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JP-2026076175-A - TREM2 stabilizing antibody

JP2026076175AJP 2026076175 AJP2026076175 AJP 2026076175AJP-2026076175-A

Abstract

[Problem] To provide an antibody that binds to and stabilizes the trigger receptor 2 (TREM2) protein expressed in human myeloid cells. [Solution] The present invention provides a nucleic acid molecule or a set of nucleic acid molecules encoding an anti-TREM2 antibody or its antigen-binding fragment, comprising three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) containing specific amino acid sequences, as defined by the Kabat numbering system, Chothia numbering system, IMGT numbering system, and combined numbering system. Furthermore, the present invention provides a vector containing the nucleic acid molecule, cells containing the vector, and a method for producing an anti-TREM2 antibody or its antigen-binding fragment, comprising culturing the cells. [Selection Diagram] None

Inventors

  • ブランド，ヴェレナ
  • フォイヤーバッハ，ドミニク
  • ガスパリーニ，ファブリジオ
  • ジョージ，ナタリー
  • シャッツ，エヴェリン
  • シムシェク，デラヤ
  • シュリニバス，ホナッパ
  • ワルドヒュバー，マークス
  • ウィルケン，レイナー

Assignees

  • ノバルティス アーゲー

Dates

Publication Date
20260511
Application Date
20251225
Priority Date
20181015

Claims (20)

  1. Human myeloid cell trigger expression 2 2) An antibody or antigen-binding fragment thereof that binds to the immunoglobulin superfamily (IgSF) domain of the (hTREM2) protein to stabilize the hTREM2 protein (e.g., SEQ ID NO: 1, 2, or 3).
  2. hTREM2's D39, S40, M41, K42, W44, G45, R46, R47, H67, N68, L69, W70, L71, L72, F74, L75, R77, D87, An antibody or antigen-binding fragment thereof according to claim 1, which binds to one or more residues selected from the group consisting of T88, L89, and G90.
  3. hTREM2's D39, S40, M41, K42, W44, G45, R46 and R47 One or more residues selected from the group consisting of H67, N68, L69, W70, L71, One or more residues selected from the group consisting of L72, F74, L75, and R77, and D Binds to one or more residues selected from the group consisting of 87, T88, L89, and G90, The antibody or antigen-binding fragment thereof according to claim 1.
  4. hTREM2's D39, S40, M41, K42, W44, G45, R46 and R47 Five or more residues selected from the group consisting of H67, N68, L69, W70, L71, Four or more residues selected from the group consisting of L72, F74, L75, and R77, and D Binds to three or more residues selected from the group consisting of 87, T88, L89, and G90. The antibody or antigen-binding fragment thereof according to claim 1.
  5. hTREM2's D39, S40, M41, K42, W44, G45, R46 and R47 Seven or more residues selected from the group consisting of H67, N68, L69, W70, L71, Four or more residues selected from the group consisting of L72, F74, L75, and R77, and D Binds to three or more residues selected from the group consisting of 87, T88, L89, and G90. The antibody or antigen-binding fragment thereof according to claim 1.
  6. hTREM2's D39, S40, M41, K42, W44, G45, R46 and R47 Five or more residues selected from the group consisting of H67, N68, L69, W70, L7 1. All of L72, F74, L75 and R77, as well as D87, T88, L89 and G9 An antibody or antigen-binding fragment thereof according to claim 1, which binds to three or more residues selected from the group consisting of 0.
  7. hTREM2 S40, M41, W44, G45, W70, L71, L72, F74, An antibody or antigen-binding fragment thereof according to claim 1, which binds to one or more residues selected from the group consisting of T88 and L89.
  8. hTREM2 S40, M41, W44, G45, W70, L71, L72, F74, An antibody or antigen-binding fragment thereof according to claim 1, which binds to two or more residues selected from the group consisting of T88 and L89.
  9. hTREM2 S40, M41, W44, G45, W70, L71, L72, F74, An antibody or antigen-binding fragment thereof according to claim 1, which binds to three or more residues selected from the group consisting of T88 and L89.
  10. hTREM2 S40, M41, W44, G45, W70, L71, L72, F74, The antibody or antigen-binding fragment thereof according to claim 1, which binds to four or more residues selected from the group consisting of T88 and L89.
  11. hTREM2 S40, M41, W44, G45, W70, L71, L72, F74, An antibody or antigen-binding fragment thereof according to claim 1, which binds to five or more residues selected from the group consisting of T88 and L89.
  12. hTREM2 S40, M41, W44, G45, W70, L71, L72, F74, An antibody or antigen-binding fragment thereof according to claim 1, which binds to six or more residues selected from the group consisting of T88 and L89.
  13. hTREM2 S40, M41, W44, G45, W70, L71, L72, F74, An antibody or antigen-binding fragment thereof according to claim 1, which binds to seven or more residues selected from the group consisting of T88 and L89.
  14. hTREM2 S40, M41, W44, G45, W70, L71, L72, F74, An antibody or antigen-binding fragment thereof according to claim 1, which binds to eight or more residues selected from the group consisting of T88 and L89.
  15. hTREM2 S40, M41, W44, G45, W70, L71, L72, F74, An antibody or antigen-binding fragment thereof according to claim 1, which binds to nine or more residues selected from the group consisting of T88 and L89.
  16. hTREM2 residues S40, M41, W44, G45, W70, L71, L72, F7 4. The antibody or antigen-binding fragment thereof according to claim 1, which binds to all of T88 and L89.
  17. An antibody or antigen-binding fragment thereof according to any one of claims 7 to 16, which binds to one or more residues selected from the group consisting of D39, K42, R46 and G90 of hTREM2.
  18. An antibody or antigen-binding fragment thereof according to any one of claims 7 to 16, which binds to two or more residues selected from the group consisting of D39, K42, R46 and G90 of hTREM2.
  19. An antibody or antigen-binding fragment thereof according to any one of claims 7 to 16, which binds to three or more residues selected from the group consisting of D39, K42, R46 and G90 of hTREM2.
  20. Claims 7 to bind to all of the residues D39, K42, R46 and G90 of hTREM2. An antibody or antigen-binding fragment thereof as described in any one of item 15.

