Anti-TREM1 antibody agents, compositions and uses thereof

Abstract

Provided herein are antibody agents that specifically bind to TREM1, nucleic acids encoding these antibody agents, compositions comprising these antibody agents, and methods of making and using these antibody agents.

Description

[0001] Cross-referencing of related patent applications This application claims priority to U.S. Provisional Application No. 63 / 461,130, filed April 21, 2023, the entire contents of which are incorporated herein by reference. Background Technology

[0002] It is reported that the incidence of immune-mediated inflammatory diseases (IMIDs) in Western civilization ranges from 5% to 7%. Various treatment strategies have been explored, but the failure rate remains high. Summary of the Invention

[0003] Among other things, this disclosure provides particularly useful antibody agents (e.g., antibodies, their antigen-binding moieties, the nucleic acids encoding them, and entities containing them) that bind to myeloid trigger receptor 1 (TREM1).

[0004] This disclosure provides the insight that the levels of specific cell types and / or products (e.g., proteins, etc.) produced by specific cell types in certain subjects (e.g., in samples from such subjects) can indicate the potential responsiveness to anti-inflammatory therapies (e.g., anti-TREM1 antibody agents or nucleic acids encoding such agents).

[0005] We note that some therapeutic strategies for addressing inflammation focus on specific targets other than TREM1 (e.g., TNFα) (see, for example, Sakemi et al., Medicine 99:e23344, 2020). Some patients may respond poorly or not at all to such alternative therapies. For example, response rates to certain TNFα therapies are frequently 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 such agents for the treatment of subjects with inflammatory diseases, disorders, or conditions who are relatively unlikely to respond to alternative therapies (e.g., therapies targeting TNFα), or in whom continued use of such therapy may be ineffective or potentially less effective, and / or in whom these subjects may be relatively more likely to respond to different therapies (e.g., therapies targeting TREM1).

[0006] In at least one aspect, this disclosure provides an antibody agent that binds to human myeloid cell trigger receptor 1 (TREM1), wherein the antibody comprises: (a) a light chain having CDR1, CDR2, and CDR3 sequences, wherein the CDR1, CDR2, and CDR3 sequences have a total identity of at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% with respect to those sequences found in SEQ ID NO: 18, and / or comprises no more than 1, 2, 3, 4, or 5 amino acid sequence differences relative to those sequences found in SEQ ID NO: 18; and / or (b) a heavy chain having CDR1, CDR2, and CDR3 sequences, wherein the CDR1, CDR2, and CDR3 sequences have a total identity of at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% with respect to those sequences found in SEQ ID NO: 14, and / or comprises no more than 1, 2, 3, 4, or 5 amino acid sequence differences relative to those sequences found in SEQ ID NO: 18; and / or comprises no more than 1, 2, 3, 4, or 5 amino acid sequence differences relative to those sequences found in SEQ ID NO: 18; and / or comprises no more than 1, 2, 3, 4, or 5 amino acid sequence differences relative to those sequences found in SEQ ID NO: 18; and / or comprises no more than 1, 2, 3, 4, or 5 amino acid sequence differences relative to those sequences found in SEQ ID NO: 18. The sequences found in 14 differ by no more than one, two, three, four, or five amino acid sequences.

[0007] In some embodiments, the antibody agent of this disclosure comprises a light chain (LC) comprising: (i) LC CDR1 having an amino acid sequence that is or comprises: 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 no more than 1, 2, 3, 4, or 5 amino acid sequence differences relative to SEQ ID NO: 19; (ii) LCCDR2 having an amino acid sequence that is or comprises: the amino acid sequence of GAS, or an amino acid sequence having no more than 1 or 2 amino acid sequence differences relative to the amino acid sequence of GAS; and (iii) LCCDR3 having an amino acid sequence that is or comprises: 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: 19, or an amino acid sequence having no more than 1, 2, 3, 4, or 5 amino acid sequence differences relative to SEQ ID NO: 19 ... 20 has an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the SEQ ID NO: 20, or has an amino acid sequence that differs from the SEQ ID NO: 20 by no more than 1, 2, 3, 4, or 5 amino acid sequences.

[0008] In some embodiments, the antibody agent of this disclosure comprises a heavy chain (HC) comprising: (i) HC CDR1 having an amino acid sequence that is or comprises: 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 no more than 1, 2, 3, 4, or 5 amino acid sequences different from SEQ ID NO: 15; (ii) HCCDR2 having an amino acid sequence that is or comprises: 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 no more than 1, 2, 3, 4, or 5 amino acid sequences different from SEQ ID NO: 16; and (iii) HC CDR3, the HC CDR1 having an amino acid sequence that is or comprises: 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 no more than 1, 2, 3, 4, or 5 amino acid sequences different from SEQ ID NO: 16; and (iii) HC CDR3 having an amino acid sequence that is or comprises: 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: 16; and (iii) HC CDR3 having an amino acid sequence that is or comprises: the amino acid sequence of SEQ ID NO: 15, an amino acid sequence having at least 85%, 90%, 95%, 9 CDR3 has an amino acid sequence that is or includes: 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 no more than 1, 2, 3, 4, or 5 amino acid sequence differences relative to SEQ ID NO: 17.

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

[0010] In some embodiments, the antibody agent of this disclosure comprises: (i) an amino acid sequence that is or comprises: the amino acid sequence of SEQ ID NO: 25, an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 25, or an amino acid sequence having no more than 1, 2, 3, 4, or 5 amino acid sequences different from SEQ ID NO: 25; and / or (ii) an amino acid sequence that is or comprises: the amino acid sequence of SEQ ID NO: 26, an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 26, or an amino acid sequence having no more than 1, 2, 3, 4, or 5 amino acid sequences different from SEQ ID NO: 26; and / or (iii) an amino acid sequence that is or comprises: 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: 25, or an amino acid sequence having no more than 1, 2, 3, 4, or 5 amino acid sequences different from SEQ ID NO: 25 ...ii) an amino acid sequence that is or comprises: the amino acid sequence of SEQ ID NO: 27, an amino acid sequence having at least 85%, 90%, 9 27 has an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 27, or has an amino acid sequence that differs from SEQ ID NO: 27 by no more than 1, 2, 3, 4, or 5 amino acid sequences; and / or (iv) an amino acid sequence that is or comprises: 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 has an amino acid sequence that differs from SEQ ID NO: 28 by no more than 1, 2, 3, 4, or 5 amino acid sequences.

[0011] In some embodiments, the antibody agent of this disclosure comprises a light chain containing a sequence of a constant region (CL). In some embodiments, the light chain comprises κCL or λCL. In some embodiments, the light chain comprises κCL. In some embodiments, the light chain comprises an amino acid sequence that is or 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 no more than 5, 10, or 20 amino acid sequences different from SEQ ID NO: 32.

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

[0013] In some embodiments, the antibody agent of this disclosure comprises: (i) an amino acid sequence that is or comprises: the amino acid sequence of SEQ ID NO: 21, an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 21, or an amino acid sequence having no more than 1, 2, 3, 4, or 5 amino acid sequences different from SEQ ID NO: 21; and / or (ii) an amino acid sequence that is or comprises: the amino acid sequence of SEQ ID NO: 22, an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 22, or an amino acid sequence having no more than 1, 2, 3, 4, or 5 amino acid sequences different from SEQ ID NO: 22; and / or (iii) an amino acid sequence that is or comprises: 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: 21 ...1; and / or (ii) an amino acid sequence that is or comprises: the amino acid sequence of SEQ ID NO: 23, an amino acid sequence having at least 85%, 90%, 9 23 has an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identity with SEQ ID NO: 23, or has an amino acid sequence that differs from SEQ ID NO: 23 by no more than 1, 2, 3, 4 or 5 amino acid sequences; and / or (iv) an amino acid sequence that is or comprises: 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 has an amino acid sequence that differs from SEQ ID NO: 24 by no more than 1, 2, 3, 4 or 5 amino acid sequences.

[0014] In some embodiments, the antibody agent of this disclosure comprises a heavy chain region containing 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 a mouse, rat, rabbit, primate, human, dog, pig, or cat Fc domain. In some embodiments, the Fc domain is selected from the Fc domains of immunoglobulin isotypes. In some embodiments, the immunoglobulin isotype comprises IgA, IgG, IgM, or IgE. In some embodiments, the Fc domain comprises the Fc domain of IgG. In some embodiments, the Fc domain comprises the Fc domain of human IgG. In some embodiments, the IgG is or comprises IgG1, IgG2, IgG3, or IgG4. In some embodiments, the IgG constant region comprises one or more modifications. In some embodiments, the one or more modifications modulate one or more properties of the antibody agent. In some embodiments, the one or more modifications comprise a PVAdelG mutation. In some embodiments, the heavy chain comprises an amino acid sequence that is or 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 no more than 5, 10, or 20 amino acid sequences different from SEQ ID NO: 30.

[0015] In some embodiments, the antibody agent of this disclosure comprises VL having an amino acid sequence that is or comprises: 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 no more than 5, 10, or 20 amino acid sequences different from SEQ ID NO: 18. In some embodiments, the antibody agent of this disclosure comprises VH having an amino acid sequence that is or comprises: 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 no more than 5, 10, or 20 amino acid sequences different from SEQ ID NO: 14.

[0016] In some embodiments, the antibody agent of this disclosure comprises a light chain (LC) having an amino acid sequence that is or comprises the amino acid sequence of SEQ ID NO: 33, having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 33, or having an amino acid sequence that differs from SEQ ID NO: 33 by no more than 5, 10, or 20 amino acids. In some embodiments, the antibody agent of this disclosure comprises a heavy chain (HC) having an amino acid sequence that is or comprises the amino acid sequence of SEQ ID NO: 31, having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 31, or having an amino acid sequence that differs from SEQ ID NO: 31 by no more than 5, 10, or 20 amino acids.

[0017] In at least one aspect, this disclosure provides an antibody agent characterized by one or more of the following: (i) the antibody agent does not bind to TREM2 or has minimal binding affinity to TREM2; (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 (K0) of about 0.1 nM to about 0.3 nM. D (iv) The antibody agent binds to the monomeric human TREM1-ECD protein; D (v) The antibody binds to the monomeric cynomolgus TREM1-ECD protein; and (v) the antibody showed a binding affinity of approximately 80 pM to approximately 95 pM in enriched human mononuclear cell binding assays (K0.05). D (vi) The antibody agent binds to human TREM1; and (vi) the antibody agent exhibits a binding affinity (K0.05) of approximately 185 pM to approximately 245 pM in enriched human neutrophil binding assays. D (vii) The antibody binds to human TREM1; and (vii) the antibody showed a binding affinity (K0.05) of approximately 90 pM to approximately 115 pM in whole blood human mononuclear cell binding assays. D (viii) The antibody binds to human TREM1; (viii) The antibody showed a binding affinity (K0.05) of approximately 110 pM to approximately 150 pM in whole blood human neutrophil binding assays. D (ix) The antibody binds to human TREM1; and (ix) the antibody showed a binding affinity (K) of approximately 235 pM to approximately 370 pM in a whole-blood cynomolgus monkey neutrophil binding assay. D(x) The antibody agent binds to TREM1 in cynomolgus monkeys; (x) The antibody agent inhibits TREM1 activity at an IC50 of about 20 pM to about 40 pM in a human whole blood-enriched primary neutrophil or monocyte cell function assay; (xi) The antibody agent inhibits TREM1 activity at an IC50 of about 4 pM to about 13 pM in a cynomolgus monkey whole blood primary cell function assay; (xii) The antibody agent can be produced at a concentration of about 4 g / L to about 7 g / L; (xiii) The antibody agent has a melting temperature of about 70 °C to about 80 °C; (xiv) The antibody agent can bind to both inactive and activated TREM1; (xv) The antibody agent does not bind to the surface of cells that do not express TREM1; or (xvi) The antibody agent antagonizes TREM1-mediated inhibition of monocyte maturation into macrophages.

[0018] In some embodiments, the antibody agent of this disclosure is characterized by reducing TREM1 activity and / or cell surface levels relative to a comparative. In some embodiments, the comparative is or comprises: (i) a sample not contacted with the TREM1 antibody agent disclosed herein; or (ii) a sample contacted with a reference TREM1 antibody agent; or (iii) a sample contacted with an isotype control antibody agent. In some embodiments, the antibody agent reduces the level of TREM1 present on the cell surface. In some embodiments, the cell is a monocyte or neutrophil. In some embodiments, the antibody agent reduces the level of TREM1 present on the cell surface by internalization and / or cleavage of TREM1. In some embodiments, the antibody agent reduces (e.g., inhibits) TREM1 activity. In some embodiments, inhibiting 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 its reduction (e.g., inhibition) of TREM1-mediated immune responses. 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) the secretion of one or more cytokines; (ii) the secretion of one or more chemokines; (iii) regulation by T cells, B cells, or other cells; (iv) the secretion of one or more factors that reduce or impair the integrity of the epithelial barrier; and (v) the secretion of one or more proteolytic enzymes. In some embodiments, the one or more cytokines are pro-inflammatory cytokines. In some embodiments, the 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, the 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, T cells, B cells, or other cells are regulated 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, the 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, the one or more proteolytic enzymes are or comprise matrix metalloproteinases (MMPs). In some embodiments, the MMP is MMP1 and / or MMP9.

[0019] In some embodiments, the antibody agents of this disclosure are characterized by their ability to prevent or reduce (e.g., inhibit) epithelial barrier damage. In some embodiments, the epithelial barrier damage is mediated by one or more cytokines. In some embodiments, the one or more cytokines are pro-inflammatory cytokines. In some embodiments, the 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 this 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 comprising antigen-binding specificity fused to an Fc domain. In some embodiments, the antibody agent is an antibody-drug conjugate (ADC). In some embodiments, the antibody agent also has 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, 2-in-1 IgG and IgG-sc-Fv, scFv-scFv, BiTE, DART, biantibodies, Fab-scFv fusions, Fab-Fab fusions, or tandem antibodies.

[0021] In some embodiments, the antibody agent of this disclosure is produced in bacterial cells, yeast cells, insect cells, or mammalian cells. In some embodiments, the antibody agent is produced in mammalian cells. In some embodiments, the mammalian cell line is or comprises CHO cells. In some embodiments, the antibody agent is produced in a cell-free system.

[0022] In at least one aspect, this disclosure provides a polypeptide having an amino acid sequence that is or comprises: (i) LC CDR1, LC CDR2, and LC CDR3 sequences having a total identity of at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% with respect to those sequences found in SEQ ID NO: 18, and / or comprising no more than 1, 2, 3, 4, or 5 amino acid sequence differences relative to those sequences found in SEQ ID NO: 18; (ii) the amino acid sequence of SEQ ID NO: 18 having an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 18, or having an amino acid sequence differing from SEQ ID NO: 18 by no more than 5, 10, or 20 amino acid sequence differences; and / or (iii) the amino acid sequence of SEQ ID NO: 33 having an amino acid sequence having a total identity of at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% with respect to SEQ ID NO: 18 ... 33 has an amino acid sequence with at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identity, or has an amino acid sequence with no more than 5, 10 or 20 amino acid sequences different from SEQ ID NO: 33.

[0023] In at least one aspect, this disclosure provides a polypeptide having an amino acid sequence that is or comprises: (i) HC CDR1, HC CDR2, and HC CDR3 sequences having a total identity of at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% with respect to those sequences found in SEQ ID NO: 14, and / or comprising no more than 1, 2, 3, 4, or 5 amino acid sequence differences relative to those sequences found in SEQ ID NO: 14; (ii) an amino acid sequence of SEQ ID NO: 14 having an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 14, or having an amino acid sequence differing from SEQ ID NO: 14 by no more than 5, 10, or 20 amino acid sequence differences; and / or (iii) an amino acid sequence of SEQ ID NO: 31 having an amino acid sequence having a total identity of at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% with respect to SEQ ID NO: 14 ... 31 has an amino acid sequence with at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identity, or has an amino acid sequence with no more than 5, 10 or 20 amino acid sequences different from SEQ ID NO: 31.

[0024] In at least one aspect, this disclosure provides a polypeptide having an amino acid sequence that is or comprises: (i) LC CDR1, LC CDR2, and LC CDR3 sequences having a total identity of at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% with respect to those sequences found in SEQ ID NO: 18, and / or comprising no more than 1, 2, 3, 4, or 5 amino acid sequence differences relative to those sequences found in SEQ ID NO: 18; and (ii) HCCDR1, HC CDR2, and HC CDR3 sequences having a total identity of at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% with respect to those sequences found in SEQ ID NO: 14, and / or comprising no more than 1, 2, 3, 4, or 5 amino acid sequence differences relative to those sequences found in SEQ ID NO: 14.

[0025] In at least one aspect, this 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), wherein the nucleotide sequence is or comprises: 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. In some embodiments, the nucleic acid has a nucleotide sequence encoding a variable heavy chain (VH), wherein the nucleotide sequence is or comprises: 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. In some embodiments, the nucleic acid has a nucleotide sequence encoding an antibody agent that binds to TREM1, wherein: (i) the nucleotide sequence comprises a first portion encoding a variable light chain (VL), wherein the first portion is or comprises: 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; and (ii) the nucleotide sequence comprises a second portion encoding a variable heavy chain (VH), wherein the second portion is or comprises: 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. In some embodiments, the antibody agent encoded by the nucleotide sequence further comprises a light chain constant region (CL) and / or at least one heavy chain constant region.

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

[0027] In at least one aspect, this disclosure provides a host cell comprising the vector described herein. In some embodiments, the host cell is a yeast cell, a bacterial cell, a mammalian cell, or an insect cell.

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

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

[0030] In at least one aspect, this disclosure provides a pharmaceutical composition comprising or delivering the antibody agent described herein. In some embodiments, the pharmaceutical composition comprises or delivers the polypeptide described herein. In some embodiments, the pharmaceutical composition further comprises an excipient and / or a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated into one or more unit dosage forms.

[0031] In at least one aspect, this disclosure provides a method for preparing a pharmaceutical composition, the method comprising the steps of: combining an antibody agent, a polypeptide, or a nucleic acid encoding part or all of the thereof as described herein with one or more pharmaceutically acceptable carriers.

[0032] In at least one aspect, this disclosure provides a method for treating a subject with a disease, disorder, or condition related to a TREM1-mediated immune response, the method comprising the step of administering the pharmaceutical composition described herein to the subject. In some embodiments, the pharmaceutical composition is characterized in that, when administered to the subject, it reduces the level and / or activity of TREM1 relative to a comparative. In some embodiments, the comparative includes other similar subjects who have not received the pharmaceutical composition or have received a reference TREM1 inhibitor.

[0033] In some implementations, the disease, disorder, or condition is an inflammatory disease, disorder, or condition. In some implementations, the inflammatory disease, disorder, or condition is selected from: inflammatory bowel disease (IBD), sepsis, fibrotic 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, liver fibrosis, NASH, sickle cell vascular occlusive crisis, Marfan syndrome, HIV infection, motor neuron developmental disorder, periodontitis / gingivitis, cancer, diabetic foot ulcer, gout, lupus, psoriasis, arthropathy (e.g., arthritis or synovitis), and Behcet's disease. In some implementations, the disease, disorder, or condition is inflammatory bowel disease (IBD) (e.g., intestinal IBD or extraintestinal manifestation (EIM) of IBD). In some implementations, the IBD is Crohn's disease (CD) or ulcerative colitis (UC). In some implementations, the disease, disorder, or condition is unresponsive to alternative therapies. In some implementations, the alternative therapy is or includes anti-TNFα therapy.

[0034] In some implementations, the subject has received or is receiving alternative therapy. In some implementations, the alternative therapy is an alternative IBD therapy. In some implementations, the alternative therapy is or includes anti-TNFα therapy (e.g., infliximab, adalimumab, golimumab, and certolizumab). pegol); JAK inhibitor therapies (including selective and non-selective inhibitors) (e.g., utpatinib, tofacitinib, and fegastinib); anti-integrin therapies (e.g., vedolizumab and natezumab); anti-IL-23 therapies (e.g., guselkumab, mirikizumab, and brazikumab); anti-IL-12 / 23 therapies (e.g., ustekinumab); anti-IL-23A therapies (e.g., risankizumab); S1PR agonist or modulator therapies (e.g., ozamod and etrasimod); 5-aminosalicylate therapies (e.g., mesalazine, olsalazine, balsalazine, 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 inhibitor therapies (e.g., ritlecitinib), TYK2 inhibitor therapies (e.g., deucravacitinib), anti-IL-36 therapies (e.g., spesolimab); anti-IL-13 therapies (e.g., dupilumab), miR-124 upregulatory therapies (e.g., obefazimod), TLR9 agonist therapies (e.g., cobitolimod); or combinations thereof.

[0035] In some embodiments, a subject has been identified to express a biomarker that: (i) is an elevated level of neutrophils and / or monocytes (e.g., inflammatory monocytes) or a substitute thereof; (ii) is or contains one or more products of neutrophils and / or monocytes (e.g., inflammatory monocytes), wherein the biomarker is associated with responsiveness to the antibody agent described herein; and / or (iii) indicates TREM1 level and / or activity. In some embodiments, the biomarker is an elevated level of activated neutrophils or a substitute thereof; in some embodiments, the biomarker is or includes one or more of the following: (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, the cell-based biomarker is a monocyte and / or neutrophil count, 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, the tissue biomarker is a mucosal ulcer, neutrophils and / or epithelial cells in the lamina propria, or lymphocytes, plasma cells, and / or eosinophils in the lamina propria. In some embodiments, the product produced by activated neutrophils is calprotectin, PGLYRP1, or soluble TREM1. In some embodiments, the product produced by inflammatory monocytes is soluble TREM1. In some embodiments, the TREM1 ligand is bacterial peptidoglycan (PGN) and / or PGLYRP1. In some embodiments, the biomarker is detected in samples selected from the group consisting of: blood, diseased tissue, feces, their components or fractions, and combinations thereof. In some embodiments, the biomarker is a 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 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 it is detected in blood and / or feces. In some embodiments, the biomarker is bacterial PGN, and it is detected in feces. In some embodiments, the biomarker is PGLYRP1, and it is detected in blood and / or feces. In some embodiments, the biomarker is a TREM1 gene activation signature, and it is detected in diseased tissue and / or blood.

[0036] In at least one aspect, this disclosure provides a method comprising the steps of: determining whether a subject expresses a biomarker, the biomarker being: (i) an elevated level of neutrophils and / or monocytes (e.g., inflammatory monocytes) or a substitute thereof; (ii) one or more products containing neutrophils and / or monocytes (e.g., inflammatory monocytes), wherein the biomarker is associated with responsiveness to an antibody agent disclosed herein; and / or (iii) an indicator of TREM1 level and / or activity; and if the subject is determined to express the biomarker, administering the antibody agent disclosed herein to the subject. In some embodiments, the biomarker is an elevated level of activated neutrophils or a substitute thereof; in some embodiments, the biomarker is or includes one or more of the following: (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, the cell-based biomarker is a monocyte and / or neutrophil count, 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, the tissue biomarker is a mucosal ulcer, neutrophils and / or epithelial cells in the lamina propria, or lymphocytes, plasma cells, and / or eosinophils in the lamina propria. In some embodiments, the product produced by activated neutrophils is calprotectin, PGLYRP1, or soluble TREM1. In some embodiments, the product produced by inflammatory monocytes is soluble TREM1. In some embodiments, the TREM1 ligand is bacterial peptidoglycan (PGN) and / or PGLYRP1. In some embodiments, the biomarker is detected in samples selected from the group consisting of: blood, diseased tissue, feces, their components or fractions, and combinations thereof. In some embodiments, the biomarker is a 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 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 is characterized by reducing TREM1 levels and / or activity relative to a comparator when administered to a subject. In some embodiments, the comparator includes other similar subjects who have not received the antibody agent or have received a reference TREM1 inhibitor.

[0037] In at least one aspect, this disclosure provides a method for inhibiting TREM1, the method comprising the steps of: contacting cells, tissues, or subjects with the pharmaceutical composition described herein to inhibit TREM1 in the cells, tissues, or subjects. In some embodiments, the inhibition of TREM1 includes a reduction in the level and / or activity of TREM1. In some embodiments, the inhibition of TREM1 is evaluated relative to a comparative.

[0038] In at least one aspect, this disclosure provides a method for antagonizing TREM1-mediated inhibition of monocyte maturation into macrophages, the method comprising the step of contacting a cell, tissue, or subject with a pharmaceutical composition described herein to antagonize TREM1-mediated inhibition of monocyte maturation into macrophages in the cell, tissue, or subject. In some embodiments, the antagonism of TREM1-mediated inhibition of monocyte maturation into macrophages is evaluated relative to a comparative. In some embodiments, the comparative includes other similar cells, tissues, or subjects not treated with the pharmaceutical composition or treated with a reference TREM1 inhibitor. In some embodiments, the contact step includes applying the pharmaceutical composition to the cell, tissue, or subject. In some embodiments, the subject is a mammal. In some embodiments, the mammal is a human. In some embodiments, the human is an adult. In some embodiments, the human is a child. Attached Figure Description

[0039] Figure 1AThis is a t-distributed random nearest neighbor embedding (tSNE) plot, which illustrates the cell subpopulations identified in single-cell transcriptomic data from samples from IBD patients. Further analysis was conducted to differentiate cell populations across clinical dimensions, such as anti-TNFα therapy responder status or inflammatory status.

[0040] Figure 1B It shows from Figure 1A tSNE diagram of myeloid cell population.

[0041] Figure 2 This is a tSNE plot of single-cell data from tissue samples of patients with inflammatory bowel disease (IBD). Cells are shaded based on the hypergeometric dominance ratio of the probability of cell neighborhood enrichment from inflamed samples. Inflammatory monocyte populations are circled and are highly correlated with inflammation.

[0042] Figure 3 This is a volcano plot, which shows the differential abundance of cell types in inflammatory samples compared to non-inflammatory samples from IBD patients. The x-axis represents the effect size (log2 (fold change)), while the y-axis represents significance (-log2). 10 (p-value)). Inflammatory mononuclear cells were the cell type most significantly associated with inflammatory samples.

[0043] Figure 4A This is a tSNE plot of single-cell data from inflamed tissue of IBD patients. Cells are shaded based on TREM1 expression levels. Inflammatory monocyte populations are circled.

[0044] Figure 4B This is a tSNE plot of single-cell data from non-inflammatory tissues of IBD patients. Cells are shaded based on TREM1 expression levels. Inflammatory monocyte populations are circled.

[0045] Figure 4C This is a tSNE plot of single-cell data from healthy tissues of non-IBD patients. Cells are shaded based on TREM1 expression levels. Inflammatory monocyte populations are circled.

[0046] Figure 5A This is a tSNE plot of single-cell data from peripheral blood mononuclear cells (PBMCs) of IBD patients. Cells were shaded based on TREM1 expression levels.

[0047] Figure 5B This is a tSNE plot of single-cell data from peripheral blood mononuclear cells (PBMCs) of healthy individuals. Cells were shaded based on TREM1 expression levels.

[0048] Figure 6AThis is a tSNE plot of single-cell data from tissue samples of IBD patients. Cells are shaded based on the hypergeometric dominance ratio of enrichment in post-treatment samples from non-responders (NR) on anti-TNFα therapy compared to responders (R). Inflammatory mononuclear cell populations are circled.

[0049] Figure 6B This is a tSNE plot of single-cell data from tissue samples of IBD patients who were unresponsive to anti-TNFα therapy after treatment. Cells were shaded based on TREM1 expression levels. Inflammatory monocyte populations are circled.

[0050] Figure 6C This is a tSNE plot of single-cell data from tissue samples of patients with Crohn's disease (CD) who are unresponsive to anti-TNFα therapy, before and after treatment. Cells are shaded based on TREM1 expression levels. Inflammatory monocyte populations are circled.

[0051] Figure 6D This is a tSNE plot of single-cell data from tissue samples of patients with ulcerative colitis (UC) who were unresponsive to anti-TNFα therapy, before and after treatment. Cells were shaded based on TREM1 expression levels. Inflammatory monocyte populations are circled.

[0052] Figure 7 This study demonstrates the association between the enrichment of TREM1+ myeloid cells (primarily monocytes) assessed by single-cell transcriptomics using mucosal biopsies and the level of neutrophil infiltration assessed using the Nancy histopathological index from adjacent biopsies in inflamed tissues from patients with active ulcerative colitis. A Nancy score ≤1 indicates no neutrophil infiltration (“None”); a score 2 indicates mild neutrophil infiltration (“Mild”); and a score ≥3 indicates severe neutrophil infiltration (“Severe”).

[0053] Figure 8A The diagram illustrates the binding of anti-TREM1 antibody agent clone A to TREM1, present on the cell surface of neutrophils in whole blood from healthy human subjects, as analyzed using flow cytometry. The figure shows data from a single donor, which is considered representative of data from eight different donors.

[0054] Figure 8B Alexa Fluor was shown ®Geometric mean fluorescence intensity (MFI) data for anti-TREM1 antibody clone A labeled with 647, which bound to enriched human primary neutrophils (CD45+ / CD66abce+) isolated from three healthy volunteer donors. Geometric MFI of anti-TREM1 antibody clone 1 was plotted against the concentration of anti-TREM1 antibody clone 1 (logarithmic scale). Error bars represent the mean ± SD from technical replicates.

[0055] Figure 8C The image shows the anti-TREM1 antibody drug clone A as analyzed by flow cytometry, and the total CD14 present in whole blood from healthy human subjects. + The binding of TREM1 on the cell surface of monocytes. The figure shows data from a single donor, which is considered to represent data from eight different donors.

[0056] Figure 8D Alexa Fluor was shown ® Geometric mean fluorescence intensity (MFI) data for anti-TREM1 antibody clone A, labeled with 647, bound to enriched human primary monocytes (CD45+ / CD14+) isolated from four healthy volunteer donors. Geometric MFI of anti-TREM1 antibody clone 1 was plotted against the concentration of anti-TREM1 antibody clone 1 (logarithmic scale). Error bars represent the mean ± SD from technical replicates.

[0057] Figure 8E The image shows the anti-TREM1 antibody drug clone A as analyzed by flow cytometry, and CD45 present in whole blood from healthy human subjects. + Lin + (CD3) + or CD7 + or CD20 + The figure shows a lack of binding to certain cells (e.g., T cells, NK cells, and B cells). Data from a single donor is presented as representative of data from eight different donors.

