical compositions described herein may be administered preoperatively or postoperatively.

[0207] In some embodiments, the dosage of any of the aforementioned therapies to be administered to a subject varies depending on the disease, disorder, or condition being treated and on the specific subject. Dosage adjustments for human administration can be carried out by methods permitted in the art.

[0208] Disease, disability, or condition In general, the TREM1 antibody agents disclosed herein are useful in any context in which the administration of anti-inflammatory therapy is intended or performed. In some embodiments, the TREM1 antibody agents of this disclosure are useful in the treatment of subjects suffering from diseases, disorders or conditions associated with abnormal (e.g., elevated) inflammation.

[0209] Other aspects of this disclosure include chronic obstructive pulmonary disease (COPD), acute lung injury or acute respiratory distress syndrome (ARDS), post-stroke injury, post-myocardial infarction injury, ischemic-reperfusion injury, dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, tauopathies, and Nasu-Hakora disease. Diseases, stroke, acute trauma, chronic trauma, cognitive impairment, memory loss, lupus, acute and chronic colitis, rheumatoid arthritis (RA), atherosclerosis, wound healing, Crohn's disease, inflammatory bowel disease (IBD), ulcerative colitis, obesity, malaria, essential tremor, central nervous system lupus, psoriasis, Behçet's disease, Parkinson's disease, Lewy body dementia, multiple system atrophy, Shy-Drager syndrome, progressive supranuclear palsy, corticobasal degeneration, acute disseminated encephalomyelitis, granulomatous disorders Disorders, sarcoidosis, age-related diseases, seizures, spinal cord injury, traumatic brain injury, age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, respiratory tract infections, sepsis, eye infections, systemic infections, lupus, arthritis, multiple sclerosis, low bone density, osteoporosis, bone formation, osteopetrosis, Paget's disease of bone, bladder cancer, brain cancer, gliomas such as low-grade glioma or glioblastoma, breast cancer, cervical cancer, colon cancer, rectal cancer, endometrial cancer Kidney cancer, renal cell carcinoma, renal pelvis cancer, leukemia, lung cancer (e.g., non-small cell lung cancer), melanoma, non-Hodgkin lymphoma, pancreatic cancer, prostate cancer, ovarian cancer, fibrosarcoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), multiple myeloma, polycythemia vera, essential thrombocytosis, fibrosis, primary or idiopathic myelofibrosis, primary or idiopathic myelosclerosis, bone marrow-derived tumors, thyroid cancer, infections, CNS herpes, parasitic infections, trypanosomiasis infections, Cruzi infection, Pseudomonas erginosa infection, Leishmania dnovaniThis invention relates to an isolated antibody agent conjugated to the TREM1 protein described herein, used to prevent, reduce the risk of, or treat individuals having a disease, disorder, or injury selected from the group consisting of donovani infection, arthropathy, Lyme arthritis, Streptococcus group B infection, Campylobacter jejuni infection, Neisseria meningiditis infection, type I HIV, and Haemophilus influenzae. In some embodiments, such an isolated antibody agent is the antibody agent described herein.

[0210] Inflammatory bowel disease (IBD) Inflammatory bowel disease (IBD) is a group of chronic inflammatory conditions affecting the gastrointestinal tract, where bacterial dysbiosis and epithelial barrier dysfunction play a major role in the pathogenesis of the disease. In particular, bacterial components have been reported to bind to a range of receptors, including Toll-like receptors (TLRs), inducing various pathways and mechanisms that can increase small intestinal inflammation. IBD can affect other parts of the body (e.g., joints, skin, bones, eyes, kidneys, and liver), which are commonly referred to as extraintestinal signs (EIMs) of IBD. Anemia is another EIM of IBD. IBD often manifests in adolescence, and the relapse / remission of the condition indicates that it negatively impacts the quality of life of the individual. Ulcerative colitis (UC) and Crohn's disease (CD) are two of the main forms of IBD. UC affects the mucosal and submucosal layers of the colon with continuous lesions, where crypt abscesses are commonly found. CD is a transmural disease that can lead to complications such as fissures, fistulas, strictures, and fissures that can cause intestinal obstruction. TREM1 and its associated downstream effects are linked to IBD.

[0211] This disclosure provides, in particular, the insight that TREM1-expressing monocytes and neutrophils are concentrated in IBD inflammatory bowel tissue (e.g., compared to healthy tissue, non-inflammatory IBD tissue, and PBMCs from IBD patients). Bacterial invasion following epithelial barrier dysfunction releases bacterial peptidoglycans (PGNs) into the intestinal mucosa or tissues, leading to activation of TLRs on endogenous neutrophils and myeloid cells (e.g., monocytes). PGN-activated monocytes and neutrophils produce an initial immune response with the release of various inflammatory cytokines (e.g., IL-23, TNFα, IL-6, IL-1β, etc.). PGN-activated neutrophils exhibit increased PGLYRP1 secretion, which, in combination with PGNs, further activates TREM1 in both neutrophils and monocytes, leading to an amplified immune response including amplified pro-inflammatory cytokine and chemokine production, potentially flooding affected tissues with increased levels of inflammatory cytokines and chemokines (e.g., IL-23, TNFα, IL-6, IL-1β, etc.).

[0212] While we do not wish to be bound by any particular theory, this disclosure offers the insight that inhibition of TREM1 in neutrophils and myeloid cells (e.g., monocytes) in the gut of IBD patients may preserve the innate antimicrobial response while simultaneously disrupting the chronic cycle of amplified immune responses. In some embodiments, such TREM1 inhibitors (e.g., TREM1 antibody agents disclosed herein) may simultaneously reduce multiple pro-inflammatory cytokines (e.g., IL-23, TNFα, IL-6, IL-1β, etc.) and / or prevent further cytokine-mediated epithelial barrier damage.

[0213] A variety of therapies are currently available for the treatment of IBD, including anti-inflammatory aminosalicylates and corticosteroids, immunosuppressants, antibiotics, and biological agents. However, many patients do not fully respond to conventional treatments, and / or treatments may lose their effectiveness over time. Approved therapies, such as the anti-TNFα antibody adalimumab (Humira®), isolate downstream inflammatory cytokines that amplify IBD pathology. However, such therapies are not effective for all patients, and some show only a partial response or no response to adalimumab administration.

[0214] While we do not wish to be bound by any particular theory, current therapies may not adequately address the primary sources of amplified inflammatory responses (e.g., activation of inflammatory monocytes and / or neutrophils). In particular, TNFα isolation alone may not limit the production and effects of other downstream inflammatory mediators (e.g., cytokines, chemokines, etc.), potentially leading to additional inflammatory damage, including damage to the intestinal epithelial barrier. There is a current need to develop therapies that can robustly treat diseases across a wide range of IBD and other inflammatory conditions. This disclosure provides insight that such therapies may be able to target certain cells and / or cell receptors, thereby reducing downstream effects, including the initiation of unwanted inflammatory responses and amplified immune responses. In some embodiments, such improved therapies may be applicable to a wide range of subjects and / or may offer improved reductions in disease action / pathology compared to reference therapies (e.g., traditional therapies or alternative therapies such as adalimumab). In some embodiments, such improved therapies can inhibit TREM1 and the corresponding TREM1-activated inflammatory / immune response (e.g., by preventing the production of TREM1-activated inflammatory mediators).

[0215] This disclosure provides, in particular, TREM1 antibody agents, nucleic acids encoding TREM1 antibody agents, and compositions thereof for the treatment of IBD. For example, TREM1 antibody agents, nucleic acids encoding TREM1 antibody agents, and compositions thereof may be used for the treatment of Crohn's disease, ulcerative colitis, monogenic and / or very early onset inflammatory bowel disease (VEO-IBD), adult Crohn's disease, pediatric Crohn's disease, postoperative Crohn's disease, ileal fibrostenotic Crohn's disease, and / or immune checkpoint therapy (ICT)-induced Crohn's disease, but are not limited thereto. In some embodiments, the treatment of Crohn's disease may include the treatment of associated complications of Crohn's disease, which may include, but are not limited to, fibrostenotic diseases and / or fistula-forming diseases.

[0216] Methods for treatment The compositions and antibody agents disclosed herein may be used to treat diseases associated with cells expressing TREM1 and / or downstream inflammatory mediators triggered by TREM1 activation. In some embodiments, the disease to be treated may be selected from any of the diseases, disorders, or conditions disclosed herein. In some embodiments, the disease to be treated may be an inflammatory disorder, e.g., a condition associated with unwanted inflammation or increased inflammation. In some embodiments, the disease to be treated is inflammatory bowel disease (IBD). In some embodiments, the subject to be treated is a mammal (e.g., an adult human or a child human).

[0217] In some embodiments, a method for treatment includes the step of assaying a subject for the presence of one or more markers of a target disease (e.g., IBD), and then administering a corresponding treatment (e.g., a TREM1 antibody agent). In some embodiments, a method for treatment includes the step of assaying a subject for the presence of one or more markers of IBD (e.g., neutrophil density / position, PGLYRP1 level, calprotectin, sTREM1, etc.), and then administering a corresponding treatment (e.g., a TREM1 antibody agent).

[0218] In some embodiments, a method for treatment includes the step of administering a pharmaceutical composition disclosed herein (e.g., a TREM1 antibody agent composition). In some embodiments, a method for treatment includes the step of administering a pharmaceutical composition comprising a TREM1 antibody agent to a subject via an administration route known in the art. In some embodiments, a method for treatment includes the step of intravenously administering a pharmaceutical composition comprising a TREM1 antibody agent to a subject. In some embodiments, a method for treatment includes the step of subcutaneously administering a pharmaceutical composition comprising a TREM1 antibody agent to a subject.

[0219] In some embodiments, a method for treatment provided includes treating a subject having an inflammatory disease, disorder or condition, wherein the subject is determined to have elevated levels of neutrophils (e.g., activated neutrophils) and / or monocytes (e.g., inflammatory monocytes). Typically, such determination is by assaying a biological sample of the subject. In some embodiments, the biological sample is a blood sample. In some embodiments, the biological sample is a fecal sample. In some embodiments, the biological sample is a tissue sample, e.g., a sample of small intestine tissue (e.g., duodenum, jejunum or ileum tissue), large intestine tissue (e.g., cecum, ascending colon, transverse colon or descending colon) or rectal tissue. In some embodiments, the method provided includes treating the subject with a TREM1 antibody agent and / or composition disclosed herein.

[0220] In some embodiments, the method for treatment provided comprises treating a subject having an inflammatory disease, disorder, or condition, wherein the subject is determined to have elevated levels of activated neutrophils and / or monocytes (e.g., inflammatory monocytes). For example, in some such embodiments, the subject is determined to have elevated levels of activated neutrophils and / or monocytes by measuring the expression of one or more activated neutrophil and / or monocyte biomarkers, and / or one or more biomarkers associated with (i.e., substitute for) activated neutrophils and / or monocytes. In some embodiments, the method provided comprises treating the subject with a TREM1 antibody agent and / or composition disclosed herein.

