WO2025199118A1

WO2025199118A1 - Anti-trem1 antibody constructs, compositions comprising anti-trem1 antibody constructs and methods of using anti-trem1 antibody constructs

Info

Publication number: WO2025199118A1
Application number: PCT/US2025/020397
Authority: WO
Inventors: Ravi Rao; Katrin Andreasson
Original assignee: Willow Neuroscience Inc
Current assignee: Willow Neuroscience Inc
Priority date: 2024-03-18
Filing date: 2025-03-18
Publication date: 2025-09-25
Anticipated expiration: 2026-09-18

Abstract

Provided herein are antibody constructs that selectively bind to human Triggering Receptor Expressed on Myeloid Cells 1 (TREM1) and compositions comprising the antibody constructs. Also provided are methods of using the antibody constructs, such as therapeutic and/or diagnostic purposes.

Description

ANTI-TREM1 ANTIBODY CONSTRUCTS, COMPOSITIONS COMPRISING ANTI-TREM1 ANTIBODY CONSTRUCTS AND METHODS OF USING ANTI-TREM1 ANTIBODY CONSTRUCTS

1. RELATED APPLICATIONS

[0001] This application claims benefit of and priority to U.S. Provisional Application No. 63/566,780, filed March 18, 2024, the disclosure of which is incorporated herein by reference in its entirety.

2. SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML format compliant with WIPO Standard ST.26 and is hereby incorporated by reference in its entirety. Said XML copy, created on February 20. 2025. is named 1 107370.00013. xml and is 75,318 bytes in size.

3. FIELD

[0003] Provided herein are antibody constructs with binding specificity for human Triggering Receptor Expressed on Myeloid Cells 1 (TREM1) and compositions comprising the antibody constructs, including pharmaceutical compositions, and kits. Also provided are methods of using anti-TREMl antibody constructs for therapeutic and/or diagnostic purposes.

4. BACKGROUND

[0004] Triggering Receptor Expressed on Myeloid Cells 1 (TREM1) is a protein that in humans is encoded by the TREM1 gene. TREM1 functions as an amplifier of pro-inflammatory reactions in response to pathogenic infections (c.g., bacterial, viral, and other pathogens), tissue damage (aseptic inflammation), and chronic inflammatory conditions. Upon ligand binding, TREM1 dimerizes/oligomerizes and engages directly a downstream signaling cascade, for example by recruiting DAP12/ZAP70/SYK, as well as synergies with the pattern recognition receptors such as TLR-4 (via TLR4-MyD88-NF-KB signaling) that enhance the expression of TREM1, increase production of proinflammatory cytokines, chemokines, and reactive oxygen species.

[0005] TREM1 is an attractive therapeutic target for regulating pro-inflammatory reactions and is also attractive as a diagnostic target for detecting, staging, and/or monitoring inflammation.

5. SUMMARY

[0006] Provided herein are antibody constructs that selectively bind to human Triggering Receptor Expressed on Myeloid Cells 1 (TREM1). wherein the antibody constructs comprise, consist, or consist essentially of a first polypeptide comprising a VH and 1, 2, or 3 of a CHI. CH2. and/or CH3, and a second polypeptide comprising, consisting, or consisting essentially of a VL and 1, 2, or 3 of a CL, CH2, and/or CH3. In some embodiments, when present, the first polypeptide comprises a VH, CHI, CH2, and CH3 in the following order: VH, CHI, CH2, and CH3, and, when present, the second polypeptide comprises a VL, CL, CH2, and CH3 in the following order: VL, CL, CH2, and CH3. Without wishing to be bound by theory', the antibody constructs described herein do not induce concentration-dependent activation.

[0007] A first aspect provides an antibody construct, wherein the antibody construct comprises, consists, or consists essentially of a first polypeptide comprising a hcayy chain variable region (VH) and one or more regions and a second polypeptide comprising a light chain variable region (VL) and one or more regions, a) the first polypeptide comprising a VH and 1. 2. or 3 of a CHI. CH2. and/or CH3, wherein the VH comprises: i) a VHCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 12-13. yvherein the CDRs are according to Chothia or ii) a VHCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 1-2. yvherein the CDRs are according to Kabat; iii) a VHCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 34-35, yvherein the CDRs are according to Chothia or iv) a VHCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 23-24, yvherein the CDRs arc according to Kabat; and/or v) a VHCDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 45-46; and b) the second polypeptide comprising a VL and 1, 2, or 3 of a CL, CH2, and/or CH3, wherein the VL comprises: i) a VLCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 55-56; ii) a VLCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 67-68; and/or iii) a VLCDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 77-78; wherein, when present, the first polypeptide comprises a VH. CHL CH2, and CH3 in the following order: VH, CHI. CH2. and CH3. and wherein, when present, the second polypeptide comprises a VL, CL, CH2, and CH3 in the following order: VL, CL. CH2, and CH3.

[0008] In some embodiments, the first polypeptide comprises, consists, or consists essentially of a VH and CHI, CH2, and CH3 in the following order: VH. CHI. CH2. and CH3. the CHI comprises the amino acid sequence set forth in SEQ ID NO: 121 or a variant thereof haying at least 85% (e.g.. at least 90%, at least 95%, or at least 98%) identity with the amino acid sequence of SEQ ID NO: 121, wherein die CH2 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 126-127 or a variant diereof having at least 85% (e.g., at least 90%, at least 95%, or at least 98%) identity with the amino acid sequence of any one of SEQ ID NOs: 126-127, and wherein the CH3 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 132-134 or a variant thereof having at least 85% (e.g., at least 90%, at least 95%, or at least 98%) identity with the amino acid sequence of any one of SEQ ID NOs: 132-134.

[0009] In some embodiments, the second polypeptide comprises, consists, or consists essentially of a VL and CL, CH2, and CH3 in the following order: VL, CL, CH2, and CH3, wherein the CL comprises die amino acid sequence set forth in SEQ ID NO: 144 or a variant thereof having at least 85% (e.g., at least 90%, at least 95%, or at least 98%) identity with the amino acid sequence of SEQ ID NO: 144, the CH2 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 126-127 or a variant diereof having at least 85% (e.g., at least 90%, at least 95%, or at least 98%) identity widi the amino acid sequence of any one of SEQ ID NOs: 126-127, and the CH3 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 132-134 or a variant thereof having at least 85% (e.g., at least 90%, at least 95%. or at least 98%) identity with the amino acid sequence of any one of SEQ ID NOs: 132-134.

[0010] In some embodiments, the first polypeptide comprises, consists, or consists essentially of: i) a VHCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, wherein the CDR is according to Chothia or ii) a VHCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, wherein the CDR is according to Kabat; iii) a VHCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34, wherein the CDR is according to Chothia or iv) a VHCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 23, wherein the CDR is according to Kabat; and/or v) a VHCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 45 ; and the second polypeptide comprises, consists, or consists essentially of: i) a VLCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 55; ii) a VLCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 67; and/or iii) a VLCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 77.

[0011] In some embodiments, the first polypeptide comprises, consists, or consists essentially of: i) a VHCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, wherein the CDR is according to Chothia or ii) a VHCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, wherein the CDR is according to Kabat; iii) a VHCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34, wherein the CDR is according to Chothia or iv) a VHCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 23, wherein the CDR is according to Kabat; v) a VHCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 45; vi) a CHI comprising the amino acid sequence set forth in SEQ ID NO: 121; vii) a CH2 comprising the amino acid sequence set forth in SEQ ID NO: 127; and viii) a CH3 comprising the amino acid sequence set forth in SEQ ID NO: 133; and the second polypeptide comprises, consists, or consists essentially of: i) a VLCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 55; ii) a VLCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 67; iii) a VLCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 77; vi) a CL comprising the amino acid sequence set forth in SEQ ID NO: 144; vii) a CH2 comprising the amino acid sequence set forth in SEQ ID NO: 127; and viii) a CH3 comprising the amino acid sequence set forth in SEQ ID NO: 134.

[0012] In some embodiments, the first polypeptide comprises, consists, or consists essentially of a VH and CHI, CH2, and CH3 in the following order: VH, CHI. CH2, and CH3, wherein the VH comprises the amino acid sequence set forth in SEQ ID NO: 89 or a variant thereof having at least 85% identity’ with the amino acid sequence of SEQ ID NO: 89, wherein the CHI comprises the amino acid sequence set forth in SEQ ID NO: 121 or a variant thereof having at least 85% identity’ with the amino acid sequence of SEQ ID NO: 121, wherein the CH2 comprises the amino acid sequence set forth in SEQ ID NO: 127 or a variant thereof having at least 85% identity with the amino acid sequence of SEQ ID NO: 127, and wherein the CH3 comprises the amino acid sequence set forth in SEQ ID NO: 133 or a variant thereof having at least 85% identity with the amino acid sequence of SEQ ID NO: 133; and the second polypeptide comprises, consists, or consists essentially of a VL and CL, CH2. and CH3 in the following order: VL. CL, CH2. and CH3, wherein the VL comprises the amino acid sequence set forth in any one of SEQ ID NO: 101 or a variant thereof having at least 85% identity with the amino acid sequence of any one of SEQ ID NO: 101. wherein the CL comprises the amino acid sequence set forth in any one of SEQ ID NO: 144 or a variant thereof having at least 85% identity with the amino acid sequence of any one of SEQ ID NO: 144, wherein the CH2 comprises the amino acid sequence set forth in SEQ ID NO: 127 or a variant thereof having at least 85% identity with the amino acid sequence of SEQ ID NO: 127, and wherein the CH3 comprises the amino acid sequence set forth in SEQ ID NO: 134 or a variant thereof having at least 85% identity with the amino acid sequence of SEQ ID NO: 134.

[0013] In some embodiments, the first polypeptide comprises one or more mutations in the CH3 and the second polypeptide comprises one or more mutations in the CH3. In some embodiments, the one or more first polypeptide CH3 mutations and the one or more second polypeptide mutations are substitutions. In some embodiments, the one or more substitutions comprise, consist, or consist essentially of substitutions of an interface amino acid residue.

[0014] In some embodiments, the antibody construct is monovalent. In some embodiments, the antibody construct is bivalent. In some embodiments, the antibody construct specifically binds human Triggering Receptor Expressed on Myeloid Cells 1 (TREM1). In some embodiments, the antibody construct modulates human Triggering Receptor Expressed on Myeloid Cells 1 (TREM1) mediated signaling. In some embodiments, the antibody construct disrupts human Triggering Receptor Expressed on Myeloid Cells 1 (TREM1) dimerization and/or oligomerization. In some embodiments, the antibody construct inhibits Triggering Receptor Expressed on Myeloid Cells 1 (TREM1) activation and/or signaling. In some embodiments, the antibody construct does not comprise concentration-dependent activation. In some embodiments, the antibody construct does not induce concentration-dependent activation. In some embodiments, the antibody construct does not comprise or induce concentrationdependent activation of TREM1 mediated signaling. In some embodiments, the antibody construct does not comprise or induce concentration-dependent activation of TREM1 dimerization and/or oligomerization.

[0015] A second aspect provides a nucleic acid molecule capable of expressing any of the antibody constructs provided herein. In some embodiments, the nucleic acid molecule comprises an expression vector. In some embodiments, provided are host cells such as a prokaryotic or eukaryotic host cell transformed with the one or more expression vectors. In some embodiments, provided arc viruses such as an oncolytic virus comprising the nucleic acid. In some embodiments, provided are methods for the production of an antibody construct of the invention comprising the steps of expressing a nucleic acid molecule provided herein in a prokaryotic or eukaryotic host cell and recovering the protein from the cell or the cell culture supernatant. In some embodiments, the antibody construct is monovalent. In some embodiments, the antibody construct is bivalent.

[0016] A third aspect provides a method of treating a disease or condition in a subject in need thereof, which comprises, consists, or consists essentially of administering to the subject an antibody construct, wherein the antibody construct comprises, consists, or consists essentially of a first polypeptide having a heavy chain variable region (VH) and one or more regions and a second polypeptide having a light chain variable region (VL) and one or more regions, a) the first polypeptide comprising a VH and 1. 2, or 3 of a CHI. CH2. and/or CH3, wherein the VH comprises: i) a VHCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 12-13, wherein the CDRs are according to Chothia or ii) a VHCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 1-2. wherein the CDRs are according to Kabat; iii) a VHCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 34-35, wherein the CDRs are according to Chothia or iv) a VHCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 23-24, wherein the CDRs are according to Kabat; and/or v) a VHCDR3 comprising the ammo acid sequence set forth in any one of SEQ ID NOs: 45-46; and b) wherein the second polypeptide comprising a VL and 1, 2. or 3 of a CL, CH2, and/or CH3, wherein the VL comprises: i) a VLCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 55-56; ii) a VLCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 67-68; and/or iii) a VLCDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 77-78.

[0017] In some embodiments, the antibody construct is monovalent. In some embodiments, the antibody construct is bivalent.

[0018] A fourth aspect provides a method of imaging a disease or condition in a subject in need thereof, which comprises, consists, or consists essentially of administering to the subject an antibody construct, wherein the antibody construct comprises, consists, or consists essentially of a first polypeptide having a heavy chain variable region (VH) and one or more regions and a second polypeptide having a light chain variable region (VL) and one or more regions, a) the first polypeptide comprising a VH and 1. 2, or 3 of a CHI. CH2. and/or CH3, wherein the VH comprises: i) a VHCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 12-13, wherein the CDRs are according to Chothia or ii) a VHCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 1-2. wherein the CDRs are according to Kabat; iii) a VHCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 34-35, wherein the CDRs are according to Chothia or iv) a VHCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 23-24, wherein the CDRs are according to Kabat; and/or v) a VHCDR3 comprising the ammo acid sequence set forth in any one of SEQ ID NOs: 45-46; and b) the second polypeptide comprising a VL and 1, 2, or 3 of a CL, CH2, and/or CH3, wherein the VL comprises: i) a VLCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 55-56; ii) a VLCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 67-68; and/or iii) a VLCDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 77-78.

[0019] In some embodiments, the antibody construct is monovalent. In some embodiments, the antibody construct is bivalent.

[0020] A fifth aspect provides a method of disabling or reducing myeloid cells that express Triggering Receptor Expressed on Myeloid Cells 1 (TREM1) on the cell surface, comprising, consisting, or consisting essentially of contacting or binding or causing the myeloid cells to bind with an antibody construct that specifically binds human TREM1, wherein the antibody construct comprises, consists, or consists essentially of a first polypeptide having a heavy chain variable region (VH) and one or more regions and a second polypeptide having a light chain variable region (VL) and one or more regions, a) the first polypeptide comprising a VH and 1. 2, or 3 of a CHI, CH2. and/or CH3, wherein the VH comprises: i) a VHCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 12-13, wherein the CDRs are according to Chothia or ii) a VHCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 1-2. wherein the CDRs arc according to Kabat; iii) a VHCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 34-35, wherein the CDRs are according to Chothia or iv) a VHCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 23-24, wherein the CDRs are according to Kabat; and/or v) a VHCDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 45-46; and b) the second polypeptide comprising a VL and 1, 2, or 3 of a CL, CH2, and/or CH3, wherein the VL comprises: i) a VLCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 55-56; ii) a VLCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 67-68; or iii) a VLCDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 77-78.

[0021] In some embodiments, the antibody construct is monovalent. In some embodiments, the antibody construct is bivalent.

[0022] A sixth aspect provides a method of disabling myeloid cells that over express Triggering Receptor Expressed on Myeloid Cells 1 (TREM1) on the cell surface, comprising, consisting, or consisting essentially of contacting or binding or causing the cells to bind with an antibody construct that specifically binds human TREM1, thereby disabling the cells, wherein the antibody construct comprises, consists, or consists essentially of a first polypeptide having a heavy chain variable region (VH) and one or more regions and a second polypeptide having a light chain variable region (VL) and one or more regions, a) the first polypeptide comprising a VH and 1, 2, or 3 of a CHI, CH2, and/or CH3, wherein the VH comprises: i) a VHCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 12-13, wherein the CDRs are according to Chothia or ii) a VHCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 1-2, wherein the CDRs are according to Kabat; iii) a VHCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 34-35, wherein the CDRs are according to Chothia or iv) a VHCDR2 comprising the ammo acid sequence set forth in any one of SEQ ID NOs: 23-24, wherein the CDRs are according to Kabat; and/or v) a VHCDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 45-46; and b) the second polypeptide comprising a VL and 1, 2, or 3 of a CL, CH2, and/or CH3, wherein the VL comprises: i) a VLCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 55-56; ii) a VLCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 67-68; or iii) a VLCDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 77-78.

[0023] In some embodiments, the antibody construct is monovalent. In some embodiments, the antibody construct is bivalent.

[0024] A seventh aspect provides a method of inhibiting or reducing Triggering Receptor Expressed on Myeloid Cells 1 (TREM1) signaling in a cell that expresses Triggering Receptor Expressed on Myeloid Cells 1 (TREM1) on the cell surface, comprising, consisting, or consisting essentially of contacting or binding or causing the cells to bind with an antibody construct that specifically binds human TREML thereby inhibiting the cells, wherein the antibody construct comprises, consists, or consists essentially of a first polypeptide having a heavy chain variable region (VH) and one or more regions and a second polypeptide having a light chain variable region (VL) and one or more regions, a) the first polypeptide comprising a VH and 1, 2, or 3 of a CHI, CH2, and/or CH3, wherein the VH comprises: i) a VHCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 12-13, wherein the CDRs are according to Chothia or ii) a VHCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 1-2, wherein the CDRs are according to Kabat; iii) a VHCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 34-35. wherein the CDRs are according to Chothia or iv) a VHCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 23-24. wherein the CDRs are according to Kabat; and/or v) a VHCDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 45-46; and b) the second polypeptide comprising a VL and 1, 2, or 3 of a CL, CH2, and/or CH3, wherein the VL comprises: i) a VLCDR1 comprising the amino acid sequence set forth hi any one of SEQ ID NOs: 55-56; ii) a VLCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 67-68; or iii) a VLCDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 77-78.

[0025] In some embodiments, the antibody construct is monovalent. In some embodiments, the antibody construct is bivalent. In some embodiments, the antibody construct specifically binds human TREM1. In some embodiments, the first polypeptide comprises, consists, or consists essentially of a VH, CHI, CH2, and CH3 in the following N-terminal to C-terminal order: VH, CHI, CH2, and CH3. In some embodiments, the second polypeptide comprises, consists, or consists essentially of a VL, CL, CH2, and CH3 in the following N-terminal to C-terminal order: VL, CL, CH2. and CH3.

[0026] In some embodiments, the first polypeptide comprises, consists, or consists essentially of a VH and CHI, CH2, and CH3 in the following order: VH. CHI, CH2, and CH3, wherein the CHI comprises the amino acid sequence set forth in SEQ ID NO: 121 or a variant thereof having 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 at least 98% identity with the amino acid sequence of SEQ ID NO: 121, wherein the CH2 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 126-127 or a variant thereof having 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 at least 98% identity with the amino acid sequence of SEQ ID NO: 126-127. and wherein the CH3 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 132-134 or a variant thereof having 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 at least 98% identity with the amino acid sequence of SEQ ID NO: 132-134. In some embodiments, the first polypeptide comprises, consists, or consists essentially of a VH and CHI, CH2, and CH3 in the following order: VH. CHI, CH2, and CH3, wherein the CHI comprises the amino acid sequence set forth in SEQ ID NO: 121 or a variant thereof having at least 85% identity with the amino acid sequence of SEQ ID NO: 121, wherein the CH2 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 126- 127 or a variant thereof having at least 85% identity’ with the amino acid sequence of SEQ ID NO: 126- 127, and wherein the CH3 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 132-134 or a variant thereof having at least 85% identity with the amino acid sequence of SEQ ID NO: 132-134. [0027] In some embodiments, the antibody construct comprises a three-dimensional (3D) conformation, binding capability, binding specificity, thermostability, cytotoxicity' and/or immunogenicity having at least 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 at least 98% identical to an antibody construct comprising a first polypeptide comprising, consisting, or consisting essentially of a VH and CHI, CH2, and CH3 in the following order: VH, CHI. CH2, and CH3, wherein the CHI comprises the amino acid sequence set forth in SEQ ID NO: 121 or a variant thereof having 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 at least 98% identity with the amino acid sequence of SEQ ID NO: 121. wherein the CH2 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 126-127 or a variant thereof having 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 at least 98% identity with the amino acid sequence of SEQ ID NO: 126-127, and wherein the CH3 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 132-134 or a variant thereof having 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 at least 98% identity with the amino acid sequence of SEQ ID NO: 132-134. In some embodiments, the first polypeptide comprises, consists, or consists essentially of a VH and CHI, CH2, and CH3 in the following order: VH. CHI, CH2, and CH3, wherein the CHI comprises the amino acid sequence set forth in SEQ ID NO: 121 or a variant thereof having at least 85% identity' with the amino acid sequence of SEQ ID NO: 121. wherein the CH2 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 126- 127 or a variant thereof having at least 85% identity with the amino acid sequence of SEQ ID NO: 126- 127, and wherein the CH3 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 132-134 or a variant thereof having at least 85% identity with the amino acid sequence of SEQ ID NO: 132-134.

[0028] In some embodiments, the second polypeptide comprises, consists, or consists essentially of a VL and CL, CH2, and CH3 in the following order: VL. CL. CH2. and CH3, wherein the CL comprises the amino acid sequence set forth in SEQ ID NO: 144 or a variant thereof having 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 at least 98% identity with the amino acid sequence of SEQ ID NO: 144, wherein the CH2 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 126-127 or a variant thereof having 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 at least 98% identity with the amino acid sequence of SEQ ID NO: 126-127, and wherein the CH3 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 132-134 or a variant thereof having 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 at least 98% identity with the amino acid sequence of SEQ ID NO: 132-134. In some embodiments, the second polypeptide comprises, consists, or consists essentially of a VL and CL, CH2, and CH3 in the following order: VL, CL, CH2, and CH3, wherein die CL comprises the ammo acid sequence set forth in SEQ ID NO: 144 or a variant thereof having at least 85% identity with the amino acid sequence of SEQ ID NO: 144, wherein the CH2 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 126-127 or a variant Uiereof having at least 85% identity with the amino acid sequence of SEQ ID NO: 126-127, and wherein the CH3 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 132-134 or a variant thereof having at least 85% identity with the amino acid sequence of SEQ ID NO: 132-134.

[0029] In some embodiments, the antibody construct comprises a three-dimensional (3D) conformation, binding capability, binding specificity, thermostability, cytotoxicity and/or immunogenicity having at least 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 at least 98% identical to an antibody construct comprising a first polypeptide comprising, consisting, or consisting essentially of a VH and CHI, CH2, and CH3 in the following order: VL, CL, CH2, and CH3, wherein the CL comprises the amino acid sequence set forth in SEQ ID NO: 144 or a variant thereof having 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 at least 98% identity with the amino acid sequence of SEQ ID NO: 144. wherein the CH2 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 126-127 or a variant thereof having 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 at least 98% identity with the amino acid sequence of SEQ ID NO: 126-127, and wherein the CH3 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 132-134 or a variant thereof having 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 at least 98% identity with the amino acid sequence of SEQ ID NO: 132-134. In some embodiments, the second polypeptide comprises, consists, or consists essentially of a VL and CL. CH2, and CH3 in the following order: VL, CL, CH2, and CH3, wherein the CL comprises the amino acid sequence set forth in SEQ ID NO: 144 or a variant thereof having at least 85% identity with the amino acid sequence of SEQ ID NO: 144, wherein the CH2 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 126-127 or a variant thereof having at least 85% identity with the amino acid sequence of SEQ ID NO: 126-127, and wherein the CH3 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 132-134 or a variant thereof having at least 85% identity with the amino acid sequence of SEQ ID NO: 132-134.

[0030] In some embodiments, the first polypeptide comprises one or more mutations in the CH3 and the second polypeptide comprises one or more mutations in the CH3. In some embodiments, the one or more first polypeptide CH3 mutations and the one or more second polypeptide mutations are substitutions. In some embodiments, the one or more substitutions are substitutions comprises, consists, or consists essentially of an interface amino acid residue. [0031] In some embodiments, the disease or condition comprises, consists, or consists essentially of one or more of multiple sclerosis, Alzheimer’s disease, Huntington’s disease, Parkinson's disease, epilepsy, inflammatory bowel disease (IBD), Human Immunodeficiency Virus (HIV), brain tumor, stroke, amyotrophic lateral sclerosis, spinal cord and/or brain trauma, a disease or condition which would benefit from enzyme replacement therapy (“ERT”), a neurological disease, chronic inflammatory conditions, acute inflammatory conditions, autoimmune diseases, infections, and/or psychiatric conditions.

[0032] In some embodiments, the antibody construct comprises an Fc region and comprises at least one of: a reduced antibody -dependent cell-mediated cytotoxicity (ADCC) activity, a reduced complement-dependent cytotoxicity (CDC) activity, and a reduced antibody-mediated phagocytosis (ADCP) activity.

[0033] In some embodiments, the Fc region comprises, consists, or consists essentially of human IgGl, IgG2, IgG3. or IgG4 Fc. In some embodiments, the Fc region comprises, consists, or consists essentially of human IgGl Fc. In some embodiments, the antibody construct comprises an Fc region comprising modified Fey Receptor (FcyR) binding. In some embodiments, the Fc region comprises reduced Fey Receptor (FcyR) binding, wherein tire FcyR is selected from the group consisting of: FcyRI, FcyRIIa, FcyRIIb, FcyRIIc, FcyRIIIa, and FcyRIIIb. In some embodiments, the antibody construct has rcccptor-ligand blocking, agonism, or antagonism activity.

[0034] In some embodiments, the antibody construct is an anti-TREMl monovalent antibody construct. In some embodiments, the antibody construct is an anti-TREMl monovalent antibody construct that specifically binds human TREM1. In some embodiments, the nucleic acid molecule encodes the anti-TREMl monovalent antibody that specifically binds human TREM1. In some embodiments, the expression vector comprises the nucleic acid molecule that encodes the anti-TREMl monovalent antibody that specifically binds human TREM1. In some embodiments, the host expresses the nucleic acid molecule that encodes tire anti-TREMl monovalent antibody that specifically binds human TREM 1.

[0035] In some embodiments, the antibody construct binds the extracellular domain of TREM1. In some embodiments, the antibody construct binds to TREM1 with a K_D less than or equal to 10 nM. In some embodiments, the method comprises contacting or binding or causing the cells to bind with the antibody construct occurring in vivo in a subject in need thereof. In some embodiments, tire subject in need thereof has a disease or condition associated with TREM1. In some embodiments, the subject in need thereof has a disease or condition associated with TREM1 expression and/or its regulation of promt! animator responses. In some embodiments, the antibody construct inhibits inflammatory’ effect of one or more cytokines selected from IL-la, IL-1 , IL-6, IL-18, IL-33, and/or MIP2/CXCL2. 6. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] FIG. 1A is an image showing representative SDS-PAGE of anti-TREMl antibody constructs described herein.

[0037] FIG. IB are chromatographs showing the purity of exemplary' monomeric TREM1 antibody constructs described herein.