[0058] Figure 9 The diagram illustrates the binding of anti-TREM1 antibody agent clone A to TREM1 on the cell surface of monocytes in response to stimulation by bacterial PGN or LPS, as analyzed using flow cytometry. The figure shows data from a single donor, which is considered representative of monocytes from eight different donors.

[0059] Figures 10A to 10F This demonstrates the inflammatory cytokines and chemokines (CCL3) secreted by primary monocytes in response to stimulation by PGLYRP1 alone, PGN alone, or a combination of PGN and PGLYRP1. Figure 10A ), CCL4 ( Figure 10B ), IL-1β ( Figure 10C ), IL-6 ( Figure 10D ), IL-23 ( Figure 10E ) and TNFα ( Figure 10F The concentration of the culture medium was used. Unstimulated cells (culture medium) were used to represent 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 = no statistical significance; ** = p < 0.01; *** = p < 0.001; **** = p < 0.0001. The figure shows data from a single donor, which is considered representative of data from 12 different donors.

[0060] Figure 11 The concentrations of inflammatory cytokines and chemokines (CCL3, CCL4, and IL-8) secreted by primary neutrophils in response to stimulation by PGLYRP1 alone, PGN alone, or a combination of PGN and PGLYRP1 are shown in the culture medium. Unstimulated cells (culture medium) were used to show baseline cytokine levels. Means and standard deviations of eight replicates are shown. Statistical significance was determined by one-way ANOVA and Tukey's multiple comparison test: ns = no statistical significance; * = p < 0.05; ** = p < 0.01; *** = p < 0.001; **** = p < 0.0001. The figure shows data from a single donor, which is considered representative of data from 19 different donors.

[0061] Figure 12 This shows an 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).

[0062] Figure 13 The maximum biological layer interference (BLI) response, measured in nanometers, is shown for the binding between human TREM2-ECD (BioLegend, 786404 and R&D Systems, 1828-T2-050) and an exemplary anti-TREM1 antibody agent. The anti-TREM2 antibody (R&D Systems, MAB17291) was used as a positive control.

[0063] Figure 14Results from a multispecific assay are shown. The binding of the anti-TREM1 antibody to each of the more than 6,000 human membrane proteins expressed on HEK293 cells was measured. Anti-TREM1 antibody clone A exhibits high selectivity for binding to TREM1.

[0064] Figure 15 The mean fluorescence intensity (MFI) of G401 cells stained with clone A of the anti-TREM1 antibody conjugated to Alexa Fluor 647 (AF647) is shown. These G401 cells were TMEM178A positive and TREM1 negative. The geometric mean (GeoMean) MFI, which is considered a set of data representing three experiments, is shown. An isotype control antibody conjugated to AF647 was used as a negative control.

[0065] Figure 16 The results of differential scanning fluorometry assays used to evaluate the thermal stability of anti-TREM1 antibody agents are shown.

[0066] Figures 17A to 17F This diagram shows the secretion of inflammatory cytokines and chemokines (CCL3) by primary monocytes stimulated with a combination of PGN and PGLYRP1 and also treated with an anti-TREM1 antibody clone A, an isotype control, or without antibody treatment. Figure 17A ), CCL4 ( Figure 17B ), IL-1β ( Figure 17C ), IL-6 ( Figure 17D ), IL-23 ( Figure 17E ) and TNFα ( Figure 17F The concentration of the culture medium was used to represent baseline cytokine levels. Unstimulated cells (culture medium) were 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 = no statistical significance; * = p < 0.05; *** = p < 0.001; **** = p < 0.0001. The figure shows data from a single donor, which is considered representative of data from 12 different donors.

[0067] Figure 18The medium concentrations of TNFα secreted by primary human monocytes from healthy volunteers stimulated with PGN, PGLYRP1, or a combination of PGN and PGLYRP1 are shown, in the presence of anti-TREM1 antibody clone A or an isotype control. Ten-point titration curves were performed for the anti-TREM1 antibody clone A or isotype control. Unstimulated cells (medium) were used to show baseline cytokine levels. The mean and standard deviation of four replicates are shown. The figure shows data from a single donor, which is considered representative of data from 12 different donors. A non-linear curve fit for the log(antibody) versus response (three parameters) is shown for the data.

[0068] Figures 19A to 19C This diagram shows the inflammatory cytokines and chemokines (CCL3) secreted by primary neutrophils stimulated with a combination of PGN and PGLYRP1 and also treated with an anti-TREM1 antibody clone A, an isotype control, or without antibody treatment. Figure 19A ), CCL4 ( Figure 19B ) and IL-8 ( Figure 19C The concentration of the culture medium was used to represent baseline cytokine levels. Unstimulated cells (culture medium) were 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 = no statistical significance; **** = p < 0.0001. The figure shows data from a single donor, which is considered representative of data from 17 different donors.

[0069] Figure 20 The medium concentrations of CCL4 secreted by primary human neutrophils from healthy volunteers stimulated with PGN, PGLYRP1, or a combination of PGN and PGLYRP1 are shown, in the presence of anti-TREM1 antibody clone A or an isotype control. Ten-point titration curves were performed for the anti-TREM1 antibody clone A or isotype control. Unstimulated cells (medium) were used to show baseline cytokine levels. The figure shows data from a single donor, which is considered representative of data from 10 different donors. A non-linear curve fit of log(antibody) versus response (three parameters) is shown for the data.

[0070] Figures 21A to 21B The results of a transepithelial electrical resistance (TEER) measurement are shown, in which samples from two donors (jejunal donor 1 (...)) are compared. Figure 21A ) and jejunal donor 5 ( Figure 21BJejunal epithelial cells were treated with differentiation medium containing different concentrations of TNFα (15 ng / mL, 30 ng / mL, and 50 ng / mL). Treatment with differentiation medium alone (untreated) or with differentiation medium containing the TNFα mediator served as controls. The mean and standard deviation of three replicates are shown.

[0071] Figures 22A to 22D The results of the TEER assay are shown, in which samples from four donors (donor 1 (…) are analyzed. Figure 22A ), donor 2 ( Figure 22B ), donor 5 ( Figure 22C ) and donor 6 ( Figure 22D Jejunal epithelial cells were treated with either untreated differentiation medium or conditioned medium supplemented with 50% total volume of unstimulated human monocytes or monocytes stimulated with PGN and PGLYRP1. Means and standard deviations from three replicates are shown.

[0072] Figures 23A to 23D The results of the TEER assay are shown, in which samples from four donors (donor 1 (…) are analyzed. Figure 23A ), donor 2 ( Figure 23B ), donor 5 ( Figure 23C ) and donor 6 ( Figure 23D Jejunal epithelial cells were treated with conditioned medium produced from cultured monocytes that were unstimulated (conditioned medium), stimulated with bacterial peptidoglycan (PGN) and PGLYRP1 (PGN:PGLYPR1), or stimulated with PGN:PGLYPR1 in the presence of anti-TREM1 antibody clone A or an isotype control. Cells untreated with conditioned medium were also included as controls. Conditioned medium was produced from four healthy volunteers (donors 1, 2, 5, and 6). Conditioned medium produced from donor 1 and donor 2 monocytes was tested on jejunal donor 1 cells, while conditioned medium produced from donor 5 and donor 6 monocytes was tested on jejunal donor 5 cells. Means and standard deviations of three replicates are shown. Statistical significance was determined by one-way ANOVA and Tukey's multiple comparison test: ns = no statistical significance; * = p < 0.05; ** = p < 0.01; *** = p < 0.001; **** = p < 0.0001.

[0073] Figures 24A to 24BThe results of the TEER assay are shown, in which epithelial cells were treated with TREM1-conditioned medium produced from monocytes that were unstimulated (untreated monocytes), stimulated with bacterial peptidoglycan (PGN) and PGLYRP1 (TREM1-ligand), or stimulated with TREM1-ligand in the presence of an allotype control antibody, anti-TREM1 antibody agent clone A, or anti-TNFα antibody. Figure 24A The results are shown from conditioned medium produced from donor monocytes with low TNFα induction (approximately 400 pg / mL) upon stimulation with PGN and PGLYRP1. This conditioned medium was responsive to the anti-TREM1 antibody agent clone A but unresponsive to the anti-TNFα antibody. Figure 24B The results are shown from conditioned medium produced from donor monocytes with high TNFα induction (approximately 1000 pg / mL) upon stimulation with PGN and PGLYRP1, which responded to both anti-TREM1 antibody clone A and anti-TNFα antibody.

[0074] Figure 25 Results from a biolayer interferometry assay are shown, used to evaluate the effect of an anti-TREM1 antibody on blocking the interaction between TREM1 and its ligand PGLYRP1. Recombinant hTREM1-chFc1 was immobilized on an Octet AHC biosensor and then incubated with anti-TREM1 antibody clone A or an isotype control, followed by incubation with PGLYRP1. Binding of PGLYRP1 to immobilized TREM1 was correlated with the measured response. Data were fitted using a sigmoid (four-parameter) nonlinear regression equation. No fitted curves were provided for the isotype control due to the lack of dose-dependent response. Data are from a single experiment representing three replicates.

[0075] Figure 26 Results from a cell-based assay used to evaluate the effect of anti-TREM1 antibody agent clone A on TREM1 cell surface levels on monocytes are shown. Human peripheral CD14 isolated from healthy volunteers was also used. + Monocytes were treated with either anti-TREM1 antibody agent clone A or an allotype control antibody. Eighteen hours later, cells were stained with different, non-competitive anti-TREM1 (clone TREM26) antibodies conjugated to a fluorescent dye, and total cell surface TREM1 levels were measured by flow cytometry to determine fluorescence intensity (regardless of the binding status of anti-TREM1 antibody agent clone A). Cell background staining is the background fluorescence intensity observed when cells were stained with an allotype control antibody conjugated to a fluorescent dye. The figure shows data from a single donor, which is considered representative of data from seven different donors.

[0076] Figure 27 Results from a cell-based assay evaluating the effect of anti-TREM1 antibody agent clone A on TREM1 cell surface levels on neutrophils are shown. Human peripheral neutrophils isolated from healthy volunteers were treated with either anti-TREM1 antibody agent clone A or an allotype control antibody. Nineteen hours later, cells were stained with different, non-competitive anti-TREM1 (clone TREM26) antibodies conjugated to a fluorescent dye, and total cell surface TREM1 levels were measured by fluorescence intensity using flow cytometry (regardless of the binding status of anti-TREM1 antibody agent clone A). Cell background staining is the background fluorescence intensity observed when cells were stained with an allotype control antibody conjugated to a fluorescent dye. The figure shows data from a single donor, which is considered representative of data from nine different donors.

[0077] Figures 28A to 28E The flow cytometry results are shown, which were used to evaluate the effects of TREM1 activation and inhibition by anti-TREM1 antibodies 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. Concurrently, 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. Further addition of the anti-TREM1 antibody clone A (10 nM) or an isotype control (10 nM) was performed to investigate the effect of TREM1 inhibition on the differentiation of inflammatory monocytes into macrophages. After 6 days in differentiation medium, differentiation status was assessed by staining for cell surface markers CD64 and MERTK and determining the percentage of cells as inflammatory monocytes (CD64+MERTK-) or macrophages (CD64+MERTK+) under each condition. Figures 28B to 28E Results from a cell-based assay are shown, which characterizes the effect of anti-TREM1 antibody agent clone A on the release of TREM-1-stimulated inflammatory cytokines from cells derived from inflammatory monocytes. Figures 28B to 28E The following figures show the TNFα levels in inflammatory monocytes treated with TGFβ and IL-10 for 6 days in the presence of: Figure 28B ), IL-1β ( Figure 28C ), IL-6 ( Figure 28D ) and MDC (CCL22; Figure 28E Production: culture medium alone; peptidoglycan and PGLYRP1 (PGN+PGLYRP1); peptidoglycan, PGLYRP1 and anti-TREM1 antibody clone A (PGN+PGLYRP1+anti-TREM1 clone A); peptidoglycan, PLYRP1 and isotype control (PGN+PGLYRP1+isotype).

[0078] Figures 29A to 29B Flow cytometry data from a cell-based assay used to characterize the potential internalization of membrane TREM1 in monocytes by anti-TREM1 antibody agent clone A are shown. Human monocytes isolated from healthy volunteers were treated with separate culture media ( Figure 29A ) or stimulated with peptidoglycan (PGN; 1 μg / ml; Figure 29B Cells were incubated together with anti-TREM1 antibody clone A or an isotype control and stained with pH-sensitive dye labeled anti-hIgG1 Fab.

[0079] Figure 30 Results from a cell-based assay are shown, which characterizes the effect of anti-TREM1 antibody agent clone A on the production levels of soluble TREM1 (sTREM1) from primary monocytes.

[0080] Figure 31 Results from a cell-based assay are shown, which characterizes the effect of anti-TREM1 antibody agent clone A on TREM1-stimulated TL1a production in primary monocytes.

[0081] Figures 32A to 32C Results from a cell-based assay are shown, which characterizes the effect of anti-TREM1 antibody agent clone A on the release of TREM-1 pathway-stimulated inflammatory cytokines from cells derived from ulcerative colitis (UC) patient samples. Figures 32A to 32C The image shows TNFα derived from cells of UC patients treated with the following methods. Figure 32A ), IL-1β ( Figure 32B ) and IL-23 ( Figure 32C Production: peptidoglycan and PGLYRP1 (PGN+PGLYRP1); peptidoglycan, PGLYRP1 and anti-TREM1 antibody clone A (PGN+PGLYRP1+anti-TREM1 clone A); peptidoglycan, PGLYRP1 and isotype control (PGN+PGLYRP1+isotype).

[0082] Figures 33A to 33CResults from a cell-based assay characterizing the effect of anti-TREM1 antibody agent clone A on epithelial barrier permeability are shown. Donor-derived epithelial cells were cultured and seeded on Transwell plate inserts until approximately 200 ohms / cm² was achieved. 2 The corrected transepithelial electrical resistance (TEER) measurements were then processed using the following methods: TREM1-conditioned medium + allotype control antibody; TREM1-conditioned medium + anti-TREM1 antibody drug clone A; or TREM1-conditioned medium + infliximab ( Figure 33A ). Figure 33B and Figure 33C This is a bar graph showing the effects of different antibody clones (anti-TREM1, infliximab, or allotype control antibody) on the production of antibodies derived from substances classified as having high TNFα induction (TREM1). Figure 33B ) or low TNFα-induced ( Figure 33C The relative permeability of the jejunal epithelial cell monolayers from two representative donors.

[0083] Figure 34 Results from a cell-based assay are shown, which characterizes the effect of anti-TREM1 antibody drug clone A on the release of TREM-1-stimulated IL-8 from primary neutrophils derived from two donors, compared to antibodies having the binding domain of anti-TREM1 antibody (mAb 0318, described in WO2019195126A1, which is incorporated herein by reference).

[0084] Figure 35 The deuterium exchange heat map of TREM1 protein mixed with anti-TREM1 antibody agent clone A is shown.

[0085] Figures 36A to 36C The image shows a bar graph illustrating the production of inflammatory cytokines / chemokines by enriched neutrophils from healthy volunteer donors. These neutrophils were cultured in separate media, with 2 mM anti-TREM1 antibody clone A, 2 mM isotype control, 50 nM PGLRYP1, or peptidoglycan (PGN; 300 ng / ml). After 24 hours, the tissue culture supernatant was harvested and analyzed against CCL3 (… Figure 36A ), CCL4 ( Figure 36B ) and IL-8 ( Figure 36C Protein quantification was performed. Error bars represent the mean ± SD from 8 technical replicates. Significance was determined by one-way ANOVA and Tukey's multiple comparison test; ns = not significant, **** = p < 0.0001.

[0086] Figures 37A to 37D The image shows a bar graph illustrating the production of inflammatory cytokines / chemokines in primary monocytes enriched from healthy volunteer donors. These primary monocytes were cultured in separate media, 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 to 24 hours, the tissue culture supernatant was harvested and analyzed against CCL3 (… Figure 37A ), CCL4 ( Figure 37B ), IL-6 ( Figure 37C ) and TNFα ( Figure 37D Protein quantification was performed. Error bars represent the mean ± SD from four technical replicates. 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.

[0087] Figure 38A Flow cytometry data on the percentage of TREM1 receptor occupancy using saturated concentrations of anti-TREM1 antibody clone A are shown. In the presence of serially diluted anti-TREM1 antibody clone A (isotype control), enriched monocytes (2 × 10⁶ cells / mL) isolated from healthy volunteer donors were activated with peptidoglycan (100 ng / mL) and PGLYRP1 (500 nM). 5 (cells / well). After 24 hours, the TREM1 level on the surface of monocytes was determined by flow cytometry.

[0088] Figure 38B The image shows TREM1 receptor occupancy on primary monocytes plotted against normalized TNFα values. TNFα values ​​were normalized relative to the maximum cytokine release in each donor.

[0089] Figures 39A to 39M Bar graphs showing the production of inflammatory cytokines / chemokines from whole blood of healthy volunteer donors, cultured with 1 μM anti-TREM1 antibody clone A, 1 μM isotype control, or 1 μg / ml LPS. After 18 to 24 hours, the tissue culture supernatant was harvested and analyzed against 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 Protein quantification was performed. 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.

[0090] Figures 40A to 40B This demonstrates the free TREM1 in neutrophils (excluding isotype control) after weekly IV administration of the anti-TREM1 antibody agent clone A to cynomolgus monkeys for 14 weeks. Figure 40A ) and total TREM1 ( Figure 40B The results of flow cytometry analysis of the baseline percentage of ).

[0091] Figure 41 The figure shows a line graph of the baseline percentage (arithmetic mean (±SD)) of free TREM1 receptor levels on neutrophils versus time following a single 1-hour IV infusion of various concentrations of anti-TREM1 antibody agent clone A in human subjects. Day 0 = infusion start.

[0092] Figure 42 The figure shows a line graph of the baseline percentage (arithmetic mean (±SD)) of free TREM1 receptor levels on monocytes over time following a single 1-hour IV infusion of various concentrations of anti-TREM1 antibody agent clone A in human subjects. Day 0 = infusion start.

[0093] Figure 43 The figure shows a line graph of the baseline percentage (arithmetic mean (±SD)) of total TREM1 receptor levels on neutrophils over time following a single 1-hour IV infusion of various concentrations of anti-TREM1 antibody agent clone A in human subjects. Day 0 = infusion start.

[0094] Figure 44 Line graphs showing the individual arithmetic mean (±SD) of the percentage of TREM1 receptor occupancy on neutrophils compared to time following a single 1-hour IV infusion of various concentrations of anti-TREM1 antibody agent clone A in human subjects. Day 0 = Infusion start.

[0095] Figure 45The figure shows a line graph of the baseline percentage (arithmetic mean (±SD)) of total TREM1 receptor levels on monocytes over time following a single 1-hour IV infusion of various concentrations of anti-TREM1 antibody agent clone A in human subjects. Day 0 = infusion start.

[0096] Figure 46 Line graphs showing the individual arithmetic mean (±SD) of the percentage of TREM1 receptor occupancy on monocytes after a single 1-hour IV infusion of various concentrations of anti-TREM1 antibody agent clone A in human subjects, compared with time. Day 0 = infusion start.

[0097] Figure 47 Line graphs showing the change in the individual arithmetic mean (±SD) of total soluble TREM1 (sTREM1) relative to baseline over time following a single 1-hour IV infusion of various concentrations of anti-TREM1 antibody agent clone A in human subjects. Day 0 = infusion start.

[0098] Figures 48A to 48B The anti-TREM1 antibody drug clone A, as determined by ELISA binding assay, is shown in human ( Figure 48A ) and crab-eating macaques ( Figure 48B Stability in serum.

[0099] definition In this application, unless otherwise stated in the context, (i) the term “a” may be understood to mean “at least one”; (ii) the term “or” may be understood to mean “and / or”; (iii) the terms “comprising” and “including” may be understood to include the listed components or steps, whether presented individually or together with one or more other components or steps; and (iv) the terms “about” and “approximately” may be understood to allow for variations in the standard, as would be understood by one of ordinary skill in the art; and (v) where a scope is provided, endpoints are included.

[0100] Approximately: When used herein with respect to values, the term “approximately” refers to a value similar to the referenced value in the context. Generally, those skilled in the art will understand the extent of relevant variation covered by “approximately” in that context. For example, in some embodiments, the term “approximately” may cover a range of values ​​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 of the reference value.

[0101] Application: As used herein, the term “application” generally refers to the administration of a composition to a subject or system, for example, to achieve the delivery of a medicament as a composition, or contained in or otherwise delivered by the composition.

[0102] Adult: As used herein, the term “adult” means a person who is eighteen years of age or older. In some implementations, an adult’s weight is in the range of approximately 90 pounds to approximately 250 pounds.

[0103] Affinity: As is known in the art, “affinity” is a measure of the tightness with which two or more binding couples associate with each other. Those skilled in the art understand that a variety of assays can be used to assess affinity, and will also understand suitable controls for such assays. In some embodiments, affinity is assessed in a quantitative assay. In some embodiments, affinity is assessed at multiple concentrations (e.g., multiple concentrations of one binding coupler at a time). In some embodiments, affinity is assessed in the presence of one or more potential competing entities (e.g., which may be present in a relevant (e.g., physiological) environment). In some embodiments, affinity is assessed relative to a reference (e.g., a reference with known affinity above a certain threshold [“positive control” reference] or a reference with known affinity below a certain threshold [“negative control” reference]). In some embodiments, affinity may be assessed relative to a contemporaneous reference; in some embodiments, affinity may be assessed relative to a historical reference. Generally, when affinity is assessed relative to a reference, affinity is assessed under comparable conditions.

[0104] Pharmaceutical: As used herein, the term “pharmaceutical” 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 phenomenon (e.g., heat, electric current or electric field, magnetic force or magnetic field, etc.).

[0105] Agonist: Those skilled in the art will understand that the term "agonist" can be used to refer to an agent, condition, or event whose presence, level, extent, type, or form is associated with an increased level or activity of another agent (i.e., an agonist or a target agent). Generally, an agonist can be or includes agents of any chemical class, including, for example, small molecules, peptides, nucleic acids, carbohydrates, lipids, metals, and / or any other entity exhibiting relevant activating activity. In some embodiments, an agonist can be direct (in which case the agonist directly exerts its effect on its target); in some embodiments, an agonist can be indirect (in which case the agonist exerts its effect by means other than binding to its target; for example, by interacting with a regulator of the target, thereby altering the level or activity of the target).

[0106] Amino acids: As used herein, the term "amino acid" refers to any compound and / or substance that can be, for example, formed by forming one or more peptide bonds rather than being bound to a polypeptide chain. In some embodiments, amino acids have the universal structure H₂N–C(H)(R)–COOH. In some embodiments, amino acids are naturally occurring amino acids. In some embodiments, amino acids are non-natural amino acids; in some embodiments, amino acids are D-amino acids; in some embodiments, amino acids are L-amino acids. As used herein, the term "standard amino acid" refers to any one of the twenty L-amino acids present in naturally occurring polypeptides. "Non-standard amino acid" refers to any amino acid other than the standard amino acid, whether or not it is of a natural origin or can be found in a natural source. In some embodiments, amino acids comprising carboxyl-terminal and / or amino-terminal amino acids in a polypeptide may contain structural modifications compared to the universal structure described above. For example, in some embodiments, amino acids may be modified by methylation, amidation, acetylation, PEGylation, glycosylation, phosphorylation, and / or substitution (e.g., substitution of amino, carboxylic acid groups, one or more protons, and / or hydroxyl groups) compared to the universal structure. In some embodiments, such modification can, for example, alter the stability or cyclic half-life of a peptide containing modified amino acids compared to a peptide containing otherwise identical, unmodified amino acids. In some embodiments, such modification does not significantly alter the relevant activity of a peptide containing modified amino acids compared to a peptide containing otherwise identical, unmodified amino acids. As will be clear from the context, in some embodiments, the term "amino acid" may be used to refer to a free amino acid; in some embodiments, it may be used to refer to amino acid residues of a peptide, for example, amino acid residues within the peptide.

[0107] Antibody: As used herein, the term "antibody" refers to a polypeptide containing a canonical immunoglobulin sequence element sufficient to confer specific binding to a particular target antigen. As is known in the art, a naturally occurring complete antibody is a tetramer of approximately 150 kDa comprising two identical heavy-chain polypeptides (each approximately 50 kDa) and two identical light-chain polypeptides (each approximately 25 kDa) associated with each other in a structure commonly referred to as a "Y-shape." Each heavy chain contains at least four domains (each approximately 110 amino acids long)—an amino-terminal variable (VH) domain (located at the tip of the Y-shape), followed by three constant domains: CH1, CH2, and a carboxyl-terminal CH3 domain (located at the base of the Y-stem). A short region, referred to as a "switch," connects the heavy-chain variable and constant regions. A "hinge" connects the CH2 and CH3 domains to the remainder of the antibody. Two disulfide bonds in this hinge region link the two heavy-chain polypeptides in the complete antibody to each other. Each light chain contains two domains separated from each other by another “switch”—an amino-terminal variable (VL) domain followed by a carboxyl-terminal constant (CL) domain. A complete antibody tetramer consists of two heavy-chain-light-chain dimers, where the heavy and light chains are linked to each other by a single disulfide bond; two additional disulfide bonds link the heavy-chain hinge regions together, causing the dimers to link together and form a tetramer. Naturally occurring antibodies are often also glycosylated at the CH2 domain. Each domain in a natural antibody has a structure characterized as an “immunoglobulin fold” formed by two β-sheets (e.g., 3-, 4-, or 5-chain sheets) pressed together in a compressed antiparallel β-barrel. Each variable domain contains three hypervariable loops (CDR1, CDR2, and CDR3) called “complementarity-determining regions” and four slightly invariant “framework” regions (FR1, FR2, FR3, and FR4). When a natural antibody folds, the FR region forms a β-sheet that provides a structural framework for the domain, and together with the CDR loop regions from both the heavy and light chains, they are placed in three-dimensional space, forming a single hypervariable antigen-binding site located at the tip of the Y structure.

[0108] The CDR of an antibody's antigen-binding site can be determined by methods described in Lefranc et al., Dev. Comp. Immunol. 27(1):55-77 (2003), Kabat et al., J. Biol. Chem. 252, 6609-6616 (1977), Kabat et al., Sequences of protein of immunological interest. (1991), Chothia et al., J. Mol. Biol. 196:901-917 (1987), and MacCallum et al., J. Mol. Biol. 262:732-745 (1996). When compared with each other, the CDRs determined under these definitions typically include overlaps or subsets of amino acid residues. In some embodiments, the term "CDR" is as defined in MacCallum et al., J. Mol. Biol. 262:732-745 (1996) and Martin A., Protein Sequence and Structure Analysis of Antibody Variable Domains, Antibody Engineering, Kontermann and Dubel (eds.), Chapter 31, pp. 422-439, Springer-Verlag, Berlin (2001). In some embodiments, the term "CDR" is as defined in Kabat et al., J. Biol. Chem. 252, 6609-6616 (1977) and Kabat et al., Sequences of protein of immunological interest. (1991). In some embodiments, the term "CDR" is as defined in Lefranc et al., Dev. Comp. Immunol. 27(1):55-77 (2003). In some embodiments, different conventions are used to define the heavy chain CDR and light chain CDR of the antibody. For example, in some implementations, the heavy chain CDR is defined according to MacCallum (ibid.), and the light chain CDR is defined according to Kabat (ibid.).

[0109] Naturally occurring antibodies bind to elements of complementary systems and also to receptors on effector cells, including, for example, effector cells mediating cytotoxicity. As is known in the art, the affinity and / or other binding properties of the Fc region of an Fc receptor can be modulated by glycosylation or other modifications. In some embodiments, antibodies generated and / or utilized according to the invention comprise glycosylated Fc domains, including modified or engineered Fc domains. For the purposes of the invention, in some embodiments, any polypeptide or polypeptide complex comprising sufficient immunoglobulin domain sequences as found in natural antibodies may be referred to as and / or used as an “antibody,” regardless of whether the polypeptide is naturally occurring (e.g., generated by an organism reacting with an antigen) or produced by recombinant engineering, chemical synthesis, or other artificial systems or methods. In some embodiments, the antibody is polyclonal; 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, as is known in the art, the antibody sequence elements are humanized, primate-derived, chimeric, etc. Furthermore, as used herein, in appropriate embodiments (unless otherwise stated or clear from the context), the term "antibody" may refer to any of the known or developed constructions or formats in the art for utilizing the structural and functional characteristics of an antibody in an alternative presentation. For example, in embodiments, the antibody utilized according to the invention is in a form selected from, but not limited to, intact IgA antibodies, IgG antibodies, IgE antibodies, or IgM antibodies; bispecific antibodies or multispecific antibodies (e.g., Zybodies). ® (etc.); antibody fragments, such as Fab fragments, Fab' fragments, F(ab')2 fragments, Fd' fragments, Fd fragments and isolated CDRs or collections thereof; single-chain Fvs; peptide-Fc fusions; single-domain antibodies (e.g., shark single-domain antibodies, such as IgNAR or fragments thereof); camelid antibodies; masking antibodies (e.g., probodies) ® Small Module Immunotherapy (SMIPs) ™ Single-chain biantibodies or tandem biantibodies (TandAbs) ® ); VHH; Anticalins ® Nanobodies ® Microantibodies; BiTE ® Ankylosing spondylogenetics or DARPINs ® Avimers ® DART; TCR-like antibodies; Adnectins ® Affilins ® Trans-bodies ®Affibodies ® TrimerX ® Microproteins; Fynomers ® Centyrins ® ; and KALBITOR ® In some embodiments, the antibody may lack the covalent modifications it would have naturally (e.g., glycan attachment). In some embodiments, the antibody may contain covalent modifications (e.g., glycan, payload [detectable portion, therapeutic portion, catalytic portion, etc.] or other side groups [e.g., polyethylene glycol, etc.]).