[0221] In some embodiments, for example, a subject is determined to have elevated levels of activated neutrophils and / or monocytes by measuring the levels of one or more activated neutrophil and / or monocyte biomarkers, and / or one or more biomarkers associated with (i.e., substitutes for) activated neutrophils and / or monocytes, compared to levels observed in a subject that does not have an inflammatory disease, disorder, or condition, or the subject does not have an active form of the disease, disorder, or condition (e.g., in the case of a historical reference). In some embodiments, a subject is determined to have elevated levels of activated neutrophils and / or monocytes by measuring the levels of one or more activated neutrophil and / or monocyte biomarkers, and / or one or more biomarkers associated with (i.e., substitutes for) activated neutrophils and / or monocytes, compared to levels observed in a suitable reference population (in some such embodiments, the suitable reference population is the population) that does not have a disease, disorder, or condition (or is not in an active phase of such a disease, disorder, or condition).

[0222] In some embodiments, the method for treatment provided includes treating a subject having an inflammatory disease, disorder, or condition, the subject being predicted to be responsive to treatment with a TREM1 inhibitor, and the subject being treated with a TREM1 antibody agent and / or composition disclosed herein. In some embodiments, the subject is predicted to be responsive to treatment with a TREM1 inhibitor if it is determined that a biological sample from the subject has elevated levels of neutrophils and / or monocytes. In some embodiments, the biological sample is a blood sample. In some embodiments, the biological sample is a fecal sample. In some embodiments, the biological sample is a tissue sample, e.g., small intestinal tissue (e.g., duodenal, jejunal, or ileal tissue), large intestinal tissue (e.g., cecum, ascending colon, transverse colon, or descending colon), or rectal tissue. In some embodiments, the subject is predicted to be responsive to treatment with a TREM1 inhibitor if it is determined that the subject has elevated levels of activated neutrophils and / or monocytes. For example, in some embodiments, it is determined that a subject has elevated levels of activated neutrophils and / or monocytes by measuring the expression of one or more activated neutrophil and / or monocyte biomarkers, and / or one or more biomarkers associated with (i.e., substitute for) activated neutrophils and / or monocytes.

[0223] In some embodiments, a subject is predicted to be responsive to treatment with a TREM1 inhibitor if it is determined that the subject has elevated levels of activated neutrophils and / or monocytes by measuring elevated levels of one or more activated neutrophil and / or monocyte biomarkers, and / or elevated levels of one or more biomarkers associated with (i.e., substitutes for) activated neutrophils and / or monocytes, compared to levels observed in subjects that do not have an inflammatory disease, disorder, or condition, or subjects that do not have an active form of the disease, disorder, or condition (e.g., in the case of a historical reference of the subject).

[0224] In some embodiments, a subject is predicted to be responsive to TREM1 inhibitor treatment if it is determined that the subject has elevated levels of activated neutrophils and / or monocytes by measuring elevated levels of one or more activated neutrophil and / or monocyte biomarkers, and / or elevated levels of one or more biomarkers associated with (i.e., substitutes for) activated neutrophils and / or monocytes, compared to levels observed in a suitable reference population (in some such embodiments, the suitable reference population is the population) that is free from disease, disorder, or condition (or not in an active phase of such disease, disorder, or condition).

[0225] In some embodiments, the methods for treatment provided include treating a subject having an inflammatory disease, disorder, or condition with the TREM1 antibody agents and / or compositions disclosed herein, based on the measurement levels of one or more activated neutrophil and / or monocyte biomarkers in the subject, and / or the measurement levels of one or more biomarkers associated with (i.e., substitutes for) activated neutrophils and / or monocytes. In some embodiments, such methods include treating a subject with the TREM1 antibody agents and / or compositions disclosed herein when such measurement levels are elevated compared to levels observed in a subject that does not have an inflammatory disease, disorder, or condition, or the subject does not have an active form of the disease, disorder, or condition. In some embodiments, such a method involves treating a subject with a TREM1 antibody agent and / or composition disclosed herein when a determined level of one or more activated neutrophil and / or monocyte biomarkers, and / or a determined level of one or more biomarkers associated with activated neutrophils and / or monocytes, is elevated compared to a suitable reference population (in some such embodiments, the suitable reference population is the population) that is free from disease, disorder, or condition (or is not in an active phase of such disease, disorder, or condition).

[0226] In some embodiments, the methods for treatment provided include treating subjects having an inflammatory disease, disorder, or condition that is resistant and / or unresponsive to one or more alternative anti-inflammatory therapies that do not directly target TREM1 (e.g., TNFα inhibitor therapy). In some embodiments, the alternative anti-inflammatory therapies are or include anti-inflammatory aminosalicylates and corticosteroids, immunosuppressants, antibiotics, and biological agents (e.g., biological agents that do not target TREM1). In some embodiments, alternative anti-inflammatory therapies include: TNFα inhibitors; Janus kinase (JAK) inhibitors (e.g., upadacitinib, tofacitinib, and filgotinib); anti-integrin therapies (e.g., α4 integrin targeters (e.g., natalizumab) or α4β7 integrin targeters (e.g., vedolizumab)); anti-IL23 therapies (e.g., guselkumab, mirikizumab, and brazicumab); anti-IL-12 / 23 therapies (e.g., ustekinumab); anti-IL-23A therapies (e.g., risankizumab); S1PR agonist or modulator therapies (e.g., ozanimod and etrasimodo); 5-aminosalicylate therapies (e.g., mesalamine, orsalazine, valsalid) and sulfasalazine); immunomodulatory therapy (e.g., azathioprine, 6-mercaptopurine and methotrexate); corticosteroid therapy (e.g., prednisone, methylprednisolone, hydrocortisone and budesonide); anti-TL1A therapy (e.g., PRA023 and RVT-3101); kinase inhibitors (e.g., ritrecitinib), TYK2 inhibitor therapy (e.g., duclavacitinib), anti-IL-36 therapy (e.g., spesolimab); anti-IL-13 therapy (e.g., dupilumab), miR-124 upregulator therapy (e.g., obefazimod), TLR9 agonist therapy (e.g., covitrimod); or combinations thereof or comprising these. In some embodiments, TNFα inhibitor therapy is accompanied by treatment with an anti-TNFα antibody.In some embodiments, TNFα inhibitor therapy includes treatment with adalimumab (Humira®), certolizumab pegol (Cimiza®), golimumab (Simponi®), infliximab (Remicade®), or a decoy circulating receptor fusion protein, such as etanercept (Enbrel®), or a biosimilar thereof.

[0227] In some embodiments, the methods for treatment provided include treating subjects having an inflammatory disease, disorder, or condition, the subjects being expected to be resistant and / or unresponsive to TNFα inhibitor therapy. In some embodiments, the methods provided include treatment with TREM1 antibody agents and / or compositions disclosed herein. In some embodiments, TNFα inhibitor therapy involves treatment with an anti-TNFα antibody agent (e.g., an anti-TNFα monoclonal antibody, an anti-TNFα humanized antibody, and / or an anti-TNFα chimeric antibody). In some embodiments, TNFα inhibitor therapy involves treatment with a decoy circulating receptor fusion protein. In some embodiments, TNFα inhibitor therapy includes treatment with adalimumab, certolizumab, golimumab, infliximab, and / or etanercept. In some embodiments, the TNFα inhibitor is or includes a biosimilar of a TNFα inhibitor. In some embodiments, if the subject has elevated levels of neutrophils (e.g., activated neutrophils), for example, by assessment of a biological sample from the subject, the subject is predicted to be resistant and / or unresponsive to TNFα inhibitor therapy. In some embodiments, if the subject has elevated levels of neutrophils (e.g., activated neutrophils) and / or monocytes (e.g., inflammatory monocytes), for example, by assessment of a biological sample from the subject, the subject is predicted to be resistant and / or unresponsive to TNFα inhibitor therapy. In some embodiments, the biological sample is a blood sample. In some embodiments, the biological sample is a fecal sample. In some embodiments, the biological sample is a tissue sample, for example, small intestinal tissue (e.g., duodenal, jejunal, or ileal tissue), large intestinal tissue (e.g., cecum, ascending colon, transverse colon, or descending colon), or rectal tissue.

[0228] In some embodiments, if a subject is determined to have elevated levels of activated neutrophils and / or monocytes, the subject is predicted to be resistant and / or unresponsive to one or more alternative anti-inflammatory therapies that do not directly target TREM1 (e.g., TNFα inhibitor therapy). For example, in some embodiments, elevated levels of activated neutrophils and / or monocytes are determined by measuring the expression of one or more activated neutrophil and / or monocyte biomarkers, and / or one or more biomarkers associated with (i.e., substitute for) activated neutrophils and / or monocytes. In some embodiments, a subject is predicted to be resistant and / or unresponsive to one or more alternative anti-inflammatory therapies that do not directly target TREM1 (e.g., TNFα inhibitor therapy) if it is determined that the subject has elevated levels of one or more activated neutrophil and / or monocyte biomarkers, and / or one or more biomarkers associated with (i.e., substitute for) activated neutrophils and / or monocytes, compared to levels observed when the subject does not have an inflammatory disease, disorder, or condition, or when the subject does not have an active form of such disease, disorder, or condition (e.g., in the case of a historical reference of the subject). In some embodiments, a subject is determined to be resistant and / or unresponsive to one or more alternative anti-inflammatory therapies that do not directly target TREM1 (e.g., TNFα inhibitor therapy) if it is determined that the subject has elevated levels compared to levels observed in a suitable reference population (in some such embodiments, the suitable reference population is the population) that does not have a disease, disorder, or condition (or is not in an active phase of such disease, disorder, or condition).

[0229] In some embodiments, the methods provided herein include methods for identifying or characterizing subjects having an inflammatory disease, disorder, or condition, and for determining subjects that are likely to be responsive (e.g., expected to be responsive) to treatment with the TREM1 antibody agents and / or compositions disclosed herein. In some embodiments, a subject is expected to be responsive to treatment if it is determined that the subject has elevated neutrophil and / or monocyte levels in a biological sample from the subject. In some embodiments, the biological sample is a blood sample. In some embodiments, the biological sample is a fecal sample. In some embodiments, the biological sample is a tissue sample, e.g., small intestinal tissue (e.g., duodenal, jejunal, or ileal tissue), large intestinal tissue (e.g., cecum, ascending colon, transverse colon, or descending colon), or rectal tissue. In some embodiments, a subject is expected to be responsive to treatment if it is determined that the subject has elevated levels of activated neutrophils and / or monocytes. In some embodiments, a subject is predicted to be responsive to treatment if, for example, the subject has elevated levels of one or more activated neutrophil and / or monocyte biomarkers, and / or elevated levels of one or more biomarkers associated with (i.e., substitutes for) activated neutrophils and / or monocytes, compared to levels observed when the subject does not have an inflammatory disease, disorder, or condition, or when the subject does not have an active form of the disease, disorder, or condition (e.g., in the case of a historical reference of the subject). In some embodiments, a subject is predicted to be responsive to treatment if, for example, the subject has elevated levels compared to levels observed in a suitable reference population (in some such embodiments, the suitable reference population is the population) that does not have a disease, disorder, or condition (or is not in an active phase of such a disease, disorder, or condition).