[0038] FIG. 2 shows TREM1 binding by representative monovalent TREM1 antibody constructs compared to bivalent TREM1 antibodies.

[0039] FIG. 3 shows improved inhibitory activity of representative monovalent anti-TREMl antibody constructs compared to representative bivalent TREM1 antibodies.

[0040] FIG. 4 shows representative monovalent TREM1 antibody constructs compared to representative bivalent TREM1 antibodies in a PGLYRP-l/PGN inhibitory assay.

[0041] FIG. 5 shows representative monovalent TREM1 antibody constructs compared to representative bivalent TREM1 antibodies in a TREM1 activation assay, respectively.

[0042] FIG. 6 shows representative monovalent TREM1 antibody constructs compared to representative bivalent TREM1 antibody in a PGLYRP-l/PGN inhibitory assay.

[0043] FIG. 7 shows representative monovalent TREM1 antibody construct concentration-dependent activation compared to representative bivalent TREM1 antibody in a TREM1 activation assay.

[0044] FIG. 8 shows a representative quantification of U937-TD-IL8 reporter activity after treatment with PGLYRP1/PGN. or PGLYRPl/PGN+anti-TREMl mAb. The scale bars represent s.e.m., * P<0.05.

[0045] FIG. 9 shows effect of using anti-TREMl mAb (4 mg/kg, i.p. for Bivalent mAb or 8.5 mg/kg, i.p. for Monovalent antibody construct) on sepsis scores 24 hour after LPS (5 mg/kg. i.p.) administration. The scale bars represent s.e.m., *** P<0.001

[0046] FIG. 10 shows that an equivalent dose of the monovalent antibody construct (W002) is as effective as its corresponding bivalent antibody on sepsis scores at 24 hours in mice with LPS-induced sepsis.

[0047] FIG. 11 shows the monovalent antibody construct suppresses cytokine and chemokine production in the spleen of mice after 24 hours of LPS stimulation, as measured using an ELISA assay.

[0048] FIGs. 12A and 12B show the inhibitory effects of treatment with increasing concentrations of the monovalent antibody construct or its corresponding bivalent antibody on a proinflammatory cytokine in BMDMs isolated from hTREMl K/I mice without LPS stimulation or Jurkat cells overexpressing TREM1 and DAP 12, respectively. [0049] FIG. 13 shows the inhibitory effects of treatment with increasing concentrations of the monovalent antibody construct or bivalent antibody on a proinflammatory cytokine in BMDMs isolated from hTREMl K/I mice with LPS stimulation and without LPS stimulation.

[0050] FIG. 14 shows results for a broader concentration range of antibodies in FIG. 13.

[0051] FIG. 15 shows the inhibitory effect of the monovalent antibody construct on TNF-a production in HuMDM as compared to its corresponding bivalent antibody. The scale bars represent s.e.m.. P<0.05. PO.OOl. *** P0.001.

7. DETAILED DESCRIPTION

[0052] Provided herein are antibody constructs that selectively bind to TREM1 and compositions comprising the antibody constructs, wherein the antibody constructs comprise, consist, or consist essentially of a first polypeptide comprising a VH and 1, 2, or 3 of a CHI, CH2, and/or CH3, and a second polypeptide comprising, consisting, or consisting essentially of a VL and 1, 2, or 3 of a CL, CH2, and/or CH3. In some embodiments, when present, the first polypeptide comprises a VH, CHI, CH2, and CH3 in the following order: VH. CHI. CH2. and CH3, and, when present, the second polypeptide comprises a VL, CL. CH2, and CH3 in the following order: VL, CL, CH2, and CH3. Also provided are methods of using the antibody constructs, such as therapeutic methods. In some embodiments, the antibody constructs described herein do not induce concentration-dependent activation.

7.1. Definitions

[0053] Unless otherwise defined, all terms of art, notations, and other scientific terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this invention pertains. In some cases, terms with commonly understood meanings arc defined herein for clarity' and/or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a difference over what is generally understood in the art. The techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodologies by those skilled in the art, such as, for example, the widely utilized molecular cloning methodologies described in Sambrook et al., Molecular Cloning: A Laboratory Manual 2nd ed. (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor. NY. As appropriate, procedures involving the use of commercially available kits and reagents are generally carried out in accordance with manufacturer defined protocols and/or parameters unless otherwise noted.

[0054] As used herein, the singular forms “a,” “an,” and “the” include the plural referents unless the context clearly indicates otherw ise.

[0055] The term “about” indicates and encompasses an indicated value and a range above and below that value. In certain embodiments, the term “about” indicates the designated value ± 10%, ± 5%, or ± 1%. In certain embodiments, the term “about’ indicates the designated value ± one standard deviation of that value.

[0056] As used herein, the phrase, “acute inflammatory condition,” refers to an immune response to inflammatory stimuli which starts after a specific injury causing soluble mediators like cytokines, acute phase proteins, and chemokines to promote the migration of neutrophils and macrophages to the area of inflammation.

[0057] “Affinity” refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless indicated otherwise, as used herein, “binding affinity ” refers to intrinsic binding affinity, which reflects a 1 :1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (K_D). Affinity can be measured by common methods known in the art, including those described herein. Affinity can be determined, for example, using surface plasmon resonance (SPR) technology, such as a Biacore® instrument, or using bio-layer interferometry technology⁷, such as an Octet® instrument.

[0058] An “affinity matured” antibody is one with one or more alterations in one or more CDRs or FRs that result in an improvement in the affinity of the antibody for its antigen, compared to a parent antibody which does not possess the alteration(s). In one embodiment, an affinity matured antibody has nanomolar or picomolar affinity for the target antigen. Affinity matured antibodies may be produced using a variety of methods known in the art. For example, Marks et al. (Bio Technology, 1992, 10:779-783, incorporated by reference in its entirety) describes affinity maturation by VH and VL domain shuffling. Random mutagenesis of CDR and/or framework residues is described by, for example, Barbas et al. (Proc. Nat. Acad. Sci. U.S.A., 1994, 91:3809-3813); Schier et al., Gene, 1995, 169:147-155; Yelton et al., J. Immunol., 1995, 155:1994-2004; Jackson et al., J. Immunol., 1995, 154:3310-33199; and Hawkins et al, J. Mol. Biol., 1992, 226:889-896, each of which is incorporated by reference in its entirety.

[0059] The term “antibody” describes a type of immunoglobulin molecule and is used herein in its broadest sense. An antibody specifically includes intact antibodies (e.g., intact immunoglobulins), and antibody fragments and antigen binding proteins. Antibodies comprise at least one antigen-binding domain. One example of an antigen-binding domain is an antigen binding domain formed by a VH-VL dimer. An “TREM1 antibody,” “anti-TREMl antibody,” “TREM1 Ab.” “TREM1 -specific antibody.” or “anti-TREMl Ab” is an antibody, as described herein, which binds specifically to the antigen TREM1. As used herein, the terms “monovalent antibody” and “anti-TREMl monovalent antibody” or “monovalent antibody construct” or “anti-TREMl monovalent antibody construct” are used interchangeably. They generally refer to an antibody construct capable of specifically binding to the antigen TREM1 with only a single functional antigen-binding site. In contrast, a bivalent antibody has tw o functional antigen-binding sites.

[0060] The term “monovalent antibody” refers to an antibody that has only one binding site for an antigen. Monovalent antibodies are highly specific and can bind to only one specific epitope on an antigen at a time. Monovalent antibodies are typically single-chain or antibody fragments (e.g.. singlechain variable fragments (scFv) or Fab fragments).

[0061] The term “bivalent antibody” refers to an antibody that has two identical antigen-binding sites. These binding sites are typically located on different heavy chain arms of the antibody molecule (e.g., on the Fab regions of an IgG antibody). IgG antibodies are examples of bivalent antibodies. The two binding sites allow the antibody to bind to two epitopes, which may be on the same or different molecules of the antigen.

[0062] The term “antibody construct” refers to an antibody molecule comprising two polypeptide chains: one polypeptide chain comprising a heavy chain variable region (V_H) and one or more regions, and one polypeptide chain comprising a light chain variable region (V_L) and one or more regions. Generally, the one or more regions comprises, consists, or consists essentially of 1, 2, or 3 of a CHI, CH2, and/or CH3 or 1, 2. or 3 of a CL, CH2. and/or CH3.

[0063] The VH and VL regions may be further subdivided into regions of hypervariability ("hypervariable regions (HVRs);” also called “complementarity detennining regions” (CDRs)) interspersed with regions that are more conserved. The more conserved regions are called framework regions (FRs). Each VH and V_L generally comprises three CDRs and four FRs, arranged in the following order (from N-terminus to C-terminus): FR1 - CDR1 - FR2 - CDR2 - FR3 - CDR3 - FR4. The CDRs are involved in antigen binding, and confer antigen specificity and binding affinity to the antibody. See Kabat et al., Sequences of Proteins of Immunological Interest 5th ed. (1991) Public Health Sendee. National Institutes of Health, Bethesda, MD, incorporated by reference in its entirety.

[0064] The light chain from any vertebrate species can be assigned to one of two types, called kappa and lambda, based on the sequence of the constant domain.

[0065] The heavy chain from any vertebrate species can be assigned to one of five different classes (or isotypes): IgA, IgD, IgE, IgG, and IgM. These classes are also designated a, 5, e, y, and p. respectively. The IgG and IgA classes are further divided into subclasses on the basis of differences in sequence and function. Humans express the following subclasses: IgGl, IgG2, IgG3, IgG4, IgAl. and IgA2.

[0066] An “antibody fragment” comprises a portion of an intact antibody, such as the antigen binding or variable region of an intact antibody. Antibody fragments include, for example, Fv fragments, Fab fragments. F(ab')2 fragments, Fab' fragments, scFv (sFv) fragments, and scFv-Fc fragments. [0067] The term “chimeric antibody” refers to an antibody in which a portion of the heavy and/or light chain is derived from a particular source or species, while the remainder of the heavy and/or light chain is derived from a different source or species.

[0068] The term “analog” or “an analog thereof’ refers to a molecule that is similar to a naturally occurring molecule that has some modifications in structure and/or function that enhance or modify its activity.

[0069] As used herein, the phrases, “chronic inflammatory disease” or “chronic inflammatory condition” are understood to mean any chronic disease or condition whose slowly and gradually evolving pathophysiology is directly related to inflammation caused by pathogenic or sterile material or autoimmune processes. In some embodiments, the hallmarks of chronic inflammation are the infiltration of the primary inflammatory cells such as macrophages, lymphocytes, and plasma cells in the tissue site, producing inflammatory cytokines, growth factors, enzymes, and hence contributing to the progression of tissue damage and secondary repair. In some embodiments, chronic inflammatory diseases comprise, consist, or consist essentially of chronic respiratory diseases, heart disorders, cancer, sarcopenia, frailty, obesity, and diabetes.

[0070] The term “combinations thereof’ includes every possible combination of elements to which the term refers.

[0071] When used herein in the context of two or more antibodies and/or antibody constructs, the term “competes with” or “cross-competes with” indicates that the two or more antibodies and/or antibody constructs compete for binding to an antigen (e.g., TREM1). In one exemplary assay, TREM1 is coated on a plate and allowed to bind a first antibody, after which a second, labeled antibody is added. If the presence of the first antibody reduces binding of the second antibody, then the antibodies compete. The term “competes with” also includes combinations of antibodies where one antibody reduces binding of another antibody, but where no competition is observed when the antibodies are added in the reverse order. However, in some embodiments, the first and second antibodies inhibit binding of each other, regardless of the order in which they are added. In some embodiments, one antibody reduces binding of another antibody to its antigen by at least 50%, at least 60%, at least 70%. at least 80%, or at least 90%.

[0072] The phrase “concentration-dependent activation,” as used herein, refers to the concentrationdependent effect of an antibody or antibody construct that results in the inhibition of a target at low concentrations of the antibody or antibody construct and results in the activation of the target at higher concentrations of the antibody or antibody construct.

[0073] A “conservative substitution” or a “conservative amino acid substitution,” refers to the substitution of one or more amino acids with one or more chemically or functionally similar amino acids. Conservative substitution tables providing similar amino acids are well known in the art. Polypeptide sequences having such substitutions are known as “conservatively modified variants.” Byway of example, the following groups of amino acids are considered conservative substitutions for one another.

[0074] Additional conservative substitutions may be found, for example, in Creighton, Proteins: Structures and Molecular Properties 2nd ed. (1993) W. H. Freeman & Co.. New York. NY. An antibody generated by making one or more conservative substitutions of amino acid residues in a parent antibody is referred to as a “conservatively modified variant.”

[0075] The term “amino acid” refers to the twenty common naturally occurring amino acids. Naturally occurring amino acids include alanine (Ala; A), arginine (Arg; R), asparagine (Asn; N). aspartic acid (Asp; D), cysteine (Cys; C); glutamic acid (Glu; E), glutamine (Gin; Q), Glycine (Gly; G); histidine (His; H), isoleucine (He; I), leucine (Leu; L), lysine (Lys; K), methionine (Met; M), phenylalanine (Phe; F), proline (Pro; P), serine (Ser; S), threonine (Thr; T), tryptophan (Trp; W), tyrosine (Tyr; Y), and valine (Vai; V).

[0076] The phrase ‘‘disease associated with expression of TREM1” or “condition associated with expression of TREM1.” includes, but is not limited to infections (e.g., sepsis, CO VID-19, and HIV), systemic conditions (e.g.. a metabolic condition such as diabetes and insulin resistance, sarcopenia, and physical frailty), organ specific diseases and conditions (e.g., pancreas such as pancreatitis; liver such as fibrosis, steatosis, and alcoholic liver disease; renal such as acute kidney injury and chronic kidney injury ; lungs such as COPD, non-small cell lung cancer, asthma, bleomycin induced fibrosis, and tuberculosis; eyes such as retinopathy; periodontitis; cardiovascular diseases such as heart disease, peripheral arterial disease, acute myocardial infarction (AMI), atherosclerosis, and restenosis of coronary arteries; and neurologic diseases or conditions such as stroke, subarachnoid haemorrhage, traumatic brain injury (TBI), multiple sclerosis (MS), Parkinson's disease, and epilepsy), autoimmune diseases or conditions (e.g., Rheumatoid arthritis (RA). colitis, irritable bowel syndrome, type-1 diabetes mellitus, psoriasis, and lupus), osteoarthritis, gout, and chromosomal conditions (e.g., Trisomy 21 (Down syndrome)).

[0077] As used herein, the term “disabling or reducing” or the phrase “disabling or reducing Triggering Receptor Expressed on Myeloid Cells 1 (TREM1) expression” or “disabling or reducing Triggering Receptor Expressed on Myeloid Cells 1 (TREM1) signaling” refers to inhibiting and/or interfering with the expression and/or function of TREM1. The term generally relates to inhibiting TREM1 function while permitting other activity of the myeloid cells.

[0078] The term “epitope” means a portion of an antigen capable of specific binding to an antibody. Epitopes frequently consist of surface-accessible amino acid residues and/or sugar side chains and may have specific three-dimensional structural characteristics, as well as specific charge characteristics. Conformational and non-conformational epitopes are distinguished in that the binding to the former but not the latter is lost in the presence of denaturing solvents. An epitope may comprise amino acid residues that are directly involved in the binding, and other amino acid residues, which are not directly involved in the binding. The epitope to which an antibody binds can be determined using known techniques for epitope determination such as, for example, testing for antibody construct binding to TREM1 variants with different point-mutations.

[0079] “Fv” fragments comprise a non-covalently -linked dimer of one heavy chain variable domain and one light chain variable domain. [0080] “Fab” fragments comprise, in addition to the heavy and light chain variable domains, the constant domain of the light chain and die first constant domain (CHI) of the heavy' chain. Fab fragments may be generated, for example, by papain digestion of a full-lengdi antibody.

[0081] "F(ab')2 fragments contain two Fab' fragments joined, near the hinge region, by disulfide bonds. F(ab')2 fragments may be generated, for example, by pepsin digestion of an intact antibody. The F(ab') fragments can be dissociated, for example, by treatment with B-mercaptoethanol.

[0082] “Humanized” forms of non-human antibodies are chimeric antibodies that contain minimal sequence derived from the non-human antibody. A humanized antibody is generally a human immunoglobulin (recipient antibody) in which residues from one or more CDRs are replaced by residues from one or more CDRs of a non-human antibody (donor antibody). The donor antibody can be any suitable non-human antibody, such as a mouse, rat. rabbit, chicken, or non-human primate antibody having a desired specificity, affinity , or biological effect. In some instances, selected framework region residues of the recipient antibody⁷ are replaced by⁷ the corresponding framework region residues from the donor antibody. Humanized antibodies may also comprise residues that are not found in either the recipient antibody or the donor antibody. Such modifications may be made to further refine antibody function. For further details, see Jones et al., Nature, 1986, 321:522-525; Riechmann et al., Nature, 1988, 332:323-329; and Presta, Curr. Op. Struct. Biol., 1992, 2:593-596, each of which is incorporated by reference in its entirety'.

[0083] A “human antibody” is one which possesses an amino acid sequence corresponding to that of an antibody produced by' a human or a human cell, or derived from a non-human source that utilizes a human antibody⁷ repertoire or human antibody-encoding sequences (e.g., obtained from human sources or designed de novo). Human antibodies specifically exclude humanized antibodies.

[0084] Percent "identity” between a polypeptide sequence and a reference sequence, is defined as the percentage of amino acid residues in the polypeptide sequence that are identical to the amino acid residues in the reference sequence, after aligning the sequences and introducing gaps, if necessary⁷, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN, MEGALIGN (DNASTAR), CLUSTALW, or CLUSTAL OMEGA software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.

[0085] The term “immunoglobulin” refers to a class of structurally related proteins generally comprising two pairs of polypeptide chains: one pair of light (L) chains and one pair of heavy (H) chains. In an “intact immunoglobulin,” all four of these chains are interconnected by disulfide bonds. The structure of immunoglobulins has been well characterized. See, e.g., Paul, Fundamental Immunology 7th ed., Ch. 5 (2013) Lippincott Williams & Wilkins, Philadelphia, PA. Briefly, each heavy chain typically comprises a heavy' chain variable region (V_H) and a heavy' chain constant region (CH). The heavy chain constant region ty pically comprises three domains, CHI, CH2, and Cnv Each light chain typically comprises a light chain variable region (VL) and a light chain constant region. The light chain constant region typically comprises one domain, abbreviated CL.

[0086] An “isolated antibody” is one that has been separated and/or recovered from a component of its natural environment. Components of the natural environment may include enzymes, hormones, and other proteinaceous or non-proteinaceous materials. In some embodiments, an isolated antibody is purified to a degree sufficient to obtain at least 15 residues of N-tcnninal or internal amino acid sequence, for example by use of a spinning cup sequenator. In some embodiments, an isolated antibody is purified to homogeneity by gel electrophoresis (e.g., SDS-PAGE) under reducing or nonreducing conditions, with detection by Coomassie blue or silver stain. An isolated antibody includes an antibody in situ within recombinant cells, since at least one component of the antibody's natural environment is not present. In some embodiments, an isolated antibody is prepared by at least one purification step.

[0087] In some embodiments, an isolated antibody is purified to at least 80%, 85%, 90%, 95%, or 99% by weight. In some embodiments, an isolated antibody is provided as a solution comprising at least 85%, 90%, 95%, 98%, 99% to 100% by weight of an antibody, the remainder of the weight comprising the weight of other solutes dissolved in the solvent.

[0088] The term “kd” (sec^-1), as used herein, refers to the dissociation rate constant of a particular antibody -antigen interaction. This value is also referred to as the k_off value.

[0089] The term “k_a” (M %cc as used herein, refers to the association rate constant of a particular antibody -antigen interaction. This value is also referred to as the k_on value.

[0090] The term “KD” (M), as used herein, refers to the dissociation equilibrium constant of a particular antibody -antigen interaction. KD = kd/k_a.

[0091] The term “K_A” (M^-1), as used herein, refers to the association equilibrium constant of a particular antibody -antigen interaction. K_A = k_a/kd.

[0092] The amino acid sequence boundaries of a CDR can be determined by one of skill in the art using any of a number of known numbering schemes, including those described by Kabat et al., supra (“Kabat” numbering scheme); Al-Lazikani et al.. 1997, J. Mol. Biol.. 273:927 -948 (“Chothia” numbering scheme); MacCallum etal., 1996. J. Mol. Biol. 262:732-745 (“Contact” numbering scheme); Lefranc et al., Dev. Comp. Immuno!., 2003, 27:55-77 (“IMGT” numbering scheme); and Honegge and Pliickthun, J. Mol. Bio!., 2001, 309:657-70 (“AHo” numbering scheme), each of which is incorporated by reference in its entirety. [0093] Table 1 provides the positions of CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR- H3 as identified by the Kabat and Chothia schemes. For CDR-H1, residue numbering is provided using both the Kabat and Chothia numbering schemes.

[0094] Unless otherw ise specified, the numbering scheme used for identification of a particular CDR herein is the Kabat/Chothia numbering scheme. Where the residues encompassed by these two numbering schemes diverge, the numbering scheme is specified as either Kabat or Chothia.

* The C-terminus of CDR-H1, when numbered using the Kabat numbering convention, varies between H32 and H34, depending on the length of the CDR.

[0095] The “EU numbering scheme” is generally used when referring to a residue in an antibody heavy chain constant region (e.g., as reported in Kabat et al., supra). Unless stated otherwise, the EU numbering scheme is used to refer to residues in antibody heavy chain constant regions described herein.

[0096] The term “monoclonal antibody” refers to an antibody or antibody construct from a population of substantially homogeneous antibodies or antibody constructs. A population of substantially homogeneous antibodies comprises antibodies that are substantially similar and that bind the same epitope(s). except for variants that may normally arise during production of the monoclonal antibody. Such variants are generally present in only minor amounts. A monoclonal antibody is typically obtained by a process that includes the selection of a single antibody from a plurality of antibodies. For example, the selection process can be the selection of a unique clone from a plurality of clones, such as a pool of hybridoma clones, phage clones, yeast clones, bacterial clones, or other recombinant DNA clones. The selected antibody can be further altered, for example, to improve affinity for the target (“affinity maturation”), to humanize the antibody , to improve its production in cell culture, and/or to reduce its immunogenicity in a subject.

[0097] As used herein, the term “myeloid cell” refers to a cell derived from a common myeloid progenitor (CMP) in the bone marrow or a macrophage originating prenatally from the embryonic sac or fetal liver.

[0098] "Single-chain Fv” or “sFv” or “scFv” antibody fragments comprise a V_H domain and a V_L domain in a single polypeptide chain. The V_H and V_L are generally linked by a peptide linker. See Pliickthun A. (1994). Antibodies from Escherichia coli. In Rosenberg M. & Moore G.P. (Eds.), The Pharmacology of Monoclonal Antibodies vol. 113 (pp. 269-315). Springer-Verlag, New York, incorporated by reference in its entirety. “scFv-Fc” fragments comprise an scFv attached to an Fc domain. For example, an Fc domain may be attached to the C-terminal of the scFv. The Fc domain may follow the VH or VL, depending on the orientation of the variable domains in the scFv (i.e., VH-VL or VL-VH). Any suitable Fc domain known in the art or described herein may be used.

[0099] With regard to the binding of an antibody to a target molecule, the terms “specific binding,” “specifically binds to,” “specific for,” “selectively binds,” and “selective for” a particular antigen (e.g., a polypeptide target) or an epitope on a particular antigen mean binding that is measurably different from a non-specific or non-selective interaction. Specific binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule. Specific binding can also be determined by competition with a control molecule that is similar to the target, such as an excess of non-labeled target. In that case, specific binding is indicated if the binding of the labeled target to a probe is competitively inhibited by the excess non-labeled target.

[0100] As used herein, the term “subject” means a mammalian subject. Exemplary subjects include, but are not limited to humans, monkeys, dogs, cats, mice, rats, cows, horses, camels, avians, goats and sheep. In certain embodiments, the subject is a human. In some embodiments, the subject has a chronic inflammatory condition, acute inflammatory' condition, systemic conditions, a chromosomal condition, cancer, an autoimmune disease or condition, and/or an infection that can be treated with an antibody construct provided herein. In some embodiments, the subject is a human that is suspected to have a chronic inflammatory condition, acute inflammatory condition, systemic conditions, a chromosomal condition, cancer, an autoimmune disease or condition, and/or an acute infection and chronic infection.

[0101] The term “Triggering receptors expressed on myeloid cells 1” or “TREM1” describes an immunoglobulin superfamily transmembrane protein. Specifically, human TREM1 is encoded by the TREM1 gene (NCBI Gene ID: 54210).

[0102] “Treating” or “treatment” of any disease, disorder, or condition refers, in certain embodiments, to ameliorating a disease, disorder, or condition that exists in a subject. In another embodiment, “treating” or “treatment” includes ameliorating at least one physical parameter, which may be indiscernible by the subject. In yet another embodiment, “treating” or “treatment” includes modulating the disease, disorder, or condition, either physically (e.g., stabilization of a discernible symptom) or physiologically (e.g., stabilization of a physical parameter) or both. In yet another embodiment, “treating” or “treatment” includes delaying or preventing the onset of the disease, disorder, or condition.

[0103] As used herein, the term “therapeutically effective amount” or “effective amount” refers to an amount of an antibody or composition that when administered to a subject is effective to treat a disease or disorder. 7.2. Antibody Constructs

[0104] Provided herein are antibody constructs that selectively bind to TREM1. wherein the antibody constructs comprise, consist, or consist essentially of a first polypeptide comprising a VH and 1. 2. or 3 of a CHI, CH2, and/or CH3, and a second polypeptide comprising, consisting, or consisting essentially of a VL and 1. 2, or 3 of a CL, CH2, and/or CH3. In some embodiments, when present, the first polypeptide comprises a VH, CHI, CH2, and CH3 in the following order: VH, CHI, CH2, and CH3, and, when present, the second polypeptide comprises a VL, CL, CH2. and CH3 in the following order: VL. CL. CH2, and CH3. In some embodiments, the antibody constructs described herein do not induce concentration-dependent activation.

[0105] A first aspect therefore provides an antibody construct, wherein the antibody construct comprises, consists, or consists essentially of a first polypeptide comprising, consisting, or consisting essentially of a heavy chain variable region (VH) and one or more regions and a second polypeptide comprising, consisting, or consisting essentially of a light chain variable region (VL) and one or more regions, a) the first polypeptide comprising a VH and 1, 2, or 3 of a CHI, CH2, and/or CH3, wherein the VH comprises: i) a VHCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 12-13, wherein the CDRs are according to Chothia or ii) a VHCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 1-2. wherein the CDRs are according to Kabat; iii) a VHCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 34-35. wherein the CDRs are according to Chothia or iv) a VHCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 23-24, wherein the CDRs are according to Kabat; and/or v) a VHCDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 45-46; and b) the second polypeptide comprising a VL and 1. 2, or 3 of a CL, CH2, and/or CH3, wherein the VL comprises: i) a VLCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 55-56; ii) a VLCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 67-68; or iii) a VLCDR3 comprising the amino acid sequence set forth hr any one of SEQ ID NOs: 77-78; wherein, when present, the first polypeptide comprises a VH. CHI, CH2, and CH3 in the following order: VH, CHI. CH2, and CH3, and wherein, when present, the second polypeptide comprises a VL, CL, CH2, and CH3 in the following order: VL, CL, CH2, and CH3.