[0110] Antibody Agent: As used herein, the term "antibody agent" refers to an agent that specifically binds to a particular antigen. In some embodiments, the term covers any polypeptide or polypeptide complex comprising 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 comprise one or more constant region sequences characteristic of canine, cat, mouse, rabbit, primate, or human antibodies. In some embodiments, as known in the art, an antibody agent may comprise one or more sequence elements that are human, humanized, primate, chimeric, etc. In some embodiments, an antibody agent may comprise one or more complementarity-determining regions (which are human) and / or one or more constant region sequences (which are characteristic of human antibodies). In many embodiments, the term "antibody agent" is used to refer to one or more of the constructs or forms known or developed in the art for utilizing the structural and functional characteristics of antibodies in alternative presentations. For example, in some embodiments, the antibody agents utilized according to this disclosure are in the form of, but not limited to, intact IgA antibodies, IgG antibodies, IgE antibodies, or IgM antibodies; bispecific antibodies or multispecific antibodies (e.g., Zybodies). ® (etc.); antibody fragments, such as Fab fragments, Fab' fragments, F(ab')2 fragments, Fd' fragments, Fd fragments, and isolated CDRs or collections 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; masking antibodies (e.g., probodies). ® Small Module Immunotherapy (SMIPs) ™” ); single-chain biantibodies or tandem biantibodies (TandAbs) ® ); VHH; Anticalins ® Nanobodies ® Microantibodies; BiTE ®Ankylosing spondylogenetics or DARPINs ® Avimers ® DART; TCR-like antibodies; Adnectins ® Affilins ® Trans-bodies ® Affibodies ® TrimerX ® Microproteins; Fynomers ® Centyrins ® ; and KALBITOR ®In some embodiments, the antibody may lack the covalent modifications (e.g., glycan attachment) that it would have naturally. In some embodiments, the antibody may contain covalent modifications (e.g., glycan, payload [detectable portion, therapeutic portion, catalytic portion, etc.] or other side groups [e.g., polyethylene glycol, etc.] attachments). In many embodiments, the antibody agent is or comprises a polypeptide whose amino acid sequence contains one or more structural elements recognized by those skilled in the art as complementarity-determining regions (CDRs); in some embodiments, the antibody agent is or comprises a polypeptide whose amino acid sequence contains at least one CDR (e.g., at least one heavy chain CDR and / or at least one light chain CDR) substantially identical to the CDR found in a reference antibody. In some embodiments, the contained CDR is identical to the reference CDR. The CDRs are substantially identical to the reference CDR because the included CDRs have a sequence identical to or contain between one and five amino acid substitutions compared to the reference CDR. In some embodiments, the included CDRs are substantially identical to the reference CDR because the included CDRs show 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 CDRs are substantially identical to the reference CDR because the included CDRs show at least 96%, 96%, 97%, 98%, or 98% sequence identity with the reference CDR. 99% or 100% sequence identity. In some embodiments, the included CDR is substantially identical to the reference CDR because at least one amino acid in the included CDR is deleted, added, or substituted compared to the reference CDR, but the included CDR has the same amino acid sequence as the reference CDR in all other respects. In some embodiments, the included CDR is substantially identical to the reference CDR because one to five amino acids in the included CDR are deleted, added, or substituted compared to the reference CDR, but the included CDR has the same amino acid sequence as the reference CDR in all other respects. In some embodiments, the included CDR... The included CDR is substantially identical to the reference CDR because at least one amino acid within it is substituted compared to the reference CDR, but the included CDR has the same amino acid sequence as the reference CDR in all other respects. In some embodiments, the included CDR is substantially identical to the reference CDR because one to five amino acids within it are deleted, added, or substituted compared to the reference CDR, but the included CDR has the same amino acid sequence as the reference CDR in all other respects. In some embodiments, the antibody agent is or comprises a polypeptide whose amino acid sequence contains structural elements recognized by those skilled in the art as variable domains of immunoglobulins.In some implementations, the antibody agent is a polypeptide protein having a binding domain that is homologous or largely homologous to an immunoglobulin binding domain.

[0111] Antibody-dependent cytotoxicity: As used herein, the term “antibody-dependent cytotoxicity” or “ADCC” refers to the phenomenon in which target cells bound by antibodies are killed by immune effector cells. Without wishing to be bound by any particular theory, we observe that ADCC is generally understood to involve effector cells carrying Fc receptors (FcRs) recognizing and subsequently killing antibody-coated target cells (e.g., cells expressing surface-specific antigens that bind to antibodies). Effector cells mediating ADCC can include immune cells, including but not limited to one or more of natural killer (NK) cells, macrophages, neutrophils, and eosinophils.

[0112] Antibody fragment: As used herein, "antibody fragment" refers to a portion of an antibody or antibody agent as described herein, and generally refers to a portion containing its antigen-binding portion or variable region. Antibody fragments can be generated in any manner. For example, in some embodiments, antibody fragments can be generated enzymatically or chemically by fragmentation of a complete antibody or antibody agent. Alternatively, in some embodiments, antibody fragments can be generated recombinantly (e.g., by expression of engineered nucleic acids). In some embodiments, antibody fragments can be generated entirely or partially synthetically. In some embodiments, antibody fragments (particularly 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 (in some embodiments, at least about 200 amino acids).

[0113] Antibody peptide: As used herein, the term "antibody peptide" refers to a peptide comprising characteristic sequence elements of an antibody (e.g., one or more CDRs, or a set of CDRs, such as each of CDR1, CDR2, and CDR3 found in a reference antibody chain, and / or one or more FR regions and / or a set of FR regions, such as complete variable regions of, for example, the heavy or light chain of a reference antibody); in many embodiments, the antibody peptide comprises sufficient such sequence elements to bind to an epitope (e.g., an epitope that binds to a reference antibody comprising the characteristic sequence elements). In some embodiments, the antibody peptide is a full-length antibody or its heavy or light chain. In some embodiments, the antibody peptide is or comprises the complete heavy and / or light chain variable regions of a reference antibody; in some such embodiments, the antibody peptide comprises sufficient characteristic antibody sequence elements to confer specific binding to the relevant epitope – i.e., such that the antibody peptide comprises at least one binding site. In some embodiments, the "antibody peptide" may comprise a binding domain that is homologous or substantially homologous to an immunoglobulin binding domain (e.g., exhibiting significant sequence homology and / or significant sequence identity in some embodiments). In some embodiments, the antibody peptide exhibits at least 99% identity with an immunoglobulin-binding domain. In some embodiments, the "antibody peptide" has a binding domain exhibiting at least 70%, 80%, 85%, 90%, or 95% identity with an immunoglobulin-binding domain (e.g., a reference immunoglobulin-binding domain). In some embodiments, the "antibody peptide" may have the same amino acid sequence as an antibody or chain found in a natural source, or a variable region (or combination of variable regions) thereof. In some embodiments, the antibody peptide can be prepared by, for example, isolation from a natural source or antibody library, recombinant generation in or using a host system, chemical synthesis, etc., or combinations thereof. In some embodiments, the antibody peptide is an antibody pharmaceutical agent as described herein.

[0114] Antigen: As used herein, the term "antigen" refers to an agent that elicits an immune response; and / or (ii) an agent that binds to T cell receptors (e.g., when presented by an MHC molecule) or to antibodies. In some embodiments, an antigen elicits a humoral response (e.g., including the production of antigen-specific antibodies); in some embodiments, an antigen elicits a cellular response (e.g., involving T cells whose receptors specifically interact with the antigen). In some embodiments, the antigen binds to antibodies and may or may not induce a specific physiological response in an organism. Generally, an antigen can be or includes any chemical entity, such as, for example, small molecules, nucleic acids, peptides, carbohydrates, lipids, polymers (in some embodiments, other than biopolymers [e.g., other than nucleic acid or amino acid polymers]), etc. In some embodiments, the antigen is or includes peptides. In some embodiments, the antigen is or includes glycans. Those skilled in the art will understand that, generally, antigens can be provided or used in isolated or pure forms, or alternatively, can be provided in crude form (e.g., together with other materials, such as in extracts like cell extracts or other relatively crude formulations containing sources of antigens). In some embodiments, the antigen utilized according to the invention is provided in crude form. In some embodiments, the antigen is a recombinant antigen.

[0115] Approximately: As used herein, when applied to one or more values ​​of interest, the term “approximately” or “about” refers to a value similar to the stated reference value. In some embodiments, the term “approximately” or “about” refers to a range of values ​​falling within or less than 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% of the stated reference value in either direction (greater or less), unless otherwise stated or otherwise obvious from the context (except where such a number would exceed 100% of the possible value).

[0116] Relevance: Two events or entities are “relevant” to each other, as used herein, if the presence, level, extent, type, and / or form of one event or entity is related to the presence, level, extent, type, and / or form of another event or entity. For example, if the presence, level, and / or form of a particular entity (e.g., peptide, genetic signature, metabolite, microorganism, etc.) is related to the incidence and / or susceptibility to a disease, disorder, or condition (e.g., across relevant populations), that particular entity is considered relevant to the particular disease, disorder, or condition. In some embodiments, two or more entities are “associated” to each other physically if they interact directly or indirectly such that they are physically close to each other and / or remain close to each other. In some embodiments, two or more physically associated entities are covalently linked to each other; in some embodiments, two or more physically associated entities are not covalently linked to each other, but are non-covalently associated, for example, through hydrogen bonds, van der Waals interactions, hydrophobic interactions, magnetism, and combinations thereof.

[0117] Binding: As used herein, those skilled in the art will understand that the term "binding" generally refers to a non-covalent association between or among two or more entities. "Direct" binding involves physical contact between entities or parts; indirect binding involves physical interaction through physical contact with one or more intermediate entities. Binding between two or more entities can generally be evaluated in any of a variety of situations, including studying interacting entities or parts in isolation or in more complex systems (e.g., when covalently or otherwise associated with a carrier entity and / or in a biological system or cell).

[0118] Biological Samples: As used herein, the term "biological sample" generally refers to a sample obtained or derived from a biological source of interest (e.g., a tissue or organism or cell culture) as described herein. In some embodiments, the source of interest includes organisms such as animals or humans. In some embodiments, biological samples are or include biological tissues or fluids. In some embodiments, biological samples may be or include bone marrow; blood; blood cells; ascites; tissue or fine-needle biopsy samples; body fluids containing cells; free-floating nucleic acids; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph; gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasal swabs; rinsing or lavage fluids, such as catheter lavage fluid or bronchoalveolar lavage fluid; aspirates; scrapings; bone marrow specimens; tissue biopsy specimens; surgical specimens; feces, other body fluids, secretions and / or excretions; and / or cells derived therefrom, etc. In some embodiments, biological samples are or include cells obtained from an individual. In some embodiments, the obtained cells are or include cells from the individual from whom the sample was obtained. In some embodiments, the sample is a “primary sample” obtained directly from the source of interest by any suitable means. 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 will be clear from the context, the term “sample” refers to a preparation obtained by processing (e.g., by removing one or more components of the primary sample and / or by adding one or more agents to the primary sample). For example, using semi-permeable membrane filtration. Such a “processed sample” may include, for example, nucleic acids or proteins extracted from the sample or obtained by techniques such as subjecting the primary sample to mRNA amplification or reverse transcription, separation and / or purification of certain components.

[0119] Carrier: As used herein, refers to a diluent, adjuvant, excipient, or medium applied together with the composition. In some exemplary embodiments, the carrier may include sterile liquids, such as water and oils, including petroleum, animal, plant, or synthetic oils, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. In some embodiments, the carrier is or comprises one or more solid components.

[0120] CDR: As used herein, refers to the complementarity-determining region within the antibody variable region. Three CDRs exist in each variable region of the heavy and light chains, designated CDR1, CDR2, and CDR3 for each variable region. A “set of CDRs” or “group of CDRs” refers to a group of three or six CDRs appearing in a single variable region capable of binding the antigen, or in CDRs of homologous heavy and light chain variable regions capable of binding the antigen. Certain systems have been established in the art for defining CDR boundaries (e.g., IMGT, Kabat, Chothia, etc.); those skilled in the art understand the differences between these systems and are able to understand CDR boundaries to the extent necessary for understanding and practicing the claimed invention.

[0121] Child: As used herein, the term "child" refers to a person between 1 day and 18 years of age. In some embodiments, a child may be an infant (e.g., an age that may be less than or equal to about 12 months, 11 months, 10 months, 9 months, 8 months, 7 months, 6 months, 5 months, 4 months, 3 months, 2 months, or 1 month); in some embodiments, a child may be older than an infant. In some embodiments, a child may be a toddler (e.g., an age that is between about 1 year and 3 years); in some embodiments, a child may be smaller or larger than a toddler. In some embodiments, a child may be a teenager (e.g., an age that is between about 12 years and about 18 years); in some embodiments, a child may be smaller than a teenager (and / or larger or smaller than a toddler or larger than an infant). Weight can vary widely with age and the specific child, typically ranging from 4 pounds to 150 pounds.

[0122] Combination therapy: As used herein, the term "combination therapy" refers to those situations where a subject is simultaneously exposed to two or more treatment regimens (e.g., two or more therapeutic agents). In some embodiments, the two or more treatment regimens may be administered simultaneously; in some embodiments, the two or more treatment regimens may be administered sequentially (e.g., the first regimen is administered before any dose of the second regimen). In some embodiments, the two or more treatment regimens are administered in an overlapping dosing regimen. In some embodiments, administration of combination therapy may involve administering additional agents or methods to a subject receiving one or more therapeutic agents or methods. In some embodiments, combination therapy does not necessarily require the administration of individual agents together (or even simultaneously) in a single composition. In some embodiments, two or more therapeutic agents or methods of combination therapy are administered to the subject individually, for example, in a single composition, via a separate route of administration (e.g., one agent is administered orally, and another agent is administered intravenously), and / or at different time points. In some embodiments, two or more therapeutic agents may be administered together in a combination composition or even in a combination compound (e.g., as part of a single chemical complex or covalent entity) via the same route of administration and / or at the same time.

[0123] Comparable: As used herein, the term "comparable" refers to two or more agents, entities, situations, condition groups, etc., that may not be completely identical to each other but are similar enough to allow comparisons between them such that a person skilled in the art will understand that reasonable conclusions can be drawn based on observed differences or similarities. In some embodiments, comparable condition groups, situations, individuals, or populations are characterized by a number of substantially identical features and one or a small number of different features. A person skilled in the art will understand, in context, how much identity is required for two or more such agents, entities, situations, condition groups, etc., to be considered comparable in any given situation. For example, a person skilled in the art will understand that multiple groups of situations, individuals, or populations are comparable to each other when characterized by substantially identical features sufficient to guarantee the following reasonable conclusion: differences in results or observed phenomena obtained or using different groups of situations, individuals, or populations are caused by or indicate changes in those modified features.

[0124] Corresponding to: As used herein, the phrase “corresponding to” refers to a relationship between two entities, events, or phenomena that share sufficient characteristics to be reasonably equivalent, making the “corresponding” attribute obvious. For example, in some embodiments, the term may be used with respect to compounds or compositions to designate the position and / or identity of structural elements in a compound or composition by comparison with a suitable reference compound or composition. For example, in some embodiments, monomeric residues in a polymer (e.g., amino acid residues in a polypeptide or nucleic acid residues in a nucleic acid) may be identified as “corresponding to” residues in a suitable reference polymer. For example, those skilled in the art will understand that, for simplicity, a canonical numbering system based on a reference related polypeptide is typically used to designate residues in a polypeptide such that the amino acid “corresponding to,” for example, a residue at position 190, is not necessarily the 190th amino acid in the amino acid chain, but rather corresponds to a residue found at position 190 in the reference polypeptide; those skilled in the art will readily understand how to identify “corresponding” amino acids. For example, those skilled in the art will understand various sequence alignment strategies, including software programs such as, for example, 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, for example, to identify “corresponding” residues in peptides and / or nucleic acids according to this disclosure.

[0125] Domain: As used herein, the term "domain" refers to a segment or portion of an entity. In some embodiments, a "domain" is associated with a specific structural and / or functional feature of an entity such that it substantially or completely retains the specific structural and / or functional feature when physically separated from the remainder of its parent entity. Alternatively or additionally, a domain may be or comprise a portion of an entity that, when separated from the (parent) entity and attached to a different (recipient) entity, substantially retains and / or imparts to the recipient entity one or more structural and / or functional features that characterize it in the parent entity. In some embodiments, a domain is a segment or portion 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; in some such embodiments, the domain is characterized by specific structural elements (e.g., specific amino acid sequences or sequence motifs, α-helical features, β-sheet features, coiled-coil features, random coil features, etc.) and / or specific functional features (e.g., binding activity, enzymatic activity, folding activity, signal transduction activity, etc.).

[0126] Dosing regimen: As used herein, the term "dosing regimen" refers to a set of unit doses (usually more than one) administered individually to a subject, typically separated by time intervals. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses. In some embodiments, the dosing regimen includes multiple doses, each of which is time-separated from the other doses. In some embodiments, individual doses are separated from each other by time intervals of equal length; in some embodiments, the dosing regimen includes multiple doses and at least two distinct time intervals separating the individual doses. In some embodiments, all doses within the dosing regimen have the same unit dose. In some embodiments, the different doses within the dosing regimen have different amounts. In some embodiments, the dosing regimen includes a first dose of a first dose, followed by one or more additional doses of a second dose different from the first dose. In some embodiments, the dosing regimen includes a first dose of a first dose, followed by one or more additional doses of a second dose identical to the first dose. In some embodiments, when administered across relevant populations, the dosing regimen is associated with a desired or beneficial outcome (i.e., it is a therapeutic dosing regimen).

[0127] As used herein, effector cells are 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 of 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 be derived from any organism (including but not limited to humans, mice, rats, rabbits, and monkeys).

[0128] Epitope: As used herein, includes any portion specifically recognized by an immunoglobulin (e.g., antibody or receptor) binding component. In some embodiments, an epitope comprises multiple chemical atoms or groups on an antigen. In some embodiments, such chemical atoms or groups are surface-exposed when the antigen adopts an associated three-dimensional conformation. In some embodiments, such chemical atoms or groups are spatially physically close to each other when the antigen adopts such a conformation. In some embodiments, at least some of such chemical atoms or groups are physically separated from each other when the antigen adopts an alternative conformation (e.g., linearization).

[0129] Excipients: As used herein, refers to non-therapeutic agents that may be included in a pharmaceutical composition, for example, to provide or contribute to a desired consistency or stabilizing effect. Suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk, glycerin, propylene, ethylene glycol, water, ethanol, etc.

[0130] Frame or frame region: As used herein, this refers to the sequence of the variable region minus the CDR. Because CDR sequences can be determined by different systems, frame sequences are also subject to correspondingly different interpretations. Six CDRs divide the frame region on 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 between FR2 and FR3, and CDR3 between FR3 and FR4. Unless a specific sub-region is designated as FR1, FR2, FR3, or FR4, as mentioned by others, a frame region refers to 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 frame region closest to the amino terminus of the variable region and located at 5' relative to CDR1, and FR represents two or more sub-regions within the sub-regions constituting the frame region.

[0131] Functionality: As used herein, a “functional” biomolecule is a biomolecule that exhibits the form that characterizes its properties and / or activities.

[0132] Fragment: A "fragment" of a material or entity as described herein has a structure that comprises discrete parts of a whole but lacks one or more parts found in the whole. In some embodiments, a fragment consists of such discrete parts. In some embodiments, a fragment consists of or includes characteristic structural elements or parts found in the whole. In some embodiments, a 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, 1 00, 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, the polymer fragment comprises or consists 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 of monomer units (e.g., residues) found throughout the polymer. In some implementations, the entire material or entity may be referred to as the “parent” of the fragment.

[0133] High-affinity binding: As used herein, the term "high-affinity binding" refers to a high degree of binding tightness between a specific ligand and its partner. Affinity can be measured by any available method, including those known in the art. In some embodiments, if the binding assay shows K... d A binding affinity of approximately 500 pM or less (e.g., below 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.) is considered high affinity. In some embodiments, if the affinity for the peptide of interest is stronger than the affinity for a selected reference peptide (e.g., K...), the binding affinity is considered high affinity. d If the Kg of the peptide of interest is lower, then the binding is considered high affinity. In some implementations, if the Kg of the peptide of interest is lower, then the binding is considered high affinity. d K with respect to the selected reference peptided A ratio of 1:1 or less (e.g., 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) is considered a high affinity. In some embodiments, if the K-peptide ratio of the peptide of interest is 1:1 or less, the binding is considered a high affinity. d K of the selected reference peptide d A concentration of approximately 100% or less (e.g., approximately 99%, approximately 98%, approximately 97%, approximately 96%, approximately 95%, approximately 90%, approximately 85%, approximately 80%, approximately 75%, approximately 70%, approximately 65%, approximately 60%, approximately 55%, approximately 50%, approximately 45%, approximately 40%, approximately 35%, approximately 30%, approximately 25%, approximately 20%, approximately 15%, approximately 10%, approximately 5%, approximately 4%, approximately 3%, approximately 2%, approximately 1%, or less) is considered a high affinity.

[0134] Homology: As used herein, the term "homology" refers to the overall correlation between polymer molecules (e.g., between polypeptide molecules). In some embodiments, polymer molecules (such as antibodies) are considered "homological" of each other if their sequences are at least 80%, 85%, 90%, 95%, or 99% identical.

[0135] Human: In some implementations, a human is an embryo, fetus, infant, child, adolescent, adult, or elderly person.

[0136] Humanization: As is known in the art, the term "humanization" is generally used to refer to antibodies (or antibody components) whose amino acid sequence includes V from a reference antibody produced in a non-human species (e.g., mouse). H and V LThe humanized antibody (or antibody component) includes not only the region sequence but also modifications in the sequence relative to the reference antibody, which are designed to make them more “human-like,” i.e., more similar to human germline variable sequences. In some embodiments, a “humanized” antibody is an antibody that binds specifically to the antigen of interest and has a framework (FR) region having an amino acid sequence that is substantially human and a complementarity-determining region (CDR) having an amino acid sequence that is substantially non-human. A humanized antibody comprises substantially all of at least one, typically two, variable domains (Fab, Fab', F(ab')2, FabC, Fv), wherein all or substantially all of the CDR regions correspond to the CDR regions of non-human immunoglobulins (i.e., donor immunoglobulins), and all or substantially all of the framework region is a framework region of a human immunoglobulin common sequence. In some embodiments, the humanized antibody also comprises at least a portion of the 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 a heavy chain variable domain. The antibody may also contain the Cc domain of the heavy chain constant region. H Zone 1, Hinge Zone, C H Zone 2, C H Zone 3 and optional C H Zone 4. In some implementation schemes, the humanized antibody contains only humanized V. L In some implementation schemes, the humanized antibody contains only humanized V. H In some implementations, the humanized antibody contains humanized V. H and V L district.

[0137] Identity: As used herein, the term "identity" refers to the overall relevance between polymer molecules (e.g., between nucleic acid molecules (e.g., DNA molecules and / or RNA molecules)) and / or polypeptide molecules. In some embodiments, polymer molecules are considered "substantially identical" to each other if their sequences are at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical. The percentage of identity between two nucleic acid or polypeptide sequences can be calculated, for example, by aligning the two sequences for optimal comparison purposes (e.g., vacancies can be introduced in one or both of the first and second sequences for optimal alignment, and dissimilar sequences can be ignored for comparison purposes). In some embodiments, the length of the sequence aligned for comparison purposes 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. The molecules are identical at that position when a 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 these sequences, taking into account the number of vacancies that need to be introduced for optimal alignment of the two sequences and the length of each vacancies. Sequence comparison and determination of the percentage of identity between two sequences can be accomplished using mathematical algorithms. For example, the percentage of identity between two nucleotide sequences can be determined using the algorithm of Meyers and Miller (CABIOS, 1989, 4: 11-17), which has been incorporated into the ALIGN program (version 2.0). In some exemplary embodiments, nucleic acid sequence comparisons performed using the ALIGN program use a PAM120 weighted residue table, a vacancy length penalty of 12, and a vacancy penalty of 4. Alternatively, the percentage of identity between two nucleotide sequences can be determined using the NWSgapdna.CMP matrix in the GCG package's GAP program.

[0138] Improvement, increase, or decrease: As used herein, the terms “improvement,” “increase,” or “decrease,” or their grammatically equivalent comparative terms, indicate a value relative to a comparable reference measurement. For example, in some embodiments, an assessment value achieved with the agent of interest may be “improved” relative to an assessment value obtained with a comparable reference reagent. Alternatively or additionally, in some embodiments, an assessment value achieved in the subject or system of interest may be “improved” relative to an assessment value obtained in the same subject or system under different conditions (e.g., before or after an event such as administration of the agent of interest), or in different comparable subjects (e.g., in the presence of one or more indicators of a particular disease, disorder, or condition of interest, or in a comparable subject or system different from the subject or system of interest after prior exposure to a condition or agent, etc.).

[0139] As used in this article, K D： It refers to the dissociation constant of a complex formed by a binder (e.g., an antibody or its binding component) and its partner (e.g., an epitope bound to an antibody or its binding component).

[0140] Low affinity binding: As used herein, the term "low affinity binding" refers to a low degree of tightness in which a particular ligand binds to its partner. As described herein, affinity can be measured by any available method, including those known in the art. In some embodiments, if K D A binding affinity of approximately 501 pM or higher (e.g., higher 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.) is considered low. In some embodiments, if the affinity for the peptide of interest is the same as or lower than the affinity for a selected reference peptide (e.g., K...), the binding affinity is considered low. D If the affinity is approximately the same or higher than that of the peptide of interest, then the binding is considered low affinity. In some embodiments, if the affinity of the peptide of interest is approximately the same or higher than that of the peptide of interest, then the binding is considered low affinity. D K with respect to the selected reference peptide D A ratio of 1:1 or greater (e.g., 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) is considered a low affinity. In some embodiments, if the K-peptide ratio of the peptide of interest is 1:1 or greater, the binding is considered low affinity. d K of the selected reference peptide DA concentration of 100% or greater (e.g., 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 greater) is considered a low affinity.

[0141] Non-responder: As used herein, the term "non-responder" refers to a subject who, after a period of time, exhibits a lack of improvement in clinical signs and symptoms following anti-inflammatory therapy (e.g., alternative anti-inflammatory therapies that do not directly target TREM1, such as anti-TNFα therapy). In some embodiments, primary non-responders do not exhibit improvement in clinical signs and symptoms after receiving anti-inflammatory therapy. In some embodiments, secondary non-responders exhibit initial improvement in clinical signs or symptoms after receiving anti-inflammatory therapy, but show a statistically significant decline in such improvement over time. Those skilled in the art will understand that the medical community can establish appropriate time periods for any particular disease or condition or for any particular patient or patient type. To name just a few examples, in some embodiments, the time period may be at least 8 weeks. In some embodiments, the time period may be at least 12 weeks. In some embodiments, the time period may be up to 14 weeks.

[0142] Pharmaceutical Composition: As used herein, the term "pharmaceutical composition" refers to an active agent formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in a unit dose suitable for administration to the relevant subject in a treatment regimen (e.g., an amount that has been shown to show a statistically significant probability of achieving the predetermined therapeutic effect at the time of administration), or in different comparable subjects (e.g., in the presence of one or more indicators of a particular disease, disorder, or condition of interest, or in comparable subjects or systems different from the subject or system of interest in the case of prior exposure to a condition or agent, etc.). In some embodiments, the comparative term refers to a statistically relevant difference (e.g., one with a prevalence and / or magnitude sufficient to achieve statistical significance). Those skilled in the art will appreciate, or will be able to readily determine, the degree and / or prevalence of a difference necessary or sufficient to achieve such statistical significance in a given situation.

[0143] Pharmaceutically acceptable: As used herein, the phrase “pharmaceutically acceptable” means those compounds, materials, combinations, and / or dosage forms that are suitable for use in human and animal tissues to the extent of sound medical judgment without causing excessive toxicity, irritation, allergic response or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0144] As used herein, a polypeptide refers to a polymer chain of amino acids. In some embodiments, the polypeptide has a naturally occurring amino acid sequence. In some embodiments, the polypeptide has an amino acid sequence that is not found in nature. In some embodiments, the polypeptide has an engineered amino acid sequence because it is designed and / or generated through artificial means. In some embodiments, the polypeptide may comprise natural amino acids, non-natural amino acids, or both, or consist of natural amino acids, non-natural amino acids, or both. In some embodiments, the polypeptide may comprise only natural amino acids, only non-natural amino acids, or consist of only natural amino acids or only non-natural amino acids. In some embodiments, the polypeptide may comprise D-amino acids, L-amino acids, or both. In some embodiments, the polypeptide may comprise only D-amino acids. In some embodiments, the polypeptide may comprise only L-amino acids. In some embodiments, the polypeptide may comprise one or more side groups or other modifications, for example, modifications or attachments to one or more amino acid side chains, at the N-terminus of the polypeptide, at the C-terminus of the polypeptide, or any combination thereof. In some embodiments, such side groups or modifications may be selected from the group consisting of acetylation, amidation, esterification, methylation, polyethylene glycolation, etc., including combinations thereof. In some embodiments, the polypeptide may be cyclic and / or may contain a cyclic portion. In some embodiments, the polypeptide is not cyclic and / or does not contain any cyclic portion. In some embodiments, the polypeptide is linear. In some embodiments, the polypeptide may be or include a stapled polypeptide. In some embodiments, the term "polypeptide" may be appended to the name of a reference polypeptide, activity, or structure; in this case, the term is used herein to refer to polypeptides sharing a related activity or structure, and thus can be considered as polypeptides of the same class or family. For each such class, exemplary polypeptides within that class are provided herein and / or will be understood by those skilled in the art, whose amino acid sequences and / or functions are known; in some embodiments, such exemplary polypeptides are reference polypeptides of that polypeptide class or family. In some embodiments, members of that polypeptide class or family exhibit significant sequence homology or identity with the reference polypeptide of that class (in some embodiments, with all polypeptides within that class), share common sequence motifs (e.g., characteristic sequence elements) with the reference polypeptide of that class, and / or share common activities with the reference polypeptide of that class (in some embodiments, at comparable levels or within a specified range).For example, in some embodiments, the member polypeptide exhibits a degree of overall sequence homology or identity with the reference polypeptide (at least about 30% to 40% and typically greater than about 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher), and / or contains at least one region (e.g., a conserved region, which in some embodiments may be or contain a characteristic sequence element) exhibiting very high sequence identity (typically greater than 90% or even 95%, 96%, 97%, 98% or 99%). Such conserved regions typically cover at least 3 to 4, and typically up to 20 or more amino acids; in some embodiments, the conserved region covers at least one extension of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more consecutive amino acids. In some embodiments, the related polypeptide may comprise or consist of a fragment of the parent polypeptide. In some implementations, a useful polypeptide may comprise or consist of multiple fragments, each of which exists in the same parent polypeptide in a spatial arrangement relative to each other that is different from that in the polypeptide of interest (e.g., fragments that are directly linked in the parent polypeptide may be spatially separated in the polypeptide of interest, and vice versa, and / or fragments may exist in the polypeptide of interest in a different order than in the parent polypeptide), such that the polypeptide of interest is a derivative of its parent polypeptide.