[0230] In some embodiments, the methods provided herein include methods for monitoring the efficacy of treatment of a subject with the TREM1 antibody agents and / or compositions disclosed herein. In some embodiments, efficacy in a subject is monitored by measuring the expression of one or more activated neutrophil and / or monocyte biomarkers, and / or one or more biomarkers associated with (i.e., substitutes for) activated neutrophils and / or monocytes. In some embodiments, efficacy in a subject is monitored by measuring the levels of one or more activated neutrophil and / or monocyte biomarkers, and / or one or more biomarkers associated with (i.e., substitutes for) activated neutrophils and / or monocytes, compared to what would be observed if the subject did not have an inflammatory disease, disorder or condition, or if the subject did not have an active form of the disease, disorder or condition (e.g., in the case of a historical reference of the subject). In some embodiments, efficacy in a subject is monitored, for example, by measuring the levels of one or more activated neutrophil and / or monocyte biomarkers, and / or the levels of one or more biomarkers associated with (i.e., substitutes for) activated neutrophils and / or monocytes, in a subject compared to a suitable reference population (in some such embodiments, the suitable reference population is the population) that does not suffer from the disease, disorder, or condition (or is not in an active phase of such disease, disorder, or condition). In some embodiments, the provided method includes modifying the amount of anti-inflammatory therapy (e.g., TREM1 antibody agents and / or compositions disclosed herein) administered to a subject based on the expression or expression level of one or more activated neutrophil and / or monocyte biomarkers, and / or the expression or expression level of one or more biomarkers associated with (i.e., substitutes for) activated neutrophils and / or monocytes.In some embodiments, the methods provided include modifying the administration of anti-inflammatory therapy (e.g., TREM1 antibody agents and / or compositions disclosed herein) to target specific tissues that express or express elevated levels of one or more activated neutrophil and / or monocyte biomarkers, and / or one or more biomarkers associated with (i.e., substitutes for) activated neutrophils and / or monocytes. For example, in some such embodiments, the anti-inflammatory therapy may be modified to specifically target small intestinal tissue (e.g., duodenal, jejunal, or ileal tissue), large intestinal tissue (e.g., cecum, ascending colon, transverse colon, or descending colon), and / or rectal tissue that express or express elevated levels of one or more activated neutrophil and / or monocyte biomarkers, and / or one or more biomarkers associated with (i.e., substitutes for) activated neutrophils and / or monocytes.

[0231] In some embodiments of the methods for treatment provided, one or more biomarkers, and / or one or more biomarkers associated with (i.e., substitutes for) activated neutrophils and / or monocytes, are cell-based biomarkers. For example, in some embodiments, the cell-based biomarkers are the number of neutrophils in the blood and / or tissue, the number of monocytes, or the number of neutrophils and monocytes. In some embodiments, one or more activated neutrophil and / or monocyte biomarkers, and / or one or more biomarkers associated with (i.e., substitutes for) activated neutrophils and / or monocytes, are TREM1 RNA in monocytes and / or neutrophils. In some embodiments, one or more activated neutrophil and / or monocyte biomarkers, and / or one or more biomarkers associated with (i.e., substitutes for) activated neutrophils and / or monocytes, are TREM1 on the cell surface of monocytes and / or neutrophils.

[0232] In some embodiments of the methods for treatment provided, one or more activated neutrophil and / or monocyte biomarkers, and / or one or more biomarkers associated with (i.e., substitutes for) activated neutrophils and / or monocytes, are tissue biomarkers. For example, in some embodiments, the tissue biomarker is a mucosal ulcer. In some embodiments, one or more activated neutrophil biomarkers and / or one or more biomarkers associated with (i.e., substitutes for) activated neutrophils are the presence of neutrophils in the lamina propria of the mucosa of the subject or in the epithelial layer. In some embodiments, one or more activated neutrophil biomarkers and / or one or more biomarkers associated with (i.e., substitutes for) activated neutrophils are the presence of lymphocytes, plasma cells and / or eosinophils in the lamina propria of the mucosa of the subject.

[0233] In some embodiments of the methods for treatment provided, one or more activated neutrophil biomarkers and / or biomarkers associated with (i.e., substitute for) activated neutrophils are neutrophil products. For example, in some embodiments, the neutrophil products are calprotectin, PGLYRP1, or soluble TREM1.

[0234] In some embodiments of the methods for treatment provided, one or more monocyte biomarkers and / or monocyte-related (i.e., substitutes for them) biomarkers are monocyte products. For example, in some embodiments, the monocyte product is soluble TREM1.

[0235] In some embodiments of the methods for treatment provided, one or more activated neutrophil and / or monocyte biomarkers, and / or one or more biomarkers associated with (i.e., substitute for) activated neutrophils and / or monocytes, are TREM1 ligands. For example, in some embodiments, the TREM1 ligand is bacterial peptidoglycan (PGN) and / or PGLYRP1.

[0236] In some embodiments of the methods for treatment provided, one or more activated neutrophil and / or monocyte biomarkers, and / or one or more biomarkers associated with (i.e., substitute for) activated neutrophils and / or monocytes, are TREM1 gene activation signatures.

[0237] In some embodiments of the methods for treatment provided, one or more activated neutrophil and / or monocyte biomarkers, and / or biomarkers associated with (i.e., substitute for) activated neutrophils and / or monocytes, include any or a combination thereof of the following: the number of neutrophils and / or monocytes detected in the affected tissue; TREM1 on the cell surface of monocytes and / or neutrophils in the affected tissue; TREM1 RNA in monocytes and / or neutrophils in the affected tissue; tissue biomarkers in the affected tissue; soluble TREM1 in blood and / or fecal samples; calprotectin in blood and / or fecal samples; bacterial PGN in fecal samples; PGLYRP1 in blood and / or fecal samples; and TREM1 gene activation signatures in the affected tissue and / or blood.

[0238] In some embodiments of the methods for treatment provided, one or more activated neutrophil and / or monocyte biomarkers, and / or one or more biomarkers associated with activated neutrophils and / or monocytes, are detected in the blood sample, affected tissue sample, fecal sample, components or fractions thereof, or combinations thereof.

[0239] In some embodiments of the methods for treatment provided, the anti-inflammatory therapy (e.g., the TREM1 antibody agents and / or compositions disclosed herein) specifically targets tissues that express one or more activated neutrophil and / or monocyte biomarkers, and / or one or more biomarkers associated with (i.e., substitutes for) activated neutrophils and / or monocytes. In some embodiments, the anti-inflammatory therapy (e.g., the TREM1 antibody agents and / or compositions disclosed herein) specifically targets tissues that express elevated levels of one or more activated neutrophil and / or monocyte biomarkers, and / or elevated levels of one or more biomarkers associated with (i.e., substitutes for) activated neutrophils and / or monocytes, compared to levels of one or more inflammatory biomarkers, and / or one or more biomarkers associated with (i.e., substitutes for) activated neutrophils and / or monocytes, when the subject does not have an inflammatory disease, disorder or condition, or when the subject does not have an active form of the disease, disorder or condition. In some embodiments, anti-inflammatory therapies (e.g., TREM1 antibody agents and / or compositions disclosed herein) specifically target tissues that express elevated levels of one or more activated neutrophil and / or monocyte biomarkers, and / or elevated levels of one or more biomarkers associated with (i.e., substitutes for) activated neutrophils and / or monocytes, compared to levels of one or more inflammatory biomarkers and / or biomarkers associated with one or more activated neutrophils and / or monocytes in the population. For example, in some embodiments, anti-inflammatory therapy specifically targets small intestinal tissue (e.g., duodenum, jejunum, or ileum), large intestinal tissue (e.g., cecum, ascending colon, transverse colon, or descending colon), and / or rectal tissue that express or express elevated levels of one or more activated neutrophil and / or monocyte biomarkers, and / or one or more biomarkers associated with (i.e., substitute for) activated neutrophils and / or monocytes.

[0240] In some embodiments of the methods for treatment provided, subjects having an inflammatory disease, disorder, or condition are treated with TREM1 antibody agents and / or compositions disclosed herein in combination with one or more alternative anti-inflammatory therapies that do not directly target TREM1 (e.g., one or more TNFα inhibitors). For example, in some embodiments, subjects are treated with TREM1 antibody agents and / or compositions disclosed herein in combination with an anti-TNFα antibody agent (e.g., an anti-TNFα monoclonal antibody, an anti-TNFα humanized antibody, and / or an anti-TNFα chimeric antibody). In some embodiments, subjects are treated with a TREM1 inhibitor in combination with adalimumab, certolizumab, golimumab, infliximab, and / or etanercept.

[0241] In some embodiments, the TREM1 antibody agents or compositions of this disclosure are administered to subjects who have previously received or are currently receiving alternative therapies. For example, in some embodiments, the alternative therapies include: anti-TNFα therapy (e.g., infliximab, adalimumab, golimumab, and certolizumab pegol); JAK inhibitor therapy (including selective and non-selective inhibitors) (e.g., upadacitinib, tofacitinib, and filgotinib); anti-integrin therapy (e.g., vedolizumab and natalizumab); anti-IL23 therapy (e.g., guselkumab, mirikizumab, and brazicumab); anti-IL-12 / 23 therapy (e.g., ustekinumab); anti-IL-23A therapy (e.g., risankizumab); S1PR agonist or modulator therapy (e.g., ozanimod and etrasimodo); 5-aminosalicylate therapy (e.g., mesalamine, orsalazine, val Alternative IBD therapies include: salazid and sulfasalazine; immunomodulatory therapies (e.g., azathioprine, 6-mercaptopurine and methotrexate); corticosteroid therapies (e.g., prednisone, methylprednisolone, hydrocortisone and budesonide); anti-TL1A therapies (e.g., PRA023 and RVT-3101); kinase inhibitors (e.g., ritrecitinib); TYK2 inhibitor therapy (e.g., duclavacitinib); anti-IL-36 therapy (e.g., spesolimab); anti-IL-13 therapy (e.g., dupilumab); miR-124 upregulator therapy (e.g., obefazimod); TLR9 agonist therapy (e.g., covitrimod); or combinations thereof.

[0242] Methods for production The TREM1 antibody preparations or parts thereof of this disclosure may be produced using recombinant expression methods commonly known to those skilled in the art. For example, the nucleic acid encoding the TREM1 antibody preparation or part thereof is isolated and inserted into a replicable vector for further cloning and amplification or expression. The DNA encoding the antibody or part thereof is isolated and sequenced using conventional procedures (e.g., using oligonucleotide probes that can specifically bind to the genes encoding the heavy and light chains of the antibody). Various expression vectors can be used and are known to those skilled in the art. The choice of vector may depend in part on the host cell used for expression. Generally, preferred host cells are cells of either prokaryotic or eukaryotic (e.g., mammalian) origin. In some embodiments, the TREM1 antibody preparation or part thereof is produced by bacterial cells, yeast cells, insect cells or mammalian cells. In some embodiments, the TREM1 antibody preparation or part thereof is produced by Chinese hamster ovary (CHO) cells. In some embodiments, the TREM1 antibody preparation or part thereof is produced by cell-free systems well known to those skilled in the art.

[0243] In some embodiments, the TREM1 antibody agent or part thereof described herein is characterized by its ability to be produced at a concentration of at least 3000 mg / mL. In some embodiments, the TREM1 antibody agent or part thereof described herein is characterized by its ability to be produced at concentrations of about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, or about 10 g / L. In some embodiments, the TREM1 antibody agents or parts thereof described herein are characterized by their ability to be produced at concentrations of about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, or about 6.5 g / L. In some embodiments, the TREM1 antibody agents or parts thereof described herein are characterized by their ability to be produced at concentrations of about 5.12, about 5.13, about 5.18, or about 5.7 g / L.