[0106] In some embodiments, the first polypeptide comprises, consists, or consists essentially of a VH and CHI, CH2, and CH3 in the following order: VH, CHI, CH2, and CH3, the CHI comprises the amino acid sequence set forth in SEQ ID NO: 121 or a variant thereof having at least 85% (e.g., at least 90%, at least 95%, or at least 98%) identity with the amino acid sequence of SEQ ID NO: 121, wherein the CH2 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 126-127 or a variant thereof having at least 85% (e.g., at least 90%, at least 95%, or at least 98%) identity with the amino acid sequence of SEQ ID NO: 126-127, and wherein the CH3 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 132-134 or a variant thereof having at least 85% (e.g., at least 90%, at least 95%, or at least 98%) identity with the amino acid sequence of SEQ ID NO: 132-134.

[0107] In some embodiments, the second polypeptide comprises, consists, or consists essentially of a VL and CL, CH2, and CH3 in the following order: VL, CL, CH2, and CH3, wherein the CL comprises the amino acid sequence set forth in SEQ ID NO: 144 or a variant thereof having at least 85% (e.g., at least 90%. at least 95%, or at least 98%) identity with the amino acid sequence of SEQ ID NO: 144. the CH2 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 126-127 or a variant thereof having at least 85% (e.g., at least 90%, at least 95%, or at least 98%) identity with the amino acid sequence of SEQ ID NO: 126-127, and the CH3 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 132-134 or a variant thereof having at least 85% (e.g., at least 90%. at least 95%, or at least 98%) identity with the amino acid sequence of SEQ ID NO: 132-134.

[0108] In some embodiments, the first polypeptide comprises, consists, or consists essentially of: i) a VHCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, wherein the CDR is according to Chothia or ii) a VHCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, wherein the CDR is according to Kabat; iii) a VHCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34, wherein the CDR is according to Chothia or iv) a VHCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 23, wherein the CDR is according to Kabat; and/or v) a VHCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 45 ; and the second polypeptide comprises, consists, or consists essentially of: i) a VLCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 55; ii) a VLCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 67; and/or iii) a VLCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 77.

[0109] In some embodiments, the first polypeptide comprises, consists, or consists essentially of: i) a VHCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 12, wherein the CDR is according to Chothia or ii) a VHCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1 or a variant thereof having at least 50%. 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 1, wherein the CDR is according to Kabat; iii) a VHCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 34, wherein the CDR is according to Chothia or iv) a VHCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 23 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 23, wherein the CDR is according to Kabat; and/or v) a VHCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 45 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 45; and the second polypeptide comprises, consists, or consists essentially of: i) a VLCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 55 or a variant thereof having at least 50%, 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 at least 98% identity with tire amino acid sequence set forth in SEQ ID NO: 55; ii) a VLCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 67 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 67; and/or iii) a VLCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 77 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 77.

[0110] In some embodiments, the antibody construct comprises a three-dimensional (3D) conformation, binding capability, binding specificity, thermostability, cytotoxicity and/or immunogenicity having at least 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 at least 98% identical to an antibody construct comprising a first polypeptide comprises, consists, or consists essentially of: i) a VHCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12. wherein the CDR is according to Chothia or ii) a VHCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, wherein the CDR is according to Kabat; iii) a VHCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34. wherein the CDR is according to Chothia or iv) a VHCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 23, wherein the CDR is according to Kabat; and/or v) a VHCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 45 ; and the second polypeptide comprises, consists, or consists essentially of: i) a VLCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 55; ii) a VLCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 67; and/or iii) a VLCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 77. [0111] In some embodiments, the first polypeptide comprises, consists, or consists essentially of: i) a VHCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, wherein the CDR is according to Chothia or ii) a VHCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, wherein the CDR is according to Kabat; iii) a VHCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34, wherein the CDR is according to Chothia or iv) a VHCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 23, wherein the CDR is according to Kabat; v) a VHCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 45; vi) a CHI comprising the amino acid sequence set forth in SEQ ID NO: 121; vii) a CH2 comprising the amino acid sequence set forth in SEQ ID NO: 127; and viii) a CH3 comprising the amino acid sequence set forth in SEQ ID NO: 133: and the second polypeptide comprises, consists, or consists essentially of: i) a VLCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 55; ii) a VLCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 67; iii) a VLCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 77; iv) a CL comprising the amino acid sequence set forth in SEQ ID NO: 144; v) a CH2 comprising the amino acid sequence set forth in SEQ ID NO: 127; and vi) a CH3 comprising the amino acid sequence set forth in SEQ ID NO: 134.

[0112] In some embodiments, the first polypeptide comprises, consists, or consists essentially of: i) a VHCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 12, wherein the CDR is according to Chothia or ii) a VHCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1 or a variant thereof having at least 50%. 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 1. wherein the CDR is according to Kabat; iii) a VHCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 34, wherein the CDR is according to Chothia or iv) a VHCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 23 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 23, wherein the CDR is according to Kabat; v) a VHCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 45 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 45; vi) a CHI comprising the amino acid sequence set forth in SEQ ID NO: 121 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 121; vii) a CH2 comprising the amino acid sequence set forth in SEQ ID NO: 127 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 127; and viii) a CH3 comprising the amino acid sequence set forth in SEQ ID NO: 133 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 133; and the second polypeptide comprises, consists, or consists essentially of: i) a VLCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 55 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 55; ii) a VLCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 67 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 67; iii) a VLCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 77 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 77; iv) a CL comprising the amino acid sequence set forth in SEQ ID NO: 144 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 144; v) a CH2 comprising the amino acid sequence set forth in SEQ ID NO: 127 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 127; and vi) a CH3 comprising the amino acid sequence set forth in SEQ ID NO: 134 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 134.

[0113] In some embodiments, the antibody construct comprises a three-dimensional (3D) conformation, binding capability, binding specificity, thermostability, cytotoxicity and/or immunogenicity having at least 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 at least 98% identical to an antibody construct comprising a first polypeptide comprises, consists, or consists essentially of: i) a VHCDR1 comprising the ammo acid sequence set forth in SEQ ID NO: 12, wherein the CDR is according to Chothia; o ii) a VHCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, wherein the CDR is according to Kabat; iii) a VHCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34, wherein the CDR is according to Chothia or iv) a VHCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 23, wherein the CDR is according to Kabat; v) a VHCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 45; vi) a CHI comprising the amino acid sequence set forth in SEQ ID NO: 121; vii) a CH2 comprising the amino acid sequence set forth in SEQ ID NO: 127; and viii) a CH3 comprising the amino acid sequence set forth in SEQ ID NO: 133; and the second polypeptide comprises, consists, or consists essentially of: i) a VLCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 55; ii) a VLCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 67; iii) a VLCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 77; iv) a CL comprising the amino acid sequence set forth in SEQ ID NO: 144; v) a CH2 comprising the amino acid sequence set forth in SEQ ID NO: 127; and vi) a CH3 comprising the amino acid sequence set forth in SEQ ID NO: 134.

[0114] In some embodiments, the first polypeptide comprises, consists, or consists essentially of a VH and CHI, CH2, and CH3 in the following order: VH, CHI, CH2, and CH3, wherein the VH comprises die amino acid sequence set forth in SEQ ID NO: 89 or a variant thereof having at least 55%, at least 65%, at least 75%. at least 85%, or at least 95% identity with the amino acid sequence of SEQ ID NO: 89, wherein the CHI comprises the amino acid sequence set forth in SEQ ID NO: 121 or a variant thereof having at least 55%, at least 65%. at least 75%, at least 85%. or at least 95% identity with the amino acid sequence of SEQ ID NO: 121, wherein the CH2 comprises the amino acid sequence set forth in SEQ ID NO: 127 or a variant thereof having at least 55%. at least 65%, at least 75%. at least 85%, or at least 95% identity with the amino acid sequence of SEQ ID NO: 127, and wherein the CH3 comprises the amino acid sequence set forth in SEQ ID NO: 133 or a variant thereof having at least 55%, at least 65%. at least 75%, at least 85%. or at least 95% identity with the amino acid sequence of SEQ ID NO: 133; and the second polypeptide comprises, consists, or consists essentially of a VL and CL, CH2, and CH3 in the following order: VL, CL, CH2, and CH3, wherein the VL comprises the amino acid sequence set forth in any one of SEQ ID NO: 101 or a variant thereof having at least 55%, at least 65%. at least 75%, at least 85%. or at least 95% identity with the amino acid sequence of any one of SEQ ID NO: 101. wherein the CL comprises the amino acid sequence set forth in any one of SEQ ID NO: 144 or a variant thereof having at least 55%, at least 65%, at least 75%, at least 85%, or at least 95% identity with the amino acid sequence of any one of SEQ ID NO: 144. wherein the CH2 comprises the amino acid sequence set forth in SEQ ID NO: 127 or a variant thereof having at least 55%, at least 65%, at least 75%, at least 85%, or at least 95% identity with the amino acid sequence of SEQ ID NO: 127, and wherein the CH3 comprises the amino acid sequence set forth in SEQ ID NO: 134 or a variant thereof having at least 55%, at least 65%, at least 75%, at least 85%. or at least 95% identity' with the amino acid sequence of SEQ ID NO: 134.

[0115] In some embodiments, the first polypeptide comprises one or more mutations in the CH3 and the second polypeptide comprises one or more mutations in the CH3. In some embodiments, the one or more first polypeptide CH3 mutations and the one or more second polypeptide mutations are substitutions. In some embodiments, the one or more substitutions comprises, consists, or consists essentially of substitutions of an interface amino acid residue.

[0116] In some embodiments, the one or more mutations are in the CH3. In some embodiments, the antibody is a human antibody. In some embodiments, the antibody is a chimeric antibody. In some embodiments, the antibody is a humanized antibody. In some embodiments, the antibody is an affinity⁷ matured antibody. In some embodiments, the antibody is an affinity matured antibody derived from an illustrative sequence provided in this disclosure.

[0117] In some embodiments, the antibody construct is monovalent. In some embodiments, the antibody construct is bivalent. In some embodiments, the antibody construct specifically binds human Triggering Receptor Expressed on Myeloid Cells 1 (TREM1). In some embodiments, the antibody construct modulates human Triggering Receptor Expressed on Myeloid Cells 1 (TREM1) mediated signaling. In some embodiments, the antibody construct disrupts human Triggering Receptor Expressed on Myeloid Cells 1 (TREM1) dimerization and/or oligomerization. In some embodiments, the antibody construct inhibits TREM1 activation and/or signaling. In some embodiments, the antibody construct does not comprise concentration-dependent activation. In some embodiments, the antibody construct does not induce concentration-dependent activation.

[0118] In some embodiments, the antibody construct competes for binding with a Triggering Receptor Expressed on Myeloid Cells 1 (TREM1) ligand. In some embodiments, the Triggering Receptor Expressed on Myeloid Cells 1 (TREM1) ligand comprises, consists, or consists essentially of peptidoglycan recognition protein-1 (PGLYRP1). In some embodiments, the Triggering Receptor Expressed on Myeloid Cells 1 (TREM1) ligand comprises, consists, or consists essentially of peptidoglycan (PGN). In some embodiments, the Triggering Receptor Expressed on Myeloid Cells 1 (TREM1) ligand comprises, consists, or consists essentially of a peptidoglycan recognition protein- 1 (PGLYRPl)/peptidoglycan (PGN) complex. In some embodiments, the antibody construct competes for binding Triggering Receptor Expressed on Myeloid Cells 1 (TREM1) with a PGLYRP1/PGN complex. When multimerized or complexed with PGN, PGLYRP1 is able to activate TREM1 and enhance cytokine production in human neutrophils and macrophages. In some embodiments, the antibody construct is capable of inhibiting or reducing PGLYRP1/PGN activation of TREM1.

[0119] In some embodiments, the antibody⁷ construct down-regulates TREM1. In some embodiments, the antibody construct down-regulates TREM1 amplification of pro-inflammatory reactions.

[0120] In some embodiments, the antibody construct down-regulates TREM1 amplification of inflammatory cytokines or chemokines. In some embodiments, the cytokines or chemokines comprise, consist essentially of, or consist of one or more of IL-6, MIP2/CXCL2, IL-la. IL- 1 [3, IL-18, IL-33, and/or a mutant or an analog thereof. In some embodiments, the cytokines or chemokines comprise, consist essentially⁷ of, or consist of one or more of receptors, ligands, or binding targets of IL-6, MIP2/CXCL2, IL-la, IL- 10, IL- 18, IL-33, and/or a mutant or an analog thereof. In some embodiments, the cytokine comprises, consists essentially of, or consists of IL- 10.

[0121] In some embodiments, the antibody construct comprises an Fc region and comprises at least one of: a reduced antibody -dependent cell-mediated cytotoxicity (ADCC) activity, a reduced complement-dependent cytotoxicity (CDC) activity, and a reduced antibody-mediated phagocytosis (ADCP) activity. In some embodiments, the antibody construct comprises one or more warheads or antibody -drug conjugates for administration to a subject having one or more diseases or conditions associated with TREM1 expression/regulation/modulation.

[0122] In some embodiments, the Fc region comprises, consists, or consists essentially of human IgGl, IgG2, IgG3. or IgG4 Fc. In some embodiments, the Fc region comprises, consists, or consists essentially of human IgGl Fc.

[0123] In some embodiments, the first polypeptide comprises an Fc region that comprises, consists, or consists essentially of the CH2 and CH3. In some embodiments, the Fc region comprises, consists, or consists essentially of an IgG Fc. In some embodiments, the Fc region comprises, consists, or consists essentially of an IgGl Fc. In some embodiments, the Fc region comprises, consists, or consists essentially of an IgG2 Fc. In some embodiments, the Fc region comprises, consists, or consists essentially of an IgG3 Fc. In some embodiments, the Fc region comprises, consists, or consists essentially of an IgG4 Fc. In some embodiments, the Fc region comprises, consists, or consists essentially of an IgA Fc. In >ome embodiments, the Fc region comprises, consists, or consists essentially of an IgD. In some embodiments, the Fc region comprises, consists, or consists essentially of an IgE. In some embodiments, the Fc region comprises, consists, or consists essentially of an IgM.

In some embodiments, the Fc region comprises, consists, or consists essentially of an IgAl. In some embodiments, the Fc region comprises, consists, or consists essentially of an IgA2.

[0124] In some embodiments, the second polypeptide comprises an Fc region that comprises, consists, or consists essentially of the CH2 and CH3. In some embodiments, the Fc region comprises, consists, or consists essentially of an IgG Fc. In some embodiments, the Fc region comprises, consists, or consists essentially of an IgGl Fc. In some embodiments, the Fc region comprises, consists, or consists essentially of an IgG2 Fc. In some embodiments, the Fc region comprises, consists, or consists essentially of an IgG3 Fc. In some embodiments, the Fc region comprises, consists, or consists essentially of an IgG4 Fc. In some embodiments, the Fc region comprises, consists, or consists essentially of an IgA Fc. In some embodiments, the Fc region comprises, consists, or consists essentially of an IgD. In some embodiments, the Fc region comprises, consists, or consists essentially of an IgE. In some embodiments, the Fc region comprises, consists, or consists essentially of an IgM. In some embodiments, the Fc region comprises, consists, or consists essentially of an IgAl. In some embodiments, the Fc region comprises, consists, or consists essentially of an IgA2 [0125] In some embodiments, the antibody construct comprises an Fc region comprising modified Fey Receptor (FcyR) binding. In some embodiments, the Fc region comprises reduced Fey Receptor (FcyR) binding, wherein the FcyR is selected from the group consisting of: FcyRI, FcyRIIa, FcyRIIb, FcyRIIc, FcyRIIIa, and FcyRIIIb. In some embodiments, the antibody construct has receptor-ligand blocking, agonism, or antagonism activity.

[0126] In some embodiments, the light chain is a kappa light chain. In some embodiments, the light chain is a lambda light chain. In some embodiments, the antibody construct binds the extracellular domain of TREM1. In some embodiments, the antibody construct binds to TREM1 with a K_D less than or equal to 10 nM. In some embodiments, the contacting or binding or causing the cells to bind with the antibody construct occurs in vivo in a subject in need thereof. In some embodiments, the subject in need thereof has a disease or condition associated with TREM1. In some embodiments, the subject in need thereof has a disease or condition associated with TREM1 expression and/or its regulation of proinflammatory responses.

7.2.1. CDR-H3 Sequences

[0127] In some embodiments, the antibody construct comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 45-46. In some embodiments, the antibody construct comprises a CDR-H3 sequence comprising, consisting of. or consisting essentially of SEQ ID NO: 45. In some embodiments, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 46.

[0128] In some embodiments, the CDR-H3 sequence comprises, consists, or consists essentially of a variant of an illustrative CDR-H3 sequence provided in this disclosure. In some embodiments, the CDR-H3 sequence comprises, consists, or consists essentially of a sequence having at least 70%, 70%, 75%, 80%. 85%. 90%, or 95% identity with any of the illustrative CDR-H3 sequences provided in this disclosure. In some embodiments, the CDR-H3 sequence comprises, consists, or consists essentially of any of the illustrative CDR-H3 sequences provided in this disclosure, with 1, 2. or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions.

7.2.2. V_H Sequences Comprising Illustrative CDRs

[0129] In some embodiments, the antibody construct comprises a VH sequence comprising one or more CDR-H sequences comprising, consisting of, or consisting essentially of one or more illustrative CDR- H sequences provided in this disclosure, and variants thereof.

7.2.3. V_H Sequences Comprising Illustrative Kabat CDRs

[0130] In some embodiments, the antibody construct comprises a VH sequence comprising one or more Kabat CDR-H sequences comprising, consisting of, or consisting essentially of one or more illustrative Kabat CDR-H sequences provided in this disclosure, and variants thereof. 7.2.4. Kabat CDR-H3

[0131] In some embodiments, the antibody construct comprises a V_H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 45-46. In some embodiments, the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 45. In some embodiments, the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 46.

7.2.5. Kabat CDR-H2

[0132] In some embodiments, the antibody construct comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 23-24. In some embodiments, the antibody construct comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 23. In some embodiments, the antibody construct comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 24.

7.2.6. Kabat CDR-H1

[0133] In some embodiments, the antibody construct comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 1-2. In some embodiments, the antibody construct comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 1. In some embodiments, the antibody construct comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 2.

7.2.7. Kabat CDR-H3 + Kabat CDR-H2

[0134] In some embodiments, the antibody construct comprises a V_H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 45-46 and a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 23-24. In some embodiments, the Kabat CDR-H3 sequence and the Kabat CDR-H2 sequence are both from a single illustrative VH sequence provided in this disclosure. For example, in some embodiments, the Kabat CDR-H3 and Kabat CDR-H2 are both from a single illustrative VH sequence selected from SEQ ID NOS: 89-90.

7.2.8. Kabat CDR-H3 + Kabat CDR-H1

[0135] In some embodiments, the antibody construct comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 45-46. and a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 1-2. In some embodiments, the Kabat CDR-H3 sequence and the Kabat CDR-H1 sequence are both from a single illustrative VH sequence provided in this disclosure. For example, in some embodiments, the Kabat CDR-H3 and Kabat CDR-H1 are both from a single illustrative VH sequence selected from SEQ ID NOS: 89-90.

7.2.9. Kabat CDR-H1 + Kabat CDR-H2

[0136] In some embodiments, the antibody construct comprises a V_H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of. or consisting essentially of a sequence selected from SEQ ID NOS: 1-2 and a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 23-24. In some embodiments, the Kabat CDR-H1 sequence and the Kabat CDR-H2 sequence are both from a single illustrative VH sequence provided in this disclosure. For example, in some embodiments, the Kabat CDR-H1 and Kabat CDR-H2 are both from a single illustrative VH sequence selected from SEQ ID NOS: 89-90.

7.2.10. Kabat CDR-H1 + Kabat CDR-H2 + Kabat CDR-H3

[0137] In some embodiments, the antibody construct comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 1-2. a Kabat CDR-H2 sequence comprising, consisting of. or consisting essentially of a sequence selected from SEQ ID NOS: 23-24. and a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 45-46. In some embodiments, the Kabat CDR-H1 sequence, Kabat CDR-H2 sequence, and Kabat CDR-H3 sequence are all from a single illustrative VH sequence provided in this disclosure. For example, in some embodiments, the Kabat CDR-H1, Kabat CDR-H2, and Kabat CDR-H3 are all from a single illustrative V_H sequence selected from SEQ ID NOS: 89-90.

[0138] In some embodiments, the antibody construct comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 1. a Kabat CDR-H2 sequence comprising SEQ ID NO: 23, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 45. In some embodiments, the antibody construct comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 2, a Kabat CDR-H2 sequence comprising SEQ ID NO: 24, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 46.

7.2.11. Variants of VH Sequences Comprising Illustrative Kabat CDRs

[0139] In some embodiments, the VH sequences provided herein comprise a variant of an illustrative Kabat CDR-H3, CDR-H2, and/or CDR-H1 sequence provided in this disclosure.

[0140] In some embodiments, the Kabat CDR-H3 sequence comprises, consists, or consists essentially of a variant of an illustrative Kabat CDR-H3 sequence provided in this disclosure. In some embodiments, the Kabat CDR-H3 sequence comprises, consists, or consists essentially of a sequence having at least 70%, 75%, 80%. 85%, 90%, or 95% identity with any of the illustrative Kabat CDR-H3 sequences provided in this disclosure. In some embodiments, the Kabat CDR-H3 sequence comprises, consists, or consists essentially of any of the illustrative Kabat CDR-H3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions.

[0141] In some embodiments, the Kabat CDR-H2 sequence comprises, consists, or consists essentially of a variant of an illustrative Kabat CDR-H2 sequence provided in this disclosure. In some embodiments, the Kabat CDR-H2 sequence comprises, consists, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Kabat CDR-H2 sequences provided in this disclosure. In some embodiments, the Kabat CDR-H2 sequence comprises, consists, or consists essentially of any of the illustrative Kabat CDR-H2 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions.

[0142] In some embodiments, the Kabat CDR-H1 sequence comprises, consists, or consists essentially of a variant of an illustrative Kabat CDR-H1 sequence provided in this disclosure. In some embodiments, the Kabat CDR-H1 sequence comprises, consists, or consists essentially of a sequence having at least 70%, 75%, 80%. 85%, 90%, or 95% identity with any of die illustrative Kabat CDR-H1 sequences provided in this disclosure. In some embodiments, the Kabat CDR-H1 sequence comprises, consists, or consists essentially of any of the illustrative Kabat CDR-H1 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions arc conservative amino acid substitutions.

7.2.12. V_H Sequences Comprising Illustrative Chothia CDRs

[0143] In some embodiments, the antibody construct comprises a V_H sequence comprising one or more Chothia CDR-H sequences comprising, consisting of, or consisting essentially of one or more illustrative Chothia CDR-H sequences provided in this disclosure, and variants thereof.

7.2.13. Chothia CDR-H3

[0144] In some embodiments, the antibody construct comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 45-46. In some embodiments, the antibody construct comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 45. In some embodiments, the antibody construct comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 46.

7.2.14. Chothia CDR-H2

[0145] In some embodiments, the antibody construct comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 34-35. In some embodiments, the antibody construct comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 34. In some embodiments, the antibody construct comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 35.

7.2.15. Chothia CDR-H1

[0146] In some embodiments, the antibody construct comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of. or consisting essentially of a sequence selected from SEQ ID NOS: 12-13. In some embodiments, the antibody construct comprises a V_H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 12. In some embodiments, the antibody construct comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 13.

7.2.15.1. Chothia CDR-H3 + Chothia CDR-H2

[0147] In some embodiments, the antibody construct comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 45-46, and a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 34-35. In some embodiments, the Chothia CDR-H3 sequence and the Chothia CDR-H2 sequence are both from a single illustrative VH sequence provided in this disclosure. For example, in some embodiments, the Chothia CDR-H3 and Chothia CDR-H2 are both from a single illustrative V_H sequence selected from SEQ ID NOS: 89-90.

7.2.15.2. Chothia CDR-H3 + Chothia CDR-H1

[0148] In some embodiments, the antibody construct comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 45-46, and a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 12-13. In some embodiments, the Chothia CDR-H3 sequence and the Chothia CDR-H1 sequence are both from a single illustrative VH sequence provided in this disclosure. For example, in some embodiments, the Chothia CDR-H3 and Chothia CDR-H1 are both from a single illustrative VH sequence selected from SEQ ID NOS: 89-90.

7.2.15.3. Chothia CDR-H1 + Chothia CDR-H2

[0149] In some embodiments, the antibody construct comprises a V_H sequence comprising a Chothia CDR-H 1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 12-13 and a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 34-35. In some embodiments, the Chothia CDR-H1 sequence and the Chothia CDR-H2 sequence are both from a single illustrative Vn sequence provided in this disclosure. For example, in some embodiments, the Chothia CDR-H 1 and Chothia CDR-H2 are both from a single illustrative VH sequence selected from SEQ ID NOS: 89-90.

7.2.15.4. Chothia CDR-H1 + Chothia CDR-H2 + Chothia CDR-H3

[0150] In some embodiments, the antibody construct comprises a VH sequence comprising a Chothia CDR-H 1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 12-13, a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 34-35, and a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 45-46. In some embodiments, the Chothia CDR-H1 sequence, Chothia CDR-H2 sequence, and Chothia CDR-H3 sequence are all from a single illustrative VH sequence provided in this disclosure. For example, in some embodiments, the Chothia CDR-H1, Chothia CDR-H2, and Chothia CDR-H3 are all from a single illustrative VH sequence selected from SEQ ID NOS: 89-90.

[0151] In some embodiments, the antibody construct comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 12, a Chothia CDR-H2 sequence comprising SEQ ID NO: 34, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 45. In some embodiments, the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 13, a Chothia CDR-H2 sequence comprising SEQ ID NO: 35, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 46.

7.2.16. Variants of VH Sequences Comprising Illustrative Chothia CDRs

[0152] In some embodiments, the VH sequences provided herein comprise a variant of an illustrative Chothia CDR-H3, CDR-H2, and/or CDR-H1 sequence provided in this disclosure.

[0153] In some embodiments, the Chothia CDR-H3 sequence comprises, consists, or consists essentially of a variant of an illustrative Chothia CDR-H3 sequence provided in this disclosure. In some embodiments, the Chothia CDR-H3 sequence comprises, consists, or consists essentially of a sequence having at least 70%. 75%, 80%, 85%, 90%. or 95% identity with any of the illustrative Chothia CDR- H3 sequences provided in this disclosure. In some embodiments, the Chothia CDR-H3 sequence comprises, consists, or consists essentially of any of the illustrative Chothia CDR-H3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions.