[0145] Reference: As used herein, the term "reference" describes a standard or control relative to which comparison is made. For example, in some embodiments, the agent, animal, individual, population, sample, sequence, or value of interest is compared with a reference or control agent, animal, individual, population, sample, sequence, or value. In some embodiments, the reference or control is tested and / or determined substantially simultaneously with the test or determination of interest. In some embodiments, the reference or control is a historical reference or control, optionally embodied in a tangible medium. Typically, as those skilled in the art will understand, the reference or control is determined or characterized under conditions or conditions equivalent to those of the conditions or environment being evaluated. Those skilled in the art will understand when sufficient similarity exists to justify dependence on and / or comparison with a particular possible reference or control.

[0146] Specific binding: As used herein, the term "specific binding" refers to the ability to distinguish potential binding partners in an environment where binding may occur. When other potential targets are present, a binder that interacts with a particular target is referred to as "specifically bound" to that target. In some embodiments, specific binding is assessed by detecting or determining the degree of association 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 counteract alternative interactions between its partner and another entity. In some embodiments, specific binding is assessed by performing such detection or determination within a concentration range.

[0147] Specificity: When used herein with reference to an active pharmaceutical agent, the term "specific" is understood by those skilled in the art to mean that the agent distinguishes a potential target entity or state. For example, in some embodiments, an agent 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 interactions depend on the presence of specific structural features of the target entity (e.g., epitopes, clefts, binding sites). It should be understood that specificity is not necessarily absolute. In some embodiments, specificity can be evaluated relative to the specificity of the binder to one or more other potential target entities (e.g., competitors). In some embodiments, specificity is evaluated relative to the specificity of a reference specific binder. In some embodiments, specificity is evaluated relative to the specificity of a reference non-specific binder. In some embodiments, the agent or entity binds undetectably to a competing alternative target while bound to its target entity. In some embodiments, the binder binds to its target entity with a higher binding rate, a lower dissociation rate, increased affinity, reduced dissociation, and / or increased stability compared to a competing alternative target.

[0148] Specificity: As is known in the art, "specificity" is a measure of a particular ligand's ability to distinguish its binding mate from other potential binding mates.

[0149] Subject: As used herein, the term "subject" refers to an organism, typically a mammal (e.g., a human, and in some embodiments, including prenatal human forms). In some embodiments, the subject suffers from 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 with one or more characteristics that are characteristic of susceptibility or risk to a disease, disorder, or condition. In some embodiments, the subject is a patient. In some embodiments, the subject is a subject to whom and / or who has been given a diagnostic and / or therapeutic treatment.

[0150] Essentially: As used herein, the term “essentially” refers to a qualitative condition that exhibits all or nearly all of the range or degree of the feature or property of interest. Those skilled in the art of biology will understand that biological and chemical phenomena rarely (if ever) reach completion and / or proceed to completion or achieve or avoid absolute results. Therefore, the term “essentially” is used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.

[0151] Fundamental identity: As used herein, this refers to a comparison between amino acid or nucleic acid sequences. As will be understood by one of ordinary skill in the art, two sequences are generally considered "fundamentally identical" if they contain the same residues at corresponding positions. As is well known in the art, any of a variety of algorithms can be used to compare amino acid or nucleic acid sequences, including those available in commercial computer programs such as BLASTN for nucleotide sequences and BLASTP for amino acid sequences, BLAST with vacancies, and PSI-BLAST. Exemplary procedures of this kind are described in the following literature: Altschul et al., Basic local alignment search tool, J. Mol. Biol., 215(3): 403-410, 1990; Altschul et al., Methods in Enzymology; Altschul et al., Nucleic Acids Res.25:3389-3402, 1997; Baxevanis et al., Bioinformatics: A Practical Guide to the Analysis of Genes and Proteins, Wiley, 1998; and Misener et al., (ed.), Bioinformatics Methods and Protocols (Methods in Molecular Biology, Vol. 132), Humana Press, 1999. In addition to identifying identical sequences, the above procedures generally provide an indication 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 the corresponding residues in the relevant extension are identical. In some embodiments, the relevant extension is a complete sequence. In some implementations, the relevant extension is 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 a CDR, reference to "substantially identical" generally refers to a CDR with no more than a few (e.g., 3, 2, or 1) amino acid sequence changes relative to a reference CDR.In some embodiments, a CDR that is substantially identical to a reference CDR differs from the reference CDR in that one or more amino acid variations at the ends of the reference CDR; 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 a length 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, which is incorporated herein by reference); thus, in some embodiments, a CDR may be considered substantially identical to a reference CDR when 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 the reference CDR.

[0152] Basic sequence homology: The phrase “basic homology” is used herein to refer to comparisons between amino acid or nucleic acid sequences. As will be understood by those skilled in the art, two sequences are generally considered to be “basically homologous” if they contain homologous residues at corresponding positions. Homologous residues can be identical residues. Alternatively, homologous residues can be dissimilar residues with 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 as “hydrophobic” or “hydrophilic” amino acids, and / or as having “polar” or “nonpolar” side chains. The substitution of one amino acid by another amino acid of the same type can generally be considered a “homologous” substitution. Typical amino acid classifications are summarized below: amino acids 3 letters 1 letter polarity electric charge Hydrophobic (Kyte-Doolittle) alanine Ala A nonpolar neutral 1.8 Arginine Arg R polarity Positive -4.5 Asparagine Asn N polarity neutral -3.5 Aspartic acid Asp D polarity Negative -3.5 Cysteine Cys C nonpolar neutral 2.5 glutamic acid Glu E polarity Negative -3.5 glutamine Gln Q polarity neutral -3.5 glycine Gly G nonpolar neutral -0.4 Histidine His H polarity Positive -3.2 Isoleucine Ile I nonpolar neutral 4.5 Leucine Leu L nonpolar neutral 3.8 Lysine Lys K polarity Positive -3.9 Methionine Met M nonpolar neutral 1.9 Phenylalanine Phe F nonpolar neutral 2.8 proline Pro P nonpolar neutral -1.6 Serine Ser S polarity neutral -0.8 threonine Thr T polarity neutral -0.7 Tryptophan Trp W nonpolar neutral -0.9 Tyrosine Tyr Y polarity neutral -1.3 Valine Val V nonpolar neutral 4.2 Unidentified amino acids 3 letters 1 letter Asparagine or aspartic acid Asx B Glutamine or glutamic acid Glx Z Leucine or Isoleucine Xle J Unspecified or unknown amino acids Xaa X As is well known in the art, any of a variety of algorithms can be used to compare amino acid or nucleic acid sequences, including those available in commercial computer programs, such as BLASTN for nucleotide sequences and BLASTP for amino acid sequences, BLAST with vacancies, and PSI-BLAST. Exemplary procedures of this kind are described in the following literature: Altschul et al., Basic local alignment search tool, J. Mol. Biol., 215(3): 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", NucleicAcids Res. 25:3389-3402, 1997; Baxevanis et al., Bioinformatics: A Practical Guide to the Analysis of Genes and Proteins, Wiley, 1998; and Misener et al., (ed.), Bioinformatics Methods and Protocols (Methods in Molecular Biology, Vol. 132), Humana Press, 1999. In addition to identifying homologous sequences, the above procedures typically provide an indication of the degree of homology. In some embodiments, two sequences are considered substantially homologous if at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% or more of the corresponding residues in the relevant extension are homologous. In some embodiments, the relevant extension is a complete sequence.In some implementations, the relevant extensions are 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.

[0153] Treatment: As used herein, the term "treatment" refers to one or more of the following: partial or complete relief, improvement, reduction, suppression, prevention of one or more symptoms or features of a disease, disorder, and / or condition; delaying the onset of one or more symptoms or features of a disease, disorder, and / or condition; reducing the severity of one or more symptoms or features of a disease, disorder, and / or condition; and / or reducing the frequency (e.g., incidence) of one or more symptoms or features of a disease, disorder, and / or condition. In some embodiments, treatment may be preventative; for example, it may be administered to subjects who do not exhibit signs of a disease, disorder, and / or condition. In some embodiments, treatment may be administered to subjects who only exhibit early signs of a disease, disorder, and / or condition, and may, for example, reduce the risk of developing a pathology associated with the disease, disorder, and / or condition, and / or delay the onset of one or more features of a disease, disorder, and / or condition, and / or reduce the rate of development or worsening of one or more features of a disease, disorder, and / or condition.

[0154] Treatment: As used herein, the term "treat" (and "treatment / treating") refers to the application of a therapy that partially or completely reduces, improves, alleviates, or inhibits one or more symptoms, features, and / or causes of a particular disease, disorder, and / or condition; delays the onset of one or more symptoms, features, and / or causes of a particular disease, disorder, and / or condition; reduces the severity of one or more symptoms, features, and / or causes of a particular disease, disorder, and / or condition; and / or reduces the incidence of one or more symptoms, features, and / or causes of a particular disease, disorder, and / or condition. In some embodiments, such treatment may be directed to subjects who do not exhibit signs of the relevant disease, disorder, and / or condition and / or to subjects exhibiting early signs of the disease, disorder, and / or condition. Alternatively or additionally, such treatment may be directed to subjects exhibiting one or more signs of the relevant disease, disorder, and / or condition. In some embodiments, treatment may be directed to subjects who have been diagnosed with the relevant disease, disorder, and / or condition. In some implementations, treatment may be targeted at subjects who are known to have one or more susceptibility factors that are statistically associated with an increased risk of developing the relevant disease, disorder, and / or condition. Therefore, in some implementations, the treatment may be preventative; in others, it may be therapeutic.

[0155] Therapeutic Effective Amount: As used herein, the term "therapeutic effective amount" refers to the amount of a substance (e.g., a therapeutic agent, composition, and / or formulation) that elicits a desired biological response when administered as part of a treatment regimen. In some embodiments, a therapeutically effective amount 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 who has or is susceptible to such disease, disorder, and / or condition. As will be understood by those skilled in the art, the effective amount of a substance can vary depending on factors such as the desired biological endpoint, the substance to be delivered, the target cells, or tissues. For example, an effective amount of a compound in a formulation for treating a disease, disorder, and / or condition is an amount that reduces, improves, alleviates, inhibits, prevents, delays the onset of one or more symptoms or features of a disease, disorder, and / or condition, reduces the severity of one or more symptoms or features of a disease, disorder, and / or condition, and / or reduces the incidence of one or more symptoms or features of a disease, disorder, and / or condition. In some implementations, the therapeutically effective dose is administered in a single dose; in other implementations, multiple unit doses are required to deliver the therapeutically effective dose.

[0156] Variants: 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 in the presence or level of one or more chemical components compared to the reference entity. In many embodiments, variants are also functionally different from their reference entities. Generally, whether a particular entity is properly considered a "variant" of a reference entity is based on the degree of structural identity between that particular entity and the reference entity. As those skilled in the art will understand, any biological or chemical reference entity has certain characteristic structural elements. By definition, a variant is a different chemical entity that shares one or more of these characteristic structural elements. To cite just a few examples, small molecules may have characteristic core structural elements (e.g., a macrocyclic core) and / or one or more characteristic overhangs, such that variants of the small molecule are variants that share the core structural elements and characteristic overhangs but differ in the type of bonds present in other overhangs and / or the core (single bond versus double bond, E versus Z, etc.). Peptides may have characteristic sequence elements comprising multiple amino acids that have designated positions relative to each other in linear or three-dimensional space and / or contribute to a specific biological function. Nucleic acids may have characteristic sequence elements comprising multiple nucleotide residues that have designated positions relative to each other in linear or three-dimensional space. For example, variant peptides may differ from reference peptides due to one or more differences in the amino acid sequence and / or one or more differences in the chemical portions (e.g., carbohydrates, lipids, etc.) covalently linked to the peptide backbone. In some embodiments, variant peptides exhibit overall sequence identity with the reference peptide of 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 peptide does not share at least one characteristic sequence element with the reference peptide. In some embodiments, the reference peptide has one or more biological activities. In some embodiments, the variant peptide shares one or more of the biological activities of the reference peptide. In some embodiments, the variant peptide lacks one or more of the biological activities of the reference peptide. In some embodiments, the variant peptide exhibits a reduced level of one or more biological activities compared to the reference peptide. In many embodiments, the peptide of interest is considered a “variant” of the parent or reference peptide if it has the same amino acid sequence as the parent peptide but with minor sequence changes at specific positions. Typically, less than 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, or 2% of residues are substituted in the variant compared to the parent peptide. In some embodiments, the variant has 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 substituted residue compared to the parent peptide.Typically, variants have a very small number (e.g., fewer than 5, 4, 3, 2, or 1) of substituted functional residues (i.e., residues involved in a specific biological activity). Furthermore, compared to the parent peptide, variants typically have no more than 5, 4, 3, 2, or 1 additions or deletions, and typically none. Additionally, any additions or deletions are typically fewer than about 25, about 20, about 19, about 18, about 17, about 16, about 15, about 14, about 13, about 10, about 9, about 8, about 7, or about 6 residues, and typically fewer than about 5, about 4, about 3, or about 2 residues. In some embodiments, the parent or reference polypeptide is a polypeptide found in nature.

[0157] Vector: As used herein, this refers to a carrier of polynucleotides (i.e., DNA or RNA molecules) that can be used to introduce polynucleotides into cells. An "expression vector" is a vector containing a sequence encoding a protein and the necessary regulatory regions required for the expression of that sequence in cells. In some embodiments, the protein-coding sequence is operatively linked to another sequence in the vector. The term "operatively linked" means placing the regulatory sequence necessary for the expression of the protein-coding sequence at the appropriate position in the polynucleotide relative to that sequence to achieve protein expression. Detailed Implementation

[0158] Among other things, this disclosure provides TREM1 inhibitor agents, which are or include anti-TREM1 antibody agents. This disclosure also provides pharmaceutical compositions comprising such TREM1 inhibitor agents and methods of using the pharmaceutical compositions to treat diseases, disorders, or conditions.

[0159] As described herein, this disclosure also provides the insight that neutrophil and / or monocyte levels can indicate potential responsiveness to certain anti-inflammatory therapies (e.g., the TREM1 antibody agent described herein). This disclosure further demonstrates that, in some embodiments, certain neutrophils (e.g., activated neutrophils) can be particularly useful indicators of potential responsiveness to certain anti-inflammatory therapies (e.g., the TREM1 antibody agent described herein). This disclosure provides various biomarkers representing neutrophil levels (e.g., activated neutrophil levels) and / or monocyte levels (e.g., inflammatory monocyte levels) and / or serving as substitutes for these levels, and describes the use of such biomarkers in anti-inflammatory therapies (e.g., with the TREM1 antibody agent described herein). In some embodiments, such biomarkers are or include neutrophil products and / or inflammatory monocyte products.

[0160] Among other things, this disclosure provides the insight that subjects with elevated levels of activated neutrophils and / or elevated levels of inflammatory monocytes may be suitable candidates for a therapy targeting TREM1 (e.g., using a TREM1 antibody agent as described herein). Alternatively or additionally, in some embodiments, such subjects may be less suitable candidates for alternative therapies (e.g., a therapy targeting TNFα).

[0161] TREM1 Myeloid trigger receptor 1 (TREM1 or TREM-1) is a member of the Ig-like immunomodulatory receptor family. This member is found on the surface of certain myeloid cells (particularly a subset of neutrophils and monocytes) that are part of the innate immune system and has been described as an “amplifier” of inflammation. See, for example, Bouchon et al., J. Immunol. 164:4991 (2000); Dantas et al., Intl. Rev. Immunol. 39(4):188-202 (2020).

[0162] TREM1 polypeptide sequences from various organisms have been reported, and UniProt accession numbers have been assigned to these sequences as described in Table 1 below.

[0163] Table 1: TREM1 protein sequence The membrane-associated form of TREM1 includes: (i) an extracellular domain containing a single Ig V-type domain; (ii) a transmembrane region; and (iii) a cytoplasmic tail that recruits DNAX-activating protein 12 (DAP12) for signal transduction. A soluble form (sTREM1) has also been described, and it is thought to be produced via proteolytic cleavage of TREM1 (potentially after activation; see, for example, Gómez-Piña et al., J. Immunol. 179(6):4065-4073 (2007); Gingras et al., Mol. Immunol. 38:817 (2002); Bostanci et al., J. Dent. Res. 92(2):161-165 (2013); Jolly et al., CellMol. Immunol. 18(8):2054-2056 (2021)); or alternative splicing of TREM1 mRNA (see, for example, Baruach et al., J. Immunol 195(12):5725-5731 (2015)). sTREM1 has been reported to competitively bind to at least some ligands of TREM1. 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, thereby reducing TREM1 activation (see, for example, WO 2022 / 258979).

[0164] It has also been reported that the monomer TREM1 is inactive; activity may require polymerization. See Carrasco et al., Cell Mol. Immunol. 16:460, 2019.

[0165] Various potential ligands for TREM1 have been proposed, including PGLYRP1, actin, HMGB1, Hsp70, extracellular cold-inducible RNA-binding protein (eCIRP), and / or one or more infectious agent-associated antigens (e.g., yeast glycans, envelope glycoproteins of HIV and / or Marburg virus, egg antigens of Schistosoma mansoni, 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).

[0166] TREM1 has been reported to be upregulated in response to factors such as hypoxia (in dendritic cells), vitamin D3, oxidized low-density lipoprotein, tumor necrosis factor α (TNFα), interleukin-1β (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 4(2):17 (2021).

[0167] Activated TREM1 leads to phosphorylation of DAP12 by Src kinase, triggering a phosphorylation cascade that ultimately results in the activation of various transcription factors associated with the production of inflammatory mediators such as IL-6, IL-8, IL-1β, and TNFα; see, for example, Dower et al., J. Immunol., 180(5):3520-2534 (2008). TREM1 activation also inhibits pro-apoptotic agents such as BID, BAD, and BAX, and also inhibits the release of cytochrome C from mitochondria; see, for example, Campbell et al., mBio, 10(6); e02638-19 (2019); Yuan et al., J. Biol. Chem. 289(21):15118-15129 (2013); and Yuan et al., Am. J. Physiol. Lung Cell. Mol. Physiol., 310(5):L426-38 (2016).

[0168] TREM1 expression is downregulated by PU.1 and anti-inflammatory cytokines such as IL-10 and TGF-β; see, for example, Zeng et al., Eur. J. Immunol., 37(8):2300-8 (2007) and Schenk et al., J. Immunol., 174(1):517-24 (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., 11:56 (2017).

[0169] Anti-inflammatory therapy Generally, inflammation can be caused by a variety of mechanisms, including but not limited to immune responses to injury and infection. Chronic inflammation is characteristic of certain diseases (such as autoimmune diseases, cancer, inflammatory diseases, etc.) and can lead to tissue damage and / or tissue death over time. Anti-inflammatory therapy can suppress inflammation and / or reduce the symptoms and / or markers of inflammation.

[0170] In some embodiments, the anti-inflammatory therapy can reduce the levels of one or more inflammatory biomarkers in a subject. In some embodiments, the anti-inflammatory therapy can reduce the levels of one or more downstream signaling molecules (e.g., proteins, cytokines, chemokines, etc.) that trigger an inflammatory response. In some embodiments, the anti-inflammatory therapy can bind to a target of interest (e.g., proteins, enzymes, etc.) associated with an inflammatory response. In some embodiments, the anti-inflammatory therapy can inhibit the function of a target of interest (e.g., proteins, enzymes, etc.) associated with an inflammatory response. In some embodiments, the anti-inflammatory therapy can inhibit the function of a target of interest (e.g., proteins, enzymes, etc.) thereby preventing an inflammatory response. In some embodiments, the anti-inflammatory therapy can inhibit the function of a target of interest (e.g., proteins, enzymes, etc.) thereby preventing the release / production of downstream signaling molecules (e.g., proteins, cytokines, chemokines, etc.) that trigger an inflammatory response. In some embodiments, the anti-inflammatory therapy can 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, the anti-inflammatory therapy can 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, the anti-inflammatory therapy can inhibit the production, processing, secretion, and / or binding of activating factors 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, the anti-inflammatory therapy can inhibit the production, processing, secretion, and / or binding of factors associated with reduced or impaired 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, the anti-inflammatory therapy can prevent or reduce (e.g., inhibit) epithelial barrier damage. In some embodiments, the anti-inflammatory therapy can inhibit the production, processing, secretion, and / or binding of particulate proteins (including but not limited to S100A and antimicrobial peptides).In some implementations, anti-inflammatory therapy can inhibit the production, processing, secretion, and / or binding of neutrophil products, including but not limited to myeloperoxidase (MPO), elastase, PR3, MMP8, MMP9, prolyl endopeptidase, lipotransferase, and Lamp-2; see, for example, Herrero-Cervera et al., Cell Mol Immunol. 19:177-191 (2022).

[0171] In many embodiments, anti-inflammatory therapy involves administering one or more compositions that deliver an anti-inflammatory agent (i.e., an agent that inhibits an inflammation by reducing the level and / or activity of a relevant target). Those skilled in the art are familiar with a variety of such agents and / or compositions (e.g., as described herein). For completeness, we note that the teachings of this disclosure are applicable to agents of various chemical classes (e.g., small molecules, nucleic acids, peptides, etc.), and those skilled in the art understand appropriate delivery modalities for different such classes. For example, in some embodiments, small molecule agents can be delivered by administering a composition comprising an agent or a prodrug thereof (e.g., once administered, the prodrug can be metabolized or otherwise converted into the agent). In some embodiments, nucleic acid agents can be delivered by administering a composition comprising an agent or a complement thereof, or a nucleic acid that otherwise encodes the agent (e.g., such that the agent can be generated in a subject administering the composition). In some embodiments, peptide drugs (e.g., peptide drugs, antibody drugs, etc.) can be delivered by administering a composition containing a drug or a precursor containing the drug (e.g., such that the drug is generated by processing in a subject administering the composition) or containing a nucleic acid encoding the drug (e.g., such that a peptide drug can be generated in the body administering the composition).

[0172] In some embodiments, the target of the anti-inflammatory therapy may be or include TREM1. In some embodiments, the target of the anti-inflammatory therapy may be or include an alternative target (e.g., TNFα). In some embodiments, an anti-inflammatory therapy targeting an alternative target (i.e., not a target of TREM1) (e.g., a TNFα inhibitor) may be referred to as an alternative therapy (e.g., an alternative anti-inflammatory therapy). As described below, certain TREM1 inhibitors and inhibitors of alternative targets (e.g., TNFα inhibitors) are known; for some, clinical formulations and regimens have been developed. In some embodiments of this disclosure, the anti-inflammatory therapy is an established therapy, for example, administered according to its established regimen (e.g., approved by an applicable regulatory agency such as the U.S. Food and Drug Administration or the European Medicines Agency). In some embodiments, the anti-inflammatory therapy is or includes the anti-TREM1 antibody agent described herein, a nucleic acid encoding such an agent, or a combination thereof.

[0173] TREM1 inhibitors In some embodiments, inflammatory diseases, disorders, or conditions can be treated by inhibiting TREM1, and specifically by administering a TREM1 inhibitor (i.e., by TREM1 inhibition therapy). In some embodiments, the TREM1 inhibitor is or includes an anti-TREM1 agent. Various TREM1 inhibitors are known in the art; see, for example, Siskind et al., Front Immunol, 13:907387 (2022), Sigalov, Front Immunol 11:173 (2020); and Brynjolfsson et al., Inflamm Bowel Dis, 22(8):1803-11 (2016).

[0174] In some embodiments, the TREM1 inhibitor is or includes a TREM1 decoy receptor. Without being bound by any particular theory, the TREM1 decoy receptor binds to the TREM1 ligand and thus prevents the TREM1 ligand from binding to TREM1 and subsequent TREM1 activation. In some embodiments, the TREM1 decoy receptor is or includes a soluble TREM1 (sTREM1) or a TREM1Fc fusion protein.

[0175] In some embodiments, the TREM1 inhibitor is or includes soluble TREM1 (sTREM1). In some embodiments, sTREM1 is a cleaved extracellular domain of TREM1. Without wishing to be bound by any particular theory, it is believed that sTREM1 acts as a decoy receptor for TREM1 by binding to TREM1 ligands and reducing TREM1 activation and subsequent inflammatory responses (e.g., release of pro-inflammatory cytokines).

[0176] In some embodiments, the TREM1 inhibitor is or includes a TREM1 Fc fusion protein. In some embodiments, the TREM1 Fc fusion protein comprises an extracellular domain of TREM1 (e.g., mouse TREM1) and an Fc domain (e.g., the Fc portion of human IgG1). Without wishing to be bound by any particular theory, it is believed that the TREM1 Fc fusion protein (i) acts as a TREM1 decoy receptor and (ii) promotes the clearance of TREM1 ligands via Fc receptor-mediated endocytosis.

[0177] In some embodiments, the TREM1 inhibitor is or comprises a TREM1 bait peptide. In some embodiments, the TREM1 bait peptide is a peptide derived from a portion of the extracellular domain of TREM1. In some embodiments, the TREM1 bait peptide is a peptide derived from a portion of a TREM1 ligand. Without wishing to be bound by any particular theory, it is believed that the TREM1 bait peptide (i) binds to TREM1 and acts as a competitive inhibitor preventing the binding of the TREM1 ligand to TREM1, and / or (ii) binds to the TREM1 ligand and thus prevents the binding of the TREM1 ligand to TREM1 and subsequent TREM1 activation. In some embodiments, the TREM1 bait peptide is or comprises an LP17 peptide having the amino acid sequence LQVTDSGLYRCVIYHPP (SEQ ID NO: 7). In some embodiments, the TREM1 bait peptide is or comprises an M3 peptide having the amino acid sequence RGFFRGG (SEQ ID NO: 8). In some embodiments, the TREM1 decoy peptide is or includes an N1 peptide having an amino acid sequence corresponding to amino acid positions 77-86 of PGLYRP1 (SEQ ID NO: 9).

[0178] In some embodiments, the TREM1 inhibitor is or includes an inhibitor of the interaction between TREM1 and DAP12. Without wishing to be bound by any particular theory, it is believed that TREM1-mediated signaling occurs via the interaction between TREM1 and DAP12. In some embodiments, the inhibitor of the TREM1-DAP12 interaction is or includes a peptide derived from a portion of the TREM1 transmembrane domain. In some embodiments, the inhibitor of the TREM1-DAP12 interaction is or includes a GF9 peptide having the amino acid sequence GLLSKSLVF (SEQ ID NO: 10). In some embodiments, the inhibitor of the TREM1-DAP12 interaction is or includes a TREM1 stealthy ligand construct (SLC-TREM1). In some embodiments, SLC-TREM1 comprises an E-selective targeting domain, Pseudomonas aeruginosa exotoxin A, and a polypeptide having the amino acid sequence LSKSLVF (SEQ ID NO: 11) derived from the transmembrane domain of TREM1.

[0179] In some embodiments, the TREM1 inhibitor is or includes a peptide derived from TREM1-like transcript 1 (TLT-1). In some embodiments, the TLT-1-derived peptide is or includes the LR17 peptide having the amino acid sequence LQEEDAGEYGCMVDGAR (SEQ ID NO: 12). In some embodiments, the TLT-1-derived peptide is or includes the LR12 peptide having the amino acid sequence LQEEDAGEYGCM (SEQ ID NO: 13). In some embodiments, the LR12 peptide may be referred to as nangibotide.

[0180] TREM1 antibody drugs This article discloses TREM1 antibody agents that, for example, bind to TREM1 with high affinity (e.g., specific binding).

[0181] Some provided TREM1 antibody agents are characterized by their ability to inhibit TREM1 activation. In some embodiments, the provided TREM1 antibody agents directly bind to and inhibit TREM1. In some embodiments, the provided TREM1 antibody agents are characterized by their ability to reduce TREM1 expression on the cell surface (e.g., reduced TREM1 expression, TREM1 internalization, TREM1 cleavage to release sTREM1, etc.). In some embodiments, the provided TREM1 antibody agents are characterized by their ability to simultaneously inhibit TREM1 activation and reduce TREM1 expression on the cell surface (e.g., reduced TREM1 expression, TREM1 internalization, TREM1 cleavage to release sTREM1, etc.). Without being bound by any theory, in some embodiments, the provided TREM1 antibody agents are characterized by their ability to simultaneously inhibit TREM1 activation and induce TREM1 internalization.

[0182] In some embodiments, the provided TREM1 antibody agent is characterized by its ability to inhibit TREM1 activation and 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.) from one or more cells (e.g., neutrophils, myeloid cells (including monocytes)), 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 various pro-inflammatory mediators (e.g., cytokines, chemokines, etc.) while maintaining the innate antibacterial response. In some embodiments, the provided TREM1 antibody agent is characterized by its ability to reduce the production of various pro-inflammatory mediators (e.g., cytokines, chemokines, etc.) while preventing further damage to the epithelial barrier by these mediators.

[0183] In some embodiments, the TREM1 antibody agents of this 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 this disclosure interfere with (i.e., reduce or block) the binding of TREM1 to actin, PGLYRP1, HMGB1, Hsp70, extracellular cold-inducible RNA-binding protein (eCIRP), and / or one or more infectious agent-associated antigens (e.g., yeast glycans, envelope glycoproteins of HIV and / or Marburg virus, egg antigens of Schistosoma mansoni, etc.). By interfering with the binding of TREM1 to one or more of its ligands, the TREM1 antibody agents of this disclosure can inhibit downstream TREM1 signaling (e.g., via DAP12) and reduce or prevent the activation of immune cells (e.g., neutrophils, monocytes, etc.). In some embodiments, the TREM1 antibody agents of this disclosure interfere with (i.e., reduce or block) the binding of TREM1 to PGLYRP1.