[0244] The compositions and antibody agents disclosed herein may be used to treat diseases, disorders, or conditions associated with cells expressing TREM1 and / or downstream inflammatory mediators triggered by TREM1 activation. In some embodiments, the disease, disorder, or condition to be treated may be selected from the diseases, disorders, or conditions disclosed herein. In some embodiments, the disease, disorder, or condition to be treated may be an inflammatory disorder, such as a condition associated with unwanted inflammation or increased inflammation. In some embodiments, the disease to be treated is inflammatory bowel disease (IBD).

[0245] Detection of activated immune cells Circulating neutrophils are generally quiescent until their activation is triggered, for example, by exposure to one or more external signals (e.g., pathogens, chemical signals, proteins, etc.). While we do not wish to be bound by any particular theory, the inventors note that neutrophils may undergo a multi-step activation process, entering a partially activated state through exposure to one or more initial signals, and then becoming fully activated (hereinafter interchangeably referred to as the “activated state”) through exposure to one or more additional signals. Activated neutrophils may, among other things, produce signaling molecules (e.g., cytokines, chemokines, degranulases, etc.) to initiate an amplified immune response in a target.

[0246] Inflammatory monocytes can sense their environment and be activated through exposure to one or more external signals (e.g., pathogens). Inflammatory monocytes selectively migrate to the site of inflammation, produce inflammatory cytokines and chemokines, and contribute to local and systemic inflammation. While not wishing to be bound by any particular theory, the inventors note that inflammatory monocytes undergo a multi-step activation process, entering a partially activated state through exposure to one or more initial signals, and then becoming fully activated (hereinafter interchangeably referred to as the “activated state”) through exposure to one or more additional signals. Activated inflammatory monocytes can, among other things, produce signaling molecules (e.g., cytokines, chemokines, etc.) to promote an amplified immune response in a target.

[0247] This disclosure teaches that the presence and / or levels of monocytes (e.g., inflammatory monocytes) and / or neutrophils (e.g., activated neutrophils) may be useful in the context of anti-inflammatory therapy. In particular, this disclosure provides the insight that subjects determined to have elevated levels of monocytes and / or activated neutrophils (e.g., compared to appropriate references, e.g., established population standards and / or historical personal references) may be particularly likely to respond to TREM1-targeting therapies (and / or may be relatively less likely to respond to alternative therapies that do not directly target TREM1, e.g., anti-TNFα therapy).

[0248] In some embodiments, monocyte and / or neutrophil activation may be triggered by a pathogen. In some embodiments, monocyte and / or neutrophil activation may be triggered by a bacterial pathogen, a viral pathogen, or a fungal pathogen.

[0249] In some embodiments, monocyte and / or neutrophil activation may be triggered by exposure to one or more bacterial markers (e.g., peptidoglycan). In some embodiments, monocyte and / or neutrophil activation may be triggered by exposure to one or more pathogen-associated molecular patterns (PAMPs). In some embodiments, monocyte and / or neutrophil activation may be triggered by lipopolysaccharide. In some embodiments, monocyte and / or neutrophil activation may be triggered by lipoteichoic acid. In some embodiments, monocyte and / or neutrophil activation may be triggered by double-stranded viral RNA. In some embodiments, monocyte and / or neutrophil activation may be triggered by bacterial DNA.

[0250] In some embodiments, monocyte and / or neutrophil activation may be triggered by a pattern of damage-related molecules released by necrotic cells. In some embodiments, monocyte and / or neutrophil activation may be triggered by high-mobility group protein B1. In some embodiments, monocyte and / or neutrophil activation may be triggered by mitochondrial formyl peptide. In some embodiments, monocyte and / or neutrophil activation may be triggered by mitochondrial DNA.

[0251] In some embodiments, monocyte and / or neutrophil activation may be triggered by inflammatory cytokines (e.g., TNFα). In some embodiments, monocyte and / or neutrophil activation may be triggered by chemokines. In some embodiments, monocyte and / or neutrophil activation may be triggered by growth factors. In some embodiments, monocyte and / or neutrophil activation may be triggered by adhesion to endothelial cells. In some embodiments, monocyte and / or neutrophil activation may be triggered by immune complexes. In some embodiments, monocyte and / or neutrophil activation may be triggered by hypoxic conditions.

[0252] Monocytes (e.g., inflammatory monocytes) and / or activated neutrophils may be characterized by the presence of one or more markers (e.g., biomarkers and / or surrogate markers). In some embodiments, the biomarkers and / or surrogate markers of activated neutrophils and / or monocytes are cell-based biomarkers. For example, in some embodiments, the cell-based biomarker is the number of neutrophils, the number of monocytes, or the number of neutrophils and monocytes in the blood and / or tissue. In some embodiments, the biomarker and / or surrogate marker is TREM1 RNA in monocytes and / or neutrophils. In some embodiments, the biomarker or surrogate marker is TREM1 on the cell surface of monocytes and / or neutrophils.

[0253] In some embodiments, the biomarker and / or surrogate marker for activated neutrophils is a tissue biomarker. For example, in some embodiments, the tissue biomarker is a mucosal ulcer. In some embodiments, the biomarker and / or surrogate marker is the presence of neutrophils in the lamina propria of the mucosa or in the epithelial layer of the mucosa in question. In some embodiments, the biomarker and / or surrogate marker is the presence of lymphocytes, plasma cells and / or eosinophils in the lamina propria of the mucosa in question.

[0254] In some embodiments, the biomarker and / or surrogate marker for activated neutrophils is a neutrophil product. For example, in some embodiments, the neutrophil product is calprotectin, PGLYRP1, or soluble TREM1.

[0255] In some embodiments, the biomarker and / or surrogate marker of a monocyte (e.g., an inflammatory monocyte) is a product of the monocyte (e.g., an inflammatory monocyte). For example, in some embodiments, the product of the monocyte (e.g., an inflammatory monocyte) is soluble TREM1.

[0256] In some embodiments, the biomarker and / or surrogate marker for activated neutrophils and / or monocytes is a TREM1 ligand. For example, in some embodiments, the TREM1 ligand is bacterial peptidoglycan (PGN) and / or PGLYRP1.

[0257] In some embodiments, the biomarker and / or surrogate marker for activated neutrophils and / or monocytes is the TREM1 gene activation signature.

[0258] In some embodiments, biomarkers and / or surrogate markers for activated neutrophils and / or monocytes include any or a combination thereof of the following: the number of neutrophils and / or monocytes detected in the affected tissue; TREM1 on the cell surface of monocytes and / or neutrophils in the affected tissue; TREM1 RNA in monocytes and / or neutrophils in the affected tissue; tissue biomarkers in the affected tissue; soluble TREM1 in blood and / or fecal samples; calprotectin in blood and / or fecal samples; bacterial PGN in fecal samples; PGLYRP1 in blood and / or fecal samples; and TREM1 gene activation signatures in affected tissue and / or blood.

[0259] In some embodiments, biomarkers and / or surrogate markers for activated neutrophils and / or monocytes are detected in the target blood sample, diseased tissue sample, fecal sample, components or fractions thereof, or combinations thereof.

[0260] In some embodiments, elevated levels of activated neutrophils and / or monocytes are determined by measuring the presence of elevated levels of one or more activated neutrophil and / or monocyte biomarkers, and / or elevated levels of one or more biomarkers associated with (i.e., substitutes for) activated neutrophils and / or monocytes, compared to the levels of one or more inflammatory biomarkers and / or biomarkers associated with activated neutrophils and / or monocytes in the subject, when the subject does not have an inflammatory disease, disorder, or condition, or when the subject does not have an active form of the disease, disorder, or condition. In some embodiments, elevated levels of activated neutrophils and / or monocytes are determined by measuring the presence of elevated levels of one or more activated neutrophil and / or monocyte biomarkers, and / or elevated levels of one or more biomarkers associated with (i.e., substitutes for) activated neutrophils and / or monocytes in the subject, compared to the levels of one or more inflammatory biomarkers and / or biomarkers associated with activated neutrophils and / or monocytes in the population. In some embodiments, elevated levels of activated neutrophils and / or monocytes are determined by measuring the presence of elevated levels of one or more activated neutrophil and / or monocyte biomarkers, and / or elevated levels of one or more biomarkers associated with (i.e., substitutes for) activated neutrophils and / or monocytes, in diseased tissue samples collected from the same subject, compared to the levels of one or more inflammatory biomarkers, and / or one or more biomarkers associated with activated neutrophils and / or monocytes, in healthy tissue samples collected from the same subject.

[0261] In some embodiments, activated neutrophils and / or monocytes, biomarkers of activated neutrophils and / or monocytes, and / or biomarkers associated with (i.e., substitutes for) activated neutrophils and / or monocytes may be detected by one or more methods available in the art. For example, in some embodiments, activated neutrophils and / or monocytes may be detected by one or more microscopy methods (e.g., fluorescence microscopy). In some embodiments, activated neutrophils and / or monocytes, biomarkers of activated neutrophils and / or monocytes, and / or biomarkers associated with (i.e., substitutes for) activated neutrophils and / or monocytes may be detected by one or more histopathological methods. In some embodiments, activated neutrophils and / or monocytes, biomarkers of activated neutrophils and / or monocytes, and / or biomarkers associated with (i.e., substitutes for) activated neutrophils and / or monocytes may be detected by one or more polynucleotide (e.g., DNA or RNA) detection methods (e.g., quantitative PCR, reverse transcription PCR, insight hybridization, in vitro hybridization, nucleic acid sequencing, etc.). In some embodiments, activated neutrophils and / or monocytes, biomarkers of activated neutrophils and / or monocytes, and / or biomarkers associated with (i.e., substitutes for) activated neutrophils and / or monocytes may be detected by one or more spatial profiling methods. In some embodiments, activated neutrophils and / or monocytes, biomarkers of activated neutrophils and / or monocytes, and / or biomarkers associated with (i.e., substitutes for) activated neutrophils and / or monocytes may be detected by one or more methods for protein confirmation and / or quantification (e.g., antibody-based detection in tissue samples collected from a subject, ELISA, competitive binding studies, mass spectrometry and / or high-performance liquid chromatography, etc.).In some embodiments, activated neutrophils and / or monocytes, biomarkers of activated neutrophils and / or monocytes, and / or biomarkers associated with (i.e., substitutes for) activated neutrophils and / or monocytes may be detected by one or more cell sorting or characterization methods (e.g., FACS, flow cytometry, etc.). [Examples]

[0262] The following examples are provided to those skilled in the art to illustrate the methods and uses of the methods and compositions described herein, and are not intended to limit the scope of this disclosure.

[0263] [Example 1] Elevation of TREM1-positive inflammatory monocytes and neutrophils in inflammatory tissue. This example involves identifying elevated inflammatory monocytes and neutrophils in patients with inflammatory bowel disease (IBD). Inflammatory monocytes were enriched in inflammatory tissue and were enriched in post-treatment samples from non-responders of anti-TNFα therapy compared to responders of anti-TNFα therapy, showing elevated TREM1 expression.

[0264] Single-cell transcriptomics data were generated from approximately 200 tissue samples (containing more than 1 million cells) from inflammatory bowel disease (IBD) patients who had not received biological therapy. Samples were collected from multiple anatomical locations both before treatment and after at least 3 months of treatment with adalimumab, an anti-TNFα therapy. Samples were annotated with anti-TNFα therapy responder status and inflammatory status.