Description

Sequence Listing This application includes a sequence listing submitted electronically in ASCII format, which is incorporated herein by reference in its entirety. A copy of the said ASCII, made on 16 September 2019, is named PAT058251_ST25.txt and has a size of 147,551 bytes. This invention provides antibodies that bind to and stabilize the trigger receptor 2 (TREM2) protein expressed in human myeloid cells, and methods for using these antibodies. The trigger receptor, or "TREM," expressed on myeloid cells, is a group of transmembrane glycoproteins expressed on various types of myeloid cells, including macrophages, dendritic cells, osteoclasts, microglia, mast cells, monocytes, lung epithelial cells, cutaneous Langerhans cells, Kupffer cells, and neutrophils (Takaki, R. et al., Immunol. Rev., 20). 06,214:118-29). TREM has immunoglobulin (I) in its extracellular domain. It has a type g) folding and therefore belongs to the immunoglobulin superfamily (IgSF). The TREM receptor contains a short intracellular domain but lacks a docking motif for signaling mediators, and requires an adapter protein such as DAP12 (a 12 kDa DNAX activating protein) for cell activation. Two members of TREM, TREM1 and TREM2, have been reported, both of which play important roles in immune and inflammatory responses. The gene encoding human TREM is TREM1. 1. It is located on chromosome 6p21.1, which carries the gene cluster encoding TREM2, TREM3, TREM4, and TREM5, as well as TREM-like genes. TREM2 is a glycoprotein with a length of approximately 40 kDa, and after N-deglycosylation, it is 26 The value decreases to kDa. The entire TREM2 protein consists of a leading signal peptide (amino acids 1-18), a single V-type IgSF extracellular domain (amino acids 19-132), a stalk domain (amino acids 133-172), a positively charged transmembrane domain (amino acids 173-197), and a cytosolic tail (amino acids 198-230) (Kober et al., El ife 5 (2016); Kober et al. , J. Mol. Biol. 429( (2017) 1607-1629). The extracellular region encoded by exon 2 consists of a single type V IgSF domain containing three potential N-glycosylation sites. The putative transmembrane region contains charged lysine residues. The cytoplasmic tail of TREM2 lacks a signaling motif and is thought to transmit signals via the signaling adapter molecule DAP12/TRYROBP. Trem2 physically associates with DAP12, and DAP12 acts as a signaling adapter protein for Trem2 and several other cell surface receptors. The cytoplasmic domain of DAP12 contains an immunoreceptor-activating tyrosine motif (ITAM) (Wunderlic (h, J. Biol. Chem. 288, 33027-33036, 2013). Following activation of this interacting receptor, DAP12 undergoes phosphorylation of a conserved ITAM tyrosine residue by Src kinase. Subsequent recruitment and activation of Syk protein kinase triggers downstream signaling pathways, including the activation of mitogen-activated protein kinase (MAPK), PI3K, NFκB, and phospholipase Cγ (PLCγ). TREM2 contains lipopolysaccharides (LPS), heat shock protein 60, neurite fragments, bacteria, apolipoprotein E, and a wide range of anionic and zwitterionic lipids, such as phosphatidic acid (PA), phosphatidylglycerol (PG), phosphatidylserine ( Trem2 can be activated by phosphatidylinositol (PI), phosphatidylcholine (PC), cardiolipin, and sphingomyelin (PS). Activation of Trem2 increases the phagocytic capacity of microglia and macrophages, reduces the release of pro-inflammatory cytokines, and suppresses TLR signaling. Trem2 maintains microglial survival through synergistic action with CSF-1 receptor signaling. Furthermore, Trem2 interacts with plexin A1 to regulate cell adhesion and motility. Trem2 is also densely present in the surface regions of microglial cells in contact with Aβ plaques or neuronal fragments (Yuan et al.). al., Neuron 90 (2016) 724-739). Recently, some ligands sensed by TREM2 in this environment, such as phospholipids and myelolipids (P oliani et al. , J. Clin. Invest. 125 (2015): 21 61-2170) and ApoE (Atagi et al., J. Biol. Chem ．． 290 (2015): 26043-26050; Bailey et al. , J. B Iol. Chem. 290 (2015): 26033-26042) has been identified. Other ligands include TREM2, which contributes to the uptake of Aβ into microglia, and therefore may be Aβ and plaque-associated neuronal fragments (Xiang et al., EMB). O Mol. Med. 8 (2016):992-1004. TREM2 also works on apoptotic cells (Takahashi et al., J. Exp. Med. 201 (200 5), 647-657), Myelin fragments (Poliani et al., J. Clin Invest. 125 (2015): 2161-2170) and bacterial beads (Cen It has also been shown to play a role in the elimination of (et al., Am. J. Respir. 188 (2013) 201-212). TREM2 signaling promotes the breakdown of ingested food and is critically important for lipid metabolism, myelin uptake, and intracellular degradation. TREM2 undergoes sequential proteolytic processing via ectodomain shedding and intramembrane proteolysis (Wunderlich, J. Biol. Chem.). 288, 33027-33036, 2013). During ectodomain shedding, A DAM (disintegrin and meta