[0184] In some embodiments, the TREM1 antibody agent of this disclosure is characterized by reducing the ability of TREM1 to be expressed on the cell surface of immune cells (e.g., neutrophils, monocytes, etc.). In some embodiments, the TREM1 antibody agent of this disclosure is characterized by promoting the internalization of TREM1 into immune cells (e.g., neutrophils, monocytes, etc.) that express TREM1 on their surface. In some embodiments, such immune cells are neutrophils or monocytes. In some embodiments, such immune cells are dendritic cells. TREM1 internalization 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, the TREM1 antibody agent can promote TREM1 internalization to varying degrees and at different times and kinetics. Not wishing to be bound by any particular theory, we propose that such variations in the ability of the TREM1 antibody agent to promote TREM1 internalization may affect one or more pharmacokinetic properties of the TREM1 antibody agent.

[0185] In some embodiments, the TREM1 antibody agent of this disclosure is characterized by its 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 agent of this disclosure promotes the proteolytic cleavage of TREM1 by matrix metalloproteinases (MMPs; e.g., MMP1 or MMP9). In promoting the proteolytic cleavage of TREM1, the TREM1 antibody agent of this 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.).

[0186] In some embodiments, the TREM1 antibody agents of this disclosure are characterized by their ability to inhibit TREM1-mediated immune responses. For example, in some embodiments, the TREM1 antibody agents of this 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.

[0187] In some embodiments, the provided TREM1 antibody agent is characterized by a binding affinity of about 5 nM or less (K0). D The antibody binds to human TREM1. In some embodiments, the provided TREM1 antibody agent is characterized by a binding affinity (K0) of no more than about 5 nM, 4 nM, 3 nM, 2 nM, 1.5 nM, 1 nM, 0.5 nM, 0.45 nM, 0.4 nM, 0.35 nM, 0.3 nM, 0.25 nM, 0.24 nM, 0.23 nM, 0.22 nM, 0.21 nM, 0.2 nM, 0.19 nM, 0.18 nM, 0.17 nM, 0.16 nM, 0.15 nM, 0.14 nM, 0.13 nM, 0.12 nM, 0.11 nM, 0.1 nM, 0.09 nM, or 0.08 nM. D The antibody binds to human TREM1. In some embodiments, the provided TREM1 antibody agent is characterized by a binding affinity of approximately 0.21 nM (K0.05). D It binds to human TREM1. In some embodiments, human TREM1 is a monomeric human TREM1 extracellular domain (ECD). In some embodiments, biolayer interference (BLI) assays are used to measure binding affinity.

[0188] In some embodiments, the provided TREM1 antibody agent is characterized by a binding affinity of about 5 nM or less (K0).D The antibody binds to TREM1 in cynomolgus monkeys. In some embodiments, the provided TREM1 antibody is characterized by a binding affinity (K0) of no more than about 5 nM, 4 nM, 3 nM, 2.5 nM, 2.4 nM, 2.3 nM, 2.2 nM, 2.1 nM, 2 nM, 1.9 nM, 1.8 nM, 1.7 nM, 1.6 nM, 1.5 nM, 1.4 nM, 1.3 nM, 1.2 nM, 1.1 nM, 1 nM, 0.5 nM, 0.45 nM, 0.4 nM, 0.35 nM, 0.3 nM, 0.25 nM, 0.2 nM, 0.15 nM, or 0.1 nM. D The antibody binds to TREM1 in cynomolgus monkeys. In some embodiments, the provided TREM1 antibody is characterized by a binding affinity of approximately 1.9 nM (K0.05). D The cynomolgus monkey TREM1 binds to it. In some embodiments, the cynomolgus monkey TREM1 is a monomeric extracellular domain (ECD) of the cynomolgus monkey TREM1. In some embodiments, a biolayer interference (BLI) assay is used to measure binding affinity.

[0189] In some embodiments, the provided TREM1 antibody agent is characterized by a binding affinity of 1 nM or less (K0.05) in cell binding assays. D The antibody binds to TREM1. In some embodiments, the provided TREM1 antibody is characterized by a binding affinity (K0.01) of no more than about 1 nM, 0.9 nM, 0.8 nM, 0.7 nM, 0.6 nM, 0.5 nM, 0.45 nM, 0.4 nM, 0.35 nM, 0.3 nM, 0.25 nM, 0.2 nM, 0.1 nM, 0.09 nM, 0.08 nM, 0.07 nM, 0.06 nM, 0.05 nM, 0.04 nM, 0.03 nM, 0.02 nM, or 0.01 nM in a cell binding assay. D( ) binds to TREM1. In some embodiments, the provided TREM1 antibody agent is characterized in that, in cell binding assays, it binds at concentrations not exceeding about 400 pM, 390 pM, 380 pM, 370 pM, 360 pM, 350 pM, 340 pM, 330 pM, 320 pM, 310 pM, 300 pM, 290 pM, 280 pM, 270 pM, 260 pM, 250 pM, 245 pM, 240 pM, 235 pM, 230 pM, 225 pM, 220 pM, 21 Binding affinity (K0) of 5 pM, 210 pM, 205 pM, 200 pM, 195 pM, 190 pM, 185 pM, 180 pM, 175 pM, 170 pM, 165 pM, 160 pM, 155 pM, 150 pM, 145 pM, 140 pM, 135 pM, 130 pM, 125 pM, 120 pM, 115 pM, 110 pM, 105 pM, 100 pM, 95 pM, 90 pM, 85 pM, 80 pM, and 75 pM D The TREM1 antibody binds to TREM1. In some embodiments, the provided TREM1 antibody is characterized by a binding affinity of approximately 87 pM (K0.05) in a cell binding assay. D The TREM1 antibody binds to TREM1. In some embodiments, the provided TREM1 antibody is characterized by a binding affinity of approximately 213 pM (K0.05) in a cell binding assay. D The TREM1 antibody binds to TREM1. In some embodiments, the provided TREM1 antibody is characterized by a binding affinity of approximately 10³ pM (K0.05) in a cell binding assay. D The TREM1 antibody binds to TREM1. In some embodiments, the provided TREM1 antibody is characterized by a binding affinity of approximately 132 pM (K0.05) in a cell binding assay. D The TREM1 antibody binds to TREM1. In some embodiments, the provided TREM1 antibody is characterized by a binding affinity of approximately 251 pM (K0.05) in a cell binding assay. D The TREM1 antibody binds to TREM1. In some embodiments, the provided TREM1 antibody is characterized by a binding affinity (K0.05) of about 23 pM to about 37 pM in a cell binding assay. D The TREM1 antibody binds to TREM1. In some embodiments, the provided TREM1 antibody is characterized by a binding affinity (K0.05) of about 4 pM to about 13 pM in a cell binding assay. DThe cell binding assay measures the binding of a TREM1 antibody to human TREM1. In some embodiments, the cell binding assay measures the binding of a TREM1 antibody to cynomolgus monkey TREM1. In some embodiments, the cell binding assay measures the binding of a TREM1 antibody to human TREM1 present on enriched human monocytes. In some embodiments, the cell binding assay measures the binding of a TREM1 antibody to human TREM1 present on enriched human neutrophils. In some embodiments, the cell binding assay measures the binding of a TREM1 antibody to human TREM1 present on whole blood human monocytes. In some embodiments, the cell binding assay measures the binding of a TREM1 antibody to human TREM1 present on whole blood human neutrophils. In some embodiments, the cell binding assay measures the binding of a TREM1 antibody to cynomolgus monkey TREM1 present on whole blood cynomolgus monkey monocytes. In some implementations, a cell binding assay measures the binding of the provided TREM1 antibody agent to cynomolgus TREM1 present on whole blood cynomolgus neutrophils.

[0190] In some embodiments, the provided TREM1 antibody agent is characterized by inhibiting TREM1 activity at IC50 values ​​of approximately 50 pM, approximately 48 pM, approximately 46 pM, approximately 44 pM, approximately 42 pM, approximately 40 pM, approximately 38 pM, approximately 36 pM, approximately 34 pM, approximately 32 pM, approximately 30 pM, approximately 28 pM, approximately 26 pM, approximately 24 pM, approximately 22 pM, approximately 20 pM, approximately 18 pM, approximately 16 pM, approximately 15 pM, approximately 14 pM, approximately 13 pM, approximately 12 pM, approximately 11 pM, approximately 10 pM, approximately 9 pM, approximately 8 pM, approximately 7 pM, approximately 6 pM, approximately 5 pM, approximately 4 pM, approximately 3 pM, or approximately 2 pM in primary cell function assays. In some embodiments, such primary cell function assays measure the inhibition of cytokine or chemokine production by activated neutrophils or monocytes. In some embodiments, primary cell function assays measure the inhibition of CCL3, CCL4, or IL-8 production by activated neutrophils. In some embodiments, the inhibition of CCL3, CCL4, or IL-8 production is defined as 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% in 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 is defined as 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% compared to levels of CCL3, CCL4, TNFα, IL-1β, IL-6, or IL-23 produced by monocytes not treated with the TREM1 antibody agent. In some embodiments, the primary cell function assay is a primary cell function assay of neutrophils or monocytes enriched in human whole blood. In some embodiments, the primary cell function assay is a primary cell function assay of cynomolgus monkey whole blood.

[0191] 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 not less than about 60°C, about 65°C, about 66°C, about 67°C, about 68°C, about 69°C, about 70°C, about 71°C, about 72°C, about 73°C, about 74°C, about 75°C, about 76°C, about 77°C, about 78°C, about 79°C, about 80°C, about 85°C, or about 90°C. In some embodiments, the provided TREM1 antibody agent is characterized by having a melting temperature of about 74°C. In some embodiments, differential scanning fluorometry is used to assess the melting temperature of the antibody agent.

[0192] In some implementations, the provided TREM1 antibody agents are characterized by their ability to antagonize TREM1-mediated inhibition of monocyte maturation into macrophages.

[0193] In some embodiments, the provided TREM1 antibody agent is characterized by its ability to bind inactive TREM1. In some embodiments, the provided TREM1 antibody agent is characterized by its ability to bind 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 both inactive and activated TREM1. Without wishing to be bound by any particular theory, it is believed that TREM1 activation leads to a conformational change in TREM1. In some embodiments, the provided TREM1 antibody agent is characterized by its ability to bind TREM1 in multiple conformational states.

[0194] In some embodiments, the provided TREM1 antibody agent is characterized by its non-binding to the surface of cells that do not express TREM1. In some embodiments, such cells may be human cells or cynomolgus monkey cells. Without wishing to be bound by any particular theory, it is believed that cells that typically do not express TREM1 include, but are not limited to, B cells, T cells, and NK cells. In some embodiments, the provided TREM1 antibody agent is characterized by its non-binding to the cell surface of B cells. In some embodiments, the provided TREM1 antibody agent is characterized by its non-binding to the cell surface of T cells. In some embodiments, the provided TREM1 antibody agent is characterized by its non-binding to the cell surface of NK cells.

[0195] In some embodiments, the provided TREM1 antibody agents are characterized by their ability to inhibit epithelial barrier damage induced by TREM1 and / or one or more TREM1 inflammatory mediators. For example, in some embodiments, the TREM1 antibody agents of this disclosure inhibit epithelial barrier damage induced by one or more TREM1-amplified cytokines (e.g., TNFα, IL-6, IL-8, and IL-1β). In some embodiments, the provided TREM1 antibody agents are characterized by their ability to inhibit epithelial barrier damage induced by TREM1-soluble factors associated with epithelial cell apoptosis (e.g., TWEAK and TRAIL).

[0196] 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 or comprises human IgG. In some embodiments, the provided TREM1 antibody agent is or comprises human IgG1k. In some embodiments, the provided TREM1 antibody agent comprises a mutant Fc backbone. In some embodiments, the provided TREM1 antibody agent comprises a mutant Fc backbone with reduced binding to the Fc receptor. In some embodiments, the TREM1 inhibitor is or comprises an anti-TREM1 chimeric antibody.

[0197] In some embodiments, the TREM1 antibody agent disclosed herein competes with a reference TREM1 antibody agent for binding to TREM1. In some embodiments, such a reference TREM1 antibody agent is or comprises an anti-TREM1 antibody as described in any one of WO2013 / 120553, WO2016 / 009086, WO2017 / 152102, WO2019 / 195126, WO2020 / 0163564, WO2021 / 011681, WO2021 / 011678, WO2022 / 233764, WO2022 / 253991, and WO2022 / 272018.

[0198] In some embodiments, the TREM1 antibody agent of this disclosure may be an immunoglobulin (e.g., IgG1, IgG2, IgG3, or IgG4), a heterodimer, Crossmab, DVD-Ig, 2-in-1 IgG, IgG-sc-Fv, scFv-scFv, BiTE, DART, a biantibody, a Fab-scFv fusion, a Fab-Fab fusion, or a tandem antibody. In some embodiments, the TREM1 antibody agent of this disclosure may be a complete IgA, IgG, IgD, IgE, or IgM antibody; an antibody fragment; a single-domain antibody; a single-chain Fv; or a polypeptide containing antigen-binding specificity fused to an Fc domain.

[0199] In some embodiments, the TREM1 antibody agent of this disclosure contains a second binding specificity against an antigen other than human TREM1. For example, the second binding specificity may target another pro-inflammatory mediator or a protein expressed on the surface of immune cells.

[0200] In various embodiments, the provided TREM1 antibody agent is characterized by CDR sequences found in the variable region sequences of the heavy chain and / or light chain polypeptides, which are included herein as SEQ ID NO: 14 and 18, respectively. In many embodiments, the provided antibody agent comprises all three CDRs from one chain (i.e., heavy chain CDR 1, CDR 2, and CDR 3, or light chain CDR 1, CDR 2, and CDR 3, or both). Those skilled in the art will understand that different systems have been described for defining CDR sequences, such as those described, for example, in Lefranc et al., Dev. Comp. Immunol. 27(1):55-77 (2003), Kabat et al., J. Biol. Chem. 252, 6609-6616 (1977), and Kabat et al., Sequences of protein of immunological interest. (1991), Chothia et al., J. Mol. Biol. 196:901-917 (1987), and MacCallum et al., J. Mol. Biol. 262:732-745 (1996). Furthermore, those skilled in the art will be able to readily define and utilize those sequences contained in SEQ ID NO: 14 and 18 that constitute CDRs in those sequences.

[0201] This disclosure provides an antibody heavy chain and its binding portion (e.g., a variable domain or CDR), and also provides an antibody light chain and its binding portion (e.g., a variable domain or CDR). In some embodiments, the provided heavy chain or its binding portion may be used in conjunction with the provided light chain or its binding portion. Alternatively or additionally, in some embodiments, the provided heavy chain or its binding portion may be used with different light chains or their binding portions, and / or the provided light chain or its binding portion may be used with different heavy chains or their binding portions.

[0202] In many embodiments, the provided antibody heavy chain or its binding portion (e.g., a variable domain or CDR) is used in conjunction 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 frame regions.

[0203] In some embodiments, the TREM1 antibody agent provided by this disclosure 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 those in SEQ ID NO:15, 16, and 17, respectively. In some embodiments, the TREM1 antibody agent provided by this disclosure 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 those in SEQ ID NO:19 and 20, respectively, and a light chain CDR2 sequence of GAS. In some embodiments, the TREM1 antibody agent provided by this disclosure comprises heavy chain CDR1, CDR2, and CDR3 sequences that are 100% identical to those in SEQ ID NO:15, 16, and 17, respectively. In some embodiments, the TREM1 antibody agent provided in this disclosure comprises light chain CDR1 and CDR3 sequences that are 100% identical to those in SEQ ID NO: 19 and 20, respectively, and light chain CDR2 sequence of GAS.

[0204] In some embodiments, the provided TREM1 antibody agent comprises 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 comprises 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 comprises 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 comprises 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 comprises a heavy chain variable domain sequence having at least 95% sequence identity with SEQ ID NO: 14 or a portion thereof. In some embodiments, the provided TREM1 antibody agent comprises 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 contains the same heavy chain variable domain sequence as SEQ ID NO: 14 or a portion thereof.

[0205] In some embodiments, the provided TREM1 antibody agent comprises 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 comprises 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 comprises 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 comprises 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 comprises a light chain variable domain sequence having at least 95% sequence identity with SEQ ID NO: 18 or a portion thereof. In some embodiments, the provided TREM1 antibody agent comprises 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 contains the same light chain variable domain sequence as SEQ ID NO: 18 or a portion thereof.

[0206] In some embodiments, the provided TREM1 antibody agent comprises a heavy chain variable domain sequence having at least 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with SEQ ID NO: 14, and a light chain variable domain sequence having at least 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with SEQ ID NO: 18. In some embodiments, the provided TREM1 antibody agent comprises 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.

[0207] 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 with 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 with SEQ ID NO: 18. In some embodiments, the provided TREM1 antibody agent is an scFv antibody that contains 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.

[0208] In some embodiments, the heavy and / or light chains of the TREM1 antibody agent of this disclosure may contain no more than one, two, three, four, or five amino acid sequence differences relative to SEQ ID NO: 14 and / or SEQ ID NO: 18, respectively.

[0209] In some embodiments, the heavy chain of the TREM1 antibody agent of this disclosure may contain one, two, three or four frame regions (FR regions) that have a total identity of at least 85%, 90%, 95%, 96%, 97%, 98% or 99% with those regions found in SEQ ID NO: 14; and / or contain no more than one, two, three, four or five amino acid sequence differences relative to those regions 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) comprising one, two, three, or four FR regions, each of which independently has an amino acid sequence that is or includes the amino acid sequence of one of SEQ ID NO: 21, 22, 23, or 24, having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with one of SEQ ID NO: 21, 22, 23, or 24, or having an amino acid sequence that differs from one of SEQ ID NO: 21, 22, 23, or 24 by no more than one, two, three, four, or five amino acid sequences.

[0210] In some embodiments, the light chain of the TREM1 antibody agent of this disclosure may contain one, two, three or four frame regions (FR regions) that have a total identity of at least 85%, 90%, 95%, 96%, 97%, 98% or 99% with those regions found in SEQ ID NO: 18; and / or contain no more than one, two, three, four or five amino acid sequence differences relative to those regions found in SEQ ID NO: 18.

[0211] In some embodiments, the light chain of the TREM1 antibody agent of this disclosure may contain one, two, three or four frame regions (FR regions) that have a total identity of at least 85%, 90%, 95%, 96%, 97%, 98% or 99% with those regions found in SEQ ID NO: 18; and / or contain no more than one, two, three, four or five amino acid sequence differences relative to those regions found in SEQ ID NO: 18. In some embodiments, the light chain of the TREM1 antibody agent of this disclosure may include a variable region (VL) comprising one, two, three, or four FR regions, each of which independently has an amino acid sequence that is or includes the amino acid sequence of one of SEQ ID NO: 25, 26, 27, or 28, having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with one of SEQ ID NO: 25, 26, 27, or 28, or having an amino acid sequence that differs from one of SEQ ID NO: 25, 26, 27, or 28 by no more than one, two, three, four, or five amino acid sequences.

[0212] In some embodiments, the provided TREM1 antibody agent comprises at least one constant region (CH), such as a CH1 region, a CH2 region, and / or a CH3 region. In some embodiments, the provided TREM1 antibody agent comprises a CH2 region and a CH3 region, such as 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 immunoglobulin isotypes (e.g., IgA, IgG, IgM, or IgE). In some embodiments, the provided TREM1 antibody agent comprises an IgG1, IgG2, IgG3, or IgG4 Fc domain. For example, in some embodiments, the TREM1 antibody agent provided in this disclosure comprises an IgG1 Fc domain. In some embodiments, the IgG1 Fc domain comprises a polypeptide 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% sequence identity with SEQ ID NO:29 or a portion thereof.

[0213] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 29) In some embodiments, the Fc domain is a wild-type Fc domain, such as the wild-type human Fc domain. In some embodiments, the Fc domain includes variants, such as Fc domains comprising the addition, substitution, or deletion of at least one amino acid residue in the Fc region, which results in, for example, a reduced or weakened affinity for at least one Fc receptor.

[0214] The Fc domain of an antibody interacts with a variety of receptors or ligands, including Fc receptors (e.g., FcγRI, FcγRIIA, FcγRIIIA), complement protein C1q, and other molecules such as proteins A and G. These interactions are crucial for a variety of effector functions and downstream signaling events, including antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC).

[0215] 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 C1q complement. In some embodiments, the reduction of any or all of properties (1)-(3) is compared with other similar antibodies having a wild-type Fc region. In some embodiments, the TREM1 antibody agent comprising the variant Fc region has reduced affinity for human Fc receptors (e.g., FcγRI, FcγRII, and / or FcγRIII) or complement components (e.g., C1q). Exemplary Fc region variants are known in the art.

[0216] 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 by PVA (“PVAdelG”). In some embodiments, the provided TREM1 antibody agent comprises 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 SEQ ID NO: 30 or a portion thereof. In some embodiments, the provided TREM1 antibody agent contains the same IgG1 Fc domain sequence as SEQ ID NO: 30 or a portion thereof.

[0217] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 30) In some embodiments, the provided TREM1 antibody agent comprises a heavy chain sequence having at least 60% sequence identity with SEQ ID NO: 31 or a portion thereof. In some embodiments, the provided TREM1 antibody agent comprises 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 comprises 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 comprises 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 comprises 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 comprises 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 comprises the same heavy chain as SEQ ID NO: 31 or a portion thereof.

[0218] In some embodiments, the TREM1 antibody agent comprises a light chain constant region (CL). For example, such a light chain CL may comprise κCL or λCL. In some embodiments, the κCL has an amino acid sequence that is or 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 no more than 5, 10, or 20 amino acid differences relative to SEQ ID NO: 32.

[0219] RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 32) In some embodiments, the provided TREM1 antibody agent comprises 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 comprises 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 comprises 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 comprises 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 comprises 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 comprises a light chain identical to SEQ ID NO: 33 or a portion thereof.

[0220] In some embodiments, the provided TREM1 antibody agent comprises a heavy chain sequence having at least 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with SEQ ID NO: 31, and a light chain sequence having at least 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with SEQ ID NO: 33. In some embodiments, the provided TREM1 antibody agent comprises a heavy chain sequence having 100% sequence identity with SEQ ID NO: 31, and a light chain sequence having 100% sequence identity with SEQ ID NO: 33.

[0221] In some embodiments, the provided TREM1 antibody agent comprises two heavy chains, each having a sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to that of SEQ ID NO: 31, and two light chains, each having a sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to that of SEQ ID NO: 33. In some embodiments, the provided TREM1 antibody agent comprises two heavy chains, each having a sequence that is 100% identical to that of SEQ ID NO: 31, and two light chains, each having a sequence that is 100% identical to that of SEQ ID NO: 33.

[0222] 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. In some embodiments, the provided TREM1 antibody agent consists of the heavy chain of SEQ ID NO: 31 and the light chain of SEQ ID NO: 33, or humanized variants thereof.

[0223] In some embodiments, the heavy and / or light chains of the TREM1 antibody agent of this disclosure may contain no more than one, two, three, four, or five amino acid sequence differences relative to SEQ ID NO: 31 and / or SEQ ID NO: 33, respectively.

[0224] Table 2 below provides exemplary TREM1 antibody drug sequences of this disclosure.

[0225] Table 2: Exemplary TREM1 antibody drug sequences TREM1 combination therapy In some implementations, inflammatory diseases, disorders, or conditions can be treated with a combination of a TREM1 antibody agent and another anti-inflammatory therapeutic agent. For example, in some implementations, a TREM1 antibody agent may be combined with one or more alternative anti-inflammatory therapies that do not target TREM1 for the treatment of inflammatory diseases, disorders, or conditions. Such alternative anti-inflammatory therapies may include, but are not limited to, anti-TNFα agents, α4 integrin targets (e.g., natezumab), α4β7 integrin targets (e.g., vedolzumab), 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., ozamod and ectremod).

[0226] In some embodiments, inflammatory diseases, disorders, or conditions can be treated with a combination of TREM1 antibody agents and integrin inhibitors, and specifically, with the administration of an integrin inhibitor (i.e., by integrin inhibition therapy). In some embodiments, the integrin inhibitor is or includes an anti-integrin agent. In some embodiments, the anti-integrin agent is or includes an α4 integrin target (e.g., nastatinumab). In some embodiments, the anti-integrin agent is or includes an α4β7 integrin target (e.g., vedolizumab).

[0227] In some embodiments, inflammatory diseases, disorders, or conditions can be treated with a combination of TREM1 antibody agents and activation of the sphingosine 1-phosphate receptor (S1PR), and specifically, with the administration of an S1PR agonist. In some embodiments, the S1PR agonist is or includes ozamod. In some embodiments, the S1PR agonist is or includes ezetimibe.

[0228] In some implementations, inflammatory diseases, disorders, or conditions can be treated with a combination of TREM1 antibody agents and TNFα inhibitors, and more specifically, with the administration of TNFα inhibitors (i.e., through TNFα inhibition therapy). In some implementations, TNFα inhibitors are or include anti-TNFα agents. Examples of anti-TNFα agents approved for use in the United States include monoclonal antibodies, such as adalimumab (Humira). ® ), Cimiza (Cisole) ® ), simponi ® ), Infliximab (Remicade ® ), and bait-circulating receptor fusion proteins, such as etanercept (Enbrel) ®These agents are currently approved for the treatment of indications such as juvenile idiopathic arthritis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, adult Crohn's disease, pediatric Crohn's disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa, and uveitis. In some implementations, the anti-TNFα agent is a biosimilar of an approved anti-TNFα agent.

[0229] In some embodiments, the TNFα inhibitor inhibits TNFα. In some embodiments, the TNFα inhibitor specifically and / or selectively inhibits TNFα. In some embodiments, the TNFα inhibitor is or comprises an anti-TNFα antibody agent. In some embodiments, the TNFα inhibitor is or comprises an anti-TNFα antibody. In some embodiments, the TNFα inhibitor is or comprises an anti-TNFα monoclonal antibody. In some embodiments, the TNFα inhibitor is or comprises an anti-TNFα humanized antibody. In some embodiments, the TNFα inhibitor is or comprises an anti-TNFα chimeric antibody.

[0230] This disclosure also provides immunoconjugates comprising, as described herein, a TREM1 antibody agent or a portion thereof, conjugated to an anti-inflammatory agent, a cytotoxic agent (e.g., a chemotherapeutic agent), a toxin (e.g., an enzyme-active toxin of bacterial, fungal, plant or animal origin or a fragment thereof), and / or a diagnostic agent (e.g., a radioisotope, etc.).

[0231] Nucleic acid Among other things, this disclosure provides nucleic acids encoding the TREM1 antibody agent described herein or the polypeptides (e.g., LC polypeptides and / or HC polypeptides) provided herein. This disclosure includes polynucleotides encoding one or more heavy chains, VH domains, heavy chain FRs, heavy chain CDRs, heavy chain constant domains, light chains, VL domains, light chain FRs, light chain CDRs, light chain constant domains, or other immunoglobulin-like sequences, antibodies, or antigen-binding fragments thereof disclosed herein. Such nucleic acids may be present in a vector. Such nucleic acids may be present in the genome of a cell, such as a cell of a subject requiring treatment or a cell used to produce antibodies, such as mammalian cells used to produce the antibody agent described herein or the polypeptides (e.g., LC polypeptides and / or HC polypeptides) provided herein.

[0232] Nucleic acids encoding antibody agents or peptides (e.g., LC peptides and / or HC peptides) provided herein can be modified to include codons optimized for expression in a specific cell type or organism. The codon-optimized sequence is a synthetic sequence and preferably encodes the same peptide (or a bioactive fragment of a full-length peptide having substantially the same activity as the full-length peptide) encoded by a non-codon-optimized reference nucleic acid. Codon optimization can be performed by commercial antibody development suppliers (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 agents described herein or peptides (e.g., LC peptides and / or HC peptides) may contain, wholly or partially, altered sequences to optimize codon usage for a specific cell type (e.g., eukaryotic or prokaryotic cells). For example, the coding sequence for the humanized heavy chain (or light chain) variable region as 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.

[0233] In some embodiments, this disclosure provides a single nucleic acid (e.g., DNA or RNA) encoding a heavy chain variable domain and a light chain variable domain of a TREM1 antibody agent. In some embodiments, this disclosure provides a single nucleic acid encoding a heavy chain variable domain and a light chain variable domain, the 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 that of SEQ ID NO: 14, and the 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 that of SEQ ID NO: 18. In some embodiments, the nucleic acid has a nucleotide sequence that is or includes 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 the nucleotide sequence of SEQ ID NO: 38 and / or SEQ ID NO: 39.

[0234] In some embodiments, this disclosure provides a single nucleic acid (e.g., DNA or RNA) encoding the heavy and light chains of a TREM1 antibody agent. In some embodiments, this disclosure provides a single polynucleotide encoding the heavy and light chains, the 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 that of SEQ ID NO: 31, and the 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 that of SEQ ID NO: 33. In some embodiments, such nucleic acid has a nucleotide sequence that is or includes 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 the nucleotide sequence of SEQ ID NO: 43.

[0235] In some embodiments, this disclosure provides compositions comprising two or more nucleic acids (e.g., DNA or RNA), wherein one nucleic acid encodes a TREM1 antibody drug heavy chain variable domain and another nucleic acid encodes a TREM1 antibody drug 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 that of 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 that of SEQ ID NO: 18. In some embodiments, the nucleic acid encoding the variable domain of the heavy chain of the TREM1 antibody drug has a nucleotide sequence that is or includes at least 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence in SEQ ID NO: 38. In some embodiments, the nucleic acid encoding the variable domain of the light chain of the TREM1 antibody drug has a nucleotide sequence that is or includes at least 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence in SEQ ID NO: 39.

[0236] In some embodiments, this disclosure provides compositions comprising two or more nucleic acids (e.g., DNA or RNA), wherein one nucleic acid encodes a TREM1 antibody drug heavy chain and another nucleic acid encodes a TREM1 antibody drug light chain. In some embodiments, such a composition comprises: a nucleic acid encoding a heavy chain having a sequence identical to at least 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of that in SEQ ID NO: 31; and another nucleic acid encoding a light chain having a sequence identical to at least 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of that in SEQ ID NO: 33. In some embodiments, the nucleic acid encoding the TREM1 antibody drug heavy chain has a nucleotide sequence that is or includes at least 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence in SEQ ID NO: 42. In some embodiments, the nucleic acid encoding the TREM1 antibody drug heavy chain has a nucleotide sequence that is or includes at least 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence in SEQ ID NO: 43.