[0154] In some embodiments, the Chothia CDR-H2 sequence comprises, consists, or consists essentially of a variant of an illustrative Chothia CDR-H2 sequence provided in this disclosure. In some embodiments, the Chothia CDR-H2 sequence comprises, consists, or consists essentially of a sequence having at least 70%. 75%, 80%, 85%, 90%. or 95% identity with any of the illustrative Chothia CDR- H2 sequences provided in this disclosure. In some embodiments, the Chothia CDR-H2 sequence comprises, consists, or consists essentially of any of the illustrative Chothia CDR-H2 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions.

[0155] In some embodiments, the Chothia CDR-H1 sequence comprises, consists, or consists essentially of a variant of an illustrative Chothia CDR-H1 sequence provided in this disclosure. In some embodiments, the Chothia CDR-H1 sequence comprises, consists, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Chothia CDR- H1 sequences provided in this disclosure. In some embodiments, the Chothia CDR-H1 sequence comprises, consists, or consists essentially of any of the illustrative Chothia CDR-H1 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions.

7.2.17. VH Sequences

[0156] In some embodiments, the antibody construct comprises a VH sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 89-90. In some embodiments, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 89. In some embodiments, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 90.

7.2.18. Variants of V_H Sequences

[0157] In some embodiments, the VH sequences provided herein comprise, consist of, or consist essentially of a variant of an illustrative VH sequence provided in this disclosure.

[0158] In some embodiments, the VH sequence comprises, consists, or consists essentially of a variant of an illustrative VH sequence provided in this disclosure. In some embodiments, the VH sequence comprises, consists, or consists essentially of a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.5% identity with any of the illustrative VH sequences provided in this disclosure.

[0159] In some embodiments, the Vn sequence comprises, consists, or consists essentially of any of the illustrative VH sequences provided in this disclosure, 20 or fewer, 19 or fewer, 18 or fewer, 17 or fewer. 16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, 11 or fewer, 10 or fewer, 9 or fewer. 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer amino acid substitutions. In some embodiments, the amino acid substitutions arc conservative amino acid substitutions.

7.2.19. VL Sequences Comprising Illustrative CDRs

[0160] In some embodiments, the antibody comprises a V_L sequence comprising one or more CDR-L sequences comprising, consisting of, or consisting essentially of one or more illustrative CDR-L sequences provided in this disclosure, and variants thereof.

7.2.19.1. CDR-L3 Sequences

[0161] In some embodiments, the antibody construct comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 77-78. In some embodiments, the antibody construct comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 77. In some embodiments, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 78. [0162] In some embodiments, the CDR-L3 sequence comprises, consists, or consists essentially of a variant of an illustrative CDR-L3 sequence provided in this disclosure. In some embodiments, the CDR-L3 sequence comprises, consists, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L3 sequences provided in this disclosure. In some embodiments, the CDR-L3 sequence comprises, consists, or consists essentially of any of the illustrative CDR-L3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions.

7.2.19.2. CDR-L2

[0163] In some embodiments, the antibody construct comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 67-68. In some embodiments, the antibody construct comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 67. In some embodiments, the antibody construct comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 68.

7.2.19.3. CDR-L1

[0164] In some embodiments, the antibody construct comprises a VL sequence comprising a CDR-L1 sequence comprising, consisting of. or consisting essentially of a sequence selected from SEQ ID NOS: 55-56. In some embodiments, the antibody construct comprises a V_L sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 55. In some embodiments, the antibody construct comprises a V_L sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 56.

7.2.19.4. CDR-L3 + CDR-L2

[0165] In some embodiments, the antibody construct comprises a VL sequence comprising a CDR-L3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 77-78 and a CDR-L2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 67-68. In some embodiments, the CDR-L3 sequence and the CDR-L2 sequence are both from a single illustrative VL sequence provided in this disclosure. For example, in some embodiments, the CDR-L3 and CDR-L2 are both from a single illustrative VL sequence selected from SEQ ID NOS: 101-102.

7.2.19.5. CDR-L3 + CDR-L1

[0166] In some embodiments, the antibody construct comprises a VL sequence comprising a CDR-L3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 77-78 and a CDR-L1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 55-56. In some embodiments, the CDR-L3 sequence and the CDR-L1 sequence are both from a single illustrative VL sequence provided in this disclosure. For example, in some embodiments, the CDR-L3 and CDR-L1 are both from a single illustrative VL sequence selected from SEQ ID NOS: 101-102.

7.2.19.6. CDR-L1 + CDR-L2

[0167] In some embodiments, the antibody construct comprises a VL sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 55-56 and a CDR-L2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 67-68. In some embodiments, the CDR-L1 sequence and the CDR-L2 sequence are both from a single illustrative VL sequence provided in this disclosure. For example, in some embodiments, the CDR-L1 and CDR-L2 are both from a single illustrative VL sequence selected from SEQ ID NOS: 101-102.

7.2.19.7. CDR-L1 + CDR-L2 + CDR-L3

[0168] In some embodiments, the antibody construct comprises a VL sequence comprising a CDR-L1 sequence comprising, consisting of. or consisting essentially of a sequence selected from SEQ ID NOS: 55-56, a CDR-L2 sequence comprising, consisting of. or consisting essentially of a sequence selected from SEQ ID NOS: 67-68, and a CDR-L3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 77-78. In some embodiments, the CDR-L1 sequence, CDR- L2 sequence, and CDR-L3 sequence are all from a single illustrative V_L sequence provided in this disclosure. For example, in some embodiments, the CDR-L1, CDR-L2, and CDR-L3 are all from a single illustrative V_L sequence selected from SEQ ID NOS: 101-102.

[0169] In some embodiments, the antibody construct comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 55, a CDR-L2 sequence comprising SEQ ID NO: 67, and a CDR- L3 sequence SEQ ID NO: 77. In some embodiments, the antibody construct comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 56, a CDR-L2 sequence comprising SEQ ID NO: 68. and a CDR-L3 sequence SEQ ID NO: 78.

7.2.20. Variants of VL Sequences Comprising Illustrative CDR-Ls

[0170] In some embodiments, the VL sequences provided herein comprise a variant of an illustrative CDR-L3, CDR-L2, and/or CDR-L1 sequence provided in this disclosure.

[0171] In some embodiments, the CDR-L3 sequence comprises, consists, or consists essentially of a variant of an illustrative CDR-L3 sequence provided in this disclosure. In some embodiments, the CDR- LS sequence comprises, consists, or consists essentially of a sequence having at least 70%. 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L3 sequences provided in this disclosure. In some embodiments, the CDR-L3 sequence comprises, consists, or consists essentially of any of the illustrative CDR-L3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. [0172] In some embodiments, the CDR-L2 sequence comprises, consists, or consists essentially of a variant of an illustrative CDR-L2 sequence provided in this disclosure. In some embodiments, the CDR- L2 sequence comprises, consists, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L2 sequences provided in this disclosure. In some embodiments, the CDR-L2 sequence comprises, consists, or consists essentially of any of the illustrative CDR-L2 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions.

[0173] In some embodiments, the CDR-L1 sequence comprises, consists, or consists essentially of a variant of an illustrative CDR-L1 sequence provided in this disclosure. In some embodiments, the CDR- L1 sequence comprises, consists, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L1 sequences provided in this disclosure. In some embodiments, die CDR-L1 sequence comprises, consists, or consists essentially of any of the illustrative CDR-L1 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions.

7.2.21. V_L Sequences

[0174] In some embodiments, the antibody construct comprises a VL sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 101-102. In some embodiments, the antibody construct comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 101. In some embodiments, the antibody construct comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 102.

7.2.22. Variants of V_L Sequences

[0175] In some embodiments, the VL sequences provided herein comprise, consist of, or consist essentially of a variant of an illustrative VL sequence provided in this disclosure.

[0176] In some embodiments, the VL sequence comprises, consists, or consists essentially of a variant of an illustrative VL sequence provided in this disclosure. In some embodiments, the VL sequence comprises, consists, or consists essentially of a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.05% identity with any of the illustrative VL sequences provided in this disclosure.

[0177] In some embodiments, the VL sequence comprises, consists, or consists essentially of any of the illustrative VL sequences provided in this disclosure. 20 or fewer, 19 or fewer, 18 or fewer, 17 or fewer. 16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, 11 or fewer, 10 or fewer, 9 or fewer. 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. 7.2.23. Pairs

7.2.23.1. CDR-H3 - CDR-L3 Pairs

[0178] In some embodiments, the antibody construct comprises a CDR-H3 sequence and a CDR-L3 sequence. In some embodiments, the CDR-H3 sequence is part of a VH and the CDR-L3 sequence is part of a V_L.

[0179] In some embodiments, the CDR-H3 sequence is a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NOS: 45-46 and the CDR-L3 sequence is a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NOS: 77-78.

[0180] In some embodiments, the CDR-H3 sequence is SEQ ID NO: 45 and the CDR-L3 sequence is selected from SEQ ID NOS: 77-78. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 77. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 78.

[0181] In some embodiments, the CDR-H3 sequence is SEQ ID NO: 46 and the CDR-L3 sequence is selected from SEQ ID NOS: 77-78. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 77. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 78.

7.2.23.2. Variants of CDR-H3 - CDR-L3 Pairs

[0182] In some embodiments, the CDR-H3 - CDR-L3 pairs provided herein comprise a variant of an illustrative CDR-H3 and/or CDR-L1 sequence provided in this disclosure.

[0183] In some embodiments, the CDR-H3 sequence comprises, consists, or consists essentially of a variant of an illustrative CDR-H3 sequence provided in this disclosure. In some embodiments, the CDR- H3 sequence comprises, consists, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-H3 sequences provided in this disclosure. In some embodiments, the CDR-H3 sequence comprises, consists, or consists essentially of any of the illustrative CDR-H3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions.

[0184] In some embodiments, the CDR-L3 sequence comprises, consists, or consists essentially of a variant of an illustrative CDR-L3 sequence provided in this disclosure. In some embodiments, the CDR- L3 sequence comprises, consists, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L3 sequences provided in this disclosure. In some embodiments, tire CDR-L3 sequence comprises, consists, or consists essentially of any of the illustrative CDR-L3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions.

7.2.23.3. VH - VL Pairs

[0185] In some embodiments, the antibody construct comprises a V_H sequence and a VL sequence. [0186] In some embodiments, the VH sequence is a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NOS: 89-90 and the VL sequence is a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NOS: 101-102.

[0187] In some embodiments, the VH sequence is SEQ ID NO: 89 and the VL sequence is selected from SEQ ID NOS: 101-102. In some embodiments, the VL sequence is SEQ ID NO: 101. In some embodiments, the VL sequence is SEQ ID NO: 102.

[0188] In some embodiments, the VH sequence is SEQ ID NO: 90 and the V_T. sequence is selected from SEQ ID NOS: 101-102. In some embodiments, the VL sequence is SEQ ID NO: 101. In some embodiments, the VL sequence is SEQ ID NO: 102.

7.2.23.4. CDR-H1 + CDR-H2 + CDR-H3 + CDR-L1 + CDR-L2 + CDR- L3

[0189] In some embodiments, the antibody construct capable of binding TREM1 comprises a VH sequence comprising a KabatCDR-Hl sequence comprising SEQ ID NO: 1, a Kabat CDR-H2 sequence comprising SEQ ID NO: 23, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 45 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 55, a CDR-L2 sequence comprising SEQ ID NO: 67, and a CDR-L3 sequence SEQ ID NO: 77. In some embodiments, the antibody construct capable of binding TREM1 comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 2, a Kabat CDR-H2 sequence comprising SEQ ID NO: 24, and a Kabat CDR- H3 sequence comprising SEQ ID NO: 46 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 56, a CDR-L2 sequence comprising SEQ ID NO: 68, and a CDR-L3 sequence SEQ ID NO: 78.

[0190] In some embodiments, the antibody construct capable of binding TREM1 comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 12, a Chothia CDR-H2 sequence comprising SEQ ID NO: 34, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 45 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 55, a CDR-L2 sequence comprising SEQ ID NO: 67. and a CDR-L3 sequence SEQ ID NO: 77. In some embodiments, the antibody construct capable of binding TREM1 comprises a VH sequence comprising a Chothia CDR- H1 sequence comprising SEQ ID NO: 13, a Chothia CDR-H2 sequence comprising SEQ ID NO: 35, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 46 and a VL sequence comprising a CDR- L1 sequence comprising SEQ ID NO: 56, a CDR-L2 sequence comprising SEQ ID NO: 68, and a CDR- L3 sequence SEQ ID NO: 78.

7.2.24. Variants of VH - VL Pairs

[0191] In some embodiments, the VH - V_L pairs provided herein comprise a variant of an illustrative V_H and/or V_L sequence provided in this disclosure. [0192] In some embodiments, the VH sequence comprises, consists, or consists essentially of a variant of an illustrative VH sequence provided in this disclosure. In some embodiments, the VH sequence comprises, consists, or consists essentially of a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.1% identity with any of the illustrative VH sequences provided in this disclosure.

[0193] In some embodiments, the VH sequence comprises, consists, or consists essentially of any of the illustrative VH sequences provided in this disclosure, 20 or fewer, 19 or fewer, 18 or fewer, 17 or fewer. 16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, 11 or fewer, 10 or fewer, 9 or fewer. 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer amino acid substitutions. In some embodiments, the amino acid substitutions arc conservative amino acid substitutions.

[0194] In some embodiments, the VL sequence comprises, consists, or consists essentially of a variant of an illustrative VL sequence provided in this disclosure. In some embodiments, the VL sequence comprises, consists, or consists essentially of a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.05% identity with any of the illustrative V_L sequences provided in this disclosure. In some embodiments, the VL sequence comprises, consists, or consists essentially of any of the illustrative VL sequences provided in this disclosure, 20 or fewer, 19 or fewer, 18 or fewer, 17 or fewer, 16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, 11 or fewer, 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions.

7.3. Inhibition of TREM1

[0195] In some embodiments, the antibody construct modulates human Triggering Receptor Expressed on Myeloid Cells 1 (TREM1) mediated signaling. In some embodiments, the antibody construct disrupts human Triggering Receptor Expressed on Myeloid Cells 1 (TREM1) dimerization and/or oligomerization. Upon ligand binding. TREM1 dimerizes/oligomerizes and engages directly a downstream signaling cascade, for example by recruiting DAP12/ZAP70/SYK, as well as synergies with the pattern recognition receptors such as TLR-4 (via TLR4-MyD88-NF-KB signaling) that enhance the expression of TREM1 and lead to elevated secretion of proinflammatory cytokines, chemokines, and reactive oxygen species. In some embodiments, the antibody construct inhibits TREM1 activation and/or TREM1 mediated cell signaling. In some embodiments, a myeloid cell comprises a granulocyte (e.g., mast cells, eosinophil, basophil, or neutrophil). In some embodiments, a myeloid cell comprises a mononuclear cell (e.g., monocyte, macrophage, dendritic cell, or fibrocyte).

[0196] In some embodiments, the antibody construct competes for binding with a Triggering Receptor Expressed on Myeloid Cells 1 (TREM1) ligand. In some embodiments, the Triggering Receptor Expressed on Myeloid Cells 1 (TREM1) ligand comprises, consists, or consists essentially of peptidoglycan recognition protein-1 (PGLYRP1). In some embodiments, the Triggering Receptor Expressed on Myeloid Cells 1 (TREM1) ligand comprises, consists, or consists essentially of peptidoglycan (PGN). In some embodiments, the Triggering Receptor Expressed on Myeloid Cells 1 (TREM1) ligand comprises, consists, or consists essentially of a peptidoglycan recognition protein-1 (PGLYRPl)/peptidoglycan (PGN) complex. In some embodiments, the antibody construct competes for binding Triggering Receptor Expressed on Myeloid Cells 1 (TREM1) with a PGLYRP1/PGN complex. When multimerized or complexed with PGN, PGLYRP1 is able to activate TREM1 and enhance cytokine production in human neutrophils and macrophages. In some embodiments, the antibody construct is capable of inhibiting or reducing PGLYRP1/PGN activation of TREM1.

[0197] In some embodiments, the antibody construct down-regulates TREM1. In some embodiments, the antibody construct down-regulates TREM1 amplification of pro-inflammatory reactions.

[0198] In some embodiments, the antibody construct down-regulates TREM1 amplification of inflammatory cytokines or chemokines. In some embodiments, the cytokines or chemokines comprise, consist essentially of, or consist of one or more of IL-6, MIP2/CXCL2, IL-la, IL-10, IL-18, IL-33, and/or a mutant or an analog thereof. In some embodiments, the cytokines or chemokines comprise, consist essentially of, or consist of one or more receptor, ligand, or binding targets of IL-6, MIP2/CXCL2, IL-la, IL-10, IL-18, IL-33, and/or a mutant or an analog thereof. In some embodiments, the cytokine comprises, consists essentially of, or consists of IL- 10.

[0199] In some embodiments, the antibody construct down-regulates TREM1 amplification of inflammatory cytokines or chemokines by about or less than a 10% decrease, about or less than a 20% decrease, about or less than a 30% decrease, about or less than a 40% decrease, about or less than a 50% decrease, about or less than a 60% decrease, about or less than a 70% decrease, about or less than an 80% decrease, about or less than a 90% decrease, or about a complete decrease.

7.4. TREM1 Assays

[0200] In some embodiments, the antibody construct binds to an epitope of TREM1. An epitope often consists of a number of contiguous amino acids such as, for example, without limitation, 5-6 amino acids. In some embodiments, the epitope comprises or consists of contiguous or non-contiguous amino acids. In some embodiments, the contiguous or non-contiguous amino acids are within a domain of TREM1.

[0201] In some embodiments, HEK293 cells expressing TREM1 and DAP12 may be used in a binding affinity assay as described herein. In some embodiments, reporter cells, such as Jurkat TREM1 DAP 12 NFAT-ePL reporter cells, may be used in an in vitro functional assay as described herein.

[0202] In some embodiments, the antibody construct competes with any of die antibody constructs set forth herein. Competition could be, for example, without limitation, binding competition, inhibition competition, or any other form of competition. 7.5. Glycosylation Variants

[0203] In some embodiments, an antibody construct is altered to increase, decrease or eliminate the extent to which it is glycosylated. Glycosylation of polypeptides is typically either “N-linked” or “O- linked.”

[0204] “N-linked” glycosylation refers to the attachment of a carbohydrate moiety to the side chain of an asparagine residue. The tripeptide sequences asparagine-X-serine and asparagine-X-threonine, where X is any amino acid except proline, are the recognition sequences for enzymatic attachment of the carbohydrate moiety to the asparagine side chain. Thus, the presence of either of these tripeptide sequences in a polypeptide creates a potential glycosylation site.

[0205] “O-linked” glycosylation refers to the attachment of one of the sugars N-acetyl galactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5- hydroxyproline or 5-hydroxylysine may also be used.

[0206] Addition or deletion of N-linked glycosylation sites to the antibody construct may be accomplished by altering the amino acid sequence such that one or more of the above-described tripeptide sequences is created or removed. Addition or deletion of O-linked glycosylation sites may be accomplished by addition, deletion, or substitution of one or more serine or threonine residues in or to (as the case may be) the sequence of an antibody construct.

[0207] In certain embodiments, the antibody is glycosylated. In certain embodiments, the antibody is deglycosylated. Carbohydrates may be removed by standard techniques. In certain embodiments, the antibody is a glycosylated, for instance by expression in a system that does not glycosylate.

7.6. Fc Variants

[0208] In some embodiments, amino acid modifications may be introduced into an Fc region of an antibody construct provided herein to generate an Fc region variant.

[0209] In some embodiments, the Fc region variant possesses some, but not all, effector functions. Such antibody constructs may be useful, for example, in applications in which the half-life of the antibody in vivo is important, yet certain effector functions are unnecessary or deleterious. Examples of effector functions include complement-dependent cytotoxicity (CDC) and antibody -directed complement-mediated cytotoxicity (ADCC). Numerous substitutions or substitutions or deletions with altered effector function are known in the art.

[0210] In some embodiments, the Fc region comprises an L234A and L235A mutations. In some embodiments, the Fc region comprises a P329 mutations (e.g., a P329G mutation). In some embodiments, the Fc region comprises one or more (e.g., one, tw o. or all) of L234A, L23 A, and P329G mutations. In some embodiments, the antibody molecule has reduced FcyR binding. [0211] In some embodiments, the antibody construct comprises an Fc region comprising modified Fey Receptor (FcyR) binding. In some embodiments, the Fc region comprises reduced Fey Receptor (FcyR) binding, wherein the FcyR is selected from the group consisting of: FcyRI, FcyRIIa, FcyRIIb, FcyRIIc, FcyRIIIa, and FcyRIIIb.

[0212] Non-limiting examples of in vitro assays to assess ADCC activity of a molecule of interest are provided in U.S. Patent Nos. 5,500.362 and 5.821,337; Hellstrom et al., Proc. Natl. Acad. Sci. U.S.A., 1986, 83:7059-7063; Hellstrom et al., Proc. Natl. Acad. Sci. U.S.A., 1985, 82:1499-1502; and Bruggemann et al., J. Exp. Med, 1987. 166:1351-1361. Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells. Alternatively, or additionally , ADCC activity of the molecule of interest may be assessed in vivo, using an animal model such as that disclosed in Clynes et al. Proc. Natl. Acad. Sci. U.S.A., 1998, 95:652-656.

[0213] Clq binding assays may also be carried out to confirm that the antibody construct is unable to bind Clq and hence lacks CDC activity. Examples of Clq binding assays include those described in WO 2006/029879 and WO 2005/100402.

[0214] Complement activation assays include those described, for example, in Gazzano-Santoro et al., J. Immunol. Methods, 1996, 202:163-171; Cragg et al., Blood. 2003. 101:1045-1052; and Cragg and Glennie. Blood, 2004, 103:2738-2743.

[0215] FcRn binding and in vivo clearance (half-life determination) can also be measured, for example, using the methods described in Petkova et al., Inti. Immunol., 2006, 18:1759-1769.

[0216] In some embodiments, amino acid modifications may be introduced into the Fc region of an antibody construct provided herein to generate an Fc region variant. In some embodiments, the Fc region comprises one or more mutations in the CH3 region. In some embodiment, tire one or more mutations are substitutions. In some embodiments, the one or more substitutions are substitutions of an interface amino acid residue.

[0217] In some embodiments, the dimerization of the antibody construct is enhanced by providing an Fc interface of a first Fc region and a second Fc region with one or more of: a paired cavity -protuberance (“knob-in-a hole”) and/or an electrostatic interaction, such that a greater ratio of heteromultimer:homomultimer forms, e.g., relative to a non-engineered interface.

[0218] In some embodiments, the first Fc region or the second Fc region comprises a T366W mutation (e.g., knob mutations). In certain embodiments, the first Fc region or the second Fc region comprises one or more (e.g., one, two, three, or all) a T366S, L368A. or Y407V mutation (e.g., hole mutations). In some embodiments, the first Fc region comprises a T366W mutation and the second Fc region comprises a T366S, L368A, and Y407V mutations. In some embodiments, the first Fc region comprises a T366S, L368A, and Y407V mutation and the second Fc region comprises a T366W mutations. [0219] In some embodiments, the first Fc region or the second Fc region comprises a D399K mutation (e.g., an electrostatic interaction mutation). In some embodiments, die first Fc region or die second Fc region comprises a D409K mutation (e.g., an electrostatic interaction mutation). In some embodiments, the first Fc region comprises a D399K mutation and the second Fc region comprises a D409K mutation. In some embodiments, the first Fc region comprises a D409K mutation and the second Fc region comprises a D399K mutation.

[0220] In some embodiments, the antibody construct comprises a paired cavity -protuberance (“knob- in-a hole”) and an electrostatic interaction. In some embodiments, the first Fc region comprises T366W mutation and a K409D mutation. In some embodiments, the second Fc region comprises one or more (e.g., one, two, or all) a T366S, L368A, or Y407V mutation and a D399K mutation. In some embodiments, the first Fc region comprises T366W mutation and a K409D mutation and the second Fc region comprises one or more (e.g., one, two, or all) a T366S, L368A, or Y407V mutation and a D399K mutation.

[0221] In some embodiments, the second Fc region comprises T366W mutation and a K409D mutation. In some embodiments, the first Fc region comprises one or more (e.g., one, two, or all) a T366S, L368A, or Y407V mutation and a D399K mutation. In some embodiments, the second Fc region comprises T366W mutation and a K409D mutation and the first Fc region comprises one or more (e.g., one, two. or all) a T366S, L368A, or Y407V mutation and a D399K mutation.

[0222] In some embodiments, the first Fc region comprises a T366W mutation, a K409D mutation, and one or more (e.g., one, two, or all) of L234A, L235A, and P329G mutations. In some embodiments, the second Fc region comprises one or more (e.g.. one, tw o. or all) a T366S. L368A, or Y407V mutation, a D399K mutation, and one or more (e.g., one, two. or all) of L234A, L235A, and P329G mutations. In some embodiments, the first Fc region comprises a T366W mutation, a K409D mutation, and one or more (e.g., one, two, or all) of L234A, L235A, and P329G mutations, and the second Fc region comprises one or more (e.g., one, two. or all) a T366S, L368A, or Y407V mutation, a D399K mutation, and one or more (e.g., one, two, or all) of L234A, L235A, and P329G mutations.

[0223] In some embodiments, the second Fc region comprises a T366W mutation, a K409D mutation, and one or more (e.g., one, two, or all) of L234A, L235A, and P329G mutations. In some embodiments, the first Fc region comprises one or more (e.g., one, two. or all) a T366S, L368A, or Y407V mutation, a D399K mutation, and one or more (e.g., one, two. or all) of L234A, L235A, and P329G mutations. In some embodiments, the second Fc region comprises a T366W mutation, a K409D mutation, and one or more (e.g., one, two, or all) of L234A, L235A, and P329G mutations, and the first Fc region comprises one or more (e.g., one, tw o. or all) a T366S, L368A, or Y407V mutation, a D399K mutation, and one or more (e.g., one, two, or all) of L234A, L235A, and P329G mutations. [0224] In some embodiments, the first Fc region comprises T366W mutation and a D399K mutation. In some embodiments, the second Fc region comprises one or more (e.g., one, two, or all) a T366S, L368A, or Y407V mutation and a K409D mutation. In some embodiments, the first Fc region comprises T366W mutation and a D399K mutation and the second Fc region comprises one or more (e.g., one, two, or all) a T366S, L368A, or Y407V mutation and a K409D mutation.

[0225] In some embodiments, the second Fc region comprises T366W mutation and a D399K mutation. In some embodiments, the first Fc region comprises one or more (e.g., one, two, or all) a T366S, L368A, or Y407V mutation and a K409D mutation. In some embodiments, the second Fc region comprises T366W mutation and a D399K mutation and the first Fc region comprises one or more (e.g., one, two. or all) a T366S, L368A, or Y407V mutation and a K409D mutation.