[0265] Single-cell transcriptomics data were clustered into cell populations annotated with cell identity (Figures 1A and 1B). These cell populations were then analyzed for differences in clinical aspects (e.g., anti-TNFα therapy responder status and / or inflammatory status).

[0266] Single-cell profiling revealed that certain cell populations (e.g., inflammatory monocytes) were enriched in inflammatory samples compared to non-inflammatory samples (Figures 2 and 3).

[0267] Analysis showed that TREM1 was highly expressed in inflammatory monocytes present in inflammatory tissues derived from IBD patients (Figure 4A). In contrast, TREM1-positive inflammatory monocytes were not enriched in non-inflammatory tissues derived from IBD patients (Figure 4B) or healthy tissues derived from non-IBD patients (Figure 4C). TREM1-positive monocytes were also not enriched in peripheral blood mononuclear cells (PBMCs) derived from IBD patients compared to healthy individuals (Figures 5A and 5B).

[0268] Inflammatory monocytes were concentrated in post-treatment samples from IBD patients who were non-responders to anti-TNFα therapy compared to post-treatment samples from IBD patients who were responders to anti-TNFα therapy (Figure 6A). Inflammatory monocytes in post-treatment samples from IBD patients who were non-responders to anti-TNFα therapy showed high levels of TREM1 (Figure 6B). High TREM1 inflammatory monocytes were concentrated in the tissues of both Crohn's disease (CD) IBD patients and ulcerative colitis (UC) IBD patients who were non-responders to anti-TNFα therapy (Figures 6C and 6D).

[0269] Histological evaluation of inflammatory tissue in patients with ulcerative colitis revealed enrichment of TREM1+ inflammatory monocytes in inflammatory tissue correlated with neutrophil infiltration (Figure 7). Neutrophils also expressed high levels of TREM1 (see Example 2).

[0270] These results indicate that inflammatory monocytes and neutrophils are enriched in inflammatory IBD tissue, and that these cell populations highly express TREM1 and are enriched in the tissues of IBD patients who are non-responders to anti-TNFα therapy compared to those who are responders to anti-TNFα therapy.

[0271] [Example 2] Anti-TREM1 antibody agent binds to cells expressing TREM1. This example demonstrates that the exemplary anti-TREM1 antibody agents disclosed herein can bind to TREM1 expressed on the cell surface of monocytes and neutrophils. The exemplary anti-TREM1 antibody agents have amino acid sequences corresponding to clone A disclosed in Table 2. Furthermore, this example shows that bacterial components (e.g., PGN or LPS) can stimulate monocytes to upregulate the cell surface level of TREM1.

[0272] The binding of anti-TREM1 antibody clone A to cell surface TREM1 was analyzed by staining cells present in whole blood samples derived from healthy human subjects, followed by flow cytometry analysis. Briefly, whole blood samples were depleted of erythrocytes (RBCs) by sedimentation, and then Fc was blocked before staining using various antibodies against various cell surface markers directly conjugated to fluorophores. Cells were also stained with anti-TREM1 antibody clone A at a saturated concentration (10 nM) directly conjugated to Alexa Fluor 647. Staining with isotype control antibodies conjugated to Alexa Fluor 647 was used as a negative control. Stained samples were then analyzed using flow cytometry. Different cell types were identified using cell surface markers, and the cell surface TREM1 staining intensity was evaluated for each cell type. Neutrophils (CD45), both known to express TREM1, were also included. + CD66 + CD16 + ) and all CD14 + Monotube (CD45) + CD14 + CD16 - or CD45 + CD14 + CD16 + ) showed binding of the anti-TREM1 antibody clone A (Figures 8A-8D), but CD45, which is not thought to express TREM1, showed binding. + Lin + (CD3 + CD7 + CD20 +Cells (corresponding to T cells, NK cells, and B cells) did not show binding to anti-TREM1 antibody clone A (Figure 8E). Since the cells were not exposed to bacterial peptidoglycan (PGN) or PGLYRP1 before staining, it is expected that the TREM1 present on the cell surface was in an inactive state. These results indicate that TREM1 is selectively expressed on the cell surface of neutrophils and monocytes, and that anti-TREM1 antibody clone A binds to TREM1 present on the cell surface of neutrophils and monocytes (e.g., inactive TREM1).

[0273] To determine whether the anti-TREM1 antibody clone A can bind to activated TREM, human primary monocytes from healthy donors were seeded, stimulated with bacterial peptidoglycan (PGN) (10 μg / mL) or LPS (100 ng / mL) for 24 hours, and subsequently stained with saturated concentration of anti-TREM1 antibody clone A (5 nM) and analyzed by flow cytometry. PGN and LPS stimulation resulted in upregulation of cell surface TREM1 (Figure 9). A slight increase in cell surface TREM1 was observed in monocytes without PGN at 24 hours (24-hour medium), consistent with the low level of monocyte activation by plating. Isotype control antibodies were used as controls for anti-TREM1 staining. These results indicate that monocyte activation by PGN or LPS results in upregulation of cell surface TREM1. While we do not wish to be bound to any particular theory, these results may be consistent with bacterial components present in lesional tissues that promote upregulation of cell surface TREM1 in monocytes. The results also show that the anti-TREM1 antibody clone A can bind to activated TREM1 present on the cell surface.

[0274] [Example 3] TREM1 amplifies inflammatory responses mediated by TREM1-positive monocytes and neutrophils. This embodiment demonstrates that TREM1 amplifies inflammatory responses mediated by TREM1-positive monocytes and neutrophils.

[0275] Primary human monocytes from healthy volunteers were isolated and stimulated with PGLYRP1 alone (500 nM), bacterial PGN alone (100 ng / mL), or a combination of PGN (100 ng / mL) and PGLYRP1 (500 nM). Unstimulated monocytes (culture medium) were used as an additional control to indicate baseline cytokine levels. After 18–24 hours, the levels of various cytokines and chemokines (e.g., CCL3, CCL4, IL-1β, IL-6, IL-23, and TNFα) secreted into the culture medium were assayed to monitor the monocyte-mediated inflammatory response. The results showed that PGLYRP1 alone stimulated monocytes and did not secrete the assayed inflammatory cytokines and chemokines (Figure 10). In contrast, PGN alone significantly stimulated monocytes and secreted some of the assayed cytokines and chemokines (e.g., CCL3, CCL4, and IL-6) (Figure 10). The combination of PGN and PGLYRP1 significantly amplified the secretion of assayed inflammatory cytokines and chemokines compared to PGN alone (Figure 10). These results indicate that bacterial PGN stimulates monocytes to produce an initial antibacterial innate immune response, including the secretion of inflammatory cytokines and chemokines amplified by the TREM1 ligand PGLYRP1.

[0276] In similar experiments, primary human monocyte-mediated inflammatory responses were monitored by assaying levels of various inflammatory mediators using a 64-plex assay panel (data not shown), demonstrating that TREM1 amplifies monocyte-mediated secretion of various inflammatory mediators, including, but not limited to, inflammatory cytokines (e.g., IL-1β, IL-6, IL-23, and TNFα), chemokines (e.g., CCL2, CCL3, CCL4, CCL8, CCL20, CCL22, CCL24, CXCL1, CXCL5, CXCL9, and CXCL13), activators of B cells, T cells, and / or other cells (e.g., APRIL, BAFF, CD30, and M-CSF), and factors involved in epithelial barrier integrity (e.g., TRAIL, TWEAK, MMP-1, IL-20, and TNFR-II).

[0277] Primary human neutrophils from healthy volunteers were isolated and stimulated with PGLYRP1 alone (50 nM), bacterial PGN alone (300 ng / mL), or a combination of PGN (300 ng / mL) and PGLYRP1 (50 nM). Unstimulated neutrophils (culture medium) were used as an additional control to indicate baseline cytokine levels. After 18–24 hours, the levels of various cytokines and chemokines (e.g., CCL3, CCL4, and IL-8) secreted into the culture medium were assayed to monitor the neutrophil-mediated inflammatory response. The results showed that PGLYRP1 alone did not stimulate neutrophils to secrete the assayed inflammatory cytokines and chemokines (Figure 11). In contrast, PGN alone significantly stimulated neutrophils to secrete the assayed cytokines and chemokines (e.g., CCL3, CCL4, and IL-8) (Figure 11). Neutrophils release endogenous PGLYRP1 in response to stimulation by PGN. The combination of PGN and PGLYRP1 significantly amplified the secretion of CCL3 and CCL4 compared to PGN alone (Figure 11). These results indicate that bacterial PGN stimulates neutrophils to elicit an initial antibacterial innate immune response, including the secretion of inflammatory cytokines and chemokines amplified by the TREM1 ligand PGLYRP1.

[0278] [Example 4] Characterization of anti-TREM1 antibody agents This embodiment provides characterization of exemplary anti-TREM1 antibody agents disclosed herein. The exemplary anti-TREM1 antibody agent is a monoclonal antibody that specifically binds to TREM1 and inhibits TREM1 activity. The exemplary anti-TREM1 antibody agent has an amino acid sequence corresponding to clone A disclosed in Table 2.

[0279] The binding affinity of TREM1 antibodies to the extracellular domain (ECD) of TREM1 from various species was investigated using biolayer interferometry (BLI). Briefly, TREM1 antibodies (5 μg / mL) were immobilized on anti-human Fc capture (AHC) sensors. The sensors were monitored to establish a baseline. The sensors were then exposed to recombinant monovalent TREM1-ECD proteins from humans, cynomolgus monkeys (cyno), dogs, rabbits, rats, mice, or pigs for 300 seconds at four different concentrations (0.03125, 0.0625, 0.25, and 1 μg / mL) for binding rate (on-rate) measurements, and then transferred to assay buffer for at least 900 seconds for dissociation rate (off-rate) measurements.

[0280] Table 4 shows the results of the BLI experiment. TREM1-ECD proteins with a maximum BLI response of less than 0.1 nm are K D The binding response to the determination was insufficient, and therefore, significant binding to the TREM1 antibody agent clone A is not considered to have occurred. The results indicate that the TREM1 antibody agent binds to the ECD of human and cyno-TREM1. Binding to the ECD of dog, rabbit, rat, mouse, and porcine TREM1 was not detected. The coefficient of determination of the 1:1 model fitted to the BLI sensorgrams is expressed by the R^2 value. The human and cynomolgus monkey data represent the mean over three replicates. The pig, dog, rabbit, rat, and mouse data represent the mean over two replicates.

[0281] [Table 6]

[0282] In addition to TREM1, the TREM gene family also includes TREM2. The ECDs of TREM1 and TREM2 share 25% sequence identity with each other (Figure 12). While we do not wish to be bound by any particular theory, TREM1 and TREM2 are thought to play opposing roles in regulating the immune response; see, for example, Sharif and Knapp, Immunobiology, 213(9-10):701-713 (2008). To determine whether TREM1 antibodies can also bind to TREM2, a biolayer interference (BLI) assay was performed. Briefly, a 10 μg / mL TREM2-ECD fused to the Fc domain was immobilized on a sensor. The sensor was quenched and monitored to establish a baseline. The sensor was then exposed to a solution containing either 3 μg / mL of anti-TREM1 antibody or anti-TREM2 antibody as a positive control (R&D Systems, MAB17291). The maximum BLI response was measured (Figure 13). The results indicate that exemplary anti-TREM1 antibody agents do not bind to TREM2-ECD.