[0237] In some embodiments, this disclosure provides two or more compositions, wherein one composition comprises a nucleic acid encoding a heavy chain variable domain of a TREM1 antibody drug, and another composition comprises a nucleic acid encoding a light chain variable domain of a TREM1 antibody drug. 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 that of SEQ ID NO: 14, and the other 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 that of SEQ ID NO: 18. In some embodiments, the nucleic acid encoding the variable domain of the heavy chain of the TREM1 antibody drug has a nucleotide sequence that is or includes at least 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence in SEQ ID NO: 38. In some embodiments, the nucleic acid encoding the variable domain of the light chain of the TREM1 antibody drug has a nucleotide sequence that is or includes at least 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence in SEQ ID NO: 39.

[0238] In some embodiments, this disclosure provides two or more compositions, wherein one composition comprises a nucleic acid encoding a heavy chain of a TREM1 antibody drug, and another composition comprises a nucleic acid encoding a light chain of a TREM1 antibody drug. 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 that of SEQ ID NO: 31, and the other 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 that of SEQ ID NO: 33. In some embodiments, the nucleic acid encoding the TREM1 antibody drug heavy chain has a nucleotide sequence that is or includes at least 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence in SEQ ID NO: 42. In some embodiments, the nucleic acid encoding the TREM1 antibody drug heavy chain has a nucleotide sequence that is or includes at least 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence in SEQ ID NO: 43.

[0239] Table 3 provides exemplary polynucleotide sequences of the heavy and light chains or portions thereof encoding the TREM1 antibody agent disclosed herein.

[0240] Table 3: Exemplary nucleic acid sequences encoding TREM1 antibody drugs In some embodiments, the sequence of one or more nucleic acids encoding the TREM1 antibody agent disclosed herein or a portion thereof (e.g., heavy chain, light chain, heavy chain variable domain, or light chain variable domain) is codon-optimized for expression in a subject (e.g., a human). The sequence of one or more nucleic acids may also be codon-optimized for a specific organ.

[0241] In short, codon optimization refers to methods of enhancing expression in a host cell of interest by modifying nucleotide sequences in such a way that at least one codon in the native sequence is replaced with a codon that is more frequently used in the host cell's genes (e.g., about 1, 2, 3, 4, 5, 10, 15, 20, 25, 50, 75, 100 or more codons), while maintaining the native amino acid sequence. Different species exhibit specific preferences for certain codons of particular amino acids. Codon bias (the difference in codon use between organisms) is generally associated with the translation efficiency of messenger RNA (mRNA), which depends at least in part on the characteristics of the codons being translated and the availability of specific transfer RNA (tRNA) molecules. The dominance of the selected tRNA in the cell broadly reflects the most frequently used codons in peptide synthesis. Therefore, genes can be tailored based on codon optimization to optimize gene expression in a given organism. Codon usage tables are readily available, for example, in the “Codon Usage Database” at www.kazusa.or.jp / codon / , and these tables can be modified in various ways. See, for example, Nakamura, Y. et al., “Codon usage tabulated from the international DNA sequence databases: status for the year 2000”, Nucl. AcidsRes.28:292 (2000). Computer algorithms for codon optimization of specific sequences for expression in specific host cells are also available, such as Gene Forge (Aptagen; Jacobus, Pa.).

[0242] Composition Among other things, this disclosure provides compositions comprising or 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 disclosed herein (e.g., TREM1 antibody agent) and one or more pharmaceutical excipients.

[0243] polymer composition Among other things, this disclosure provides compositions comprising a TREM1 antibody agent or a portion thereof (e.g., a heavy chain, a light chain, a heavy chain variable domain, or a light chain variable domain) or encoding one or more nucleic acids of a TREM1 antibody agent or a portion thereof, and one or more polymers to 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, polylactic acid, glycolide-L(-)lactide, poly(ε-caprolactone, poly(ε-caprolactone-CO-lactic acid), poly(ε-caprolactone-CO-glycolic acid), poly(β-hydroxybutyric acid), polyoxyethylene, polyethylene, poly(alkyl cyanoacrylate), poly(hydroxyethyl methacrylate), polyamide, poly(amino acid), poly(2-hydroxyethyl DL-asparagine), poly(urea ester), poly(L-phenylalanine / ethylene glycol / 1,6-diisocyanate hexane), or poly(methyl methacrylate).

[0244] Among other things, this disclosure provides a composition comprising microspheres, microparticles, nanoparticles, nanospheres, or liposomes of nucleic acids encapsulating heavy chain and light chain variable domains encoding a TREM1 antibody agent.

[0245] Among other things, this disclosure provides a composition comprising microspheres, microparticles, nanoparticles, nanospheres, or liposomes encapsulating at least two nucleic acids, wherein one nucleic acid encapsulates a heavy chain variable domain of a TREM1 antibody agent, and the other nucleic acid encapsulates a light chain variable domain of a TREM1 antibody agent. Among other things, this disclosure provides a composition comprising microspheres, microparticles, nanoparticles, nanospheres, or liposomes encapsulating at least two nucleic acids, wherein one nucleic acid encapsulates a heavy chain of a TREM1 antibody agent, and the other nucleic acid encapsulates a light chain of a TREM1 antibody agent.

[0246] Among other things, this disclosure provides at least two compositions, one of which comprises microspheres, microparticles, nanoparticles, nanospheres, or liposomes encapsulating the heavy chain variable domain of a TREM1 antibody agent, and the other composition comprises microspheres, microparticles, nanoparticles, nanospheres, or liposomes encapsulating the light chain variable domain of a TREM1 antibody agent. Among other things, this disclosure provides at least two compositions, one of which comprises microspheres, microparticles, nanoparticles, nanospheres, or liposomes encapsulating the heavy chain of a TREM1 antibody agent, and the other composition comprises microspheres, microparticles, nanoparticles, nanospheres, or liposomes encapsulating the light chain of a TREM1 antibody agent. Among other things, at least two compositions are delivered to cells simultaneously. Among other things, at least two compositions are delivered to cells at different times.

[0247] Viral Composition Among other things, this disclosure provides compositions for delivering one or more nucleic acids encoding a TREM1 antibody agent 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, such as vaccinia, fowlpox, self-replicating alpha virus, marabavirus, adenovirus (see, for example, Tatsis et al., Adenoviruses, Molecular Therapy (2004) 10, 616-629), lentiviruses (including, but not limited to, second-generation, third-generation, or second / third-generation hybrid lentiviruses), and any generation of recombinant lentiviruses designed to target specific cell types or receptors (see, for example, Hu et al., Immunization Delivered by Lentiviral Vectors for Cancer and Infectious Diseases, Immunol Rev. (2011) 239(1): 45-61, Sakuma et al., Lentiviral vectors: basic to translational, Biochem J. (2012)). 443(3):603-18, Cooper et al., Rescue of splitting-mediated intron loss maximizes expression in lentiviral vectors containing the human ubiquitin C promoter, Nucl. Acids Res. (2015) 43 (1): 682-690, Zufferey et al., Self-Inactivating Lentivirus Vector for Safe and Efficient In Vivo Gene Delivery, J. Virol. (1998) 72 (12): 9873-9880), or adeno-associated virus (“AAV”) vectors, such as US Patent No. 5,173,414; Tratschin et al., Mol. Cell. Biol. 5:3251-3260 (1985); Tratschin et al., Mol. Cell, Biol. 4:2072-2081 (1984); Hermonat and Muzyczka, PNAS 81:64666470 (1984); and more detailed in Samuiski et al., J. Virol.63:03822-3828 (1989).As is well understood by those skilled in the art, in order to promote cell expression of an antibody drug or a portion thereof, viral delivery of one or more nucleic acids encoding an antibody drug or a portion thereof may involve genome editing, such as by using nuclease-based genome editing systems (e.g., genome editing systems based on clustered regularly spaced short palindromic repeats (CRISPR), transcription activator-like effector nucleases (TALENs), zinc finger nucleases (ZFNs), and homing endonuclease (HE)-based genome editing systems or derivatives thereof).

[0248] Pharmaceutical Composition Among other things, this disclosure provides pharmaceutical compositions comprising or otherwise delivering a TREM1 antibody agent; typically, such pharmaceutical compositions comprise 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, ed., Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Co. (Easton, Pa.) 1990.

[0249] When “therapeutic effective amount” or “immunologic effective amount” is indicated, the precise amount of a pharmaceutical composition containing or delivering the TREM1 antibody agent described herein may be determined by a physician taking into account, for example, individual differences in the patient’s (subject’s) age, weight, immune response, and condition.

[0250] In some embodiments, the pharmaceutical compositions described herein may comprise a pharmaceutically acceptable carrier selected for suitability in terms of administration mode, solubility, and / or stability against 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 a nucleic acid encoding the TREM1 antibody agent or a portion thereof.

[0251] In some embodiments, the pharmaceutical compositions described herein may comprise excipients and additives, including but not limited to proteins, peptides, amino acids, lipids, and carbohydrates (e.g., sugars, including monosaccharides, disaccharides, trisaccharides, tetrasaccharides, and oligosaccharides; derivatized sugars, such as sugar alcohols, aldonic acids, esterified sugars, etc.; and polysaccharides or sugar polymers), which may be present alone or in combination, comprising 1% to 99.99% of the total weight or volume, alone or in combination. Exemplary protein excipients include serum albumin, such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, etc. Representative amino acid / antibody components that may also function in buffering capacity include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, etc. Carbohydrate excipients suitable for the compositions of this disclosure include, for example, monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbitol, etc.; disaccharides such as lactose, sucrose, trehalose, cellobiose, etc.; polysaccharides such as raffinose, melitriose, maltodextrin, dextran, starch, etc.; and sugar alcohols such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (sorbitol), and inositol. In some embodiments, the excipients or additives are polymeric excipients or additives, such as, but not limited to, polyvinylpyrrolidone, ficolls (polymeric sugars), 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).

[0252] In some embodiments, the pharmaceutical compositions described herein may comprise buffers, including neutral buffered saline or phosphate buffered saline (PBS); carbohydrates, such as glucose, mannose, sucrose, dextran, or mannitol; proteins, peptides, 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 (such as salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, and phthalic acid), Tris, tromethamine hydrochloride, and phosphate buffer. In some embodiments, the pharmaceutical composition is substantially free of contaminants, for example, there are no detectable levels of contaminants (e.g., endotoxins).

[0253] In some embodiments, the pharmaceutical compositions described herein may be administered in a manner suitable for treating or preventing a disease, disorder, or condition. In some embodiments, the amount 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 an appropriate dosage may be determined through clinical trials.

[0254] In some embodiments, the pharmaceutical compositions provided herein may be in the form of liquids, semi-solids, and solid dosage forms, such as liquid solutions (e.g., injectable and infusionable solutions), dispersions or suspensions, liposomes, and suppositories. Typically, pharmaceutical compositions containing or delivering antibody agents are injectable or infusionable solutions; in some such embodiments, such compositions may be formulated for intravenous, subcutaneous, intradermal, intratumoral, intralymphatic, intramedullary, intramuscular, transarterial, sublingual, intranasal, local, or intraperitoneal administration. In some embodiments, the provided pharmaceutical compositions are formulated for intravenous administration. In some embodiments, the provided pharmaceutical compositions are formulated for subcutaneous administration.

[0255] The pharmaceutical compositions described herein can be formulated for administration using infusion techniques known in the art (see, for example, Rosenberg et al., New Eng. J. of Med. 319:1676, 1988, which is incorporated herein by reference).

[0256] In some embodiments, the pharmaceutical composition described herein is administered in combination with (e.g., before, during, or after) other therapies for the symptoms, disease, or disorder (e.g., standard of care for the symptoms, disease, or disorder). In some embodiments, the pharmaceutical composition described herein may be administered before or after surgery.

[0257] In some implementations, the dosage of any of the above-described therapies to be administered to a subject will vary depending on the disease, disorder, or condition being treated and on a subject-specific basis. Dosage scaling for human administration may be performed in accordance with practices accepted in the art.

[0258] Disease, disability or ailment In general, the TREM1 antibody agents disclosed herein can be used in any situation where an anti-inflammatory therapy is covered or administered. In some embodiments, the TREM1 antibody agents of this disclosure can be used to treat subjects suffering from diseases, disorders, or conditions associated with abnormal (e.g., elevated) inflammation.

[0259] Other aspects of this disclosure relate to an isolated antibody agent that binds to the TREM1 protein as described herein, for the prevention, reduction of risk of, or treatment of an individual suffering from a disease, disorder, or injury selected from the following groups: chronic obstructive pulmonary disease (COPD), acute lung injury or acute respiratory distress syndrome (ARDS), post-stroke injury, post-myocardial infarction injury, ischemia-reperfusion injury, dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia, Creutzfeldt-Jakob disease (CJD). Diseases including: normal pressure hydrocephalus, amyotrophic lateral sclerosis (ALS), Huntington's disease, tau proteinosis, Nasu-Hakoia disease, 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, Behcet's disease, Parkinson's disease, Lewy body dementia, multiple system atrophy, and Shy-Drager syndrome. Syndrome), progressive supranuclear palsy, corticobasal degeneration, acute disseminated encephalomyelitis, granulomatous disorders, sarcoidosis, age-related diseases, seizures, spinal cord injury, traumatic brain injury, age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, respiratory infections, sepsis, eye infections, systemic infections, lupus, arthritis, multiple sclerosis, low bone density, osteoporosis, osteogenesis imperfecta, osteosclerotic diseases, Paget's disease, bladder cancer, brain cancer (e.g., gliomas, such as low-grade gliomas or glioblastomas);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's 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 thrombocythemia, fibrosis, primary or idiopathic myelofibrosis, primary or idiopathic myelosclerosis, myeloid-derived tumors, thyroid cancer, infections, CNS herpes, parasitic infections, trypanosomiasis infections, Trypanosoma krusei infections, Pseudomonas aeruginosa infections, Leishmania donovani infections, arthropathy, Lyme arthritis, Group B streptococcal infections, Campylobacter jejuni. Infections including Neisseria meningitidis, HIV type I, and Haemophilus influenzae. In some embodiments, this isolated antibody agent is the antibody agent described herein.

[0260] Inflammatory bowel disease (IBD) Inflammatory bowel disease (IBD) is a group of chronic inflammatory conditions affecting the gastrointestinal tract, in which bacterial dysbiosis and epithelial barrier dysfunction play major roles in the pathogenesis of the disease. Specifically, bacterial components have been reported to bind to a range of receptors, including Toll-like receptors (TLRs), and induce various pathways and mechanisms that increase intestinal inflammation. IBD can affect other parts of the body, such as joints, skin, bones, eyes, kidneys, and liver, which is often referred to as extraintestinal manifestations (EIMs) of IBD. Anemia is another EIM of IBD. IBD typically manifests in early adulthood, and the relapsing / remission nature of the condition has been shown to adversely affect the quality of life of subjects. Ulcerative colitis (UC) and Crohn's disease (CD) are two major forms of IBD. UC affects the mucosa and submucosa of the colon, with continuous lesions, in which crypt abscesses are often found. CD is a transmural disease that leads to complications such as anal fissures, fistulas, stenosis, and linear fissures, which can result in intestinal obstruction. TREM1 and its associated downstream effects have been shown to be associated with IBD.

[0261] Among other things, this disclosure provides the following insight: monocytes and neutrophils expressing TREM1 are enriched in inflamed intestinal tissue of IBD (e.g., compared to healthy tissue, non-inflammatory IBD tissue, and PBMCs from IBD patients). Bacterial invasion following epithelial barrier dysfunction releases bacterial peptidoglycan (PGN) into the intestinal mucosa or tissue, leading to activation of TLRs on endogenous neutrophils and myeloid cells (e.g., monocytes). PGN-activated monocytes and neutrophils generate an initial immune response by releasing various inflammatory cytokines (e.g., IL-23, TNFα, IL-6, IL-1β, etc.). PGN-activated neutrophils exhibit increased secretion of PGLYRP1, which, in combination with PGN, can further activate TREM1 on neutrophils and monocytes, leading to an amplified immune response, including the amplified production of pro-inflammatory cytokines and chemokines, thereby flooding affected tissues with increased levels of inflammatory cytokines and chemokines (e.g., IL-23, TNFα, IK-6, IL-1β, etc.).

[0262] Without being bound by any particular theory, this disclosure provides the following insight: the inhibition of neutrophils and myeloid cells (e.g., monocytes) in the intestines of IBD patients by TREM1 can preserve the innate antibacterial response while disrupting the chronic cycle of amplified immune responses. In some embodiments, such TREM1 inhibitors (e.g., the TREM1 antibody agents disclosed herein) can simultaneously reduce multiple pro-inflammatory cytokines (e.g., IL-23, TNFα, IK-6, IL-1β, etc.) and / or prevent further epithelial barrier damage mediated by cytokines.

[0263] Currently, there are various therapies available for treating IBD, including anti-inflammatory aminosalicylate and corticosteroids, immunosuppressants, antibiotics, and biologics. However, many patients do not fully respond to conventional treatments, and / or treatment may lose its effectiveness over time. Approved therapies, such as the anti-TNFα antibody adalimumab (Humira), offer alternative treatment options. ® This therapy blocks downstream inflammatory cytokines, which amplify IBD pathology. However, such therapies are not effective in all patients; some patients have shown only a partial or no response to adalimumab administration.

[0264] Without being bound by specific theories, current therapies may not adequately address the primary sources of amplified inflammatory responses (e.g., activation of inflammatory monocytes and / or neutrophils). Specifically, it is possible that isolation of TNFα alone does not limit the production and action of other downstream inflammatory mediators (e.g., cytokines, chemokines, etc.) that contribute to additional inflammatory damage, including damage to the intestinal epithelial barrier. There is a current need to develop therapies that can robustly treat IBD and other inflammatory conditions. This disclosure provides the insight that such therapies can target certain cellular and / or cellular receptors that may trigger unwanted inflammatory responses, thereby reducing downstream effects, including amplified immune responses. In some embodiments, such improved therapies may be applicable to a wider range of subjects and / or provide improved reductions in disease impact / pathology compared to reference (e.g., conventional or alternative therapies, such as, for example, adalimumab). In some embodiments, such improved therapies can inhibit TREM1 and corresponding TREM1-activated inflammatory / immune responses (e.g., prevent the production of TREM1-activated inflammatory mediators).

[0265] Among other things, this disclosure provides a TREM1 antibody agent for treating IBD, a nucleic acid encoding the agent, and compositions thereof. For example, the TREM1 antibody agent, the nucleic acid encoding the agent, and compositions thereof can be used for, but are not limited to, 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 fibrous stricture Crohn's disease, and / or immune checkpoint therapy (ICT)-induced Crohn's disease. In some embodiments, treatment of Crohn's disease may include treatment of Crohn's disease-related complications, which may include, but are not limited to, fibrous stricture diseases and / or fistula diseases.

[0266] Treatment The compositions and antibody agents disclosed herein can be used to treat diseases associated with TREM1-expressing cells and / or any downstream inflammatory mediators triggered by TREM1 activation. In some embodiments, the disease to be treated may be selected from any disease, disorder, or condition disclosed herein. In some embodiments, the disease 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). In some embodiments, the subject to be treated is a mammal (e.g., an adult or a human child).

[0267] In some embodiments, the treatment method includes assessing the presence of one or more biomarkers of the disease of interest (e.g., IBD) in the subject, and then administering a corresponding treatment (e.g., a TREM1 antibody agent). In other embodiments, the treatment method includes assessing the presence of one or more biomarkers of IBD in the subject (e.g., neutrophil density / location, PGLYRP1 level, calprotectin, sTREM1, etc.), and then administering a corresponding treatment (e.g., a TREM1 antibody agent).

[0268] In some embodiments, the treatment method includes the step of administering a pharmaceutical composition disclosed herein (e.g., a TREM1 antibody pharmaceutical composition). In some embodiments, the treatment method includes the step of administering a pharmaceutical composition comprising a TREM1 antibody pharmaceutical composition to a subject via a route of administration known in the art. In some embodiments, the treatment method includes the step of administering a pharmaceutical composition comprising a TREM1 antibody pharmaceutical composition intravenously to a subject. In some embodiments, the treatment method includes the step of administering a pharmaceutical composition comprising a TREM1 antibody pharmaceutical composition subcutaneously to a subject.

[0269] In some embodiments, the provided treatment method includes treating a subject with an inflammatory disease, disorder, or condition, wherein the subject is identified as having elevated levels of neutrophils (e.g., activated neutrophils) and / or monocytes (e.g., inflammatory monocytes). Typically, this assay is performed by evaluating 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, such as a sample of small intestinal tissue (e.g., duodenal tissue, jejunal tissue, or ileal tissue), large intestinal tissue (e.g., cecum, ascending colon, transverse colon, or descending colon), or rectal tissue. In some embodiments, the provided method includes treating the subject with a TREM1 antibody agent and / or composition as disclosed herein.

[0270] In some embodiments, the provided treatment methods include treating a subject with an inflammatory disease, disorder, or condition, wherein the subject is identified as having elevated levels of activated neutrophils and / or monocytes (e.g., inflammatory monocytes). For example, in some such embodiments, the subject is identified as having elevated levels of activated neutrophils and / or monocytes by measuring the expression of one or more biomarkers of activated neutrophils and / or monocytes and / or one or more biomarkers associated with activated neutrophils and / or monocytes (i.e., as substitutes for activated neutrophils and / or monocytes). In some embodiments, the provided methods include treating the subject with a TREM1 antibody agent and / or composition as disclosed herein.

[0271] In some implementations, a subject is identified as having elevated levels of activated neutrophils and / or monocytes by measuring, for example, the levels observed 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 (e.g., historical reference), one or more biomarkers of activated neutrophils and / or monocytes and / or biomarkers associated with activated neutrophils and / or monocytes (i.e., as substitutes for activated neutrophils and / or monocytes). In some embodiments, a subject is identified as having elevated levels of one or more activated neutrophil and / or monocyte biomarkers and / or one or more biomarkers associated with activated neutrophils and / or monocytes (i.e., as substitutes for activated neutrophils and / or monocytes) by comparing the levels observed in an appropriate reference population that does not have the disease, disorder, or condition (or is not in an active phase of such disease, disorder, or condition); in some such embodiments, the appropriate reference population is the general population.

[0272] In some embodiments, the provided treatment method includes treating a subject with an inflammatory disease, disorder, or condition, wherein the subject is predicted to respond to treatment with a TREM1 inhibitor, and the subject is treated with a TREM1 antibody agent and / or composition as disclosed herein. In some embodiments, a subject is predicted to respond to treatment with a TREM1 inhibitor when an elevated level of neutrophils and / or monocytes is determined 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, such as a sample of small intestinal tissue (e.g., duodenal tissue, jejunal tissue, or ileal tissue), large intestine (e.g., cecum, ascending colon, transverse colon, or descending colon), or rectal tissue. In some embodiments, a subject is predicted to respond to treatment with a TREM1 inhibitor when an elevated level of activated neutrophils and / or monocytes is determined. For example, in some embodiments, a subject is identified as having elevated levels of activated neutrophils and / or monocytes by measuring the expression of one or more biomarkers of activated neutrophils and / or monocytes and / or one or more biomarkers associated with activated neutrophils and / or monocytes (i.e., as substitutes for activated neutrophils and / or monocytes).

[0273] In some implementations, a subject is predicted to be responsive to treatment with a TREM1 inhibitor when the subject has elevated levels of one or more biomarkers of activated neutrophils and / or monocytes and / or one or more biomarkers associated with activated neutrophils and / or monocytes (i.e., as substitutes for activated neutrophils and / or monocytes) are determined to be responsive to treatment with a TREM1 inhibitor when the subject has elevated levels of activated neutrophils and / or monocytes, compared to levels observed 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 (e.g., a historical reference of the subject).

[0274] In some implementations, a subject is predicted to be responsive to treatment with a TREM1 inhibitor when the subject is determined to have elevated levels of one or more biomarkers of activated neutrophils and / or monocytes and / or one or more biomarkers associated with activated neutrophils and / or monocytes (i.e., as substitutes for activated neutrophils and / or monocytes) by measuring elevated levels of one or more biomarkers of activated neutrophils and / or monocytes compared to levels observed in an appropriate reference population that does not have the disease, disorder, or condition (or is not in an active phase of such disease, disorder, or condition); in some such implementations, the appropriate reference population is the general population.

[0275] In some embodiments, the provided treatment method includes treating the subject with a TREM1 antibody agent and / or composition as disclosed herein, based on the measurement level of one or more activated neutrophil and / or monocyte biomarkers and / or one or more biomarkers associated with activated neutrophils and / or monocytes (i.e., as substitutes for activated neutrophils and / or monocytes). In some embodiments, such a method includes treating the subject with a TREM1 antibody agent and / or composition as disclosed herein when such measurement levels are elevated compared to levels observed 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, such a method includes treating the subject with a TREM1 antibody agent and / or composition as disclosed herein when the determined level of one or more activated neutrophil and / or monocyte biomarkers and / or one or more biomarkers associated with activated neutrophils and / or monocytes is elevated compared to the level observed in an appropriate reference population that does not have a disease, disorder, or condition (or is not in an active phase of such disease, disorder, or condition); in some such embodiments, the appropriate reference population is the general population.

[0276] In some embodiments, the provided treatment methods include treating subjects with inflammatory diseases, disorders, or conditions who are resistant to and / or unresponsive to one or more alternative anti-inflammatory therapies that do not directly target TREM1 (e.g., TNFα inhibitor therapies). In some embodiments, the alternative anti-inflammatory therapy is or includes anti-inflammatory aminosalicylates and corticosteroids, immunosuppressants, antibiotics, and biologics (e.g., biologics that do not target TREM1). In some implementations, alternative anti-inflammatory therapies are or include TNFα inhibitors, Janus kinase (JAK) inhibitors (e.g., utpatinib, tofacitinib, and frigidinib), anti-integrin therapies (e.g., α4 integrin targets (e.g., natezumab) or α4β7 integrin targets (e.g., vedolizumab)), anti-IL23 therapies (e.g., guselkizumab, migezumab, and brecurumab); anti-IL-12 / 23 therapies (e.g., ustekinumab); anti-IL-23A therapies (e.g., ressazolidinumab); S1PR agonist or modulator therapies (e.g., ozamod and ectremod); and 5-aminosalicylate therapies (e.g., mesalazine). Therapeutic agents include: azithromycin, olsalazine, balsalazine, 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., litexicitinib), TYK2 inhibitor therapies (e.g., deuterocelexicitinib), anti-IL-36 therapies (e.g., sparsoribimab); anti-IL-13 therapies (e.g., dupilumab), miR-124 upregulatory therapies (e.g., obelafazmod), TLR9 agonist therapies (e.g., cobimod); or combinations thereof. In some embodiments, TNFα inhibitor therapy involves treatment with an anti-TNFα antibody agent. In some embodiments, TNFα inhibitor therapy includes treatment with adalimumab (Humira). ® ), Cimiza (Cisole) ® ), simponi ® ), Infliximab (Remicade ® ) or bait-circulating receptor fusion proteins (such as etanercept (Enbrel) ® Treatment can be administered using either their biosimilars or other similar products.

[0277] In some embodiments, the provided treatment methods include treating a subject with an inflammatory disease, disorder, or condition, wherein the subject is predicted to be resistant and / or unresponsive to TNFα inhibitor therapy. In some embodiments, the provided methods include treatment with a TREM1 antibody agent and / or composition as 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, pecelizumab, golimumab, infliximab, and / or etanercept. In some embodiments, the TNFα inhibitor is or includes a biosimilar of a TNFα inhibitor. In some embodiments, a subject is predicted to be resistant and / or unresponsive to TNFα inhibitor therapy when, for example, an assessment of a biological sample from the subject determines that the subject has elevated levels of neutrophils (e.g., activated neutrophils). In some embodiments, a subject is predicted to be resistant and / or unresponsive to TNFα inhibitor therapy when, for example, an assessment of a biological sample from the subject determines that the subject has elevated levels of neutrophils (e.g., activated neutrophils) and / or monocytes (e.g., inflammatory 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, such as a sample of small intestinal tissue (e.g., duodenal tissue, jejunal tissue, or ileal tissue), large intestine (e.g., cecum, ascending colon, transverse colon, or descending colon), or rectal tissue.

[0278] In some embodiments, when a subject is identified as having 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 (e.g., TNFα inhibitor therapies) that do not directly target TREM1. For example, in some embodiments, a subject is identified as having elevated levels of activated neutrophils and / or monocytes by measuring the expression of one or more biomarkers of activated neutrophils and / or monocytes and / or one or more biomarkers associated with activated neutrophils and / or monocytes (i.e., as substitutes for activated neutrophils and / or monocytes). In some embodiments, when a subject is determined to have elevated levels of one or more activated neutrophil and / or monocyte biomarkers and / or one or more biomarkers associated with activated neutrophils and / or monocytes (i.e., as 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 such disease, disorder, or condition (e.g., a historical reference for the subject), the subject is predicted to be resistant and / or unresponsive to one or more alternative anti-inflammatory therapies (e.g., TNFα inhibitor therapy) that do not directly target TREM1. In some embodiments, when a subject is determined to have elevated levels relative to levels observed in an appropriate reference population that does not have a disease, disorder, or condition (or is not in an active phase of such disease, disorder, or condition), the subject is predicted to be resistant and / or unresponsive to one or more alternative anti-inflammatory therapies (e.g., TNFα inhibitor therapy) that do not directly target TREM1. In some such embodiments, the appropriate reference population is the general population.

[0279] In some embodiments, the methods provided in this disclosure include identifying or characterizing subjects suffering from inflammatory diseases, disorders, or conditions, and determining subjects who are likely to respond to treatment with TREM1 antibody agents and / or compositions as disclosed herein (e.g., predicted to respond). In some embodiments, a subject is predicted to respond to treatment when an elevated level of neutrophils and / or monocytes is determined in a biological sample from that 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, such as a sample of small intestinal tissue (e.g., duodenal tissue, jejunal tissue, or ileal tissue), large intestine (e.g., cecum, ascending colon, transverse colon, or descending colon), or rectal tissue. In some embodiments, a subject is predicted to respond to treatment when an elevated level of activated neutrophils and / or monocytes is determined. In some embodiments, a subject is predicted to be responsive to treatment when, for example, an elevated level of one or more activated neutrophil and / or monocyte biomarkers and / or one or more biomarkers associated with activated neutrophils and / or monocytes (i.e., as substitutes for activated neutrophils and / or monocytes) is determined in comparison 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., a historical reference of the subject). In some embodiments, a subject is predicted to be responsive to treatment when an elevated level is determined in a suitable reference population that does not have a disease, disorder, or condition (or is not in an active phase of such disease, disorder, or condition); in some such embodiments, the suitable reference population is the general population.