[0226] In some embodiments, the first Fc region comprises a T366W mutation, a D399K mutation, and one or more (e.g., one, two. or all) of L234A, L235A, and P329G mutations. In some embodiments, the second Fc region comprises one or more (e.g.. one, tw o. or all) a T366S. L368A, or Y407V mutation, a K409D mutation, and one or more (e.g., one, two. or all) of L234A, L235A, and P329G mutations. In some embodiments, the first Fc region comprises a T366W mutation, a D399K mutation, and one or more (e.g., one, two, or all) of L234A, L235A, and P329G mutations, and the second Fc region comprises one or more (e.g., one, tw o, or all) a T366S, L368A, or Y407V mutation, a K409D mutation, and one or more (e.g., one, two, or all) of L234A, L235A, and P329G mutations.

[0227] In some embodiments, the second Fc region comprises a T36 W mutation, a D399K mutation, and one or more (e.g., one, two, or all) of L234A, L235A, and P329G mutations. In some embodiments, the first Fc region comprises one or more (e.g., one, two. or all) a T366S, L368A, or Y407V mutation, a K409D mutation, and one or more (e.g., one, two. or all) of L234A, L235A, and P329G mutations. In some embodiments, the second Fc region comprises a T366W mutation, a D399K mutation, and one or more (e.g., one, two, or all) of L234A, L235A, and P329G mutations, and the first Fc region comprises one or more (e.g., one, tw o. or all) a T366S, L368A, or Y407V mutation, a K409D mutation, and one or more (e.g., one, two, or all) of L234A, L235A, and P329G mutations.

7.7. Method for Generation and/or Production of Antibody Constructs

[0228] In some embodiments, described are methods for generating the antibody construct capable of specifically and/or selectively binding to TREM1. In some embodiments, the anti-TREMl monovalent antibody construct is a chimeric antibody. In some embodiments, the method comprises generating mouse or human chimeric antibody constructs capable of binding to TREM1. In some embodiments, the mouse/human chimeric antibody constructs are generated by replacing the hyper-variable regions of the human IgGl LALAPG (huVH and huVL) with the mouse counterparts (m VH and mVL). In some embodiments, production of the corresponding bivalent antibodies (mAbs) is performed using an inVH- huIgGlCHl,2.3 (with LALAPG mutation) and mVL-huIgGICL to transfect HEK293 cells. In some embodiments, the method comprises introducing Knob-into-Hole (KiH) and/or charge based (D to K) mutations of the human IgGlCH3 domain to generate the antibody construct (e.g., anti-TREMl monovalent antibody construct). In some embodiments, the method comprises culturing the antibody constructs (e.g., monovalent or bivalent) in a host cell. Non limiting examples of suitable host cells are HEK293 cells, Vero cells, COS cells, MDCK cells, NIH 3T3 cells, HELA cells, and BHK-21 cells. In some embodiments, the host cells are HEK293 cells. In some embodiments, the combined conditioned HEK293 supernatant is purified using a Protein A column followed by a second step purification on an ion exchange chromatography (IEX) column. Aggregated antibodies are removed by size exclusion chromatography (SEC) and buffer exchanged into the final antibody formulation (e g., 10 mM Histidine, 5% sucrose, pH 6.0). The purity and monomeric status of the monovalent antibody construct may be assessed by SDS-PAGE and size exclusion chromatography (SEC). In some embodiments, the final products (i.e., the antibody construct) has between about 50% to about 100%, between about 60% to about 99%. between about 70% to about 90%. between about 80% to about 95%, between about 90% to about 99%, or between about 95% to about 100% monomeric. FIGs. 1A and IB show purity of exemplary antibody construct, which are approximately 95%-98% monomeric.

[0229] In some embodiments, the method further comprises evaluating binding affinity of the TREM1 binding antibody construct described herein. In some embodiments, antibody binding is performed using, for example, HEK293 parental (HEK 293-P) cells and HEK293 cells expressing TREM1 and DAP 12 (HEK293-TD). Binding is initiated by incubating monovalent antibody constructs or corresponding bivalent antibodies at increasing concentrations between, e.g., 0.001-20 pg/mL. for 1 hour at room temperature (RT), followed by the addition of fluorescent (e.g., Alexa FLUOR™ 594) conjugated anti-human IgG antibodies. The fluorescence intensity is measured by Fluorescence- activated Cell Sorting (FACS) and mean fluorescence intensity’ (MFI) is calculated using, e.g., FlowJo (Becton Dickinson). Binding affinity curves are generated by plotting the MFI against the tested mAb concentrations. The curve is fitted using a sigmoidal dose-response with variable slope (four-parameter) with using Prism 8. FIG. 2 shows TREM 1 binding by representative monovalent anti-TREM 1 antibody constructs compared to representative bivalent anti-TREMl antibodies. Monovalent TREM1 antibody (W002) has a binding affinity to TREM1 w ith a K_D of 2.4 nM compared to the bivalent antibody with a K_D of 0.34 nM.

[0230] In some embodiments, the method further comprises evaluating the function of the TREM1 binding antibody construct described herein. In some embodiments, Jurkat TREM1 DAP 12 NFAT-ePL reporter cells are seeded at about 2,000 cells per well, about 3,000 cells per well, about 4,000 cells per w ell, about 5,000 cells per well. 8.000 cells per well, or about 10,000 cells per well. For example, about 5,000 cells per well of a 384 well plate and pre-incubated with a serial dilution of the corresponding mAb for 1 hour at 37°C. 5% CO2. The initial antibody concentration may range from, e.g., 80-100 pg/mL. In some embodiments, the method further comprises evaluating TREM1 inhibition, disabling, and/or reducing TREM1 expressing cells and/or TREM1 downstream signaling in the cells. In some embodiments, to assess the TREM1, Peptidoglycan Recognition Protein 1 (PGLYRPl)/hydrolase peptide glycan (PGN) is added to a final concentration of, e.g., 10 pg/mL/20 pg/mL PGLYRP1/PGN- ECndi, followed by an overnight (16 hours) incubation at 37°C, 5% CO2. In some embodiments, the method further comprises evaluating activation of TREM1. In some embodiments, to assess mAb TREM1 activation, no PGLYRP1/PGN is added for the overnight (16 hours) incubation. The NF AT reporter luminescence is detected by the PathHunter PL/PK Detection mix and read on a Perkin-Elmer Envision luminometer. The dose-response curve is analyzed using GraphPad Prism 8. fitted using a sigmoidal dose-response with variable slope (four-parameter) with no constraints. FIG. 3 shows improved inhibitory activity of representative monovalent anti-TREMl antibody constructs compared to representative and/or corresponding bivalent anti-TREMl antibodies. FIG. 4 and FIG. 5 show representative monovalent anti-TREMl antibody constructs compared to representative and/or corresponding bivalent anti-TREMl antibodies in PGLYRP-l/PGN inhibitory assay and the activation assay, respectively. FIG. 6 and FIG. 7 show representative monovalent anti-TREMl antibody constructs (W002-monovalent) concentration-dependent activation compared to representative bivalent anti-TREMl antibodies (W002-bivalent) in PGLYRP-l/PGN inhibitory assay and the activation assay, respectively.

[0231] In some embodiments, human myelomonocytic cell line U937 (ATCC, CRL-1593.2) stably transduced with TREM1, DAP12 and a human IL-8 Promoter Luciferase Reporter (BPS Bioscience, Catalog#79827) (U937-TD-1L8 cells), is seeded in RPM1-1640 supplemented with 10% fetal bovine serum (FBS) plus G418 (0.5 mg/ml). Puromycin (0.1 jrg/ml), and Blasticidin (10 pg/ml). For 96 well format in vitro assays, the U937-TD-IL8 cells are seeded at 40,000 per well in RPMI-1640 plus 2 % FBS, pre-incubated with anti-TREMl mAb at 10 pg/mL for 1 hour at 37°C, 5% CO2. followed by 23 hours of incubation with PGLYRP1/PGN. Firefly luciferase activity is quantified using One-Step ™ Luciferase Assay System (BPS Bioscience, Catalog#60690) on a GloMax® Plate Reader (Promage). FIG. 8 shows a representative quantification of U937-TD-IL8 reporter activity after treatment with PGLYRP1/PGN. or PGLYRPl/PGN+anti-TREMl mAb (bivalent). The scale bars represent s.e.m., * P<0.05.

7.8. Preparation of Antibodies

7.8.1. Antigen Preparation

[0232] The TREM1 antigen to be used for production of antibody constructs may be intact TREM1 or a fragment of TREM1. The intact TREM1, or fragment of TREM1, may be in the form of an isolated protein or expressed by a cell. Other forms of TREM1 useful for generating antibody constructs will be apparent to those skilled in the art. 7.8.2. Monoclonal Antibodies

[0233] Monoclonal antibodies may be obtained, for example, using the hybridoma method first described by Kohler et al., Nature, 1975, 256:495-497, and/or by recombinant DNA methods (see e.g., U.S. Patent No. 4,816,567). Monoclonal antibodies may also be obtained, for example, using phage or yeast-based libraries. See e.g., U.S. Patent Nos. 8,258,082 and 8,691,730.

[0234] In the hybridoma method, a mouse or other appropriate host animal is immunized to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the protein used for immunization. Alternatively, lymphocytes may be immunized in vitro. Lymphocytes are then fused with myeloma cells using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell. See Goding J.W., Monoclonal Antibodies: Principles and Practice 3^rd ed. (1986) Academic Press, San Diego, CA.

[0235] The hybridoma cells are seeded and grown in a suitable culture medium that contains one or more substances that inhibit the growth or survival of the unfused, parental myeloma cells. For example, if the parental myeloma cells lack the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT or HPRT), the culture medium for the hybridomas typically will include hypoxanthine, aminopterin, and thymidine (HAT medium), which substances prevent the growth of HGPRT -deficient cells.

[0236] Useful myeloma cells are those that fuse efficiently, support stable high-level production of antibody by the selected antibody -producing cells, and are sensitive media conditions, such as the presence or absence of HAT medium. Among these, preferred myeloma cell lines are murine myeloma lines, such as those derived from MOP-21 and MC-11 mouse tumors (available from the Salk Institute Cell Distribution Center, San Diego, CA), and SP-2 or X63-Ag8-653 cells (available from the American Type Culture Collection, Rockville, MD). Human myeloma and mouse-human heteromyeloma cell lines also have been described for the production of human monoclonal antibodies. See e.g., Kozbor, J. Immunol.. 1984. 133:3001.

[0237] After the identification of hybridoma cells that produce antibodies of the desired specificity, affinity, and/or biological activity, selected clones may be subcloned by limiting dilution procedures and grown by standard methods. See Goding, supra. Suitable culture media for this purpose include, for example, D-MEM or RPMI-1640 medium. In addition, the hybridoma cells may be grown in vivo as ascites tumors in an animal.

[0238] DNA encoding the monoclonal antibodies may be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of the monoclonal antibodies). Thus, the hybridoma cells can serve as a useful source of DNA encoding antibodies with the desired properties. Once isolated, the DNA may be placed into expression vectors, which are then transfected into host cells such as bacteria (e.g., E. coli), yeast (e.g., Saccharomyces or Pichia sp.), COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce antibody, to produce the monoclonal antibodies or monoclonal antibody constructs.

7.8.3. Humanized Antibodies

[0239] Humanized antibody constructs may be generated by replacing most, or all, of the structural portions of a monoclonal antibody with corresponding human antibody sequences. Consequently, a hybrid molecule is generated in which only the antigen-specific variable, or CDR, is composed of nonhuman sequence. Methods to obtain humanized antibodies include those described in. for example, Winter and Milstein. Nature, 1991, 349:293-299; Rader et al., Proc. Nat. Acad. Set. U.S.A., 1998, 95:8910-8915; Steinberger et al.. J. Biol. Chem., 2000, 275:36073-36078; Queen et al., Proc. Natl. Acad. Sci. U.S.A., 1989, 86:10029-10033; and U.S. Patent Nos. 5,585,089, 5.693.761, 5,693,762, and 6,180.370.

7.8.4. Human Antibodies

[0240] Human antibodies can be generated by a variety of techniques known in the art, for example by using transgenic animals (e.g.. humanized mice). See, e.g, Jakobovits et al., Proc. Natl. Acad. Sci. U.S.A., 1993, 90:2551; Jakobovits et al., Nature, 1993, 362:255-258; Bruggermann et al., Year in Immuno., 1993, 7:33; and U.S. Patent Nos. 5,591,669, 5.589.369 and 5.545.807. Human antibodies can also be derived from phage-display libraries (see e.g., Hoogenboom et al.. J. Mol. Biol., 1991, 227:381- 388; Marks et al., J. Mol. Biol., 1991, 222:581-597; and U.S. Pat. Nos. 5,565,332 and 5,573,905). Human antibodies may also be generated by in vitro activated B cells (see e.g., U.S. Patent. Nos. 5,567.610 and 5.229.275). Human antibodies may also be derived from yeast-based libraries (see e.g., U.S. Patent No. 8,691,730).

7.9. Vectors, Host Cells, and Recombinant Methods

[0241] An other aspect provides a nucleic acid molecule capable of expressing any of the antibody construct provided herein. In some embodiments, the nucleic acid comprises an expression vector. Some embodiments provide a prokaryotic or eukaryotic host cell transformed with the one or more expression vectors. Some embodiments provide an oncolytic virus encoding the nucleic acid. Some embodiments provide a method for the production of an antibody of the invention comprising the steps of expressing a nucleic acid provided herein in a prokaryotic or eukaryotic host cell and recovering the protein from the cell or the cell culture supernatant.

[0242] For recombinant production of the antibody construct or antibody , the nucleic acid encoding it may be isolated and inserted into a replicable vector for further cloning (i.e., amplification of the DNA) or expression. In some embodiments, the nucleic acid may be produced by homologous recombination, for example as described in U.S. Patent No. 5.204,244. [0243] Many different vectors are known in the art. The vector components generally include, but are not limited to, one or more of the following: a signal sequence, an origin of replication, one or more marker genes, an enhancer element, a promoter, and a transcription termination sequence, for example as described in U.S. Patent No. 5,534,615.

[0244] Suitable host cells include any prokaryotic (e.g., bacterial), lower eukaryotic (e.g., yeast), or higher eukary otic (e.g., mammalian) cells. Suitable prokaryotes include eubacteria, such as Gramnegative or Gram-positive organisms, for example, Enterobacteriaceae such as Escherichia (E. coli), Enterobacter, Erwinia, Klebsiella, Proteus, Salmonella (S. typhimurium), Serratia (S. marcescans), Shigella, Bacilli (B. subtilis and B. licheniformis), Pseudomonas (P. aeruginosa), and Streptomyces. One useful E. coli cloning host is E. coli 294, although other strains such as E. coli B, E. coli X1776, and E. coli W3110 are suitable.

[0245] In addition to prokaryotes, eukaryotic microbes such as filamentous fungi or yeast are also suitable cloning or expression hosts for antibody construct-encoding vectors. Saccharomyces cerevisiae, or common baker's yeast, is a commonly used lower eukaryotic host microorganism. However, a number of other genera, species, and strains are available and useful, such as Schizosaccharomyces pombe, Kluyveromyces (K. lactis. K. fragilis, K. bulgaricus K. wickeramii, K. waltii, K. drosophilarum, K. thermotolerans, and K. marxianus), Yarrowia, Pichia pastoris, Candida (C. albicans), Trichoderma reesia, Neurospora crassa, Schwanniomyces (S. occidentalis), and filamentous fungi such as, for example Penicillium, Tolypocladium, and Aspergillus (A. nidulans and A. niger).

[0246] Useful mammalian host cells include COS-7 cells, HEK293 cells; baby hamster kidney (BHK) cells; Chinese hamster ovary’ (CHO); mouse sertoli cells; African green monkey kidney cells (VERO- 76), and the like.

[0247] The host cells used to produce the antibody construct described herein may be cultured in a variety of media. Commercially available media such as. for example, Ham's F10, Minimal Essential Medium (MEM), RPMI-1640, and Dulbecco's Modified Eagle's Medium (DMEM) are suitable for culturing the host cells. In addition, any of the media described in Ham et al., Meth. Enz., 1979. 58:44; Barnes et al., Anal. Biochem. , 1980, 102:255; and U.S. Patent Nos. 4,767,704, 4.657.866. 4,927,762, 4,560.655. and 5,122,469, or WO 90/03430 and WO 87/00195 may be used.

[0248] Any of these media may be supplemented as necessary with hormones and/or other growth factors (such as insulin, transferrin, or epidermal growth factor), salts (such as sodium chloride, calcium, magnesium, and phosphate), buffers (such as HEPES), nucleotides (such as adenosine and thymidine), antibiotics, trace elements (defined as inorganic compounds usually present at final concentrations in the micromolar range), and glucose or an equivalent energy source. Any other necessary supplements may also be included at appropriate concentrations that would be known to those skilled in the art. [0249] The culture conditions, such as temperature, pH, and the like, are those previously used with die host cell selected for expression, and will be apparent to the ordinarily skilled artisan.

[0250] When using recombinant techniques, the antibody can be produced intracellularly, in the periplasmic space, or directly secreted into the medium. If the antibody is produced intracellularly, as a first step, the particulate debris, either host cells or lysed fragments, is removed, for example, by centrifugation or ultrafiltration. For example, Carter et al. (Bio/Technology, 1992, 10:163-167) describes a procedure for isolating antibodies which are secreted to the periplasmic space of E. coli. Briefly, cell paste is thawed in the presence of sodium acetate (pH 3.5), EDTA, and phcnylmcthylsulfonylfluoridc (PMSF) over about 30 minutes. Cell debris can be removed by centrifugation.

[0251] In some embodiments, the antibody is produced in a cell-free system. In some embodiments, the cell-free system is an in vitro transcription and translation system as described in Yin et al., mAbs, 2012, 4:217-225, incorporated by reference in its entirety. In some embodiments, the cell-free system utilizes a cell-free extract from a eukary otic cell or from a prokaryotic cell. In some embodiments, the prokary otic cell is E. coli. Cell-free expression of the antibody may be useful, for example, where the antibody accumulates in a cell as an insoluble aggregate, or where yields from periplasmic expression are low.

[0252] Where the antibody is secreted into the medium, supernatants from such expression systems are generally first concentrated using a commercially available protein concentration filter, for example, an Amicon® or Millipore® Pellcon® ultrafiltration unit. A protease inhibitor such as PMSF may be included in any of the foregoing steps to inhibit proteolysis and antibiotics may be included to prevent the growth of adventitious contaminants.

[0253] The antibody composition prepared from the cells can be purified using, for example, hydroxyapatite chromatography, gel electrophoresis, dialysis, and affinity chromatography, with affinity chromatography being a particularly useful purification technique. The suitability of protein A as an affinity ligand depends on the species and isotype of any immunoglobulin Fc domain that is present in the antibody. Protein A can be used to purify antibodies that are based on human yl, y2. or y4 heavy chains (Lindmark et al., J. Immunol. Meth.. 1983. 62:1-13). Protein G is useful for all mouse isotypes and for human y3 (Guss et al., EMBOJ., 1986, 5:1567-1575).

[0254] The matrix to which the affinity ligand is attached is most often agarose, but other matrices are available. Mechanically stable matrices such as controlled pore glass or poly(styrenedivinyl)benzene allow for faster flow rates and shorter processing times than can be achieved with agarose. Where the antibody comprises a Cm domain, the BakerBond ABX® resin is useful for purification.

[0255] Other techniques for protein purification, such as fractionation on an ion-exchange column, ethanol precipitation, Reverse Phase HPLC, chromatography on silica, chromatography on heparin Sepharose®, chromatofocusing, SDS-PAGE, and ammonium sulfate precipitation are also available, and can be applied by one of skill in the art.

[0256] Following any preliminary purification step(s). the mixture comprising the antibody of interest and contaminants may be subjected to low pH hydrophobic interaction chromatography using an elution buffer at a pH between about 2.5 to about 4.5, generally performed at low salt concentrations (e.g.. from about 0 to about 0.25 M salt).

7.10. Treatment of Diseases and/or Conditions

[0257] A third aspect provides a method of treating a disease or condition in a subject in need thereof, which comprises, consists, or consists essentially of administering to the subject an antibody construct, wherein the antibody construct comprises, consists, or consists essentially of a first polypeptide having a heavy chain variable region (VH) and one or more regions and a second polypeptide having a light chain variable region (VL) and one or more regions. a) the first polypeptide comprising a VH and 1, 2, or 3 of a CHI, CH2, and/or CH3, wherein the VH comprises: i) a VHCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 12-13, wherein the CDRs are according to Chothia or ii) a VHCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 1-2, wherein the CDRs are according to Kabat; iii) a VHCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 34-35, wherein the CDRs are according to Chothia or iv) a VHCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 23-24, wherein the CDRs are according to Kabat; and/or v) a VHCDR3 comprising the amino acid sequence set forth in any one of SEQ

ID NOs: 45-46; and b) wherein the second polypeptide comprising a VL and 1, 2, or 3 of a CL, CH2, and/or

CH3, wherein the VL comprises: i) a VLCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 55-56; ii) a VLCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 67-68; or iii) a VLCDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 77-78.

[0258] In some embodiments, the antibody construct is monovalent. In some embodiments, the antibody construct is bivalent. [0259] In some embodiments, the antibody construct is monovalent. In some embodiments, the antibody construct is bivalent. In some embodiments, the antibody construct specifically binds human TREM1. In some embodiments, the first polypeptide comprises, consists, or consists essentially of a VH, CHI, CH2, and CH3 in the following order: VH, CHI, CH2, and CH3. In some embodiments, the second polypeptide comprises, consists, or consists essentially of a VL, CL, CH2, and CH3 in the following order: VL. CL, CH2. and CH3.

[0260] In some embodiments, the first polypeptide comprises, consists, or consists essentially of a VH and CHI, CH2, and CH3 in the following order: VH, CHI, CH2, and CH3, wherein the CHI comprises die amino acid sequence set forth in SEQ ID NO: 121 or a variant thereof having at least 85% (c.g., at least 90%, at least 95%, or at least 98%) identity with the amino acid sequence of SEQ ID NO: 121, wherein the CH2 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 126-127 or a variant thereof having at least 85% (e.g., at least 90%, at least 95%, or at least 98%) identity with the amino acid sequence of SEQ ID NO: 126-127, and wherein the CH3 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 132-134 or a variant thereof having at least 85% (e.g., at least 90%, at least 95%. or at least 98%) identity with the amino acid sequence of SEQ ID NO: 132-134.

[0261] In some embodiments, the second polypeptide comprises, consists, or consists essentially of a VL and CL, CH2, and CH3 in the following order: VL, CL, CH2, and CH3, wherein the CL comprises die amino acid sequence set forth in SEQ ID NO: 144 or a variant thereof having at least 85% (c.g., at least 90%, at least 95%, or at least 98%) identity with the amino acid sequence of SEQ ID NO: 144, wherein the CH2 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 126-127 or a variant thereof having at least 85% (e.g., at least 90%, at least 95%, or at least 98%) identity with the amino acid sequence of SEQ ID NO: 126-127, and wherein the CH3 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 132-134 or a variant thereof having at least 85% (e.g., at least 90%, at least 95%. or at least 98%) identity with the amino acid sequence of SEQ ID NO: 132-134.

[0262] In some embodiments, the first polypeptide comprises, consists, or consists essentially of: i) a VHCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, wherein the CDR is according to Chothia or ii) a VHCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, wherein the CDR is according to Rabat; iii) a VHCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34, wherein the CDR is according to Chothia or iv) a VHCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 23, wherein the CDR is according to Kabat; and/or v) a VHCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 45 ; and the second polypeptide comprises, consists, or consists essentially of: i) a VLCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 55; ii) a VLCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 67; and/or iii) a VLCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 77. [0263] In some embodiments, the first polypeptide comprises, consists, or consists essentially of: i) a VHCDR1 comprising the ammo acid sequence set forth in SEQ ID NO: 12 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 12, wherein the CDR is according to Chothia or ii) a VHCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 1, wherein the CDR is according to Kabat; iii) a VHCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 34, wherein the CDR is according to Chothia or iv) a VHCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 23 or a variant thereof having at least 50%. 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 23, wherein the CDR is according to Kabat; and/or v) a VHCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 45 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 45; and the second polypeptide comprises, consists, or consists essentially of: i) a VLCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 55 or a variant thereof having at least 50%, 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 at least 98% identity with tire amino acid sequence set forth in SEQ ID NO: 55; ii) a VLCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 67 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 67; and/or iii) a VLCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 77 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: T1.

[0264] In some embodiments, the antibody construct comprises a three-dimensional (3D) conformation, binding capability, binding specificity, thermostability, cytotoxicity and/or immunogenicity having at least 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 at least 98% identical to an antibody construct comprising a first polypeptide comprises, consists, or consists essentially of: i) a VHCDR1 comprising the ammo acid sequence set forth in SEQ ID NO: 12, wherein the CDR is according to Chothia or ii) a VHCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, wherein the CDR is according to Kabat; iii) a VHCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34, wherein the CDR is according to Chothia or iv) a VHCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 23, wherein the CDR is according to Kabat; and/or v) a VHCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 4 ; and the second polypeptide comprises, consists, or consists essentially of: i) a VLCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 55; ii) a VLCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 67; and/or iii) a VLCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 77.

[0265] In some embodiments, the first polypeptide comprises, consists, or consists essentially of: i) a VHCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, wherein the CDR is according to Chothia or ii) a VHCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, wherein the CDR is according to Kabat; iii) a VHCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34, wherein the CDR is according to Chothia or iv) a VHCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 23, wherein the CDR is according to Kabat; v) a VHCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 45; vi) a CHI comprising the amino acid sequence set forth in SEQ ID NO: 121; vii) a CH2 comprising the amino acid sequence set forth in SEQ ID NO: 127; and viii) a CH3 comprising the amino acid sequence set forth in SEQ ID NO: 133; and the second polypeptide comprises, consists, or consists essentially of: i) a VLCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 55; ii) a VLCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 67; iii) a VLCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 77; iv) a CL comprising the amino acid sequence set forth in SEQ ID NO: 144; v) a CH2 comprising the amino acid sequence set forth in SEQ ID NO: 127; and vi) a CH3 comprising the amino acid sequence set forth in SEQ ID NO: 134.

[0266] In some embodiments, the first polypeptide comprises, consists, or consists essentially of: i) a VHCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 12, wherein the CDR is according to Chothia or ii) a VHCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1 or a variant thereof having at least 50%. 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 1, wherein the CDR is according to Kabat; iii) a VHCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 34, wherein the CDR is according to Chothia or iv) a VHCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 23 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 23. wherein the CDR is according to Kabat; v) a VHCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 45 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 45; vi) a CHI comprising the amino acid sequence set forth in SEQ ID NO: 121 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 121; vii) a CH2 comprising die amino acid sequence set forth in SEQ ID NO: 127 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 127; and viii) a CH3 comprising the amino acid sequence set forth in SEQ ID NO: 133 or a variant thereof having at least 50%. 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 133; and the second polypeptide comprises, consists, or consists essentially of: i) a VLCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 55 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 55; ii) a VLCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 67 or a variant thereof having at least 50%. 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 67; iii) a VLCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 77 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 77; iv) a CL comprising the amino acid sequence set forth in SEQ ID NO: 144 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 144; v) a CH2 comprising the ammo acid sequence set forth in SEQ ID NO: 127 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 127; and vi) a CH3 comprising the amino acid sequence set forth in SEQ ID NO: 134 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 134.