[0283] The target specificity profile of the anti-TREM1 antibody was further evaluated using a multispecificity assay. Transient transfection was used to express each of over 6,000 human membrane proteins, including TREM2 and other TREM family members, on the surface of HEK293 cells. HEK293...

Claims

1. An antibody agent that binds to human-induced receptor 1 (TREM1) expressed on myeloid cells, (a) Light chains having CDR1, CDR2 and CDR3 sequences that collectively have at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with the sequence found in SEQ ID NO: 18, and / or collectively include differences of 1, 2, 3, 4, or 5 or fewer amino acids compared to the sequence found in SEQ ID NO: 18, and / or (b) Heavy chains having CDR1, CDR2, and CDR3 sequences that collectively have at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with the sequence found in SEQ ID NO: 14, and / or collectively include differences of 1, 2, 3, 4, or 5 or fewer amino acids compared to the sequence found in SEQ ID NO:

14. Antibody agents, including those mentioned above.

2. The light chain (LC) is (i) LC CDR1 having an amino acid sequence which is the amino acid sequence of SEQ ID NO: 19, an amino acid sequence which is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 19, or an amino acid sequence which is one, two, three, four, or five or fewer amino acid sequences different from SEQ ID NO: 19, or an amino acid sequence which includes these (ii) LC CDR2, which has an amino acid sequence that is the amino acid sequence of GAS or has an amino acid sequence that differs from the amino acid sequence of GAS by one or two or fewer amino acids, or has an amino acid sequence that includes these, (iii) LC CDR3 having an amino acid sequence which is the amino acid sequence of SEQ ID NO: 20, an amino acid sequence which is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 20, or an amino acid sequence which has one, two, three, four, or five or fewer amino acid sequences different from SEQ ID NO: 20, or an amino acid sequence which includes these. The antibody agent according to claim 1, comprising:

3. The heavy chain (HC) is (i) HC CDR1 having an amino acid sequence which is the amino acid sequence of SEQ ID NO: 15, an amino acid sequence which is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 15, or an amino acid sequence which has one, two, three, four, or five or fewer amino acid sequences different from SEQ ID NO: 15, or an amino acid sequence which includes these (ii) HC CDR2 having an amino acid sequence which is the amino acid sequence of SEQ ID NO: 16, an amino acid sequence which is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 16, or an amino acid sequence which has one, two, three, four, or five or fewer amino acid sequences different from SEQ ID NO: 16, or an amino acid sequence which includes these, and (iii) HC CDR3 having an amino acid sequence which is the amino acid sequence of SEQ ID NO: 17, an amino acid sequence which is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 17, or an amino acid sequence which has one, two, three, four, or five or fewer amino acid sequences different from SEQ ID NO: 17, or an amino acid sequence which includes these. The antibody agent according to claim 1 or 2, comprising:

4. The antibody agent according to any one of claims 1 to 3, wherein the light chain comprises a variable region (VL) comprising one, two, three, or four FR regions, which collectively have at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with the sequence found in SEQ ID NO: 18, and / or collectively include one, two, three, four, or five or fewer amino acid sequence differences compared to the sequence found in SEQ ID NO:

18.

5. The antibody agent according to claim 4, comprising a variable region (VL) comprising one, two, three, or four FR regions, each independently having an amino acid sequence that is one of SEQ ID NOs: 25, 26, 27, or 28, an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to one of SEQ ID NOs: 25, 26, 27, or 28, or an amino acid sequence that has a difference of 1, 2, 3, 4, or 5 or fewer amino acid sequences compared to one of SEQ ID NOs: 25, 26, 27, or 28, or an amino acid sequence containing these.

6. (i) an amino acid sequence which is the amino acid sequence of SEQ ID NO: 25, an amino acid sequence which is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 25, or an amino acid sequence which is one, two, three, four, or five or fewer amino acid sequences different from SEQ ID NO: 25, or an amino acid sequence which includes these and / or (ii) an amino acid sequence which is the amino acid sequence of SEQ ID NO: 26, an amino acid sequence which is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 26, or an amino acid sequence which is one, two, three, four, or five or fewer amino acid sequences different from SEQ ID NO: 26, or an amino acid sequence which includes these and / or (iii) an amino acid sequence of SEQ ID NO: 27, an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 27, or an amino acid sequence having one, two, three, four, or five or fewer amino acid sequences different from SEQ ID NO: 27, or an amino acid sequence containing these, and / or (iv) The amino acid sequence of SEQ ID NO: 28, an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 28, or an amino acid sequence having one, two, three, four, or five or fewer amino acid sequences different from SEQ ID NO: 28, or an amino acid sequence containing these. The antibody agent according to claim 4 or 5, comprising:

7. The antibody agent according to any one of claims 1 to 6, wherein the light chain further comprises a sequence of constant regions (CL).

8. The antibody agent according to claim 7, wherein the light chain comprises kappa CL or lambda CL.

9. The antibody agent according to claim 7 or 8, wherein the light chain contains kappa CL.

10. The antibody agent according to any one of claims 7 to 9, wherein the light chain comprises the amino acid sequence of SEQ ID NO: 32, an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 32, or an amino acid sequence having 5, 10, or 20 or fewer amino acid sequences different from SEQ ID NO: 32, or an amino acid sequence containing these.

11. The antibody agent according to any one of claims 1 to 10, wherein the heavy chain comprises a variable region (VH) comprising one, two, three, or four FR regions, which collectively have at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with the sequence found in SEQ ID NO: 14, and / or collectively include a difference of one, two, three, four, or five or fewer amino acid sequences compared to the sequence found in SEQ ID NO:

14.

12. The antibody agent according to claim 11, wherein the heavy chain comprises a variable region (VH) containing one, two, three, or four FR regions, each independently having an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to one of sequence numbers 21, 22, 23, or 24, or an amino acid sequence that differs by one, two, three, four, or five or fewer amino acid sequences from one of sequence numbers 21, 22, 23, or 24.

13. (i) an amino acid sequence which is the amino acid sequence of SEQ ID NO: 21, an amino acid sequence which is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 21, or an amino acid sequence which is one, two, three, four, or five or fewer amino acid sequences different from SEQ ID NO: 21, or an amino acid sequence which includes these and / or (ii) an amino acid sequence which is the amino acid sequence of SEQ ID NO: 22, an amino acid sequence which is identical to SEQ ID NO: 22 by at least 85%, 90%, 95%, 96%, 97%, 98%, or 99%, or an amino acid sequence which is different from SEQ ID NO: 22 by 1, 2, 3, 4, or 5 or fewer amino acid sequences, or an amino acid sequence which includes these, and / or (iii) an amino acid sequence of SEQ ID NO: 23, an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 23, or an amino acid sequence having one, two, three, four, or five or fewer amino acid sequences different from SEQ ID NO: 23, or an amino acid sequence containing these, and / or (iv) The amino acid sequence of SEQ ID NO: 24, an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 24, or an amino acid sequence having 1, 2, 3, 4, or 5 or fewer amino acid sequences compared to SEQ ID NO: 2, or an amino acid sequence containing these. The antibody agent according to claim 11 or 12, comprising:

14. The antibody agent according to any one of claims 1 to 13, wherein the heavy chain region further comprises a sequence of at least one constant region (CH).

15. The antibody agent according to claim 14, wherein at least one constant region includes an Fc domain.

16. The antibody agent according to claim 15, wherein the Fc domain comprises an Fc domain of a mouse, rat, rabbit, primate, human, dog, pig, or cat.

17. The antibody agent according to claim 15 or 16, wherein the Fc domain is selected from the Fc domains of immunoglobulin isotypes.

18. The antibody agent according to claim 17, wherein the immunoglobulin isotype comprises IgA, IgG, IgM, or IgE.

19. The antibody agent according to claim 17 or 18, wherein the Fc domain comprises the Fc domain of IgG, or optionally human IgG.

20. The antibody agent according to claim 19, wherein the IgG is IgG1, IgG2, IgG3, or IgG4, or comprises these.

21. The antibody agent according to claim 20, wherein the constant region of IgG includes one or more modifications.

22. The antibody agent according to claim 21, wherein the one or more modifications modulate one or more properties of the antibody agent.

23. The antibody agent according to claim 21 or 22, wherein one or more of the modifications include a PVAdelG mutation.

24. The antibody agent according to any one of claims 21 to 23, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 30, an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 30, or an amino acid sequence having 5, 10, or 20 or fewer amino acid sequences different from SEQ ID NO: 30, or an amino acid sequence containing these.

25. The antibody agent according to any one of claims 1 to 24, comprising a VL having an amino acid sequence of SEQ ID NO: 18, an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 18, or an amino acid sequence having 5, 10, or 20 or fewer amino acid sequences different from SEQ ID NO: 18, or an amino acid sequence containing these.

26. The antibody agent according to any one of claims 1 to 25, comprising VH having an amino acid sequence of SEQ ID NO: 14, an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 14, or an amino acid sequence having 5, 10, or 20 or fewer amino acid sequences different from SEQ ID NO: 14, or an amino acid sequence containing these.

27. An antibody agent according to any one of claims 1 to 26, comprising an amino acid sequence of SEQ ID NO: 33, an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 33, or an amino acid sequence having 5, 10, or 20 or fewer amino acid sequences different from SEQ ID NO: 33, or a light chain (LC) having an amino acid sequence containing these.

28. An antibody agent according to any one of claims 1 to 27, comprising an amino acid sequence of SEQ ID NO: 31, an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 31, or an amino acid sequence having 5, 10, or 20 or fewer amino acid sequences different from SEQ ID NO: 31, or a heavy chain (HC) having an amino acid sequence containing these.

29. (i) Not binding to TREM2 or having minimal binding affinity, (ii) Competition for binding with the reference antibody agent that binds to TREM1, (iii) Binding affinity (K) of approximately 0.1 nM to approximately 0.3 nM Ｄ ) to bind to the monomer human TREM1-ECD protein, (iv) Binding affinity (K) of approximately 1.4 nM to approximately 2.4 nM Ｄ ) to bind to the monomer cynoTREM1-ECD protein, (v) In enriched human monocyte cell binding assay, binding affinity (K) of approximately 80 pM to approximately 95 pM Ｄ ) to bind to human TREM1, (vi) In enriched human neutrophil cell binding assays, binding affinity (K) of approximately 185 pM to approximately 245 pM Ｄ ) to bind to human TREM1, (vii) In whole blood human monocyte cell binding assays, binding affinity (K) of approximately 90 pM to approximately 115 pM Ｄ ) to bind to human TREM1, (viiii) In whole blood human neutrophil cell binding assays, binding affinity (K) of approximately 110 pM to approximately 150 pM was observed. Ｄ ) to bind to human TREM1, (ix) In whole blood cyno-neutrophil cell binding assay, binding affinity (K) was approximately 235 pM to approximately 370 pM. Ｄ ) to connect to cynoTREM1, (x) In human whole blood concentrated neutrophil or primary monocyte function assays, inhibiting TREM1 activity with an IC50 of approximately 20 pM to approximately 40 pM. In the (xi)cyno-whole blood primary cell function assay, TREM1 activity was inhibited with an IC50 of approximately 4 M to approximately 13 pM. (xi) It can be produced at a concentration of approximately 4 g / L to approximately 7 g / L. (xiiii) Having a melting temperature of approximately 70°C to approximately 80°C. (xiv) Capable of binding to inactivated TREM1 and activated TREM1, (xv) Not binding to the surface of cells that do not express TREM1, or (xvi) Antagonizing TREM1-mediated inhibition of monocyte-to-macrophage maturation. An antibody agent according to any one of claims 1 to 28, characterized by one or more of the following.