[0280] In some embodiments, the methods provided in this disclosure include methods for monitoring the efficacy of treatment administered to a subject using a TREM1 antibody agent and / or composition as 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 activated neutrophils and / or monocytes (i.e., as 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 activated neutrophils and / or monocytes (i.e., as substitutes for activated neutrophils and / or monocytes) in the subject, for example, by measuring 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., a historical reference of the subject). In some embodiments, efficacy in subjects is monitored by measuring, for example, the levels of one or more activated neutrophil and / or monocyte biomarkers and / or one or more biomarkers associated with activated neutrophils and / or monocytes (i.e., as substitutes for activated neutrophils and / or monocytes) in a suitable reference population, such as those not suffering from the disease, disorder, or condition (or not in an active phase of such disease, disorder, or condition); in some such embodiments, the suitable reference population is the general population. In some embodiments, the provided treatment includes modifying the amount of anti-inflammatory therapy (e.g., TREM1 antibody agents and / or compositions as disclosed herein) administered to the subject based on the expression or expression level of one or more activated neutrophil and / or monocyte biomarkers and / or one or more biomarkers associated with activated neutrophils and / or monocytes (i.e., as substitutes for activated neutrophils and / or monocytes). In some embodiments, the provided treatment methods include the application of modified anti-inflammatory therapies (e.g., TREM1 antibody agents and / or compositions as disclosed herein) to target specific tissues expressing (or expressing elevated levels of) one or more activated neutrophil and / or monocyte biomarkers and / or biomarkers associated with activated neutrophils and / or monocytes (i.e., as alternatives to 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 tissue, jejunal tissue, or ileal tissue), large intestine (e.g., cecum, ascending colon, transverse colon, or descending colon), and / or rectal tissue that express (or express elevated levels of) one or more biomarkers of activated neutrophils and / or monocytes and / or one or more biomarkers associated with activated neutrophils and / or monocytes (i.e., as a substitute for activated neutrophils and / or monocytes).

[0281] In some embodiments of the provided treatment methods, the one or more biomarkers and / or biomarkers associated with activated neutrophils and / or monocytes (i.e., as alternatives to activated neutrophils and / or monocytes) are cell-based biomarkers. For example, in some embodiments, the cell-based biomarkers are blood and / or tissue neutrophil counts, monocyte counts, or neutrophil and monocyte counts. In some embodiments, the one or more activated neutrophil and / or monocyte biomarkers and / or biomarkers associated with activated neutrophils and / or monocytes (i.e., as alternatives to activated neutrophils and / or monocytes) are TREM1 RNA in monocytes and / or neutrophils. In some embodiments, the one or more activated neutrophil and / or monocyte biomarkers and / or one or more biomarkers associated with activated neutrophils and / or monocytes (i.e., as alternatives to activated neutrophils and / or monocytes) are TREM1 on the cell surface of monocytes and / or neutrophils.

[0282] In some embodiments of the provided treatment methods, the one or more activated neutrophil and / or monocyte biomarkers and / or one or more biomarkers associated with activated neutrophils and / or monocytes (i.e., as 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, the one or more activated neutrophil biomarkers and / or one or more biomarkers associated with activated neutrophils (i.e., as substitutes for activated neutrophils) are the presence of neutrophils in the lamina propria or in the epithelial layer of the subject. In some embodiments, the one or more activated neutrophil biomarkers and / or one or more biomarkers associated with activated neutrophils (i.e., as substitutes for activated neutrophils) are the presence of lymphocytes, plasma cells, and / or eosinophils in the lamina propria of the subject.

[0283] In some embodiments of the provided treatment, the one or more activated neutrophil biomarkers and / or one or more biomarkers associated with activated neutrophils (i.e., as substitutes for activated neutrophils) are neutrophil products. For example, in some embodiments, the neutrophil product is calprotectin, PGLYRP1, or soluble TREM1.

[0284] In some embodiments of the provided treatment, the one or more monocyte biomarkers and / or one or more monocyte-related (i.e., monocyte substitutes) biomarkers are monocyte products. For example, in some embodiments, the monocyte product is soluble TREM1.

[0285] In some embodiments of the provided treatment, the one or more biomarkers of activated neutrophils and / or monocytes and / or biomarkers associated with activated neutrophils and / or monocytes (i.e., as alternatives to activated neutrophils and / or monocytes) are TREM1 ligands. For example, in some embodiments, the TREM1 ligand is bacterial peptidoglycan (PGN) and / or PGLYRP1.

[0286] In some embodiments of the provided treatment, one or more biomarkers of activated neutrophils and / or monocytes and / or biomarkers associated with activated neutrophils and / or monocytes (i.e., as alternatives to activated neutrophils and / or monocytes) are TREM1 gene activation features.

[0287] In some embodiments of the provided treatment methods, the one or more activated neutrophil and / or monocyte biomarkers and / or one or more biomarkers associated with activated neutrophils and / or monocytes (i.e., as alternatives to activated neutrophils and / or monocytes) include any one or a combination of the following: neutrophil and / or monocyte counts detected in diseased tissue; TREM1 on the cell surface of monocytes and / or neutrophils in diseased tissue; TREM1 RNA in monocytes and / or neutrophils in diseased tissue; tissue biomarkers in diseased 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; TREM1 gene activation signature in diseased tissue and / or blood.

[0288] In some embodiments of the provided treatment methods, 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 a subject's blood sample, diseased tissue sample, fecal sample, their components or fractions or combinations thereof.

[0289] In some embodiments of the provided treatments, anti-inflammatory therapies (e.g., TREM1 antibody agents and / or compositions as disclosed herein) are specifically targeted to tissues expressing one or more biomarkers of activated neutrophils and / or monocytes and / or biomarkers associated with activated neutrophils and / or monocytes (i.e., as alternatives to activated neutrophils and / or monocytes). In some embodiments, anti-inflammatory therapy (e.g., TREM1 antibody agents and / or compositions as disclosed herein) is specifically targeted to tissues expressing elevated levels of one or more inflammatory biomarkers and / or one or more biomarkers associated with activated neutrophils and / or monocytes (i.e., as substitutes for activated neutrophils and / or monocytes) compared to the levels of one or more inflammatory biomarkers and / or one or more biomarkers associated with activated neutrophils and / or monocytes (i.e., as substitutes for activated neutrophils and / or monocytes). In some embodiments, anti-inflammatory therapies (e.g., TREM1 antibody agents and / or compositions as disclosed herein) are specifically targeted to tissues expressing elevated levels of one or more inflammatory biomarkers and / or biomarkers associated with activated neutrophils and / or monocytes (i.e., as 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 general population. For example, in some embodiments, the anti-inflammatory therapy is specifically targeted to small intestinal tissue (e.g., duodenal tissue, jejunal tissue, or ileal tissue), large intestine (e.g., cecum, ascending colon, transverse colon, or descending colon), and / or rectal tissue that express (or express elevated levels of) one or more biomarkers of activated neutrophils and / or monocytes and / or one or more biomarkers associated with activated neutrophils and / or monocytes (i.e., as a substitute for activated neutrophils and / or monocytes).

[0290] In some embodiments of the provided treatments, subjects suffering from inflammatory diseases, disorders, or conditions are treated with a combination of TREM1 antibody agents and / or compositions as disclosed herein 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 a combination of TREM1 antibody agents and / or compositions as disclosed herein 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 combination of a TREM1 inhibitor with adalimumab, pecelizumab, golimumab, infliximab, and / or etanercept.

[0291] In some embodiments, the TREM1 antibody agent or composition of this disclosure is administered to a subject who has received or is receiving alternative therapy. For example, in some embodiments, the alternative therapy is an alternative IBD therapy, such as anti-TNFα therapy (e.g., infliximab, adalimumab, golimumab, and pecelizumab); JAK inhibitor therapy (including selective and non-selective inhibitors) (e.g., utpatinib, tofacitinib, and fegortinib); anti-integrin therapy (e.g., vedolizumab and natezumab); anti-IL23 therapy (e.g., gusejinumab, migizumab, and brecurumab); anti-IL-12 / 23 therapy (e.g., ustekinumab); anti-IL-23A therapy (e.g., resalizumab); S1PR agonist or modulator therapy (e.g., ozamod and ectomod); 5-aminosalicylate therapy. Therapeutic agents include: (e.g., mesalazine, olsalazine, balsalazine, 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., litexicitinib), TYK2 inhibitor therapies (e.g., deuterocelexicitinib), anti-IL-36 therapies (e.g., sparsoribimab); anti-IL-13 therapies (e.g., dupilumab), miR-124 upregulatory therapies (e.g., oberazimod), TLR9 agonist therapies (e.g., cobimod); or combinations thereof.

[0292] Generation method The TREM1 antibody agent or a portion thereof disclosed herein can be produced using recombinant expression methods commonly known to those skilled in the art. For example, nucleic acids encoding the TREM1 antibody agent or a portion thereof are isolated and inserted into a reproducible vector for further cloning and amplification or for expression. DNA encoding the antibody or a portion thereof is isolated and sequenced using conventional procedures, e.g., by using oligonucleotide probes capable of specifically binding to genes encoding the heavy and light chains of the antibody. Various expression vectors can be used, and these expression vectors are known to those skilled in the art. The choice of vector may depend in part on the host cell to be used for expression. Typically, preferred host cells are of prokaryotic or eukaryotic (e.g., mammalian) origin. In some embodiments, the TREM1 antibody agent or a portion thereof is produced in bacterial cells, yeast cells, insect cells, or mammalian cells. In some embodiments, the TREM1 antibody agent or a portion thereof is produced in Chinese hamster ovary (CHO) cells. In some embodiments, the TREM1 antibody agent or a portion thereof is produced in cell-free systems as well known to those skilled in the art.

[0293] In some embodiments, the TREM1 antibody agent or a portion thereof described herein is characterized by its ability to produce at a concentration of at least 3000 mg / mL. In some embodiments, the TREM1 antibody agent or a portion thereof described herein is characterized by its ability to produce at concentrations of about 3.5 g / L, about 4 g / L, about 4.5 g / L, about 5 g / L, about 5.5 g / L, about 6 g / L, about 6.5 g / L, about 7 g / L, about 7.5 g / L, about 8 g / L, about 8.5 g / L, about 9 g / L, about 9.5 g / L, or about 10 g / L. In some embodiments, the TREM1 antibody agent or a portion thereof described herein is characterized by its ability to produce at concentrations of about 4.5 g / L, about 4.6 g / L, about 4.7 g / L, about 4.8 g / L, about 4.9 g / L, about 5 g / L, about 5.1 g / L, about 5.2 g / L, about 5.3 g / L, about 5.4 g / L, about 5.5 g / L, about 5.6 g / L, about 5.7 g / L, about 5.8 g / L, about 5.9 g / L, about 6.0 g / L, about 6.1 g / L, about 6.2 g / L, about 6.3 g / L, about 6.4 g / L, or about 6.5 g / L. In some embodiments, the TREM1 antibody agent or a portion thereof described herein is characterized by its ability to produce at concentrations of about 5.12 g / L, about 5.13 g / L, about 5.18 g / L, or about 5.7 g / L.

[0294] The compositions and antibody agents disclosed herein can be used to treat diseases, disorders, or conditions associated with TREM1-expressing cells and / or any downstream inflammatory mediators triggered by TREM1 activation. In some embodiments, the disease, disorder, or condition to be treated may be selected from those 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).

[0295] Detection of activated immune cells Circulating neutrophils are typically quiescent until activation is triggered, for example, by exposure to one or more external signals (e.g., pathogens, chemical signals, proteins, etc.). Not wishing to be bound by any particular theory, we note that neutrophils may undergo a multi-step activation process: entering a partially activated state upon exposure to one or more initial signals, and then entering a fully activated state upon exposure to one or more additional signals (which are interchangeably referred to herein as the “activated state”). Among other things, activated neutrophils can produce signaling molecules (e.g., cytokines, chemokines, degranulases, etc.) to elicit an amplified immune response in a subject.

[0296] Inflammatory monocytes sense their environment and can be activated by exposure to one or more external signals (e.g., pathogens, etc.). Inflammatory monocytes selectively transport to sites of inflammation, producing inflammatory cytokines and chemokines, and contributing to local and systemic inflammation. Not wishing to be bound by any particular theory, we note that inflammatory monocytes may undergo a multi-step activation process: entering a partially activated state upon exposure to one or more initial signals, and then entering a fully activated state upon exposure to one or more additional signals (which are interchangeably referred to herein as the “activated state”). Among other things, activated inflammatory monocytes can produce signaling molecules (e.g., cytokines, chemokines, etc.) to promote an amplified immune response in subjects.

[0297] This disclosure teaches that the presence and / or level of monocytes (e.g., inflammatory monocytes) and / or neutrophils (e.g., activated neutrophils) may be used in situations where anti-inflammatory therapy is appropriate. Specifically, this disclosure provides the insight that subjects identified as having elevated levels of monocytes and / or activated neutrophils (e.g., relative to appropriate references, such as, for example, established population norms and / or historical individual references) may be particularly likely to respond to therapies targeting TREM1 (and / or relatively unlikely to respond to alternative therapies that do not directly target TREM1 (e.g., anti-TNFα therapy)).

[0298] In some embodiments, monocyte and / or neutrophil activation may be triggered by pathogens. In some embodiments, monocyte and / or neutrophil activation is triggered by bacterial pathogens, viral pathogens, or fungal pathogens.

[0299] In some embodiments, monocyte and / or neutrophil activation can be triggered by exposure to one or more bacterial markers (e.g., peptidoglycan). In some embodiments, monocyte and / or neutrophil activation can be triggered by exposure to one or more pathogen-associated molecular patterns (PAMPs). In some embodiments, monocyte and / or neutrophil activation can be triggered by lipopolysaccharide. In some embodiments, monocyte and / or neutrophil activation can be triggered by lipoteichoic acid. In some embodiments, monocyte and / or neutrophil activation can be triggered by double-stranded viral RNA. In some embodiments, monocyte and / or neutrophil activation can be triggered by bacterial DNA.

[0300] In some embodiments, monocyte and / or neutrophil activation may be triggered by damage-associated molecular patterns released from necrotic cells. In some embodiments, monocyte and / or neutrophil activation may be triggered by high-mobility group box 1 (HMP-B1). In some embodiments, monocyte and / or neutrophil activation may be triggered by mitochondrial formyelin. In some embodiments, monocyte and / or neutrophil activation may be triggered by mitochondrial DNA.

[0301] 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.

[0302] Monocytes (e.g., inflammatory monocytes) and / or activated neutrophils can 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 for activated neutrophils and / or monocytes are cell-based biomarkers. For example, in some embodiments, the cell-based biomarkers are blood and / or tissue neutrophil counts, monocyte counts, or neutrophil and monocyte counts. In some embodiments, the biomarker and / or surrogate marker is TREM1 RNA in monocytes and / or neutrophils. In some embodiments, the biomarker and / or surrogate marker is TREM1 on the cell surface of monocytes and / or neutrophils.

[0303] In some embodiments, the biomarker and / or surrogate biomarker of 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 biomarker is the presence of neutrophils in the lamina propria or the epithelial layer of the subject. In some embodiments, the biomarker and / or surrogate biomarker is the presence of lymphocytes, plasma cells, and / or eosinophils in the lamina propria of the subject.

[0304] In some embodiments, the biomarkers and / or substitutes for activated neutrophils are neutrophil products. For example, in some embodiments, the neutrophil products are calprotectin, PGLYRP1, or soluble TREM1.

[0305] In some embodiments, the biomarker and / or surrogate biomarker for monocytes (e.g., inflammatory monocytes) is a product of monocytes (e.g., inflammatory monocytes). For example, in some embodiments, the product of monocytes (e.g., inflammatory monocytes) is soluble TREM1.

[0306] In some embodiments, the biomarker and / or surrogate marker for activated neutrophils and / or monocytes is the TREM1 ligand. For example, in some embodiments, the TREM1 ligand is bacterial peptidoglycan (PGN) and / or PGLYRP1.

[0307] In some implementations, biomarkers and / or substitutes for activated neutrophils and / or monocytes are characterized by TREM1 gene activation.

[0308] In some embodiments, biomarkers and / or substitutes for activated neutrophils and / or monocytes include any one or a combination of the following: neutrophil and / or monocyte counts detected in diseased tissue; TREM1 on the cell surface of monocytes and / or neutrophils in diseased tissue; TREM1 RNA in monocytes and / or neutrophils in diseased tissue; tissue biomarkers in diseased 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 diseased tissue and / or blood.

[0309] In some implementations, biomarkers and / or substitute biomarkers of activated neutrophils and / or monocytes are detected in subject blood samples, diseased tissue samples, fecal samples, their components or fractions, or combinations thereof.

[0310] In some implementations, the elevated level of one or more inflammatory biomarkers and / or one or more biomarkers associated with activated neutrophils and / or monocytes is determined by measuring the level of one or more inflammatory biomarkers and / or biomarkers associated with activated neutrophils and / or monocytes (i.e., as substitutes for activated neutrophils and / or monocytes) in the subject, compared to the level of one or more inflammatory biomarkers and / or biomarkers associated with activated neutrophils and / or monocytes (i.e., as substitutes for activated neutrophils and / or monocytes) in the subject. In some implementations, the elevated level of activated neutrophils and / or monocytes is determined by measuring the levels of one or more inflammatory biomarkers and / or one or more biomarkers associated with activated neutrophils and / or monocytes in the subject, compared to the levels of one or more inflammatory biomarkers and / or one or more biomarkers associated with activated neutrophils and / or monocytes (i.e., as a substitute for activated neutrophils and / or monocytes). In some implementations, the elevated level of activated neutrophils and / or monocytes is determined by measuring the levels of one or more inflammatory biomarkers and / or one or more biomarkers associated with 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 biomarkers associated with activated neutrophils and / or monocytes (i.e., as substitutes for activated neutrophils and / or monocytes) in healthy tissue samples collected from the subject.

[0311] In some embodiments, activated neutrophils and / or monocytes, activated neutrophil and / or monocyte biomarkers, and / or biomarkers associated with activated neutrophils and / or monocytes (i.e., as substitutes for activated neutrophils and / or monocytes) can be detected by one or more methods available in the art. For example, in some embodiments, activated neutrophils and / or monocytes can be detected by one or more microscopic methods (e.g., fluorescence microscopy). In some embodiments, activated neutrophils and / or monocytes, activated neutrophil and / or monocyte biomarkers, and / or biomarkers associated with activated neutrophils and / or monocytes (i.e., as substitutes for activated neutrophils and / or monocytes) can be detected by one or more histopathological methods. In some embodiments, activated neutrophils and / or monocytes, activated neutrophil and / or monocyte biomarkers, and / or biomarkers associated with activated neutrophils and / or monocytes (i.e., as substitutes for activated neutrophils and / or monocytes) can be detected by one or more polynucleotide (e.g., DNA or RNA) detection methods (e.g., quantitative PCR, reverse transcription PCR, in situ hybridization, in vitro hybridization, nucleic acid sequencing, etc.). In some embodiments, activated neutrophils and / or monocytes, activated neutrophil and / or monocyte biomarkers, and / or biomarkers associated with activated neutrophils and / or monocytes (i.e., as substitutes for activated neutrophils and / or monocytes) can be detected by one or more spatial profiling methods. In some embodiments, activated neutrophils and / or monocytes, activated neutrophil and / or monocyte biomarkers, and / or biomarkers associated with activated neutrophils and / or monocytes (i.e., as substitutes for activated neutrophils and / or monocytes) can be detected by one or more methods for protein identification and / or quantification (e.g., antibody-based detection, ELISA, competitive binding studies, mass spectrometry, and / or high-performance liquid chromatography of tissue samples collected from subjects, etc.). In some embodiments, activated neutrophils and / or monocytes, activated neutrophil and / or monocyte biomarkers, and / or biomarkers associated with activated neutrophils and / or monocytes (i.e., as substitutes for activated neutrophils and / or monocytes) can be detected by one or more cell sorting or characterization methods (e.g., FACS, flow cytometry, etc.).

[0312] Example The following examples are provided to describe to those skilled in the art how to prepare and use the methods and compositions described herein, and these examples are not intended to limit the scope of this disclosure.

[0313] Example 1: Elevated TREM1-positive inflammatory monocytes and neutrophils in inflamed tissue This embodiment includes the identification of elevated inflammatory monocytes and neutrophils in patients with inflammatory bowel disease (IBD). Inflammatory monocytes were enriched in inflamed tissues, enriched in post-treatment samples from non-responders of anti-TNFα therapy compared to responders of anti-TNFα therapy, and showed elevated TREM1 expression.

[0314] Single-cell transcriptomics data were generated from approximately 200 tissue samples (containing over 1 million cells) from patients with inflammatory bowel disease (IBD) who had not received biologic therapy. Samples were collected from multiple anatomical sites before treatment and at least 3 months after treatment with adalimumab (an anti-TNFα therapy). Samples were annotated with anti-TNFα therapy responder status and inflammatory status.

[0315] Clustering single-cell transcriptomics data into cell populations annotated with cell identities ( Figure 1A and Figure 1B Then, the differences in cell populations across clinical dimensions (e.g., anti-TNFα therapy responder status and / or inflammatory status) were analyzed.

[0316] Single-cell profiling revealed that certain cell populations (e.g., inflammatory mononuclear cells) were enriched in inflammatory samples compared to non-inflammatory samples. Figure 2 and Figure 3 ).

[0317] Analysis showed that TREM1 was highly expressed in inflammatory mononuclear cells present in inflamed tissues from IBD patients. Figure 4A In contrast, TREM1-positive inflammatory mononuclear cells were found in non-inflammatory tissues from IBD patients. Figure 4B ) or in healthy tissues from non-IBD patients ( Figure 4C TREM1-positive monocytes were not enriched in peripheral blood monocytes (PBMCs) from IBD patients compared to healthy individuals. Figure 5A and Figure 5B ).

[0318] Inflammatory mononuclear cells were enriched in post-treatment samples from IBD patients who were responders to anti-TNFα therapy compared to post-treatment samples from tissues of IBD patients who were non-responders to anti-TNFα therapy. Figure 6A Inflammatory mononuclear cells 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 enriched in tissues of patients with Crohn's disease (CD) and ulcerative colitis (UC) IBD who were non-responders to anti-TNFα therapy. Figure 6C and Figure 6D ).

[0319] As assessed histologically, in patients with ulcerative colitis, the enrichment of TREM1+ inflammatory mononuclear cells in inflamed tissue is associated with neutrophil infiltration in inflamed tissue. Figure 7 Neutrophils also express high levels of TREM1 (see Example 2).

[0320] These results demonstrate that inflammatory monocytes and neutrophils are enriched in inflamed IBD tissues, and that these cell populations highly express TREM1. Furthermore, these cell populations are enriched in the tissues of IBD patients who are non-responders to anti-TNFα therapy, relative to responders to anti-TNFα therapy.

[0321] Example 2: Binding of anti-TREM1 antibody agent to cells expressing TREM1 This embodiment demonstrates that the exemplary anti-TREM1 antibody agent disclosed herein can bind to TREM1 expressed on the cell surface of monocytes and neutrophils. The exemplary anti-TREM1 antibody agent has an amino acid sequence corresponding to clone A as disclosed in Table 2. Furthermore, this embodiment shows that bacterial components (e.g., PGN or LPS) can stimulate monocytes to upregulate TREM1 levels on the cell surface.

[0322] The binding of anti-TREM1 antibody agent clone A to TREM1 on the cell surface was analyzed by staining cells present in whole blood samples from healthy human subjects followed by flow cytometry. In short, whole blood samples were depleted of red blood cells (RBCs) by sedimentation, followed by Fc blocking before staining with various antibodies targeting various cell surface markers directly conjugated to fluorophores. Cells were also stained with a saturated concentration (10 nM) of anti-TREM1 antibody agent clone A directly conjugated to Alexa Fluor 647. Staining with an isotype control antibody conjugated to Alexa Fluor 647 served as a negative control. The stained samples were then analyzed by flow cytometry. Different cell types were identified using cell surface markers, and the intensity of TREM1 staining on the cell surface for each cell type was assessed. Neutrophils (CD45) + CD66 + CD16 + ) and total CD14 + Monocytes (CD45) + CD14 + CD16 -Or CD45 + CD14 + CD16 + (Both are known to express TREM1) showed binding to anti-TREM1 antibody drug clone A. Figures 8A to 8D CD45, which is considered not to express TREM1, + 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 prior to staining, TREM1 present on the cell surface was expected to be in an inactive state. These results demonstrate that TREM1 is selectively expressed on the cell surface of neutrophils and monocytes, and that the anti-TREM1 antibody agent clone A binds to TREM1 (e.g., inactive TREM1) present on the cell surface of neutrophils and monocytes.

[0323] To determine whether the anti-TREM1 antibody clone A could bind to activated TREM, primary human monocytes from healthy donors were plated and stimulated with bacterial peptidoglycan (PGN) (10 µg / mL) or LPS (100 ng / mL) for 24 hours, followed by staining with a saturated concentration of anti-TREM1 antibody clone A (5 nM) and flow cytometry analysis. PGN stimulation and LPS stimulation led to upregulation of TREM1 on the cell surface. Figure 9 A modest increase in TREM1 on the cell surface was observed in monocytes at 24 hours (24-hour culture medium) in the absence of PGN, consistent with the low-level activation of monocytes due to plating. An isotype control antibody was used as a control for anti-TREM1 staining. These results demonstrate that monocyte activation by PGN or LPS leads to the upregulation of TREM1 on the cell surface. Without wishing to be bound by any particular theory, these results may be consistent with bacterial components present in diseased tissues that promote the upregulation of TREM1 on the cell surface of monocytes. The results also demonstrate that the anti-TREM1 antibody agent clone A is able to bind to activated TREM1 present on the cell surface.

[0324] Example 3: TREM1 amplifies the inflammatory response mediated by TREM1-positive monocytes and neutrophils. This example demonstrates that TREM1 amplifies the inflammatory response mediated by TREM1-positive monocytes and neutrophils.

[0325] Primary human monocytes were isolated from healthy volunteers and stimulated with either PGLYRP1 (500 nM) alone, 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 show baseline cytokine levels. Monocyte-mediated inflammatory responses were monitored 18 to 24 hours later by measuring the levels of various cytokines and chemokines (e.g., CCL3, CCL4, IL-1β, IL-6, IL-23, and TNFα) secreted into the culture medium. The results showed that PGLYRP1 alone did not stimulate monocytes to secrete the measured inflammatory cytokines and chemokines (Figure 10). In contrast, PGN alone significantly stimulated monocytes to secrete several of the measured cytokines and chemokines (e.g., CCL3, CCL4, and IL-6) (Figure 10). Compared to PGN alone, the combination of PGN and PGLYRP1 significantly amplified the secretion of the measured inflammatory cytokines and chemokines (Figure 10). These results demonstrate that bacterial PGN stimulates monocytes to produce an initial antibacterial innate immune response, which includes the secretion of inflammatory cytokines and chemokines amplified by the TREM1 ligand PGLYRP1.

[0326] In a similar experiment, the inflammatory response mediated by primary human monocytes was monitored by measuring the levels of various inflammatory mediators using a 64-fold assay panel (data not shown). This assay panel demonstrated that TREM1 amplifies the secretion of a variety of inflammatory mediators by monocytes, 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), activating factors of B cells, T cells, and other cells (e.g., APRIL, BAFF, CD30, and M-CSF), and factors related to epithelial barrier integrity (e.g., TRAIL, TWEAK, MMP-1, IL-20, and TNFR-II).

[0327] Primary human neutrophils were isolated from healthy volunteers and stimulated with either PGLYRP1 (50 nM) alone, 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 show baseline cytokine levels. Neutrophil-mediated inflammatory responses were monitored 18 to 24 hours later by measuring the levels of various cytokines and chemokines (e.g., CCL3, CCL4, and IL-8) secreted into the culture medium. The results showed that PGLYRP1 alone did not stimulate neutrophils to secrete the measured inflammatory cytokines and chemokines (e.g., CCL3, CCL4, and IL-8). Figure 11 In contrast, PGN alone significantly stimulated neutrophils to secrete measured cytokines and chemokines (e.g., CCL3, CCL4, and IL-8). Figure 11 Neutrophils release endogenous PGLYRP1 in response to PGN stimulation. The combination of PGN and PGLYRP1 significantly amplifies the secretion of CCL3 and CCL4 compared to PGN alone. Figure 11 These results demonstrate that bacterial PGN stimulates neutrophils to produce an initial antibacterial innate immune response, which includes the secretion of inflammatory cytokines and chemokines amplified by the TREM1 ligand PGLYRP1.

[0328] Example 4: Characterization of anti-TREM1 antibody agents This embodiment provides characterization of the exemplary anti-TREM1 antibody agent 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 the amino acid sequence corresponding to clone A as disclosed in Table 2.

[0329] Biological layer interference (BLI) was used to examine the binding affinity of the TREM1 antibody to the extracellular domain (ECD) of TREM1 from various species. Briefly, the TREM1 antibody (5 µg / mL) was used to immobilize an anti-human Fc capture (AHC) sensor. The sensor was monitored to establish a baseline. The sensor was then exposed to four concentrations (0.03125 μg / mL, 0.0625 μg / mL, 0.25 μg / mL, and 1 μg / mL) of recombinant monovalent TREM1-ECD protein from humans, cynomolgus monkeys, dogs, rabbits, rats, mice, or pigs for 300 seconds to measure the binding rate, followed by transfer to assay buffer for at least 900 seconds to measure the dissociation rate.

[0330] Table 4 shows the results of the BLI experiment. The TREM1-ECD protein with the maximum BLI response less than 0.1 nm showed a response to K... D Insufficient associative response was identified, and therefore no significant binding was considered to have occurred with TREM1 antibody agent clone A. Results demonstrated that the TREM1 antibody agent bound to the ECD of TREM1 in humans and cynomolgus monkeys. No binding was detected to the ECD of TREM1 in dogs, rabbits, rats, mice, and pigs. The coefficient of determination for the 1:1 model fitted to the BLI sensor map is expressed as the R^2 value. Data for humans and cynomolgus monkeys represent the mean of three replicates. Data for pigs, dogs, rabbits, rats, and mice represent the mean of two replicates.