[0267] In some embodiments, the antibody construct comprises a three-dimensional (3D) conformation, binding capability, binding specificity, thermostability, cytotoxicity and/or immunogenicity having at least 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 at least 98% identical to an antibody construct comprising a first polypeptide comprises, consists, or consists essentially of: i) a VHCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, wherein the CDR is according to Chothia; o ii) a VHCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, wherein the CDR is according to Kabat; iii) a VHCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34, wherein the CDR is according to Chothia or iv) a VHCDR2 comprising tire amino acid sequence set forth in SEQ ID NO: 23, wherein the CDR is according to Kabat; v) a VHCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 45; vi) a CHI comprising the amino acid sequence set forth in SEQ ID NO: 121; vii) a CH2 comprising the amino acid sequence set forth in SEQ ID NO: 127; and viii) a CH3 comprising the amino acid sequence set forth in SEQ ID NO: 133: and the second polypeptide comprises, consists, or consists essentially of: i) a VLCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 55; ii) a VLCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 67; iii) a VLCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 77; iv) a CL comprising the amino acid sequence set forth in SEQ ID NO: 144; v) a CH2 comprising the amino acid sequence set forth in SEQ ID NO: 127; and vi) a CH3 comprising the amino acid sequence set forth in SEQ ID NO: 134.

[0268] In some embodiments, the first polypeptide comprises, consists, or consists essentially of a VH and CHI, CH2, and CH3 in the following order: VH, CHI, CH2. and CH3, wherein the VH comprises the amino acid sequence set forth in SEQ ID NO: 89 or a variant thereof having at least 55%. at least 65%, at least 75%. at least 85%, or at least 95% identity with the amino acid sequence of SEQ ID NO: 89, wherein the CHI comprises the amino acid sequence set forth in SEQ ID NO: 121 or a variant thereof having at least 55%, at least 65%. at least 75%, at least 85%. or at least 95% identity with the amino acid sequence of SEQ ID NO: 121, wherein the CH2 comprises the amino acid sequence set forth in SEQ ID NO: 127 or a variant thereof having at least 55%, at least 65%, at least 75%, at least 85%, or at least 95% identity with the amino acid sequence of SEQ ID NO: 127. and wherein the CH3 comprises the amino acid sequence set forth in SEQ ID NO: 133 or a variant thereof having at least 55%, at least 65%, at least 75%, at least 85%, or at least 95% identity with the amino acid sequence of SEQ ID NO: 133; and the second polypeptide comprises, consists, or consists essentially of a VL and CL, CH2, and CH3 in the following order: VL, CL, CH2, and CH3, wherein the VL comprises the amino acid sequence set forth in any one of SEQ ID NO: 101 or a variant thereof having at least 55%, at least 65%, at least 75%, at least 85%, or at least 95% identity’ with the amino acid sequence of any one of SEQ ID NO: 101, wherein the CL comprises the amino acid sequence set forth in any one of SEQ ID NO: 144 or a variant thereof having at least 55%, at least 65%, at least 75%, at least 85%, or at least 95% identity with the amino acid sequence of any one of SEQ ID NO: 144, wherein the CH2 comprises the amino acid sequence set forth in SEQ ID NO: 127 or a variant thereof having at least 55%, at least 65%, at least 75%, at least 85%, or at least 95% identity with the amino acid sequence of SEQ ID NO: 127, and wherein the CH3 comprises the amino acid sequence set forth in SEQ ID NO: 134 or a variant thereof having at least 55%, at least 65%, at least 75%, at least 85%, or at least 95% identity with the amino acid sequence of SEQ ID NO: 134.

[0269] In some embodiments, the subject has a disease or condition associated with TREM1 aberrant expression and/or regulation of downstream signaling in a cell expressing TREM1. In some embodiments, the disease or condition is associated with overexpression of TREM1. In some embodiments, the disease or condition is associated with activation of TREM1. In some embodiments, the disease or condition comprises one or more of multiple sclerosis. Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, epilepsy, inflammatory bowel disease (IBD), Human Immunodeficiency Virus (HIV), brain tumor, stroke, amyotrophic lateral sclerosis, spinal cord and/or brain trauma, a disease or condition which would benefit from enzy me replacement therapy (“ERT”), a neurological disease, chronic inflammatory conditions, acute inflammatory conditions, autoimmune diseases, infections, and/or psychiatric conditions. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0270] In some embodiments, described are methods for treating a subject having one or more inflammatory conditions. In some embodiments, the method prevents and/or reduces the incidents of having one or more inflammatory’ conditions. In some embodiments, the subject has chronic inflammatory’ conditions. In some embodiments, the subject has acute inflammatory’ conditions. In some embodiments, the subject is prone to have inflammatory conditions. In some embodiments, the subject has sepsis, rheumatoid arthritis, and/or inflammatory bowel disease (IBD).

[0271] For illustrative purposes, in vivo assays to assess prophylactic treatment of the monovalent anti- TREM1 antibody construct may be carried out in a knock-in mouse line with the extracellular domain (ECD) of mouse TREM1 replaced by the ECD of human TREM1 (Biocytogen, hTREMl mice). To induce short-term inflammation, the hTREMl mice are administered Lipopolysaccharide from E. coli 0111:B4 (LPS, Invivogen) by intraperitoneal injection (i.p.) at 5 mg/kg. The mice are scored after 24 hours following a scoring scheme described in Carlson ML. et. al., Mol Imaging Biol . 2023 ;25(6): 1063- 1072. doi: 10.1007/sl 1307-023-01850-5. For preventive treatment, the Bivalent antibody and Monovalent antibody constructs are injected (i.p.) at 4 mg/kg and 8.5 mg/kg 2 hours prior to the LPS injection. FIG. 9 shows the effect of using anti-TREMl antibody construct (4 mg/kg, i.p. for Bivalent mAb or 8.5 mg/kg, i.p. for Monovalent antibody construct) on sepsis scores 24 hour after LPS (5 mg/kg, i.p.) administration in male and female mice. The scale bars represent s.e.m., *** P<0.001. FIG. 10 shows that an equivalent dose of the monovalent antibody construct (W002) based on its affinity was as effective as the dose of its corresponding bivalent antibody on sepsis scores at 24 hours in mice with LPS-induced sepsis in a dose escalation study using female hTREMl-tg mice. In some embodiments, the anti-TREMl monovalent antibody construct is effective in preventing, reducing, and/or treating sepsis. In some embodiments, the anti-TREMl monovalent antibody construct is effective in preventing, reducing, and/or treating one or more acute inflammatory conditions. [0272] In some embodiments, the anti-TREMl monovalent antibody construct is effective in preventing, reducing, and/or treating sepsis, an example of acute inflammatory conditions. In some embodiments, the anti-TREMl monovalent antibody construct prevents, reduces, and/or treats sepsis acute inflammatory conditions by at least 10%, at least 20%, 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 higher as compared to a subject who has not been administered with the anti-TREMl monovalent antibody construct, or a subject who has been administered with a corresponding anti-TREMl bivalent antibody.

[0273] In some embodiments, the anti-TREMl monovalent antibody construct is effective in suppressing cytokine and/or chcmokinc production in a subject under stimulated conditions. For example, mice stimulated with LPS as described herein may be euthanized with CO2 or Isoflurane and tissues (e.g., spleen) are collected and frozen on dry ice before transferring to -80 °C for long-term storage. Each spleen (~300 mg) is homogenized in 1 mL of lysis buffer containing 50 mM Tris HC1, PH 7-8, 0.1 M NaCl, 1% Triton X-100, supplemented with protease inhibitors including 100 ug/ml Aprotinin. 100 ug/ml Leupeptin, 50 ug/ml Pep-statin, and 100 mM PMSF using a Dunce homogenizer followed by centrifugation at 14,000 g for 15 min at 4 °C. Approximately 400 pL of the supernatants may be transferred to prechilled protein low binding Eppendorf tubes. Protein concentrations may be quantified, for example, using a BCA Protein Assay Kit (Pierce 23225) and adjusted to a final concentration of 4 mg/mL. The lysates are aliquoted and frozen on dry ice for > 15 min before storing at -80 °C. 10-50 pL of tissue lysates are used for an individual assay. Levels of cytokines and chemokines in the tissue lysates are measured using Multiplex Luminex Assays (Luminex) or ELISA (R&D, IL- 18 DY7625-05. IL-1|3 DY401-05. IL- la DY400-05. IL-33 DY3626-05, IL-6 DY406-05. MIP2 DY452-05) following manufacturer’s instructions.

[0274] FIG. 11 shows a monovalent antibody construct suppresses the production of pro -inflammatory cytokines and chemokines in the spleen of mice after 24 horns of LPS stimulation, as measured using an ELISA assay. Administration of the monovalent antibody construct at the equivalent binding affinity dose to the corresponding bivalent antibody exhibited higher reduction of IL-33 and inflammasome products IL-la, IL- IB. and IL-18 compared to its corresponding bivalent antibody. Both monovalent and bivalent reduced IL-6 and MIP2/CXCL2. The scale bars represent s.e.m.. *** P<0.001. **** PO.OOOl. In some embodiments, the monovalent antibody construct reduces production of IL-la. IL- 6. IL- 18, IL-33. IL- IB, and/or MIP2/CXCL2. In some embodiments, the inhibitory effect on pro- inflammatory cytokine is significantly higher for monovalent antibody compared to bivalent antibody.

[0275] In some embodiments, the inhibitory effect on IL-1 is significantly higher for monovalent antibody compared to a bivalent antibody. In some embodiments, the inhibitory effect on IL-6 is similar between monovalent antibody and to bivalent antibody. In some embodiments, the signaling or agonism of TREM1 is better and/or more effectively modulated by monovalent than bivalent molecule. In some embodiments, ligand induced oligomerization causes 'inward signaling'. Without being bound to any thcory . bivalent does not completely eliminate this 'inward signaling', for example, due to cross-linking effect, although it might block ligand binding, whereas monovalent completely eliminates this signaling.

[0276] In some embodiments, the anti-TREMl monovalent antibody construct is effective in preventing, reducing, and/or disabling cytokine and/or chemokine production in a cell expressing TREM1. In some embodiments, the anti-TREMl monovalent antibody construct prevents, reduces, and/or disables cytokine and/or chemokine production in a cell expressing TREM1 by at least 10%, at least 20%, 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 higher as compared to corresponding TREM1 expressing cells in a subject who has not been administered with the anti-TREMl monovalent antibody construct, or a subject who has been administered with a corresponding anti-TREMl bivalent antibody.

[0277] In some embodiments, the anti-TREMl monovalent antibody construct is effective in preventing, reducing, and/or disabling cytokine and/or chemokine production in macrophages. Nonlimiting examples of macrophages are bone marrow-derived macrophages, alveola macrophages, Kupffer cells, microglia, osteoclasts, peritoneal macrophages, Ml macrophages, M2 microphages, monocyte-derived macrophages, tumor-associated macrophages, Langerhans cells, sinusoidal macrophages, and/or intestinal macrophages. In some embodiments, the anti-TREMl monovalent antibody construct is effective in preventing, reducing, and/or disabling cytokine and/or chemokine production in bone marrow-derived macrophages. In some embodiments, the cytokines or chemokines comprise, consist essentially of, or consist of one or more of receptors, ligands, or binding targets of IL-6, MIP2/CXCL2, IL- la, IL- 1(3, IL- 18, IL-33, and/or a mutant or an analog thereof.

[0278] In some embodiments, the inhibitory effects of the anti-TREMl monovalent antibody construct on proinflammatory cytokines are independent of increasing concentrations of the anti-TREMl monovalent antibody construct. In some embodiments, the cytokine is IL-1 [3. In some embodiments, the subject is under quiescent conditions. In some embodiments, the anti-TREMl monovalent antibody construct maintained persistently low levels of IL- 1 P in BMDMs isolated from a subject (e.g., hTREMl K/I mouse or human), independent of concentration. In some embodiments, the TREM1 monovalent antibody construct has a better safety profile than the bivalent and could be used for prophylactic treatment to maintain low levels of proinflammatory cytokines under quiescent conditions or stimulated conditions.

[0279] For example. FIG. 12A shows the inhibitory’ effects of treatment with increasing concentrations of monovalent or bivalent antibodies on a proinflammatory cytokine in BMDMs isolated from hTREMl K/I mice without LPS stimulation (under quiescent conditions). Monovalent antibody constructs maintained persistently low levels of IL- 1(3 in BMDMs from hTREMl K/I mouse, independent of concentration (FIG. 12A). In contrast, IL-i production began to increase at 200 nM of bivalent antibody. Similarly, in FIG. 12B, increasing doses of bivalent W002 led to increased TREM1 activation in Jurkat TREM1-DAP12 overexpressing NF AT reporter cells, whereas increasing concentrations of monovalent W002 did not change TREM1 activation.

[0280] FIG. 13 shows the inhibitory effects of treatment with increasing concentrations of monovalent or bivalent antibodies on a proinflammatory cytokine in BMDMs isolated from hTREMl K/I mice stimulated with LPS ( 0 ng/ml LPS for 20 hours; under stimulated conditions) and without LPS (under quiescent conditions), compared to BMDMs under quiescent conditions treated with an iso type control. FIG. 14 shows results for a broader concentration range of antibodies. One-way ANOVA for both monovalent and bivalent antibodies is pO.OOOl. As shown in FIG. 14, the monovalent antibody construct, at a concentration as low as 1 nM, effectively reduced IL- 10 in BMDMs isolated from hTREMl K/I mice in response to LPS stimulation, whereas the referenced bivalent antibody required 10 nM to achieve tire same result. The data demonstrate that the monovalent antibody construct exhibited higher efficiency hi reducing IL- 10 in BMDMs expressing hTREMl than the referenced bivalent antibody. The data indicate that the TREM1 monovalent antibody construct has a better safety profile than the bivalent and could be used for prophylactic treatment to maintain low levels of proinflammatory cytokines under quiescent conditions or stimulated conditions.

[0281] FIG. 15 shows the inhibitory effect of the monovalent antibody construct on TNF-a production in HuMDM as compared to the corresponding dose of bivalent antibody based on affinity binding which is 5.2-fold tighter than that of the monovalent. The scale bars represent s.e.m.,. One way ANOVA was performed on cells + antibodies, no PGLYRP-PGN (left side of graph); here, bivalent TREM1 antibody at 60 pg/ml showed significant activation of TREM1 production of TNFa *** P<0.001. . With the addition of PGLYRP-PGN (right side of graph), both monovalent and bivalent TREM1 antibodies reduced TNF-a production, but monovalent TREM1 antibodies at 312 pg/ml inhibited TNF-a production better than the corresponding concentration of bivalent antibody at 60 pg/ml.

[0282] In some embodiments, the effective amount of the anti-TREMl monovalent antibody construct is between about 0.001 nM to about 10,000 nM, between about 0.01 nM to about 2,000 nM, between about 0.1 nM to about 1,000 nM, between about 0.1 nM to about 10 nM, between about 0.5 nM to about 2 nM, between about 1 nM to about 600 nM, betw een about 10 nM to about 500 nM, betw een about 5 nM to about 30 nM, between about 50 nM to about 400 nM, between about 100 nM to about 300 nM, between about 300 nM to about 1,000 nM.

7.11. Pharmaceutical Compositions and Methods of Administration

[0283] Another aspect provides a pharmaceutical composition comprising one or more of the antibody constructs set forth herein. Any of the antibody constructs provided herein can be provided in any appropriate pharmaceutical composition and be administered by any suitable route of administration. Suitable routes of administration include, but are not limited to, the inhalation, intra-arterial, intradermal, intramuscular, intraperitoneal, intravenous, nasal, parenteral, pulmonary’, and subcutaneous routes.

[0284] The pharmaceutical composition may comprise one or more pharmaceutical excipients. Any suitable pharmaceutical excipient may be used, and one of ordinary skill in the art is capable of selecting suitable pharmaceutical excipients. Accordingly, the pharmaceutical excipients provided below are intended to be illustrative, and not limiting. Additional pharmaceutical excipients include, for example, those described in the Handbook of Pharmaceutical Excipients, Rowe et al. (Eds.) 6th Ed. (2009), incorporated by reference in its entirety.

[0285] In some embodiments, the pharmaceutical composition comprises an anti-foaming agent. Any suitable anti-foaming agent may be used. In some embodiments, the anti-foaming agent is selected from an alcohol, an ether, an oil, a wax. a silicone, a surfactant, and combinations thereof. In some embodiments, tire anti-foaming agent is selected from a mineral oil. a vegetable oil, ethylene bis stearamide, a paraffin wax. an ester wax, a fatty alcohol wax, a long chain fatty⁷ alcohol, a fatty acid soap, a fatty acid ester, a silicon glycol, a fluorosilicone, a polyethylene glycol-polypropylene glycol copolymer, polydimethylsiloxane-silicon dioxide, ether, octy l alcohol, capryl alcohol, sorbitan trioleate, ethyl alcohol, 2-ethyl-hexanol, dimethicone. oleyl alcohol, simethicone, and combinations thereof.

[0286] In some embodiments, the pharmaceutical composition comprises a cosolvent. Illustrative examples of cosolvents include ethanol, poly (ethylene) glycol, butylene glycol, dimethylacetamide, glycerin, and propylene glycol.

[0287] In some embodiments, the pharmaceutical composition comprises a buffer. Illustrative examples of buffers include acetate, borate, carbonate, lactate, malate, phosphate, citrate, hydroxide, diethanolamine, monoethanolamine, glycine, methionine, guar gum, and monosodium glutamate.

[0288] In some embodiments, the pharmaceutical composition comprises a carrier or filler. Illustrative examples of carriers or fillers include lactose, maltodextrin, mannitol, sorbitol, chitosan, stearic acid, xanthan gum, and guar gum.

[0289] In some embodiments, the pharmaceutical composition comprises a surfactant. Illustrative examples of surfactants include -alpha tocopherol, benzalkonium chloride, benzethonium chloride, cetrimide, cetylpyridinium chloride, docusate sodium, gly cery l behenate, gly cery l monooleate, lauric acid, macrogol 15 hydroxystearate, myristyl alcohol, phospholipids, polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty’ acid esters, polyoxyethylene stearates, polyoxylglycerides, sodium lauryl sulfate, sorbitan esters, and vitamin E polyethylene(glycol) succinate.

[0290] In some embodiments, the pharmaceutical composition comprises an anti-caking agent. Illustrative examples of anti-caking agents include calcium phosphate (tribasic), hydroxymethyl cellulose, hy droxy propyl cellulose, and magnesium oxide. [0291] Other excipients that may be used with the pharmaceutical compositions include, for example, albumin, antioxidants, antibacterial agents, antifungal agents, bioabsorbable polymers, chelating agents, controlled release agents, diluents, dispersing agents, dissolution enhancers, emulsify ing agents, gelling agents, ointment bases, penetration enhancers, preservatives, solubilizing agents, solvents, stabilizing agents, and sugars. Specific examples of each of these agents are described, for example, in the Handbook of Pharmaceutical Excipients, Rowe et al. (Eds.) 6th Ed. (2009), The Pharmaceutical Press, incorporated by reference in its entirety.

[0292] In some embodiments, the pharmaceutical composition comprises a solvent. In some embodiments, the solvent is saline solution, such as a sterile isotonic saline solution or dextrose solution. In some embodiments, the solvent is water for injection.

[0293] In some embodiments, the pharmaceutical compositions are in a particulate form, such as a microparticle or a nanoparticle. Microparticles and nanoparticles may be formed from any suitable material, such as a polymer or a lipid. In some embodiments, the microparticles or nanoparticles are micelles, liposomes, or polymersomes. In certain embodiments, a composition provided herein is a pharmaceutical composition or a single unit dosage form. Pharmaceutical compositions and single unit dosage forms provided herein comprise a prophy tactically or therapeutically effective amount of one or more prophylactic or therapeutic antibody constructs.

[0294] Further encompassed herein are anhydrous pharmaceutical compositions and dosage forms comprising an antibody, since water can facilitate the degradation of some antibodies.

[0295] Anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine can be anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.

[0296] An anhydrous phannaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions can be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

7.11.1. Parenteral Dosages Forms

[0297] In some embodiments parenteral dosage forms are provided. Parenteral dosage forms can be administered to subjects by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intra-arterial. Because their administration typically bypasses subjects’ natural defenses against contaminants, parenteral dosage forms are typically, sterile or capable of being sterilized prior to administration to a subject. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.

[0298] Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art. Examples include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer’s Injection, Dextrose Injection. Dextrose and Sodium Chloride Injection, and Lactated Ringer’s Injection; water miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzy l benzoate.

[0299] Excipients that increase the solubility of one or more of the antibody constructs disclosed herein can also be incorporated into the parenteral dosage forms.

7.11.2. Dosage and Unit Dosage Forms

[0300] In human therapeutics, the doctor will determine the dosology which she considers most appropriate according to a preventive or curative treatment and according to the age, weight, condition and other factors specific to the subject to be treated.

[0301] The amount of the antibody construct or composition which will be effective in the prevention or treatment of a disorder or one or more symptoms thereof will vary with the nature and severity of the disease or condition, and the route by which the antibody construct is administered. The frequency and dosage will also vary according to factors specific for each subject depending on the specific therapy (e.g., therapeutic or prophylactic agents) administered, the severity of the disorder, disease, or condition, the route of administration, as well as age, body, weight, response, and the past medical history of the subject. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0302] The dose can be administered according to a suitable schedule, for example, once, two times, three times, or for times weekly. It may be necessary to use dosages of the antibody outside the ranges disclosed herein in some cases, as will be apparent to those of ordinary skill in the art. Furthermore, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with subject response.

[0303] Different therapeutically effective amounts may be applicable for different diseases, disorders, and conditions, as will be readily known by those of ordinary skill in the art. Similarly, amounts sufficient to prevent, manage, treat or ameliorate such diseases, disorders, and conditions, but insufficient to cause, or sufficient to reduce, adverse effects associated with the antibody constructs provided herein are also encompassed by the herein described dosage amounts and dose frequency schedules. Further, when a subject is administered multiple dosages of a composition provided herein, not all of the dosages need be the same. For example, the dosage administered to the subject may be increased to improve the prophylactic or therapeutic effect of the composition or it may be decreased to reduce one or more side effects that a particular subject is experiencing.

[0304] In some embodiments, treatment or prevention can be initiated with one or more loading doses of an antibody construct or composition provided herein followed by one or more maintenance doses.

[0305] In some embodiments, a dose of an antibody construct or composition provided herein can be administered to achieve a steady -state concentration of the antibody construct in blood or serum of the subject. The steady-state concentration can be determined by measurement according to techniques available to those of skill or can be based on the physical characteristics of the subject such as height, weight and age.

[0306] In some embodiments, administration of the same composition may be repeated and the administrations may be separated by at least 1 day, 2 days, 3 days. 5 days, 10 days, 15 days, 30 days, 45 days, 2 months. 75 days, 3 months, or 6 months. In some embodiments, administration of the same prophylactic or therapeutic agent may be repeated and the administration may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.

7.12. Other Applications

[0307] A fourth aspect provides a method of imaging a disease or condition in a subject in need thereof, which comprises, consists, or consists essentially of administering to the subject an antibody construct, wherein the antibody construct comprises, consists, or consists essentially of a first polypeptide having a heavy chain variable region (VH) and one or more regions and a second polypeptide having a light chain variable region (VL) and one or more regions, a) the first polypeptide comprising a VH and 1. 2, or 3 of a CHI, CH2, and/or CH3, wherein the VH comprises: i) a VHCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 12-13, wherein the CDRs are according to Chothia or ii) a VHCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 1-2, wherein the CDRs are according to Kabat; iii) a VHCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 34-35, wherein the CDRs are according to Chothia or iv) a VHCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 23-24, wherein the CDRs are according to Kabat; and/or v) a VHCDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 45-46; and b) the second polypeptide comprising a VL and 1, 2, or 3 of a CL, CH2, and/or CH3, wherein the VL comprises: i) a VLCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 55-56; ii) a VLCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 67-68; or iii) a VLCDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 77-78.

[0308] In some embodiments, the antibody construct is monovalent. In some embodiments, the antibody construct is bivalent.

[0309] A fifth aspect provides a method of disabling or reducing myeloid cells that express Triggering Receptor Expressed on Myeloid Cells 1 (TREM1) on the cell surface, comprising contacting or binding or causing the myeloid cells to bind with an antibody construct that specifically binds human TREM1, wherein the antibody construct comprises, consists, or consists essentially of a first polypeptide having a heavy chain variable region (VH) and one or more regions and a second polypeptide having a light chain variable region (VL) and one or more regions, a) the first polypeptide comprising a VH and 1, 2, or 3 of a CHI, CH2, and/or CH3, wherein the VH comprises: i) a VHCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 12-13, wherein the CDRs are according to Chothia or ii) a VHCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 1-2, wherein the CDRs are according to Kabat; iii) a VHCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 34-35, wherein the CDRs are according to Chothia or iv) a VHCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 23-24, wherein the CDRs are according to Kabat; and/or v) a VHCDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 45-46; and b) the second polypeptide comprising a VL and 1, 2, or 3 of a CL, CH2, and/or CH3, wherein the VL comprises: i) a VLCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 55-56; ii) a VLCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 67-68; or iii) a VLCDR3 comprising the amino acid sequence set forth in any one of SEQ

ID NOs: 77-78. [0310] In some embodiments, the antibody construct is monovalent. In some embodiments, the antibody construct is bivalent.

[0311] An sixth aspect provides a method of disabling myeloid cells that over express Triggering Receptor Expressed on Myeloid Cells 1 (TREM1) on the cell surface, comprising contacting or binding or causing the myeloid cells to bind with an antibody construct that specifically binds human TREM1, wherein the antibody construct comprises, consists, or consists essentially of a first polypeptide having a heavy chain variable region (VH) and one or more regions and a second polypeptide having a light chain variable region (VL) and one or more regions, a) the first polypeptide comprising a VH and 1. 2. or 3 of a CHI. CH2. and/or CH3, wherein the VH comprises: i) a VHCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 12-13. wherein the CDRs are according to Chothia or ii) a VHCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 1-2. wherein the CDRs are according to Kabat; iii) a VHCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 34-35, wherein the CDRs are according to Chothia or iv) a VHCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 23-24, wherein the CDRs arc according to Kabat; and/or v) a VHCDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 45-46; and b) the second polypeptide comprising a VL and 1, 2, or 3 of a CL, CH2, and/or CH3, wherein the VL comprises: i) a VLCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 55-56; ii) a VLCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 67-68; or iii) a VLCDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 77-78.