30. An antibody agent that binds to human-induced receptor 1 (TREM1) expressed on myeloid cells, (i) Not binding to TREM2 or having minimal binding affinity, (ii) Competition for binding with the reference antibody agent that binds to TREM1, (iii) Binding affinity (K) of approximately 0.1 nM to approximately 0.3 nM Ｄ ) to bind to the monomer human TREM1-ECD protein. (iv) Binding to monomeric cynoTREM1-ECD protein with a binding affinity (K Ｄ ) of about 1.4 nM to about 2.4 nM, (v) In enriched human monocyte cell binding assay, binding affinity (K) of approximately 80 pM to approximately 95 pM Ｄ ) to bind to human TREM1, (vi) In enriched human neutrophil cell binding assays, binding affinity (K) of approximately 185 pM to approximately 245 pM Ｄ ) to bind to human TREM1, (vii) In whole blood human monocyte cell binding assays, binding affinity (K) of approximately 90 pM to approximately 115 pM Ｄ ) to bind to human TREM1, (viiii) In whole blood human neutrophil cell binding assays, binding affinity (K) of approximately 110 pM to approximately 150 pM was observed. Ｄ ) to bind to human TREM1, (ix) In whole blood cyno-neutrophil cell binding assay, binding affinity (K) was approximately 235 pM to approximately 370 pM. Ｄ ) to connect to cynoTREM1, (x) In human whole blood concentrated neutrophil or primary monocyte function assays, inhibiting TREM1 activity with an IC50 of approximately 20 pM to approximately 40 pM. In the (xi)cyno-whole blood primary cell function assay, TREM1 activity was inhibited with an IC50 of approximately 4 M to approximately 13 pM. (xi) It can be produced at a concentration of approximately 4 g / L to approximately 7 g / L. (xiiii) Having a melting temperature of approximately 70°C to approximately 80°C. (xiv) Capable of binding to inactivated TREM1 and activated TREM1, (xv) Not binding to the surface of cells that do not express TREM1, or (xvi) Antagonizing TREM1-mediated inhibition of monocyte-to-macrophage maturation. An antibody agent characterized by one or more of the following.

31. An antibody agent according to any one of claims 1 to 30, characterized by reducing TREM1 activity and / or cell surface level compared to a comparative agent.

32. The aforementioned comparative body, (i) Samples that do not come into contact with the TREM1 antibody agent disclosed herein, or (ii) Samples that come into contact with the reference TREM1 antibody agent, or (iii) Samples that come into contact with isotype control antibody agents The antibody agent according to claim 31, which is or includes these.

33. The antibody agent according to claim 31 or 32, wherein the antibody agent reduces the level of TREM1 present on the surface of cells, and optionally the cells are monocytes or neutrophils.

34. The antibody agent according to claim 33, which reduces the level of TREM1 present on the cell surface by internal migration and / or clipping of TREM1.

35. An antibody agent according to any one of claims 31 to 34, which reduces (e.g., inhibits) TREM1 activity.

36. The antibody agent according to claim 35, wherein inhibition of TREM1 activity includes inhibiting the binding of TREM1 to a TREM1 ligand, and the TREM1 ligand is optionally PGLYRP1.

37. An antibody agent according to any one of claims 31 to 36, which reduces the activity and / or level of TREM1 by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.

38. An antibody agent according to any one of claims 31 to 37, characterized by reducing (e.g., inhibiting) the TREM1-mediated immune response.

39. The antibody agent according to claim 38, wherein the TREM1-mediated immune response is an amplified immune response and / or not an innate immune response (e.g., a TLR-mediated immune response).

40. The antibody agent according to claim 38, wherein the TREM1-mediated immune response is mediated by monocytes (e.g., inflammatory monocytes) and / or neutrophils (e.g., activated neutrophils).

41. The aforementioned TREM1-mediated immune response (i) Secretion of one or more cytokines, wherein one or more cytokines are optionally selected to be pro-inflammatory cytokines, and further optionally selected from the group consisting of IL-1α, IL-1β, IL-6, IL-8, IL-10, IL-23, GM-CSF, TNF-RII, and TNFα, (ii) Secretion of one or more chemokines, wherein the one or more chemokines are arbitrarily selected from the group consisting of CCL2, CCL3, CCL4, CCL8, CCL20, CCL22, CCL24, CXCL1, CXCL5, CXCL9, CXCL10 and CXCL13. (iii) Modulation of T cells, B cells or other cells, wherein the modulation is optionally performed by one or more of IL-1α, IL-1β, IL-6, IL-10, IL-23, APPRIL, BAFF, CD30, M-CSF, TNF-RII, and TNFα. (iv) Secretion of one or more factors that reduce or impair the integrity of the epithelial barrier, wherein the one or more factors that reduce or impair the integrity of the epithelial barrier are optionally selected from the group consisting of IL-1α, IL-1β, IL-6, IL-8, IL-10, IL-23, GM-CSF, TRAIL, TWEAK, MMP-1, IL-20, TNFR-II and TNFα, and (v) Secretion of one or more proteolytic enzymes, wherein one or more proteolytic enzymes are or contain matrix metalloproteinases (MMPs), and further optionally the MMPs are MMP1 and / or MMP9. An antibody agent according to any one of claims 38 to 40, wherein it is one or more of the above, or includes one or more of the above.

42. An antibody agent according to any one of claims 1 to 41, characterized by preventing or reducing (e.g., inhibiting) epithelial barrier damage.

43. The antibody agent according to claim 42, wherein the epithelial barrier damage is mediated by one or more cytokines, one or more cytokines are optionally pro-inflammatory cytokines, and one or more cytokines are optionally selected from the group consisting of IL-1β, IL-6, IL-8, IL-23, and TNFα.

44. (i) intact IgA, IgG, IgD, IgE, or IgM antibodies, (ii) antibody fragment, (iii) Single-domain antibody, (iv) Single-chain Fv, or (v) Polypeptide containing antigen-binding specificity fused to the Fc domain An antibody agent according to any one of claims 1 to 43, which is or includes these.

45. An antibody agent according to any one of claims 1 to 44, which is an antibody-drug conjugate (ADC).

46. The antibody agent according to any one of claims 1 to 45, further comprising a second binding specificity, wherein the second binding specificity optionally confers binding to an antigen other than human TREM1.

47. The antibody agent according to claim 46, selected from heterodimer, Crossmab, DVD-Ig, two-in-one IgG and IgG-sc-Fv, scFv-scFv, BiTE, DART, diabody, Fab-scFv fusion, Fab-Fab fusion, or tandem antibody.

48. An antibody agent according to any one of claims 1 to 47, produced by bacterial cells, yeast cells, insect cells, and mammalian cells.

49. The antibody agent according to claim 48, wherein the antibody agent is produced by mammalian cells, and the mammalian cell line is optionally a CHO cell or comprises one.

50. An antibody agent according to any one of claims 1 to 47, produced by a cell-free system.

51. (i) LC CDR1, LC CDR2 and LC CDR3 sequences that collectively have at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with the sequence found in SEQ ID NO: 18, and / or collectively include differences of 1, 2, 3, 4, or 5 or fewer amino acids compared to the sequence found in SEQ ID NO: 18, (ii) the amino acid sequence of SEQ ID NO: 18, an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 18, or an amino acid sequence having 5, 10, or 20 or fewer amino acid sequences compared to SEQ ID NO: 18, and / or (iii) The amino acid sequence of SEQ ID NO: 33, an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 33, or an amino acid sequence having 5, 10, or 20 or fewer amino acid sequences compared to SEQ ID NO: 33 A polypeptide having an amino acid sequence that is or contains these.

52. (i) HC CDR1, HC CDR2 and HC CDR3 sequences that collectively have at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with the sequence found in SEQ ID NO: 14, and / or collectively include differences of 1, 2, 3, 4, or 5 or fewer amino acids compared to the sequence found in SEQ ID NO: 14, (ii) the amino acid sequence of SEQ ID NO: 14, an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 14, or an amino acid sequence having 5, 10, or 20 or fewer amino acid sequences different from SEQ ID NO: 14, and / or (iii) The amino acid sequence of SEQ ID NO: 31, an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 31, or an amino acid sequence having 5, 10, or 20 or fewer amino acid sequences compared to SEQ ID NO: 31 A polypeptide having an amino acid sequence that is or contains these.

53. (i) LC CDR1, LC CDR2 and LC CDR3 sequences that collectively have at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with the sequence found in SEQ ID NO: 18, and / or collectively include differences of 1, 2, 3, 4, or 5 or fewer amino acids compared to the sequence found in SEQ ID NO: 18, and (ii) HC CDR1, HC CDR2, and HC CDR3 sequences that collectively have at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with the sequence found in SEQ ID NO: 14, and / or collectively contain 1, 2, 3, 4, or 5 or fewer amino acid sequence differences compared to the sequence found in SEQ ID NO:

14. A polypeptide having an amino acid sequence that is or contains these.

54. A nucleic acid having a nucleotide sequence encoding the antibody agent according to any one of claims 1 to 50.

55. A nucleic acid having a nucleotide sequence encoding the polypeptide described in any one of claims 51 to 54.

56. A nucleic acid having a nucleotide sequence encoding a variable light chain (VL), wherein the nucleotide sequence is the nucleotide sequence of SEQ ID NO: 39 or a nucleotide sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 39, or contains such a sequence.

57. A nucleic acid having a nucleotide sequence encoding a variable heavy chain (VH), wherein the nucleotide sequence is the nucleotide sequence of SEQ ID NO: 38 or a nucleotide sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 38, or contains such a sequence.

58. A nucleic acid having a nucleotide sequence encoding an antibody agent that binds to TREM1, (i) The nucleotide sequence includes a first portion that codes for a variable light chain (VL), and the first portion is a nucleotide sequence that has at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with the nucleotide sequence of SEQ ID NO: 39, or includes these: (ii) The nucleotide sequence includes a second portion encoding a variable heavy chain (VH), wherein the second portion is a nucleotide sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with the nucleotide sequence of SEQ ID NO: 38, or includes such a sequence. Nucleic acid.

59. The nucleic acid according to claim 58, wherein the antibody agent further comprises a light chain constant region (CL) and / or at least one heavy chain constant region.

60. A vector comprising the nucleic acid described in any one of claims 54 to 59.

61. A host cell comprising the vector according to claim 60.

62. The host cell according to claim 61, wherein the host cell is a yeast cell, a bacterial cell, a mammalian cell, or an insect cell.

63. A method for producing an antibody agent that binds to TREM1, comprising culturing the host cells described in claim 62 or 62 under conditions in which the antibody agent is expressed by the host cells.