[0331] Table 4: Results of BLI Measurement TREM1-ECD species Maximum BLI response (nm) <![CDATA[K D (nM)]]> <![CDATA[K a (1 / Ms)]]> <![CDATA[K dis (1 / s)]]> R^2 people 0.385±0.012 0.21±0.10 <![CDATA[4.21×10 5 ]]> <![CDATA[9.20×10 -5 ]]> > 0.99 Crab-eating macaques 0.343±0.008 1.90±0.46 <![CDATA[3.92×10 5 ]]> <![CDATA[7.70×10 -4 ]]> > 0.99 pig 0.013±0.012 n / a n / a n / a n / a dog 0.006±0.001 n / a n / a n / a n / a rabbit 0.005±0.001 n / a n / a n / a n / a rats 0.018±0.003 n / a n / a n / a n / a mice 0.005±0.003 n / a n / a n / a n / a 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 Without being bound by any particular theory, TREM1 and TREM2 are thought to play opposing roles in regulating immune responses; see, for example, Sharif and Knapp, Immunobiology, 213(9-10):701-713 (2008). To determine whether TREM1 antibody agents could also bind to TREM2, a biolayer interference (BLI) assay was performed. Briefly, 10 μg / mL TREM2-ECD fused to the Fc domain was immobilized on the sensor. The sensor was quenched and monitored to establish a baseline. The sensor was then exposed to a solution containing 3 μg / mL anti-TREM1 antibody agent or an anti-TREM2 antibody agent (R&D Systems, MAB17291) as a positive control. The maximum BLI response was measured ( Figure 13 The results showed that the exemplary anti-TREM1 antibody did not bind to TREM2-ECD.

[0332] Multispecific assays were used to further evaluate the target specificity profile of the anti-TREM1 antibody. An array of over 6,000 human membrane proteins, including TREM2 and other TREM family members, expressing each protein, was used on the surface of HEK293 cells transiently transfected. HEK293 cells were treated with 5 μg / mL of the anti-TREM1 antibody, followed by staining with 3.75 μg / mL of a secondary antibody conjugated to Alexa Fluor 647 (Jackson ImmunoResearch, 109-606-008), and then examined by flow cytometry. The multispecific assays showed strong, intermediate-target binding of the anti-TREM1 antibody to TREM1. Figure 14Of the human membrane proteins tested, only one (TMEM178A) showed weak off-target binding close to the background, while the other tested membrane proteins did not show target binding beyond the background. Figure 14 TMEM178A is an intracellular protein located in the endoplasmic reticulum; see, for example, Decker et al., Proc. Natl. Acad. Sci., 112(51):15654-9 (2015). Identification of TMEM178A by multispecific assays was not considered biologically relevant because flow cytometry did not detect the binding of anti-TREM1 clone A to cells endogenously expressing TMEM178A.

[0333] To confirm that the anti-TREM1 antibody did not bind to cells expressing TMEM178A, TMEM178A-positive and TREM1-negative G401 cells were stained with an anti-TREM1 antibody directly conjugated to Alexa Fluor 647. An isotype control antibody directly conjugated to Alexa Fluor 647 was used as a negative control. G401 cells stained with the anti-TREM1 antibody or the isotype control antibody showed comparable fluorescence intensity at a range of antibody concentrations. Figure 15 These results demonstrate that the anti-TREM1 antibody agent does not bind significantly to cells expressing TMEM178A.

[0334] The thermal stability of the anti-TREM1 antibody was assessed using differential scanning fluorometry. In short, the antibody was incubated with a protein heat transfer dye (Applied Biosystems...

Claims

1. An antibody agent that binds to human myeloid cell trigger receptor 1 (TREM1), wherein the antibody comprises: (a) A light chain having CDR1, CDR2, and CDR3 sequences, wherein the CDR1, CDR2, and CDR3 sequences have a total identity of at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% with respect to those sequences found in SEQ ID NO: 18, and / or contains no more than 1, 2, 3, 4, or 5 amino acid sequence differences relative to those sequences found in SEQ ID NO: 18; and / or (b) A heavy chain having CDR1, CDR2 and CDR3 sequences, wherein the CDR1, CDR2 and CDR3 sequences have a total identity of at least 85%, 90%, 95%, 96%, 97%, 98% or 99% with respect to those sequences found in SEQ ID NO: 14, and / or contain no more than 1, 2, 3, 4 or 5 amino acid sequence differences relative to those sequences found in SEQ ID NO:

14.

2. The antibody agent according to claim 1, wherein the light chain (LC) comprises: (i) LC CDR1, wherein the LC CDR1 has an amino acid sequence, the amino acid sequence being or comprising: 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 no more than 1, 2, 3, 4 or 5 amino acid sequences different from SEQ ID NO: 19; (ii) LC CDR2, wherein the LC CDR2 has an amino acid sequence that is or comprises: the amino acid sequence of GAS, or an amino acid sequence having no more than one or two amino acid sequence differences relative to the amino acid sequence of GAS; and (iii) LC CDR3, wherein the LC CDR3 has an amino acid sequence, the amino acid sequence being or comprising: 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 no more than 1, 2, 3, 4 or 5 amino acid sequences different from SEQ ID NO:

20.

3. The antibody agent according to claim 1 or 2, wherein the heavy chain (HC) comprises: (i) HC CDR1, wherein the HC CDR1 has an amino acid sequence, the amino acid sequence being or comprising: 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 no more than 1, 2, 3, 4 or 5 amino acid sequences different from SEQ ID NO: 15; (ii) HC CDR2, wherein the HC CDR2 has an amino acid sequence, the amino acid sequence being or comprising: 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 no more than 1, 2, 3, 4, or 5 amino acid sequence differences relative to SEQ ID NO: 16; and (iii) HC CDR3, wherein the HC CDR3 has an amino acid sequence, the amino acid sequence being or comprising: 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 no more than 1, 2, 3, 4 or 5 amino acid sequences different from SEQ ID NO:

17.

4. The antibody agent according to any one of claims 1 to 3, wherein the light chain comprises a variable region (VL), the variable region (VL) comprising one, two, three or four FR regions, the FR regions having a total identity of at least 85%, 90%, 95%, 96%, 97%, 98% or 99% with respect to those regions found in SEQ ID NO: 18; and / or comprising no more than one, two, three, four or five amino acid sequence differences relative to those regions found in SEQ ID NO:

18.

5. The antibody agent according to claim 4, wherein the light chain comprises a variable region (VL), the variable region (VL) comprising one, two, three or four FR regions, each of the FR regions independently having an amino acid sequence, the amino acid sequence being or comprising an amino acid sequence of one of SEQ ID NO: 25, 26, 27 or 28, having an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identity with one of SEQ ID NO: 25, 26, 27 or 28, or having an amino acid sequence differing from one of SEQ ID NO: 25, 26, 27 or 28 by no more than 1, 2, 3, 4 or 5 amino acid sequences.

6. The antibody agent according to claim 4 or 5, wherein the antibody agent comprises: (i) an amino acid sequence, said amino acid sequence being or comprising: the amino acid sequence of SEQ ID NO: 25, an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 25, or an amino acid sequence having a difference of no more than 1, 2, 3, 4, or 5 amino acid sequences relative to SEQ ID NO: 25; and / or (ii) an amino acid sequence, said amino acid sequence being or comprising: the amino acid sequence of SEQ ID NO: 26, an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 26, or an amino acid sequence having a difference of no more than 1, 2, 3, 4, or 5 amino acid sequences relative to SEQ ID NO: 26; and / or (iii) An amino acid sequence, said amino acid sequence being or comprising: 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 no more than 1, 2, 3, 4, or 5 amino acid sequence differences relative to SEQ ID NO: 27; and / or (iv) An amino acid sequence, said amino acid sequence being or comprising: 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 no more than 1, 2, 3, 4 or 5 amino acid sequences different from SEQ ID NO:

28.

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

8. The antibody agent according to claim 7, wherein the light chain comprises κCL or λCL.

9. The antibody agent according to claim 7 or 8, wherein the light chain comprises κCL.

10. The antibody agent according to any one of claims 7 to 9, wherein the light chain comprises an amino acid sequence, the amino acid sequence being or comprising 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 no more than 5, 10, or 20 amino acid sequences different from SEQ ID NO:

32.

11. The antibody agent according to any one of claims 1 to 10, wherein the heavy chain comprises a variable region (VH), the variable region (VH) comprising one, two, three or four FR regions, the FR regions having a total identity of at least 85%, 90%, 95%, 96%, 97%, 98% or 99% with respect to those regions found in SEQ ID NO: 14, and / or containing no more than one, two, three, four or five amino acid sequence differences relative to those regions found in SEQ ID NO:

14.

12. The antibody agent of claim 11, wherein the heavy chain comprises a variable region (VH), the variable region (VH) comprising one, two, three or four FR regions, each of the FR regions independently having an amino acid sequence, the amino acid sequence being or comprising an amino acid sequence of one of SEQ ID NO: 21, 22, 23 or 24, having an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identity with one of SEQ ID NO: 21, 22, 23 or 24, or having an amino acid sequence differing from one of SEQ ID NO: 21, 22, 23 or 24 by no more than one, two, three, four or five amino acid sequences.

13. The antibody agent according to claim 11 or 12, wherein the antibody agent comprises: (i) an amino acid sequence, said amino acid sequence being or comprising: the amino acid sequence of SEQ ID NO: 21, an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 21, or an amino acid sequence having a difference of no more than 1, 2, 3, 4, or 5 amino acid sequences relative to SEQ ID NO: 21; and / or (ii) an amino acid sequence, said amino acid sequence being or comprising: the amino acid sequence of SEQ ID NO: 22, an amino acid sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 22, or an amino acid sequence having a difference of no more than 1, 2, 3, 4, or 5 amino acid sequences relative to SEQ ID NO: 22; and / or (iii) An amino acid sequence, said amino acid sequence being or comprising: 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 no more than 1, 2, 3, 4, or 5 amino acid sequence differences relative to SEQ ID NO: 23; and / or (iv) An amino acid sequence, said amino acid sequence being or comprising: 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 no more than 1, 2, 3, 4 or 5 amino acid sequence differences relative to SEQ ID NO:

24.

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

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

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

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

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, optionally human IgG.

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

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

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

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

24. The antibody agent according to any one of claims 21 to 23, wherein the heavy chain comprises an amino acid sequence, said amino acid sequence being or comprising 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 no more than 5, 10, or 20 amino acid sequences different from SEQ ID NO:

30.

25. The antibody agent according to any one of claims 1 to 24, wherein the antibody agent comprises VL, the VL having an amino acid sequence, the amino acid sequence being or comprising: 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 no more than 5, 10 or 20 amino acid sequences different from SEQ ID NO:

18.

26. The antibody agent according to any one of claims 1 to 25, wherein the antibody agent comprises VH, the VH having an amino acid sequence, the amino acid sequence being or comprising: 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 no more than 5, 10 or 20 amino acid sequences different from SEQ ID NO:

14.

27. The antibody agent according to any one of claims 1 to 26, wherein the antibody agent comprises a light chain (LC) having an amino acid sequence, the amino acid sequence being or comprising the amino acid sequence of SEQ ID NO: 33, having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 33, or having an amino acid sequence differing from SEQ ID NO: 33 by no more than 5, 10, or 20 amino acid sequences.

28. The antibody agent according to any one of claims 1 to 27, wherein the antibody agent comprises a heavy chain (HC) having an amino acid sequence, the amino acid sequence being or comprising the amino acid sequence of SEQ ID NO: 31, having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 31, or having an amino acid sequence differing from SEQ ID NO: 31 by no more than 5, 10, or 20 amino acid sequences.

29. The antibody agent according to any one of claims 1 to 28, wherein the antibody agent is characterized by one or more of the following: (i) The antibody agent does not bind to TREM2 or has minimal binding affinity to TREM2; (ii) The antibody agent competes with a reference antibody agent that binds to TREM1 for binding; (iii) The antibody agent has a binding affinity (K0.1 nM to about 0.3 nM) of approximately 0.1 nM. D It binds to the monomeric human TREM1-ECD protein; (iv) The antibody agent has a binding affinity (K0.05) of about 1.4 nM to about 2.4 nM. D It binds to the monomeric cynomolgus monkey TREM1-ECD protein; (v) The antibody agent showed a binding affinity (K0.05) of approximately 80 pM to approximately 95 pM in an enriched human mononuclear cell binding assay. D It binds to human TREM1; (vi) The antibody agent exhibited a binding affinity (K0.05) of approximately 185 pM to approximately 245 pM in an enriched human neutrophil binding assay. D It binds to human TREM1; (vii) The antibody agent described herein exhibits a binding affinity (K0.05) of approximately 90 pM to approximately 115 pM in whole blood human mononuclear cell binding assays. D It binds to human TREM1; (viii) The antibody agent described herein exhibits a binding affinity (K0.05) of approximately 110 pM to approximately 150 pM in whole blood human neutrophil binding assays. D It binds to human TREM1; (ix) The antibody agent described herein exhibited a binding affinity (Kb) of approximately 235 pM to approximately 370 pM in a whole-blood cynomolgus monkey neutrophil binding assay. D ) binds to TREM1 in cynomolgus monkeys; (x) The antibody agent inhibited TREM1 activity at an IC50 of about 20 pM to about 40 pM in a human whole blood enriched primary neutrophil or monocyte cell function assay. (xi) The antibody drug inhibited TREM1 activity at an IC50 of about 4 pM to about 13 pM in the whole blood primary cell function assay of cynomolgus monkeys. (xii) The antibody agent can be produced at a concentration of about 4 g / L to about 7 g / L; (xiii) The antibody agent has a melting temperature of about 70°C to about 80°C; (xiv) The antibody agent described is able to bind to both inactive and activated TREM1; (xv) The antibody agent does not bind to the surface of cells that do not express TREM1; or (xvi) The antibody antagonizes TREM1-mediated inhibition of monocyte maturation into macrophages.

30. An antibody agent that binds to human myeloid cell trigger receptor 1 (TREM1), wherein the antibody agent is characterized by one or more of the following: (i) The antibody agent does not bind to TREM2 or has minimal binding affinity to TREM2; (ii) The antibody agent competes with a reference antibody agent that binds to TREM1 for binding; (iii) The antibody agent has a binding affinity (K0.1 nM to about 0.3 nM) of approximately 0.1 nM. D It binds to the monomeric human TREM1-ECD protein; (iv) The antibody agent has a binding affinity (K0.05) of about 1.4 nM to about 2.4 nM. D It binds to the monomeric cynomolgus monkey TREM1-ECD protein; (v) The antibody agent showed a binding affinity (K0.05) of approximately 80 pM to approximately 95 pM in an enriched human mononuclear cell binding assay. D It binds to human TREM1; (vi) The antibody agent exhibited a binding affinity (K0.05) of approximately 185 pM to approximately 245 pM in an enriched human neutrophil binding assay. D It binds to human TREM1; (vii) The antibody agent described herein exhibits a binding affinity (K0.05) of approximately 90 pM to approximately 115 pM in whole blood human mononuclear cell binding assays. D It binds to human TREM1; (viii) The antibody agent described herein exhibits a binding affinity (K0.05) of approximately 110 pM to approximately 150 pM in whole blood human neutrophil binding assays. D It binds to human TREM1; (ix) The antibody agent described herein exhibited a binding affinity (Kb) of approximately 235 pM to approximately 370 pM in a whole-blood cynomolgus monkey neutrophil binding assay. D ) binds to TREM1 in cynomolgus monkeys; (x) The antibody agent inhibited TREM1 activity at an IC50 of about 20 pM to about 40 pM in a human whole blood enriched primary neutrophil or monocyte cell function assay. (xi) The antibody drug inhibited TREM1 activity at an IC50 of about 4 pM to about 13 pM in the whole blood primary cell function assay of cynomolgus monkeys. (xii) The antibody agent can be produced at a concentration of about 4 g / L to about 7 g / L; (xiii) The antibody agent has a melting temperature of about 70°C to about 80°C; (xiv) The antibody agent described is able to bind to both inactive and activated TREM1; (xv) The antibody agent does not bind to the surface of cells that do not express TREM1; or (xvi) The antibody antagonizes TREM1-mediated inhibition of monocyte maturation into macrophages.

31. The antibody agent according to any one of claims 1 to 30, wherein the antibody agent is characterized in that it reduces TREM1 activity and / or cell surface levels relative to the comparison.

32. The antibody agent according to claim 31, wherein the comparative agent is or comprises: (i) Samples that have not come into contact with the TREM1 antibody agent disclosed herein; or (ii) Samples that have come into contact with the reference TREM1 antibody agent; or (iii) Samples that have come into contact with the same type of control antibody drug.

33. The antibody agent according to claim 31 or 32, wherein the antibody agent reduces the level of TREM1 present on the cell surface, optionally wherein the cell is a monocyte or a neutrophil.

34. The antibody agent of claim 33, wherein the antibody agent reduces the level of TREM1 present on the cell surface by internalization and / or cleavage of TREM1.

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

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

37. The antibody agent according to any one of claims 31 to 36, wherein 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%.

38. The antibody agent according to any one of claims 31 to 37, wherein the antibody agent is characterized in that it reduces (e.g., inhibits) TREM1-mediated immune responses.

39. The antibody agent of 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 of 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 antibody agent according to any one of claims 38 to 40, wherein the TREM1-mediated immune response is or includes one or more of the following: (i) secretion of one or more cytokines, optionally, wherein the one or more cytokines are pro-inflammatory cytokines, and further optionally wherein the 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. (ii) secretion of one or more chemokines, optionally wherein the one or more chemokines are selected from the group consisting of: CCL2, CCL3, CCL4, CCL8, CCL20, CCL22, CCL24, CXCL1, CXCL5, CXCL9, CXCL10 and CXCL13; (iii) Regulation by T cells, B cells or other cells, optionally said regulation is carried out by one or more of IL-1α, IL-1β, IL-6, IL-10, IL-23, APRIL, 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, optionally, wherein said one or more factors that reduce or impair the integrity of the epithelial barrier 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; and (v) Secretion of one or more proteolytic enzymes, optionally, wherein the one or more proteolytic enzymes are or include matrix metalloproteinases (MMPs), and further optionally wherein the MMPs are MMP1 and / or MMP9.

42. The antibody agent according to any one of claims 1 to 41, wherein the antibody agent is characterized in that it prevents or reduces (e.g., inhibits) epithelial barrier damage.

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

44. The antibody agent according to any one of claims 1 to 43, wherein the antibody agent is or comprises: (i) intact IgA, IgG, IgD, IgE or IgM antibodies; (ii) Antibody fragments; (iii) Single-domain antibodies; (iv) Single-chain Fv; or (v) Contains an antigen-binding specific polypeptide fused to the Fc domain.

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

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

47. The antibody agent according to claim 46, wherein the antibody agent is selected from: heterodimer, Crossmab, DVD-Ig, 2-in-1 IgG and IgG-sc-Fv, scFv-scFv, BiTE, DART, biantibody, Fab-scFv fusion, Fab-Fab fusion or tandem antibody.

48. The antibody agent according to any one of claims 1 to 47, wherein the antibody agent is produced in bacterial cells, yeast cells, insect cells or mammalian cells.

49. The antibody agent of claim 48, wherein the antibody agent is produced in mammalian cells, optionally wherein the mammalian cell line is or includes CHO cells.

50. The antibody agent according to any one of claims 1 to 47, wherein the antibody agent is produced in a cell-free system.

51. A polypeptide having an amino acid sequence, said amino acid sequence being or comprising: (i) LC CDR1, LC CDR2 and LC CDR3 sequences, wherein the LC CDR1, LC CDR2 and LC CDR3 sequences have a total identity of at least 85%, 90%, 95%, 96%, 97%, 98% or 99% with respect to the sequences found in SEQ ID NO: 18, and / or contain no more than 1, 2, 3, 4 or 5 amino acid sequence differences relative to the sequences found in SEQ ID NO: 18; (ii) The amino acid sequence of SEQ ID NO: 18, having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 18, or having an amino acid sequence that differs from SEQ ID NO: 18 by no more than 5, 10, or 20 amino acids; and / or (iii) The amino acid sequence of SEQ ID NO: 33, having at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identity with SEQ ID NO: 33, or having an amino acid sequence that differs from SEQ ID NO: 33 by no more than 5, 10 or 20 amino acid sequences.

52. A polypeptide having an amino acid sequence, said amino acid sequence being or comprising: (i) HC CDR1, HC CDR2 and HC CDR3 sequences, wherein the HC CDR1, HC CDR2 and HC CDR3 sequences have a total identity of at least 85%, 90%, 95%, 96%, 97%, 98% or 99% with respect to those sequences found in SEQ ID NO: 14, and / or contain no more than 1, 2, 3, 4 or 5 amino acid sequence differences relative to those sequences 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 no more than 5, 10, or 20 amino acid differences relative to SEQ ID NO: 14; and / or (iii) The amino acid sequence of SEQ ID NO: 31, having at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identity with SEQ ID NO: 31, or having an amino acid sequence that differs from SEQ ID NO: 31 by no more than 5, 10 or 20 amino acid sequences.

53. A polypeptide having an amino acid sequence, said amino acid sequence being or comprising: (i) LC CDR1, LC CDR2, and LC CDR3 sequences, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences have a total identity of at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% with respect to the sequences found in SEQ ID NO: 18, and / or contain no more than 1, 2, 3, 4, or 5 amino acid sequence differences relative to the sequences found in SEQ ID NO: 18; and (ii) HC CDR1, HC CDR2, and HC CDR3 sequences, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences have a total identity of at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% with respect to the sequences found in SEQ ID NO: 14, and / or contain no more than 1, 2, 3, 4, or 5 amino acid sequence differences relative to the sequences found in SEQ ID NO:

14.

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

55. A nucleic acid having a nucleotide sequence encoding a polypeptide according to 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 or comprises: 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.

57. A nucleic acid having a nucleotide sequence encoding a variable heavy chain (VH), wherein the nucleotide sequence is or comprises: 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.

58. A nucleic acid having a nucleotide sequence encoding an antibody agent that binds to TREM1, wherein: (i) The nucleotide sequence comprises a first portion encoding a variable light chain (VL), wherein the first portion is or comprises: 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; and (ii) The nucleotide sequence comprises a second portion encoding a variable heavy chain (VH), wherein the second portion is or comprises: 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.

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 a nucleic acid according to 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 preparing an antibody agent that binds to TREM1, the method comprising: The host cells are cultured under conditions in which the antibody agent is expressed by the host cells according to claim 61 or 62.

64. A composition comprising an antibody agent according to any one of claims 1 to 50.

65. A composition comprising a polypeptide according to 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, wherein the pharmaceutical composition further comprises an excipient and / or a pharmaceutically acceptable carrier.

69. The pharmaceutical composition according to any one of claims 66 to 68, wherein the pharmaceutical composition is formulated into one or more unit dosage forms.

70. A method for preparing a pharmaceutical composition, the method comprising the following steps: The antibody agent according to any one of claims 1 to 50, the polypeptide or nucleic acid encoding part or all of it according to any one of claims 51 to 53, is combined with one or more pharmaceutically acceptable carriers.

71. A method for treating a subject for a disease, disorder, or condition related to a TREM1-mediated immune response, the method comprising the steps of: The drug composition according to any one of claims 66 to 69 is administered to the subject.

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

73. The method of claim 72, wherein the comparative subjects include other similar subjects who have not been given the pharmaceutical composition or who have been given a reference TREM1 inhibitor.

74. The method according to claims 71 to 73, wherein the disease, disorder, or symptom is an inflammatory disease, disorder, or symptom, optionally wherein the inflammatory disease, disorder, or symptom is selected from: inflammatory bowel disease (IBD), sepsis, fibrotic 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, liver fibrosis, NASH, sickle cell vascular occlusive crisis, Marfan syndrome, HIV infection, motor neuron developmental disorder, periodontitis / gingivitis, cancer, diabetic foot ulcer, gout, lupus, psoriasis, arthropathy (e.g., arthritis or synovitis), and Behcet'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) (e.g., intestinal IBD or extraintestinal manifestation (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 symptom is unresponsive to alternative therapies.

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

79. The method according to any one of claims 71 to 78, wherein the subject has received or is receiving alternative therapy, optionally wherein the alternative therapy is an alternative IBD therapy, further optionally wherein the alternative therapy is or includes anti-TNFα therapy (e.g., infliximab, adalimumab, golimumab, and pecelizumab); JAK inhibitor therapy (including selective and non-selective inhibitors) (e.g., utpatinib, tofacitinib, and fegortinib); anti-integrin therapy (e.g., vedolizumab and natezumab); anti-IL-23 therapy (e.g., gusejinumab, migelizumab, and brecurumab); anti-IL-12 / 23 therapy (e.g., ustekinumab); anti-IL-23A therapy (e.g., resalizumab); S1PR agonist or modulator. Anti-TL1A therapy (e.g., ozamod and ectremod); 5-aminosalicylate therapy (e.g., mesalazine, ozamodine, balsalazine, 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 inhibitor therapy (e.g., litexicitinib), TYK2 inhibitor therapy (e.g., deuterocelexicitinib), anti-IL-36 therapy (e.g., sparsoribimab); anti-IL-13 therapy (e.g., dupilumab), miR-124 upregulatory therapy (e.g., obelafazmod), TLR9 agonist therapy (e.g., cobimod); or combinations thereof.

80. The method according to any one of claims 71 to 79, wherein the subject has been determined to express a biomarker, said biomarker: (i) is an elevated level of neutrophils and / or monocytes (e.g., inflammatory monocytes) or alternatives thereof, optionally wherein the biomarker is an elevated level of activated neutrophils or alternatives thereof; (ii) is or comprises one or more products of neutrophils and / or monocytes (e.g., inflammatory monocytes), wherein the biomarker is related to responsiveness to the antibody agent according to any one of claims 1 to 50; and / or (iii) Indicates TREM1 level and / or activity.

81. The method of claim 80, wherein the biomarker is or includes one or more of the following: (i) Cell-based biomarkers, optionally wherein the 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. (ii) Tissue biomarkers, optionally wherein the biomarkers are mucosal ulcers, neutrophils and / or epithelial cells in the lamina propria, 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) A product produced by inflammatory mononuclear cells, wherein the biomarker is optionally soluble TREM1; (v) TREM1 ligand, optionally wherein the TREM1 ligand is bacterial peptidoglycan (PGN) and / or PGLYRP1; and (vi) TREM1 gene activation characteristics.

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

83. The method according to any one of claims 80 to 82, wherein: (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 tissues; (iii) The biomarker is TREM1, which is present in monocytes and / or neutrophils, and the biomarker is detected in diseased tissues; (iv) The biomarker is TREM1, which is present on the cell surface of monocytes and / or neutrophils, and the biomarker is detected in diseased tissues; (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; (viii) The biomarker is a bacterial PGN, and the biomarker is detected in fecal matter; (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 tissues and / or blood; or (xi) Their combination.

84. A method comprising the following steps: Determine whether the subject expresses a biomarker, wherein the biomarker is: (i) is an elevated level of neutrophils and / or monocytes (e.g., inflammatory monocytes) or alternatives thereof, optionally wherein the biomarker is an elevated level of activated neutrophils or alternatives thereof; (ii) is or comprises one or more products of neutrophils and / or monocytes (e.g., inflammatory monocytes), wherein the biomarker is related to responsiveness to the antibody agent according to any one of claims 1 to 50; and / or (iii) Indicating TREM1 levels and / or activity; and If it is determined that the subject expresses the biomarker, the antibody agent according to any one of claims 1 to 50 is administered to the subject.

85. The method of claim 84, wherein the biomarker is or includes one or more of the following: (i) Cell-based biomarkers, optionally wherein the 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. (ii) Tissue biomarkers, optionally wherein the biomarkers are mucosal ulcers, neutrophils and / or epithelial cells in the lamina propria, 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) A product produced by inflammatory mononuclear cells, wherein the biomarker is optionally soluble TREM1; (v) TREM1 ligand, optionally wherein the TREM1 ligand is bacterial peptidoglycan (PGN) and / or PGLYRP1; and (vi) TREM1 gene activation characteristics.

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

87. The method according to any one of claims 85 to 87, wherein: (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 tissues; (iii) The biomarker is TREM1, which is present in monocytes and / or neutrophils, and the biomarker is detected in diseased tissues; (iv) The biomarker is TREM1, which is present on the cell surface of monocytes and / or neutrophils, and the biomarker is detected in diseased tissues; (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; (viii) The biomarker is a bacterial PGN, and the biomarker is detected in fecal matter; (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 tissues and / or blood; or (xi) Their combination.

88. The method according to any one of claims 84 to 87, wherein the antibody agent is characterized in that, when administered to the subject, it reduces the level and / or activity of TREM1 relative to the comparison agent.

89. The method of claim 88, wherein the comparative subjects include other similar subjects who have not been given the antibody agent or have been given a reference TREM1 inhibitor.

90. A method for suppressing TREM1, the method comprising the following steps: Contacting cells, tissues, or a subject with the pharmaceutical composition according to any one of claims 66 to 69 This inhibits TREM1 in the cells, tissues, or subjects.

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

92. The method of claim 91, wherein the inhibition of TREM1 is evaluated relative to a comparison.

93. A method for antagonizing TREM1-mediated inhibition of monocyte maturation into macrophages, the method comprising the following steps: Contacting cells, tissues, or a subject with the pharmaceutical composition according to any one of claims 66 to 69 This antagonizes TREM1-mediated inhibition of monocyte maturation into macrophages in the cells, tissues, or subjects.

94. The method of claim 93, wherein the antagonism of TREM1-mediated inhibition of monocyte maturation into macrophages is evaluated relative to a comparison.

95. The method of claim 92 or claim 94, wherein the comparative comprises other similar cells, tissues or subjects that have not been treated with the pharmaceutical composition or have been treated with a reference TREM1 inhibitor.

96. The method according to any one of claims 90 to 95, wherein the contact step comprises applying the pharmaceutical composition to the cells, tissues, or subject.

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

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

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

100. The method of claim 98, wherein the person is a child.

Images