[0312] A seventh aspect provides a method of inhibiting or reducing Triggering Receptor Expressed on Myeloid Cells 1 (TREM1) signaling in a cell that expresses Triggering Receptor Expressed on Myeloid Cells 1 (TREM 1) on the cell surface, comprising contacting or binding or causing the cells to bind with an antibody construct that specifically binds human TREM1. thereby inhibiting or reducing TREM1 signaling in the cell, wherein the antibody construct comprises, consists, or consists essentially of a first polypeptide having a heavy chain variable region (VH) and one or more regions and a second polypeptide having a light chain variable region (VL) and one or more regions, a) the first polypeptide comprising a VH and 1, 2, or 3 of a CHI, CH2, and/or CH3, wherein the VH comprises: i) a VHCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 12-13, wherein the CDRs are according to Chothia or ii) a VHCDR1 comprising the ammo acid sequence set forth in any one of SEQ ID NOs: 1-2, wherein the CDRs are according to Kabat; iii) a VHCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 34-35, wherein the CDRs are according to Chothia or iv) a VHCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 23-24, wherein the CDRs are according to Kabat; or v) a VHCDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 45-46; and/or b) the second polypeptide comprising a VL and 1, 2, or 3 of a CL, CH2, and/or CH3. wherein the VL comprises: i) a VLCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 55-56; ii) a VLCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 67-68; or iii) a VLCDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 77-78.

[0313] In some embodiments, the antibody construct is monovalent. In some embodiments, the antibody construct is bivalent.

[0314] In some embodiments, the antibody construct is monovalent. In some embodiments, the antibody construct is bivalent. In some embodiments, the antibody construct specifically binds human TREM1. In some embodiments, the first polypeptide comprises, consists, or consists essentially of a VH. CHI, CH2, and CH3 in the following order: VH, CHI. CH2. and CH3. In some embodiments, the second polypeptide comprises, consists, or consists essentially of a VL, CL, CH2, and CH3 in the following order: VL, CL. CH2, and CH3.

[0315] In some embodiments, the first polypeptide comprises, consists, or consists essentially of a VH and CHI, CH2, and CH3 in the following order: VH. CHI. CH2, and CH3, wherein the CHI comprises the amino acid sequence set forth in SEQ ID NO: 121 or a variant thereof having at least 85% (e.g.. at least 90%. at least 95%, or at least 98%) identity with the amino acid sequence of SEQ ID NO: 121, wherein the CH2 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 126-127 or a variant thereof having at least 85% (e.g.. at least 90%, at least 95%, or at least 98%) identity with the amino acid sequence of SEQ ID NO: 126-127, and wherein the CH3 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 132-134 or a variant thereof having at least 85% (e.g., at least 90%, at least 95%, or at least 98%) identity with the amino acid sequence of SEQ ID NO: 132-134.

[0316] In some embodiments, the second polypeptide comprises, consists, or consists essentially of a VL and CL, CH2, and CH3 in the following order: VL. CL, CH2. and CH3, wherein the CL comprises the amino acid sequence set forth in SEQ ID NO: 144 or a variant thereof having at least 85% (e.g., at least 90%. at least 95%, or at least 98%) identity with the amino acid sequence of SEQ ID NO: 144, wherein the CH2 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 126-127 or a variant thereof having at least 85% (e.g., at least 90%, at least 95%, or at least 98%) identity with the amino acid sequence of SEQ ID NO: 126-127, and wherein the CH3 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 132-134 or a variant thereof having at least 85% (e.g., at least 90%, at least 95%, or at least 98%) identity with the amino acid sequence of SEQ ID NO: 132-134.

[0317] In some embodiments, the first polypeptide comprises, consists, or consists essentially of: i) a VHCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, wherein the CDR is according to Chothia or ii) a VHCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, wherein the CDR is according to Kabat; iii) a VHCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34, wherein the CDR is according to Chothia or iv) a VHCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 23, wherein the CDR is according to Kabat; and/or v) a VHCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 45 ; and the second polypeptide comprises, consists, or consists essentially of: i) a VLCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 55; ii) a VLCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 67; and/or iii) a VLCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 77.

[0318] In some embodiments, the first polypeptide comprises, consists, or consists essentially of: i) a VHCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 12, wherein the CDR is according to Chothia or ii) a VHCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 1, wherein tire CDR is according to Kabat; iii) a VHCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 34, wherein the CDR is according to Chothia or iv) a VHCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 23 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 23, wherein the CDR is according to Kabat; and/or v) a VHCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 45 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 45; and the second polypeptide comprises, consists, or consists essentially of: i) a VLCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 55 or a variant thereof having at least 50%, 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 at least 98% identity with die amino acid sequence set forth in SEQ ID NO: 55; ii) a VLCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 67 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 67; and/or iii) a VLCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 77 or a variant thereof having at least 50%. 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 77.

[0319] In some embodiments, the antibody construct comprises a three-dimensional (3D) conformation, binding capability, binding specificity, thermostability, cytotoxicity and/or immunogenicity having at least 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 at least 98% identical to an antibody construct comprising a first polypeptide comprises, consists, or consists essentially of: i) a VHCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, wherein the CDR is according to Chothia or ii) a VHCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1. wherein the CDR is according to Kabat; iii) a VHCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34, wherein the CDR is according to Chothia or iv) a VHCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 23. wherein the CDR is according to Kabat; and/or v) a VHCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 45 ; and the second polypeptide comprises, consists, or consists essentially of: i) a VLCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 55; ii) a VLCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 67; and/or iii) a VLCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 77.

10320| In some embodiments, the first polypeptide comprises, consists, or consists essentially of: i) a VHCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, wherein the CDR is according to Chothia or ii) a VHCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1. wherein the CDR is according to Kabat; iii) a VHCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34. wherein the CDR is according to Chothia or iv) a VHCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 23. wherein the CDR is according to Kabat; v) a VHCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 45; vi) a CHI comprising the amino acid sequence set forth in SEQ ID NO: 121; vii) a CH2 comprising the amino acid sequence set forth in SEQ ID NO: 127; and viii) a CH3 comprising the amino acid sequence set forth in SEQ ID NO: 133; and the second polypeptide comprises, consists, or consists essentially of: i) a VLCDR1 comprising die amino acid sequence set forth in SEQ ID NO: 55; ii) a VLCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 67; iii) a VLCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 77; iv) a CL comprising the amino acid sequence set forth in SEQ ID NO: 144; v) a CH2 comprising the amino acid sequence set forth in SEQ ID NO: 127; and vi) a CH3 comprising the amino acid sequence set forth in SEQ ID NO: 134.

[0321] In some embodiments, the first polypeptide comprises, consists, or consists essentially of: i) a VHCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12 or a variant thereof having at least 50%, 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 at least 98% identity’ with die amino acid sequence set forth in SEQ ID NO: 12, wherein the CDR is according to Chothia or ii) a VHCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 1, wherein die CDR is according to Kabat; iii) a VHCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 34, wherein the CDR is according to Chothia or iv) a VHCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 23 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 23, wherein the CDR is according to Kabat; v) a VHCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 45 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 45; vi) a CHI comprising the amino acid sequence set forth in SEQ ID NO: 121 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 121; vii) a CH2 comprising the amino acid sequence set forth in SEQ ID NO: 127 or a variant thereof having at least 50%. 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 127; and viii) a CH3 comprising the amino acid sequence set forth in SEQ ID NO: 133 or a variant thereof having at least 50%, 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 at least 98% identity' with the amino acid sequence set forth in SEQ ID NO: 133; and the second polypeptide comprises, consists, or consists essentially of: i) a VLCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 55 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 55; ii) a VLCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 67 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 67; iii) a VLCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 77 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 77; iv) a CL comprising the amino acid sequence set forth in SEQ ID NO: 144 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 144; v) a CH2 comprising the amino acid sequence set forth in SEQ ID NO: 127 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 127; and vi) a CH3 comprising the amino acid sequence set forth in SEQ ID NO: 134 or a variant thereof having at least 50%, 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 at least 98% identity with the amino acid sequence set forth in SEQ ID NO: 134.

[0322] In some embodiments, the antibody construct comprises a three-dimensional (3D) conformation, binding capability, binding specificity, thermostability, cytotoxicity and/or immunogenicity having at least 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 at least 98% identical to an antibody construct comprising a first polypeptide comprises, consists, or consists essentially of: i) a VHCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, wherein the CDR is according to Chothia; o ii) a VHCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, wherein the CDR is according to Kabat; iii) a VHCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34. wherein the CDR is according to Chothia or iv) a VHCDR2 comprising die amino acid sequence set forth in SEQ ID NO: 23, wherein the CDR is according to Kabat; v) a VHCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 45; vi) a CHI comprising the amino acid sequence set forth in SEQ ID NO: 121; vii) a CH2 comprising the amino acid sequence set forth in SEQ ID NO: 127; and viii) a CH3 comprising the amino acid sequence set forth in SEQ ID NO: 133; and the second polypeptide comprises, consists, or consists essentially of: i) a VLCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 55; ii) a VLCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 67; iii) a VLCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 77; iv) a CL comprising the amino acid sequence set forth in SEQ ID NO: 144; v) a CH2 comprising the amino acid sequence set forth in SEQ ID NO: 127; and vi) a CH3 comprising the amino acid sequence set forth in SEQ ID NO: 134. [0323] In some embodiments, the first polypeptide comprises, consists, or consists essentially of a VH and CHI, CH2, and CH3 in the following order: VH, CHI, CH2, and CH3, wherein the VH comprises die amino acid sequence set forth in SEQ ID NO: 89 or a variant thereof having at least 55%, at least 65%, at least 75%. at least 85%, or at least 95% identity with the amino acid sequence of SEQ ID NO: 89, wherein the CHI comprises the amino acid sequence set forth in SEQ ID NO: 121 or a variant thereof having at least 55%, at least 65%. at least 75%, at least 85%. or at least 95% identity with the amino acid sequence of SEQ ID NO: 121, wherein the CH2 comprises the amino acid sequence set forth in SEQ ID NO: 127 or a variant thereof having at least 55%. at least 65%, at least 75%. at least 85%, or at least 95% identity with the amino acid sequence of SEQ ID NO: 127, and wherein the CH3 comprises the amino acid sequence set forth in SEQ ID NO: 133 or a variant thereof having at least 55%, at least 65%. at least 75%, at least 85%. or at least 95% identity with the amino acid sequence of SEQ ID NO: 133; and the second polypeptide comprises, consists, or consists essentially of a VL and CL. CH2. and CH3 in the following order: VL, CL, CH2, and CH3, wherein the VL comprises the amino acid sequence set forth in any one of SEQ ID NO: 101 or a variant thereof having at least 55%, at least 65%. at least 75%, at least 85%. or at least 95% identity with the amino acid sequence of any one of SEQ ID NO: 101. wherein the CL comprises the amino acid sequence set forth in any one of SEQ ID NO: 144 or a variant thereof having at least 55%, at least 65%, at least 75%, at least 85%, or at least 95% identity with the amino acid sequence of any one of SEQ ID NO: 144. wherein the CH2 comprises the amino acid sequence set forth in SEQ ID NO: 127 or a variant thereof having at least 55%, at least 65%, at least 75%, at least 85%, or at least 95% identity with the amino acid sequence of SEQ ID NO: 127, and wherein the CH3 comprises the amino acid sequence set forth in SEQ ID NO: 134 or a variant thereof having at least 55%, at least 65%, at least 75%, at least 85%. or at least 95% identity’ with the amino acid sequence of SEQ ID NO: 134.

[0324] In some embodiments, the first polypeptide comprises one or more mutations in the CH3 and the second polypeptide comprises one or more mutations in the CH3. In some embodiments, the one or more first polypeptide CH3 mutations and the one or more second polypeptide mutations are substitutions. In some embodiments, the one or more substitutions are substitutions comprises, consists, or consists essentially of an interface amino acid residue.

[0325] In some embodiments, the disease or condition comprises, consists, or consists essentially of one or more of multiple sclerosis. Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, epilepsy, inflammatory bowel disease (IBD), Human Immunodeficiency Virus (HIV), brain tumor, stroke, amyotrophic lateral sclerosis, spinal cord and/or brain trauma, a disease or condition which would benefit from enzyme replacement therapy (“ERT”). a neurological disease, chronic inflammatory conditions, acute inflammatory conditions, autoimmune diseases, infections, and/or psychiatric conditions. [0326] In some embodiments, the disease or condition is associated with TREM1. In some embodiments, the disease or condition associated with TREM1 comprises, consists, or consists essentially of an infection, such as sepsis, COVID- 19, and HIV. In some embodiments, the disease or condition is associated with TREM1 comprises, consists, or consists essentially of a systemic conditions, for example a metabolic condition such as diabetes or insulin resistance, sarcopenia, or physical frailty.

[0327] In some embodiments, the disease or condition associated with TREM1 comprises, consists, or consists essentially of an organ specific disease or condition.

[0328] In some embodiments, the organ specific disease or condition comprises, consists, or consists essentially of a pancreatic disease or condition such as pancreatitis.

[0329] In some embodiments, the organ specific disease or condition comprises, consists, or consists essentially of a liver disease or condition such as fibrosis, steatosis, or alcoholic liver disease. In some embodiments, the liver disease or condition is fibrosis. In some embodiments, the liver disease or condition is steatosis. In some embodiments, the liver disease or condition is alcoholic liver disease.

[0330] In some embodiments, the organ specific disease or condition comprises, consists, or consists essential of a renal disease or condition such as acute kidney injury or chronic kidney injury. In some embodiments, the renal disease or condition is acute kidney injury'. In some embodiments, the renal disease or condition is chronic kidney injury'.

[0331] In some embodiments, the organ specific disease or condition comprises, consists, or consists essentially of a lung specific disease or condition such as COPD, non-small cell lung cancer, asthma, bleomycin induced fibrosis, or tuberculosis. In some embodiments, the lung specific disease or condition is COPD. In some embodiments, the lung specific disease or condition is non-small cell lung cancer. In some embodiments, the lung specific disease or condition is astluna. In some embodiments, the lung specific disease or condition is bleomycin induced fibrosis. In some embodiments, the lung specific disease or condition is tuberculosis.

[0332] In some embodiments, the organ specific disease or condition comprises, consists, or consists essentially of an eye specific disease or condition such as retinopathy.

[0333] In some embodiments, the organ specific disease or condition comprises, consists, or consists essentially of periodontitis.

[0334] In some embodiments, the organ specific disease or condition comprises, consists, or consists essentially of cardiovascular disease such as heart disease, peripheral arterial disease, acute myocardial infarction (AMI), atherosclerosis, or restenosis of coronary arteries. In some embodiments, the cardiovascular disease is heart disease. In some embodiments, the cardiovascular disease is peripheral arterial disease. In some embodiments, the cardiovascular disease is acute myocardial infarction (AMI). In some embodiments, the cardiovascular disease is atherosclerosis. In some embodiments, the cardiovascular disease is restenosis of coronary arteries.

[0335] In some embodiments, the organ specific disease or condition comprises, consists, or consists essentially of autoimmune diseases or conditions such as Rheumatoid arthritis (RA), colitis, irritable bowel syndrome, type-1 diabetes mellitus. psoriasis, or lupus. In some embodiments, the autoimmune disease or condition is Rheumatoid arthritis (RA). In some embodiments, the autoimmune disease or condition is colitis. In some embodiments, the autoimmune disease or condition is irritable bowel syndrome. In some embodiments, the autoimmune disease or condition is type-1 diabetes mellitus. In some embodiments, the autoimmune disease or condition is psoriasis. In some embodiments, the autoimmune disease or condition is lupus.

[0336] In some embodiments, the organ specific disease or condition comprises, consists, or consists essentially of osteoarthritis.

[0337] In some embodiments, the organ specific disease or condition comprises, consists, or consists essentially of gout.

[0338] In some embodiments, the organ specific disease or condition comprises, consists, or consists essentially of chromosomal conditions such as Trisomy 21 (Down syndrome).

[0339] The antibody constructs provided herein may be useful for the treatment of any disease or condition, such as infections (e.g., sepsis, COVID-19, and HIV), systemic conditions (e.g., a metabolic condition such as diabetes and insulin resistance, sarcopcnia, and phy sical frailty), organ specific diseases and conditions (e.g., pancreas such as pancreatitis; liver such as fibrosis, steatosis, and alcoholic liver disease; renal such as acute kidney injury and chronic kidney injury'; lungs such as COPD, non-small cell lung cancer, asthma, bleomycin induced fibrosis, and tuberculosis; eyes such as retinopathy; macular degeneration, periodontitis; cardiovascular diseases such as heart disease, peripheral arterial disease, acute myocardial infarction (AMI), atherosclerosis, and restenosis of coronary arteries; and neurologic diseases or conditions such as stroke, subarachnoid haemorrhage, traumatic brain injury (TBI), multiple sclerosis (MS), Parkinson’s disease, and epilepsy), autoimmune diseases or conditions (e.g., Rheumatoid arthritis (RA). colitis, irritable bowel syndrome, type-1 diabetes mellitus, psoriasis, and lupus), osteoarthritis, gout, chromosomal conditions (e.g.. Trisomy 21 (Down syndrome)), and psychiatric conditions (e.g., bipolar disorder, schizophrenia, depression, anxiety disorders, obsessive-compulsive disorder, post-traumatic stress disorder, attention- deficit/hyperactivity disorder, eating disorders, borderline personality disorder, autism spectrum disorders, substance use disorders, somatic symptom disorder, panic disorder, dissociative disorders, delusional disorder, and/or sleep disorders).

[0340] In some embodiments, the disease or condition comprises, consists, or consists essentially of an infection. In some embodiments, the infection comprises, consists, or consists essentially of sepsis. In some embodiments, the antibody construct down-re gulates TREM1 amplification of inflammatory cytokines or chemokines associated with sepsis. In some embodiments, die cytokines or chemokines associated with sepsis comprise, consist essentially of, or consist of one or more of IL-6, MIP2/CXCL2, IL-la, IL-1 P, IL-18, IL-33, and/or a mutant or an analog thereof. In some embodiments, the cytokines or chemokines comprise, consist essentially of, or consist of one or more receptor, ligand, or binding targets of IL-6, MIP2/CXCL2, IL-la, IL-10, IL-18, IL-33, and/or a mutant or an analog thereof. In some embodiments, the cytokine associated with sepsis comprises, consists essentially of, or consists of IL-10. In some embodiments, the antibody construct inhibits inflammatory effect of one or more cytokines selected from IL-la, IL-10. IL-6, IL-18. IL-33, and/or MIP2/CXCL2.

[0341] Some embodiments provide for treatment of a subject in need thereof, comprising the step of administering to die subject a pharmaceutical composition comprising an effective amount of any of the antibody constructs set forth herein. Some embodiments provide for treatment of a subject suffering from cancer, a chronic infection, or from an inflammatory disease, comprising the step of administering to the subject a pharmaceutical composition comprising an effective amount of any of the antibody constructs set forth herein.

[0342] Some embodiments provide a method for modulating immune system function in a subject in need thereof, comprising the step of contacting or binding or causing a population of TREM 1 expressing cells of the subject to bind with a pharmaceutical composition comprising an effective amount of any antibody construct as set forth herein, under conditions such that the immune system is modulated.

8. KITS

[0343] In some embodiments, an antibody construct provided herein is provided in the form of a kit, i.e., a packaged combination of reagents in predetermined amounts with instructions for performing a procedure. In some embodiments, the procedure is a diagnostic assay. In other embodiments, the procedure is a therapeutic procedure.

[0344] In some embodiments, the kit further comprises a solvent for the reconstitution of the antibody construct. In some embodiments, the antibody construct is provided in the form of a pharmaceutical composition.

9. EXAMPLES

9.1. Example 1: Production of exemplary TREM1 Antibody Constructs

[0345] The mouse/human chimeric antibody constructs were generated by replacing the hyper-variable regions of the human IgGl LALAPG (huVH and huVL) with the mouse counterparts (inVH and mVL). Production of the corresponding bivalent mAbs was performed using an mVH-huIgGlCHl,2,3 (with LALAPG mutation) and niVL-huIgGICL to transfect HEK293 cells. Production of the monovalent mAbs (i.e. monovalent antibody constructs) comprising both Knob-into-Hole (KiH) and charge based (D to K) mutations of the human IgGlCH3 domain were introduced. The combined conditioned HEK293 supernatant was purified using a Protein A column followed by a second step purification on an ion exchange chromatography (IEX) column. Aggregated antibodies were removed by size exclusion chromatography (SEC) and buffer exchanged into the final antibody formulation (10 mM Histidine, 5% sucrose. pH 6.0).

[0346] The purity and monomeric status of the monovalent mAbs were assessed by SDS-PAGE and size exclusion chromatography (SEC). The final products were approximately 95%-98% monomeric (FIGs. 1A and IB).

9.2. Example 2: mAb Binding Affinity Assay

[0347] mAb binding was performed using HEK293 parental (HEK 293-P) cells and HEK293 cells expressing TREM1 and DAP 12 (HEK293-TD). Binding was initiated by incubating monovalent antibodies or corresponding bivalent antibodies at increasing concentrations between 0.001-20 pg/mL for 1 hour at RT, followed by the addition of Alexa FLUOR™ 594 conjugated anti-human IgG antibodies. The fluorescence intensity was measured by Fluorescence-activated Cell Sorting (FACS) and mean fluorescence intensity (MFI) was calculated using FlowJo (Becton Dickinson). Binding affinity curves were generated by plotting the MFI against the tested antibody concentrations. The curve was fitted using a sigmoidal dose-response with variable slope (four-parameter) with using Prism 8.

[0348] FIG. 2 shows TREM1 binding by representative monovalent anti-TREMl antibody constructs compared to representative bivalent anti-TREMl antibodies to HEK cells overexpressing TREM1 and DAP12. FIG. 2 shows monovalent TREM1 antibody has a binding affinity to TREM1 with a K_D of 2.4 nM compared to that of the bivalent with a KD of 0.34 nM.

9.3. Example 3: In Vitro Functional Assay Protocol

[0349] The Jurkat TREM1 DAP12 NF AT -ePL reporter cells were seeded at 5,000 cells per well of a 384 well plate and pre-incubated with a serial dilution of the corresponding mAb for 1 hour at 37°C, 5% CO2. The initial antibody (mAb) concentration ranged from 80-100 pg/ L.

[0350] To assess mAb TREM1 inhibition, Peptidoglycan Recognition Protein 1 (PGLYRPlj/hydrolase peptide glycan (PGN) was added to a final concentration of 10 pg/mL/20 pg/mL PGLYRP1/PGN, followed by an overnight (16 horns) incubation at 37°C, 5% CO2. To assess TREM1 activation with antibodies alone, no PGLYRP1/PGN was added for the overnight (16 hours) incubation. The NF AT reporter luminescence was detected by the PathHunter PL/PK Detection mix and read on a Perkin-Elmer Envision luminometer. The dose-response curve was analyzed using GraphPad Prism 8, fitted using a sigmoidal dose-response with variable slope (four-parameter) with no constraints.

[0351] FIG. 3 shows improved inhibitory activity of representative monovalent anti-TREMl antibodies constructs compared to representative and/or corresponding bivalent anti-TREMl antibodies. [0001] FIG. 4 and FIG. 5 show representative monovalent anti-TREMl antibody compared to representative and/or corresponding bivalent anti-TREMl antibodies in PGLYRP-l/PGN inhibitory assay with PGLYRP-PGN stimulation (FIG. 4) and the activation assay with no PGLYRP-PGN (FIG. 5).

[0002] FIG. 6 and FIG. 7 show concentration-dependent function of representative monovalent anti- TREMl antibody (W002-monovalent) and bivalent anti-TREMl antibodies dose-dependent responses in PGLYRP-l/PGN inhibitor}’ assay (FIG. 6) and activation assay (FIG. 7), respectively. This data show that the monovalent construct inhibits in a dose dependent manner in this assay similar to the bivalent antibody.

[0003] The human myelomonocytic cell line U937 (ATCC. CRL-1593.2) stably transduced with TREM1. DAP12 and a human IL-8 Promoter Luciferase Reporter (BPS Bioscience, Catalog#79827) (U937-TD-IL8 cells), was selected in RPMI-1640 supplemented with 10% fetal bovine serum (FBS) plus G418 (0.5 mg/ml), Puromycin (0.1 pg/ml), and Blasticidin (10 pg/ml). For 96 well format in vitro assays, the U937-TD-IL8 cells were seeded at 40,000 per well in RPMI-1640 plus 2 % FBS, preincubated with anti-TREMl mAh at 10 pg/mL for 1 hour at 37° C, 5% CO2, followed by 23 hours of incubation with PGLYRP1/PGN. Firefly luciferase activity was quantified using One-Step ™ Luciferase Assay System (BPS Bioscience, Catalog#60690) on a GloMax® Plate Reader (Promage).

[0352] FIG. 8 shows a representative quantification of U937-TD-IL8 reporter activity’ after treatment with PGLYRP1/PGN, or PGLYRPl/PGN+anti-TREMl mAb (bivalent). The scale bars represent s.e.m., * PO.05.

9.4. Example 4: Short Term Inflammation Mouse Model and In Vivo Assessment of Anti-inflammatory Effects of Monovalent and Bivalent Antibodies

[0353] In vivo assays were carried out in a knock-in mouse line where the extracellular domain (ECD) of mouse TREM1 was replaced by the ECD of human TREM1 (Biocytogen, hTREMl mice). To induce short-term inflammation, the hTREMl mice were administered with Lipopolysaccharide from E. coli Oll i :B4 (LPS, Invivogen) by intraperitoneal injection (i.p.) at 5 mg/kg. Symptoms 24 hours after LPS challenge were assessed using a standard murine sepsis score (MSS) focused on primarily assessing: Appearance, Level of consciousness, Activity, Response to stimulus. Eyes (adapted from Shrum B et. al., A robust scoring system to evaluate sepsis severity in an animal model. BMC Res Notes. 2014 Apr 12:7:233). For prophylactic treatment. the Bivalent and Monovalent mAbs were injected (i.p.) at 4 mg/kg and 8.5 mg/kg 2 hours prior to the LPS injection.

[0354] FIG. 9 shows the effect of using anti-TREMl antibody construct (4 mg/kg, i.p. for Bivalent W002 antibody or 8.5 mg/kg, i.p. for Monovalent W002 antibody) on sepsis scores 24 hour after LPS (5 mg/kg, i.p.) administration in male and female mice. The scale bars represent s.e.m.. *** PO.OOL The data demonstrate that the anti-TREMl monovalent antibody is effective in preventing, reducing, and/or treating sepsis, an example of an acute inflammatory condition.

9.5. Example 5: Short Term Inflammation Model with Prophylactic Treatment

[0355] This example illustrates a dosc-cscalation study on the impact of the monovalent antibody construct on short-term inflammation using female mice.

[0356] Female hTREMl-tg mice (C57BL/6-7rem7^te7f7R£M^ZBcgen. Biocytogen, 10 weeks of age) w ere randomized into three groups (n=4 per group) and given an intraperitoneal injection (i.p.) of either saline (0.9% NaCl. Sigma S8776), monoclonal antibody W002-bivalent (1.7 mg/ml), or an equivalent dose of W002-monovalent antibody construct (8.4 mg/ml) one hour prior to intraperitoneal administration of LPS (5 mg/kg, InvivoGen tlrl-eblps). Monovalent antibody was given at 1.0 and 8.5 mg/kg; bivalent antibody w as given in dose range of 0.2 mg/kg, 0.6 mg/kg, 1.7 mg/kg and 4 mg/kg.