64. A composition comprising the antibody agent described in any one of claims 1 to 50.

65. A composition comprising the polypeptide described in any one of claims 51 to 53.

66. A pharmaceutical composition comprising or delivering an antibody agent according to any one of claims 1 to 50.

67. A pharmaceutical composition comprising or delivering a polypeptide according to any one of claims 51 to 53.

68. The pharmaceutical composition according to claim 66 or 67, further comprising an excipient and / or a pharmaceutically acceptable carrier.

69. A pharmaceutical composition according to any one of claims 66 to 68, formulated in one or more unit dosage forms.

70. A method for preparing a pharmaceutical composition, A method comprising the step of combining an antibody agent according to any one of claims 1 to 50, a polypeptide according to any one of claims 51 to 53, or a nucleic acid encoding part or all of the same, with one or more pharmaceutically acceptable carriers.

71. A method for treating diseases, disorders, or conditions related to TREM1-mediated immune responses in a subject, A method comprising the step of administering a pharmaceutical composition according to any one of claims 66 to 69 to a subject.

72. The method according to claim 71, characterized in that when the pharmaceutical composition is administered to the subject, it reduces the level and / or activity of TREM1 compared to the comparator.

73. The method according to claim 72, wherein the comparative subject includes a subject that is similar in that it is not administered the pharmaceutical composition or is administered a reference TREM1 inhibitor.

74. The method according to claims 71 to 73, wherein the disease, disorder or condition is an inflammatory disease, disorder or condition, and the inflammatory disease, disorder or condition is optionally selected from inflammatory bowel disease (IBD), sepsis, fibrous disease, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), COVID-19, Post-MI (ischemic reperfusion), atherosclerosis, acute stroke (ischemic reperfusion), stroke (hemorrhagic), renal ischemia-reperfusion injury, pancreatitis, renal fibrosis, hepatic fibrosis, NASH, sickle cell occlusive attack, Marfan syndrome, HIV infection, motor neuron dysfunction, periodontitis / gingivitis, cancer, diabetic foot ulcer, gout, lupus, psoriasis, arthropathy (e.g., arthritis or synovitis), and Behçet's disease.

75. The method according to any one of claims 71 to 74, wherein the disease, disorder, or condition is inflammatory bowel disease (IBD) (for example, intestinal IBD or extraintestinal signs (EIM) of IBD).

76. The method according to any one of claims 71 to 75, wherein the IBD is Crohn's disease (CD) or ulcerative colitis (UC).

77. The method according to any one of claims 71 to 76, wherein the disease, disorder, or condition is unresponsive to alternative therapy.

78. The method according to claim 77, wherein the alternative therapy is or includes anti-TNFα therapy.

79. The subjects have received or are receiving alternative therapy, and optionally, said alternative therapy is alternative IBD therapy, and optionally, said alternative therapy is anti-TNFα therapy (e.g., infliximab, adalimumab, golimumab, and certolizumab pegol); JAK inhibitor therapy (including selective and non-selective inhibitors) (e.g., upadacitinib, tofacitinib, and filgotinib); anti-integrin therapy (e.g., vedolizumab and natalizumab); anti-IL-23 therapy (e.g., guselkumab, mirikizumab, and brazicumab); anti-IL-12 / 23 therapy (e.g., ustekinumab); anti-IL-23A therapy (e.g., risankizumab); S1PR agonist or modulator therapy (e.g., ozanimod and etrasimodo); 5-aminosalicylate therapy (e.g., mesalamine) The method according to any one of claims 71 to 78, which is or comprises: orgalazide, valsalazide, and sulfasalazine; immunomodulator therapy (e.g., azathioprine, 6-mercaptopurine, and methotrexate); corticosteroid therapy (e.g., prednisone, methylprednisolone, hydrocortisone, and budesonide); anti-TL1A therapy (e.g., PRA023 and RVT-3101); kinase inhibitor therapy (e.g., ritrecitinib), TYK2 inhibitor therapy (e.g., duclavacitinib), anti-IL-36 therapy (e.g., spesolimab); anti-IL-13 therapy (e.g., dupilumab), miR-124 upregulator therapy (e.g., obefazimod), TLR9 agonist therapy (e.g., covitrimod); or a combination thereof.

80. The aforementioned subject is, (i) Biomarkers relating to or surrogating elevated neutrophil and / or monocyte (e.g., inflammatory monocyte) levels, which are optionally relating to or surrogating elevated activated neutrophil levels, (ii) A biomarker which is or comprises one or more products of neutrophils and / or monocytes (e.g., inflammatory monocytes), and / or a biomarker which correlates with reactivity to an antibody agent according to any one of claims 1 to 50. (iii) Biomarkers showing TREM1 level and / or activity The method according to any one of claims 71 to 79, which is determined to express the following.

81. The aforementioned biomarker, (i) A cell-based biomarker which is optionally selected to be the number of monocytes and / or neutrophils, TREM1 RNA present in monocytes and / or neutrophils, TREM1 present in monocytes and / or neutrophils, or TREM1 present on the cell surface of monocytes and / or neutrophils. (ii) A tissue biomarker which is optionally a neutrophil in a mucosal ulcer, lamina propria and / or epithelial cells, or lymphocytes, plasma cells and / or eosinophils in the lamina propria, (iii) A product produced by activated neutrophils, wherein the biomarker is optionally calprotectin, PGLYRP1, or soluble TREM1. (iv) Products produced by inflammatory monocytes, wherein the biomarker is optionally soluble TREM1, (v) TREM1 ligands which are optionally bacterial peptidoglycan (PGN) and / or PGLYRP1, and (vi) TREM1 gene activation signature The method according to claim 80, wherein one or more of the above are included.

82. The method according to claim 80 or 81, wherein the biomarker is detected in a sample selected from the group consisting of blood, diseased tissue, feces, components or fractions thereof, and combinations thereof.

83. (i) The biomarker is a monocyte and / or neutrophil count, and the biomarker is detected in diseased tissue. (ii) The biomarker is TREM1 RNA present in monocytes and / or neutrophils, and the biomarker is detected in diseased tissue. (iii) The biomarker is TREM1 present in monocytes and / or neutrophils, and the biomarker is detected in diseased tissue. (iv) The biomarker is TREM1 present on the cell surface of monocytes and / or neutrophils, and the biomarker is detected in diseased tissue. (v) The biomarker is a tissue biomarker and the biomarker is detected in diseased tissue. (vi) The biomarker is soluble TREM1, and the biomarker is detected in blood and / or feces. (vii) The biomarker is calprotectin, and the biomarker is detected in blood and / or feces. (viiii) The biomarker is bacterial PGN, and the biomarker is detected in feces. (ix) The biomarker is PGLYRP1, and the biomarker is detected in blood and / or feces. (x) The biomarker is a TREM1 gene activation signature, and the biomarker is detected in diseased tissue and / or blood, or (xi) The method according to any one of claims 80 to 82, which is a combination of these.

84. The target is, (i) Biomarkers relating to or surrogating elevated neutrophil and / or monocyte (e.g., inflammatory monocyte) levels, which are optionally relating to or surrogating elevated activated neutrophil levels, (ii) A biomarker which is or comprises one or more products of neutrophils and / or monocytes (e.g., inflammatory monocytes), and / or a biomarker which correlates with reactivity to an antibody agent according to any one of claims 1 to 50. (iii) Biomarkers showing TREM1 level and / or activity A step of determining whether or not to express, and If it is determined that the subject expresses the biomarker, the step of administering the antibody agent according to any one of claims 1 to 50 to the subject. Methods that include...

85. The aforementioned biomarker, (i) A cell-based biomarker which is optionally selected to be the number of monocytes and / or neutrophils, TREM1 RNA present in monocytes and / or neutrophils, TREM1 present in monocytes and / or neutrophils, or TREM1 present on the cell surface of monocytes and / or neutrophils. (ii) A tissue biomarker which is optionally a neutrophil in a mucosal ulcer, lamina propria and / or epithelial cells, or lymphocytes, plasma cells and / or eosinophils in the lamina propria, (iii) A product produced by activated neutrophils, wherein the biomarker is optionally calprotectin, PGLYRP1, or soluble TREM1. (iv) Products produced by inflammatory monocytes, wherein the biomarker is optionally soluble TREM1, (v) TREM1 ligands which are optionally bacterial peptidoglycan (PGN) and / or PGLYRP1, and (vi) TREM1 gene activation signature The method according to claim 84, wherein one or more of the above are included.

86. The method according to claim 84 or 85, wherein the biomarker is detected in a sample selected from the group consisting of blood, diseased tissue, feces, components or fractions thereof, and combinations thereof.

87. (i) The biomarker is a monocyte and / or neutrophil count, and the biomarker is detected in diseased tissue. (ii) The biomarker is TREM1 RNA present in monocytes and / or neutrophils, and the biomarker is detected in diseased tissue. (iii) The biomarker is TREM1 present in monocytes and / or neutrophils, and the biomarker is detected in diseased tissue. (iv) The biomarker is TREM1 present on the cell surface of monocytes and / or neutrophils, and the biomarker is detected in diseased tissue. (v) The biomarker is a tissue biomarker and the biomarker is detected in diseased tissue. (vi) The biomarker is soluble TREM1, and the biomarker is detected in blood and / or feces. (vii) The biomarker is calprotectin, and the biomarker is detected in blood and / or feces. (viiii) The biomarker is bacterial PGN, and the biomarker is detected in feces. (ix) The biomarker is PGLYRP1, and the biomarker is detected in blood and / or feces. (x) The biomarker is a TREM1 gene activation signature, and the biomarker is detected in diseased tissue and / or blood, or (xi) The method according to any one of claims 85 to 87, which is a combination of these.

88. The method according to any one of claims 84 to 87, characterized in that when the antibody agent is administered to a target, it reduces the level and / or activity of TREM1 compared to a comparator.

89. The method according to claim 88, wherein the comparative subject includes a subject that is similar in that it was not administered the antibody agent or was administered a reference TREM1 inhibitor.

90. A method for inhibiting TREM1, Cells, tissues, or subjects are brought into contact with the pharmaceutical composition according to any one of claims 66 to 69. The step of thereby inhibiting TREM1 in the cells, tissues, or target. Methods that include...

91. The method according to claim 90, wherein inhibition of TREM1 includes a reduction in the level and / or activity of TREM1.

92. The method according to claim 91, wherein the inhibition of TREM1 is assessed in comparison to a comparative sample.

93. A method to counteract TREM1-mediated inhibition of monocyte maturation into macrophages, Cells, tissues, or subjects are brought into contact with the pharmaceutical composition according to any one of claims 66 to 69. This step involves counteracting TREM1-mediated inhibition of monocyte-to-macrophage maturation in the cells, tissues, or subjects. Methods that include...

94. The method according to claim 93, wherein the antagonism of TREM1-mediated inhibition of monocyte maturation to macrophage is assessed in comparison with a comparator.

95. The method according to claim 92 or claim 94, wherein the comparative subject includes cells, tissues, or subjects that are similar in that they were not administered the pharmaceutical composition or were not administered a reference TREM1 inhibitor.

96. The method according to any one of claims 90 to 95, wherein the contact step includes administering the pharmaceutical composition to the cells, tissue or subject.

97. The method according to any one of claims 70 to 96, wherein the subject is a mammal.

98. The method according to claim 97, wherein the mammal is a human.

99. The method according to claim 98, wherein the person is an adult.

100. The method according to claim 98, wherein the human is a child.

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