[0357] FIG. 10 shows a dose escalation of monovalent and bivalent (W002) antibodies and the resulting effect on sepsis score. The equivalent dose of the monovalent antibody construct (W002) was as effective as the corresponding bivalent antibody dose on sepsis scores at 24 horns in mice with LPS- induced sepsis in this dose escalation study using female hTREMl-tg mice.

9.6. Example 6: Suppression of Cytokine and Chemokine Production in Mice Stimulated with LPS

[0358] Mice stimulated with LPS as described in Example 5 were euthanized with CO₂ or Isoflurane and tissues (e.g.. spleen) were collected and frozen on dry ice before transferring to -80 °C for longterm storage. Each spleen (~300 mg) was homogenized in 1 mL of lysis buffer containing 50 mM Tris HC1, PH 7-8, 0.1 M NaCl, 1% Triton X-100, supplemented w ith protease inhibitors including 100 ug/ml Aprotinin, 100 ug/ml Leupeptin, 50 ug/ml Pep-statin, and 100 mM PMSF using a Dunce homogenizer follow ed by centrifugation at 14,000 g for 15 min at 4 °C. Approximately 400 pL of the supernatants were transferred to prechilled protein low' binding Eppendorf tubes. Protein concentrations were quantified using a BCA Protein Assay Kit (Pierce 23225) and adjusted to a final concentration of 4 mg/mL. The lysates were aliquoted and frozen on dry ice for > 15 min before storing at -80 °C. 10-50 pL of tissue lysates were used for an individual assay. Levels of cytokines and chemokines in the tissue lysates were measured using Multiplex Luminex Assays (Luminex) or ELISA (R&D, IL-18 DY7625- 05, IL-10 DY401-05. IL-la DY400-05, IL-33 DY3626-05, IL-6 DY406-05, MIP2 DY452-05) following manufacturer's instructions.

[0359] FIG. 11 show s monovalent antibody construct suppresses the production of pro-inflammatory’ cytokines and chemokines in the spleen of mice after 24 hours of LPS stimulation, as measured using an ELISA assay. Administration of the monovalent antibody exhibited higher reduction of IL-33 and inflammasome products IL-la, IL- IB, and IL- 18 compared to its corresponding bivalent antibody. Both monovalent and bivalent reduced IL-6 and MIP2/CXCL2. The scale bars represent s.e.m., *** P<0.001, **** PO.OOOl. The data show that the pro-inflammatory cytokines, e.g., IL-1, were significantly lower for monovalent antibody vs bivalent antibody, whereas there was similar inhibitory' effect on IL-6. The data indicates that the signaling or agonism of TREM1 is better modulated by monovalent than bivalent molecule.

9.7. Example 7: Inhibitory Effects of Monovalent and Bivalent Antibodies on Cytokine Production in Bone Marrow-derived Macrophages Derived from hTREMl Mice

[0360] This example illustrates the inhibitory' effects of the monovalent TREM1 antibody construct, as described herein, and a referenced bivalent antibody on IL-10 production of marrow-derived macrophages isolated from hTREMl mice (transgenic mice expressing human TREM1) without LPS (under quiescent conditions) or with LPS (stimulated conditions).

[0361] Bone marrow' (BM) was isolated from the tibia and femur of 2.5-month or older females or males (5-10 mice pooled) and kept in a cold Dulbecco's Modified Eagle Medium (DMEM, high Glucose, with glutamine, with HEPES) supplemented with 10% FBS (Gibco, Premium, A5670502) and 1% Penicillin/Streptomycin (Gibco, 15140). To remove red blood cells (RBC), 2-3 ml of RBC Lysis Buffer (Biolegend 420301) was added to the pelleted BM followed by a 3-5-minute incubation on ice before quenching the reaction by the addition of 10 ml DMEM culture medium followed by a centrifuge at 300 g for 5 min. The BM was dissociated in 2 ml of DMEM culture medium by mechanic trituration using a 1 mL pipet and subsequently passed through a 70-pm cell strainer. After cell counting, the isolated BM cells were resuspended in a prewarmed DMEM culture medium supplemented with 40 ng/ml M-CSF (R&D, 416-ML) and plated at a density of 0.5 x 10^A7 cells per well in a 6-well plate. The next morning (Day 1), unattached cells were washed away by 2x PBS rinses, while macrophages remained attached to the surface of the dish. 2 ml of the DMEM culture medium supplemented with 40-100 ng/ml M-CSF was added to each of the 6 well-plate and replenished on Day 3 or 4. At high M- CSF (40-100 ng/mL). the macrophages continued to proliferate, reaching confluence by Day 5-6. remaining good for assay till Day 10.

[0362] For setting up assays, BMDMs were dislodged using pre-wanned StemPro™ Accutase™ (Gibco, Al 110501) by incubating at 37 °C for 5 minutes and removing carefully. DMEM culture medium was added to quench the reaction followed by a centrifugation at 300 g, 5 min. The cells were subsequently resuspended in DMEM culture medium at ~1 x 10^A6 cells per mL and seeded at 100 k per well (100 pL of 10^A6/mL) in 96-well white assay plates (Thermal 165306). The cells were >90% confluent the next day. For antibody activation assay. 24 hours before harvesting, BMDMs were replenished with DMEM culture media containing monoclonal antibodies. Lipopolysaccharide (LPS) purified from the Gram-negative E. coli 0111 :B4 (InvivoGen, -50-200 ng/mL) was added overnight as a challenge. Culture supernatants were collected the next day for ELISA assays. [0363] FIG. 12A shows the effects of increasing concentrations of monovalent or bivalent antibodies on levels of a proinflammatory cytokine in BMDMs isolated from hTREMl K/I mice without LPS stimulation (under quiescent conditions). Increasing concentrations of monovalent antibody did not alter levels of IL- 1 [3 in BMDMs from hTREMl K/I mouse, regardless of concentration (FIG. 12A). In contrast, IL- 1 P production increased beginning at ~200 nM of bivalent antibody, indicating activation of TREM1 activity by the bivalent and not the monovalent antibody in the absence of any immune stimulus.

[0364] FIG. 12B shows the effects on TREM1 activity’ with increasing concentrations of monovalent or bivalent antibodies on Jurkat NF AT reporter cells overexpressing TREM1 and DAP12. Monovalent antibody maintained persistently low levels of TREM1 activity (expressed as RLU, or luminescence units), independent of concentration in Jurkat NF AT reporter cells overexpressing TREM1 and DAP 12. In contrast, TREM1 activity began to increase at about 200 nM of bivalent antibody. The data demonstrate that the TREM1 monovalent antibody does not activate at higher concentrations whereas the bivalent antibody does in the absence of any inflammatory stimulus. This suggests an enhanced safety profile of the monovalent versus the bivalent antibody.

[0365] FIG. 13 shows the inhibitory effects of treatment with increasing concentrations of monovalent or bivalent antibodies on production of a proinflammatory’ cytokine in BMDMs isolated from hTREMl K/I mice stimulated with LPS (50 ng/ml LPS for 20 hours; under stimulated conditions) and without LPS (under quiescent conditions), compared to BMDMs under quiescent conditions treated with an isotype control. FIG. 14 shows results for a broader concentration range of antibodies. One-way ANOVA dose response for both monovalent and bivalent antibodies in the presence of LPS is p<0.0001. As shown in FIG. 14, the monovalent antibody, at a concentration as low as 1 nM, reduced IL- 1(3 in BMDMs isolated from hTREMl K/I mice in response to LPS stimulation, whereas the referenced bivalent antibody required 10 nM to achieve the same result. The data demonstrate that the monovalent antibody exhibited higher efficiency in reducing IL-1(3 in BMDMs expressing hTREMl than the referenced bivalent antibody. The data indicate that die TREM1 monovalent antibody has a better safety profile than the bivalent and could be used for prophylactic treatment to maintain low levels of proinflammatory' cytokines under quiescent conditions or stimulated conditions.

9.8. Example 8: Human monocyte derived macrophage based assays

[0366] This example illustrates the inhibitory effects of the monovalent TREM1 antibody construct, as described herein, and a referenced bivalent antibody on TNF-a production of human monocyte- derived macrophages (HuMDM) stimulated with PGLYRP1-PGN (under stimulated conditions).

[0367] HuMDM isolated from human blood were prepared and polarized to the Ml activation state with overnight incubation with LPS. Vehicle or PGLYRP-PGN were added along with bivalent or monovalent antibodies for 24h and TNF-a was measured. In brief, after crosslinking on ice for 1 hour, 20 pL of the PGYLRP1 (R&D 2590-PGB-050) and PGN (InvivoGen tlrl-kipgn) mixture were added to each well to achieve a final concentration of 20 ug/mL and 10 ug/mL, respectively. Twenty four (24) hours later, die level of human TNF-a was measured using a Lumit ® TNF-a Immunoassay kit (Promega W6050) following the manufacturer’s instructions.

[0368] FIG. 15 shows the inhibitory effect of the monovalent antibody on TNF-a production in HuMDM as compared to the corresponding concentration of bivalent antibody (based on binding affinity). The scale bars represent s.e.m. *P<0.05, **P<0.001, ***P<0.0001. One way ANOVA was performed on cells + antibodies, no PGLYRP-PGN (left side of graph); here, bivalent TREM1 antibody at 60 pg/ml showed significant activation of TREM1 production of TNF-a. With the addition of PGLYRP-PGN (right side of graph), both monovalent and bivalent TREM1 antibodies reduced TNF- a production, but monovalent TREM1 antibodies at 312 pg/ml inhibited TNF-a production better than the corresponding concentration of bivalent antibody at 60 pg/ml. These data are consistent with the results in FIG. 12A and FIG. 12B indicating an increase in TREM1 activation with increasing concentrations of the bivalent antibody compared to monovalent antibody (at the corresponding binding affinity); they also demonstrate stronger inhibition of TREM1 in the presence of the ligand PGLYRP- PGN for monovalent antibody compared to bivalent antibody (at the corresponding binding affinity).

Example S: Sequences

[0369] Table S provides sequences referred to herein.

10. EQUIVALENTS AND INCORPORATION BY REFERNCE

[0370] The disclosure set forth above may encompass multiple distinct inventions with independent utility. Although each of these inventions has been disclosed in its preferred form(s), the specific embodiments thereof as disclosed and illustrated herein are not to be considered in a limiting sense, because numerous variations are possible. It should be understood that various changes in form and details may be made therein by those skilled in the relevant art without departing from the spirit and scope of the present invention. The subject matter of the inventions includes all novel and nonobvious combinations and subcombinations of the various elements, features, functions, and/or properties disclosed herein. The following claims particularly point out certain combinations and subcombinations regarded as novel and nonobvious. Inventions embodied in other combinations and subcombinations of features, functions, elements, and/or properties may be claimed in this application, in applications claiming priority from this application, or in related applications. Such claims, whether directed to a different invention or to the same invention, and whether broader, narrower, equal, or different in scope in comparison to the original claims, also are regarded as included within the subject matter of the inventions of the present disclosure.

[0371] All references, issued patents, and patent applications cited within the text of this specification are incorporated herein by reference in their entirety for all purposes.

Claims

CLAIMS WHAT IS CLAIMED IS:

1 . An antibody construct, wherein the antibody construct comprises a first polypeptide comprising a heavy chain variable region (VH) and one or more regions and a second polypeptide comprising a light chain variable region (VL) and one or more regions, a) the first polypeptide comprising a VH and 1. 2, or 3 of a CHI, CH2. and/or CH3, wherein the VH comprises: i) a VHCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 12-13, wherein the CDRs are according to Chothia or ii) a VHCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 1-2. wherein the CDRs arc according to Kabat; iii) a VHCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 34-35, wherein the CDRs are according to Chothia or iv) a VHCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 23-24, wherein the CDRs are according to Kabat; and/or v) a VHCDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 45-46; and b) the second polypeptide comprising a VL and 1, 2, or 3 of a CL, CH2, and/or CH3, wherein the VL comprises: i) a VLCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 55-56; ii) a VLCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 67-68; or iii) a VLCDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 77-78; wherein, when present, the first polypeptide comprises a VH, CHI, CH2, and CH3 in the following order: VH, CHI, CH2. and CH3. and wherein, when present, the second polypeptide comprises a VL, CL. CH2, and CH3 in the following order: VL, CL, CH2, and CH3.

2. The antibody construct according to claim 1, wherein the first polypeptide comprises a VH and CHI, CH2, and CH3 in the following order: VH, CHI, CH2, and CH3, wherein the CHI comprises the amino acid sequence set forth in SEQ ID NO: 121 or a variant thereof having at least 85% identity with the amino acid sequence of SEQ ID NO: 121, wherein the CH2 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 126-127 or a variant thereof having at least 85% identity with the amino acid sequence of any one of SEQ ID NOs: 126-127, and wherein the CH3 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 132-134 or a variant thereof having at least 85% identity with the amino acid sequence of any one of SEQ ID NOs: 132-134.

3. The antibody construct according to claim 1, wherein the second polypeptide comprises a VL and CL. CH2. and CH3 in the following order: VL. CL, CH2, and CH3, wherein the CL comprises the amino acid sequence set forth in SEQ ID NO: 144 or a variant thereof having at least 85% identity with the amino acid sequence of SEQ ID NO: 144, wherein the CH2 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 126-127 or a variant thereof having at least 85% identity with the amino acid sequence of any one of SEQ ID NOs: 126- 127. and wherein the CH3 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 132-134 or a variant thereof having at least 85% identity with the amino acid sequence of any one of SEQ ID NOs: 132-134.

4. The antibody construct of claim 1, wherein: a) the first polypeptide comprises: i) a VHCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, wherein the CDR is according to Kabat or ii) a VHCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, wherein the CDR is according to Chothia; iii) a VHCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 23, wherein the CDR is according to Kabat or iv) a VHCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34, wherein the CDR is according to Chothia; and/or v) a VHCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 45; and b) the second polypeptide comprises: i) a VLCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 55; ii) a VLCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 67; and/or iii) a VLCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 77.

5. The antibody construct of claim 1, wherein: a) the first polypeptide comprises: i) a VHCDR1 comprising the amino acid sequence set forth SEQ ID NO: 1, wherein the CDR is according to Kabat or ii) a VHCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, wherein the CDR is according to Chothia; iii) a VHCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 23, wherein the CDR is according to Kabat or iv) a VHCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34, wherein the CDR is according to Chothia; v) a VHCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 45; vi) a CHI comprising the amino acid sequence set forth in SEQ ID NO: 121; vii) a CH2 comprising the amino acid sequence set forth in SEQ ID NO: 127; and viii) a CH3 comprising the amino acid sequence set forth in SEQ ID NO: 133; and b) the second polypeptide comprises: i) a VLCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 55; ii) a VLCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 67; iii) a VLCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 77; vi) a CL comprising the amino acid sequence set forth in SEQ ID NO: 144; vii) a CH2 comprising the amino acid sequence set forth in SEQ ID NO: 127; and viii) a CH3 comprising the amino acid sequence set forth in SEQ ID NO: 134.

6. The antibody construct according to claim 1, wherein the first polypeptide comprises a VH and CHI, CH2, and CH3 in the following order: VH, CHI, CH2, and CH3, wherein the VH comprises the amino acid sequence set forth in SEQ ID NO: 89 or a variant thereof having at least 85% identity with the amino acid sequence of SEQ ID NO: 89; wherein the CHI comprises the amino acid sequence set forth in SEQ ID NO: 121 or a variant thereof having at least 85% identity with the amino acid sequence of SEQ ID NO: 121; wherein the CH2 comprises the amino acid sequence set forth in SEQ ID NO: 127 or a variant thereof having at least 85% identity with the amino acid sequence of SEQ ID NO: 127; and wherein the CH3 comprises the amino acid sequence set forth in SEQ ID NO: 133 or a variant thereof having at least 85% identity with the amino acid sequence of SEQ ID NO: 133; and wherein tire second polypeptide comprises a VL and CL, CH2, and CH3 in the following order: VL, CL, CH2, and CH3, wherein the VL comprises the amino acid sequence set forth in any one of SEQ ID NO: 101 or a variant thereof having at least 85% identity with the amino acid sequence of any one of SEQ ID NO: 101; wherein the CL comprises the amino acid sequence set forth in any one of SEQ ID NO: 144 or a variant thereof having at least 85% identity with the amino acid sequence of any one of SEQ ID NO: 144, wherein the CH2 comprises the amino acid sequence set forth in SEQ ID NO: 127 or a variant thereof having at least 85% identity with the amino acid sequence of SEQ ID NO: 127; and wherein the CH3 comprises the amino acid sequence set forth in SEQ ID NO: 134 or a variant thereof having at least 85% identity with the amino acid sequence of SEQ ID NO: 134.

7. The antibody construct according to any one of claims 1-6, wherein the first polypeptide comprises one or more mutations in the CH3 and/or the second polypeptide comprises one or more mutations in the CH3.

8. The antibody construct according to claim 7, wherein the one or more first polypeptide CH3 mutations and/or the one or more second polypeptide mutations comprise substitutions of an interface amino acid residue.

9. The antibody construct according to any one of claims 1-8, wherein the antibody specifically binds human Triggering Receptor Expressed on Myeloid Cells 1 (TREM1).

10. The antibody construct according to any one of claims 1-9. wherein the antibody modulates human Triggering Receptor Expressed on Myeloid Cells 1 (TREM1) mediated signaling, disrupts human Triggering Receptor Expressed on Myeloid Cells 1 (TREM1) dimerization and/or oligomerization, and/or inhibits TREM1 activation and/or TREM1 mediated cell signaling.

11. The antibody construct according to any one of claims 1-10, wherein the antibody construct does not comprise concentration-dependent activation of TREM1 and/or TREM1 mediated cell signaling.

12. A nucleic acid molecule capable of expressing any of the antibody construct of any one of claims 1-11.

13. An expression vector comprising the nucleic acid molecule of claim 12.

14. A prokaryotic or eukary otic host cell comprising the vector of claim 13.

15. A method of treating a disease or condition in a subject in need thereof, comprising administering to the subject an antibody construct, wherein the antibody construct comprises a first polypeptide having a heavy chain variable region (VH) and one or more regions and a second polypeptide having a light chain variable region (VL) and one or more regions, a) the first polypeptide comprising a VH and 1, 2, or 3 of a CHI, CH2, and/or CH3, wherein the VH comprises: i) a VHCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 12-13, wherein the CDRs are according to Chothia or ii) a VHCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 1-2. wherein the CDRs are according to Kabat; iii) a VHCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 34-35, wherein the CDRs are according to Chothia or iv) a VHCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 23-24, wherein the CDRs are according to Kabat; and/or v) a VHCDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 45-46; and b) the second polypeptide comprising a VL and 1, 2, or 3 of a CL. CH2. and/or CH3, wherein the VL comprises: i) a VLCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 55-56: ii) a VLCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 67-68; or iii) a VLCDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 77-78.

16. A method of disabling or reducing one or more myeloid cells that express Triggering Receptor Expressed on Myeloid Cells 1 (TREM1) on the cell surface, comprising contacting or binding or causing the myeloid cells to bind with an antibody construct that specifically binds human TREM1, thereby disabling or reducing the one or more myeloid cells that express TREM1 on the cell surface, wherein the antibody construct comprises a first polypeptide having a heavy chain variable region (VH) and one or more regions and a second polypeptide having a light chain variable region (VL) and one or more regions. a) the first polypeptide comprising a VH and 1, 2. or 3 of a CHI, CH2, and/or CH3, wherein the VH comprises: i) a VHCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 12-13, wherein the CDRs are according to Chothia or ii) a VHCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 1-2, wherein the CDRs are according to Kabat; iii) a VHCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 34-35, wherein the CDRs are according to Chothia or iv) a VHCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 23-24, wherein the CDRs are according to Kabat; and/or v) a VHCDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 45-46; and b) the second polypeptide comprising a VL and 1, 2, or 3 of a CL, CH2, and/or CH3, wherein the VL comprises: i) a VLCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 55-56; ii) a VLCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 67-68; or iii) a VLCDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 77-78.

17. A method of disabling or reducing one or more myeloid cells that over express Triggering Receptor Expressed on Myeloid Cells 1 (TREM1) on the cell surface, comprising contacting or binding or causing the myeloid cells to bind with an antibody construct that specifically binds human TREM1, thereby disabling or reducing the one or more myeloid cells that over express TREM1 on the cell surface, wherein the antibody construct comprises a first polypeptide having a heavy chain variable region (VH) and one or more regions and a second polypeptide having a light chain variable region (VL) and one or more regions, | a) the first polypeptide comprising a VH and 1, 2, or 3 of a CHI, CH2, and/or CH3, wherein the VH comprises: i) a VHCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 12-13, wherein the CDRs are according to Chothia or ii) a VHCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 1-2. wherein the CDRs are according to Kabat; iii) a VHCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 34-35, wherein the CDRs are according to Chothia or iv) a VHCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 23-24, wherein the CDRs are according to Kabat; and/or v) a VHCDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 45-46; and b) the second polypeptide comprising a VL and 1 , 2, or 3 of a CL, CH2. and/or CH3, wherein the VL comprises: i) a VLCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 55-56; ii) a VLCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs; 67-68; and/or iii) a VLCDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs; 77-78.

A method of inhibiting or reducing Triggering Receptor Expressed on Myeloid Cells 1 (TREM1) signaling in a cell that expresses Triggering Receptor Expressed on Myeloid Cells 1 (TREM 1) on the cell surface, comprising contacting or binding or causing the cells to bind with an antibody construct that specifically binds human TREM 1 , thereby inhibiting or reducing TREM1 signaling in the myeloid cells that express TREM1 on the cell surface, wherein the antibody construct comprises a first polypeptide having a heavy chain variable region (VH) and one or more regions and a second polypeptide having a light chain variable region (VL) and one or more regions, a) the first polypeptide comprising a VH and 1, 2, or 3 of a CHI, CH2, and/or CH3, wherein the VH comprises: i) a VHCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 12-13. wherein the CDRs arc according to Chothia or ii) a VHCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs; 1-2, wherein the CDRs are according to Kabat; iii) a VHCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs; 34-35, wherein the CDRs are according to Chothia or iv) a VHCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 23-24, wherein the CDRs are according to Kabat; and/or v) a VHCDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 45-46; and b) the second polypeptide comprising a VL and 1, 2, or 3 of a CL, CH2, and/or CH3, wherein the VL comprises: i) a VLCDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 55-56; ii) a VLCDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 67-68; or iii) a VLCDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 77-78.

19. The method according to any one of claims 15-18, wherein the antibody construct specifically binds human TREM1 or wherein the antibody construct specifically binds the extracellular domain of TREM1 and/or binds to TREM1 with a KD less than or equal to 10 nM.

20. The method according to any one of claims 17-19. wherein: a) the first polypeptide comprises a VH, CHI, CH2. and CH3 in the following N- terminal to C-terminal order: VH, CHI, CH2, and CH3; and/or b) the second polypeptide comprises a VL, CL, CH2, and CH3 in the following N-terminal to C-terminal order: VL. CL. CH2, and CH3.

21. The method according to any one of claims 15-20, wherein: a) the first polypeptide comprises a VH and CHI, CH2, and CH3 in the following order: VH, CHI, CH2, and CH3, wherein the CHI comprises the amino acid sequence set forth in SEQ ID NO: 121 or a variant thereof having at least 85% identity with the amino acid sequence of SEQ ID NO: 121, wherein the CH2 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 126-127 or a variant thereof having at least 85% identity with the amino acid sequence of SEQ ID NOs: 126-127, and wherein the CH3 comprises the amino acid sequence set forth in SEQ ID NOs: 132-134 or a variant thereof having at least 85% identity with the amino acid sequence of SEQ ID NOs: 132-134; and/or b) the second polypeptide comprises a VL and CL, CH2. and CH3 in the following order: VL. CL, CH2. and CH3, wherein the CL comprises the amino acid sequence set forth in SEQ ID NO: 144 or a variant thereof having at least 85% identity with the amino acid sequence of SEQ ID NO: 144, wherein the CH2 comprises the amino acid sequence set forth in SEQ ID NOs: 126-127 or a variant thereof having at least 85% identity with the amino acid sequence of SEQ ID NOs: 126-127, and wherein the CH3 comprises the amino acid sequence set forth in SEQ ID NOs: 132-134 or a variant thereof having at least 85% identity with the amino acid sequence of SEQ ID NOs: 132-134.

22. The method according to any one of claims 15-21, wherein the first polypeptide comprises one or more mutations in the CH3 and the second polypeptide comprises one or more mutations in the CH3, optionally the one or more substitutions comprise one or more substitutions at an interface amino acid residue in the CH3.

23. The method according to any one of claims 15-22, wherein the subject in need thereof has a disease or condition associated with TREM1 or wherein the disease or condition comprises one or more of multiple sclerosis. Alzheimer’s disease, Huntington’s disease. Parkinson’s disease, epilepsy, inflammatory bowel disease (IBD). Human Immunodeficiency Virus (HIV), brain tumor, stroke, amyotrophic lateral sclerosis, spinal cord and/or brain trauma, a disease or condition which would benefit from enzyme replacement therapy (“ERT”), a neurological disease, chronic inflammatory conditions, acute inflammatory conditions, autoimmune diseases, infections, and/or psychiatric conditions.

24. The method according to any one of claims 15-23, wherein the antibody construct comprises an Fc region and comprises at least one of: a reduced antibody-dependent cell-mediated cytotoxicity (ADCC) activity, a reduced complement-dependent cytotoxicity (CDC) activity, and a reduced antibody -mediated phagocytosis (ADCP) activity.

25. The method according to claim 24, wherein the Fc region comprises human IgGl, IgG2, IgG3, or IgG4 Fc.

26. The method according to any one of claims 15-25, wherein the antibody construct comprises an Fc region comprising modified Fey Receptor (FcyR) binding, optionally wherein the modified FcyR binding is a reduced FcyR binding selected from the group consisting of: FcyRI, FcyRIIa, FcyRIIb, FcyRIIc. FcyRIIIa, and FcyRIIIb.

27. The method according to any one of claims 15-26, wherein the antibody construct has receptorligand blocking, agonism, and/or antagonism activity.

28. The method according to any one of claims 16-27, wherein the antibody construct inhibits inflammatory effect of one or more cytokines selected from IL- la, IL-ip, IL-6. IL- 18, IL-33, and/or MIP2/CXCL2.

29. The method according to any one of claims 15-28, wherein the antibody construct comprises the antibody construct according to any one of claims 1-11.

30. The antibody construct according to any one of claims 1-11. the nucleic acid molecule according to claim 12, the expression vector according to claim 13, the host according to claim 14, or the method according to any one of claims 15-29, wherein the antibody construct is a monovalent antibody construct specifically binds human TREM1.