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NZ729157B2 - Anti-trem2 antibodies and methods of use thereof - Google Patents
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NZ729157B2 - Anti-trem2 antibodies and methods of use thereof - Google Patents

Anti-trem2 antibodies and methods of use thereof Download PDF

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Publication number
NZ729157B2
NZ729157B2 NZ729157A NZ72915715A NZ729157B2 NZ 729157 B2 NZ729157 B2 NZ 729157B2 NZ 729157 A NZ729157 A NZ 729157A NZ 72915715 A NZ72915715 A NZ 72915715A NZ 729157 B2 NZ729157 B2 NZ 729157B2
Authority
NZ
New Zealand
Prior art keywords
amino acid
seq
acid sequence
hvr
chain variable
Prior art date
Application number
NZ729157A
Other versions
NZ729157A (en
Inventor
Connors Francesca Avogadri
Helen Lam
Kate Monroe
Arnon Rosenthal
Tina Schwabe
Ilaria Tassi
Original Assignee
Alector Llc
Filing date
Publication date
Application filed by Alector Llc filed Critical Alector Llc
Priority to NZ766877A priority Critical patent/NZ766877B2/en
Priority claimed from PCT/US2015/044396 external-priority patent/WO2016023019A2/en
Publication of NZ729157A publication Critical patent/NZ729157A/en
Publication of NZ729157B2 publication Critical patent/NZ729157B2/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/283—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against Fc-receptors, e.g. CD16, CD32, CD64
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/55—Fab or Fab'
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/75—Agonist effect on antigen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Abstract

The invention is generally directed to methods and compositions that include antibodies, e.g., monoclonal, chimeric, humanized antibodies, antibody fragments, etc., that specifically bind a TREM2 protein, e.g., a mammalian TREM2 and/or human TREM2. The methods provided herein find use in preventing, reducing risk, or treating an individual having dementia, frontotemporal dementia, Alzheimer's disease, Nasu-Hakola disease, or multiple sclerosis.

Claims (16)

1. An isolated human or humanized antibody that binds to a TREM2 protein and, when cross-linked or plate-bound, promotes survival of one or more innate immune cells selected from macrophages and microglial cells, wherein the isolated antibody comprises a heavy chain variable domain and a light chain variable domain, wherein: (a) the heavy chain variable domain comprises an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 404, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 405, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 406, and the light chain variable domain comprises an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 407, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 408, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 409; (b) the heavy chain variable domain comprises an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 11, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 34, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 60, and the light chain variable domain comprises an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 123, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 141, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 173; (c) the heavy chain variable domain comprises an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 398, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 399, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 400, and the light chain variable domain comprises an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 401, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 402, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 403; or (d) the heavy chain variable domain comprises an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 29, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 87, and the light chain variable domain comprises an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 120, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 138, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 196.
2. An isolated human or humanized antibody that binds to a TREM2 protein, wherein the isolated antibody comprises a heavy chain variable domain and a light chain variable domain, and wherein: (a) the heavy chain variable domain comprises an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 404, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 405, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 406, and the light chain variable domain comprises an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 407, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 408, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 409; (b) the heavy chain variable domain comprises an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 11, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 34, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 60, and the light chain variable domain comprises an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 123, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 141, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 173; (c) the heavy chain variable domain comprises an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 398, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 399, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 400, and the light chain variable domain comprises an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 401, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 402, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 403; or (d) the heavy chain variable domain comprises an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 29, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 87, and the light chain variable domain comprises an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 120, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 138, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 196.
3. The isolated antibody of claim 1 or claim 2, wherein the antibody competes for binding of TREM2 with one or more TREM2 ligands.
4. The isolated antibody of claim 3, wherein the one or more TREM2 ligands are selected from the group consisting of E. coli cells, phosphatidylserine, and sphingomyelin.
5. The isolated antibody of any one of claims 1 to 4, wherein the TREM2 protein is a human TREM2 protein.
6. The isolated antibody of any one of claims 1 to 5, wherein the antibody: (i) increases expression of CD83 and CD86; and/or (ii) induces Syk phosphorylation; and/or (iii) increases expression of IL-6; and/or (iv) increases expression of MCP-1.
7. The isolated antibody of any one of claims 1 to 6, wherein the isolated antibody: (i) has a dissociation constant (K ) for human TREM2-Fc fusion protein that ranges from 0.34 nM to 1.51 nM; and/or (ii) has a dissociation constant (K ) for human monomeric TREM2 protein that ranges from 1.14 nM to 5.75 nM.
8. The isolated antibody of any one of claims 1 to 7, wherein when the antibody is not cross-linked or plate-bound, the antibody does not inhibit survival of macrophages.
9. The isolated antibody of any one of claims 1 to 7, wherein when the antibody is not cross-linked or plate-bound, the antibody inhibits survival of macrophages.
10. The isolated antibody of any one of claims 1 to 8, wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 410, and the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 411.
11. The isolated antibody of any one of claims 1 to 8, wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 262, and the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 279.
12. The isolated antibody of any one of claims 1 to 7 and 9, wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 412, and the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 413.
13. The isolated antibody of any one of claims 1 to 7 and 9, wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 322, and the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 323.
14. The isolated antibody of any one of claims 1 to 13, wherein the antibody is of the IgG class, the IgM class, or the IgA class.
15. The isolated antibody of claim 14, wherein the antibody is of the IgG class and has an IgG1, IgG2, IgG3, or IgG4 isotype.
16. The isolated antibody of claim 15, wherein: i. the isolated antibody has a human IgG2 isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of V234A, G237A, H268Q, V309L, A330S, P331S, C232S, C233S, S267E, L328F, M252Y, S254T, T256E, and any combination thereof, wherein the numbering of the residues is according to the EU numbering system; ii. the isolated antibody has a human IgG2 isotype, wherein the human IgG2 comprises a constant region, and wherein the human IgG2 constant region comprises a light chain constant region comprising a C214S amino acid substitution, wherein the numbering of the residues is according to the EU numbering system; iii. the isolated antibody has a human or mouse IgG1 isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of N297A, D265A, L234A, L235A, G237A, C226S, C229S, E233P, L234V, L234F, L235E, P331S, S267E, L328F, A330L, M252Y, S254T, T256E, and any combination thereof, wherein the numbering of the residues is according to the EU numbering system, optionally wherein the Fc region further comprises one or more additional amino acid substitutions at a position selected from the group consisting of A330L, L234F; L235E, P331S, and any combination thereof, wherein the numbering of the residues is according to the EU numbering system; iv. the isolated antibody has an IgG1 isotype and comprises an IgG2 isotype heavy chain constant domain 1(CH1) and hinge region, optionally wherein the IgG2 isotype CH1 and hinge region comprise the amino acid sequence of ASTKGPSVFP LAPCSRSTSE STAALGCLVK DYFPEPVTVS WNSGALTSGVHTFPAVLQSS GLYSLSSVVT VPSSNFGTQT YTCNVDHKPS NTKVDKTVERKCCVECPPCP (SEQ ID NO: 397), and optionally wherein the antibody Fc region comprises a S267E amino acid substitution, a L328F amino acid substitution, or both, and/or a N297A or N297Q amino acid substitution, wherein the numbering of the residues is according to the EU numbering system; v. the isolated antibody has a human or mouse IgG4 isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of L235A, G237A, S228P, L236E, S267E, E318A, L328F, M252Y, S254T, T256E, and any combination thereof, wherein the numbering of the residues is according to the EU numbering system, optionally wherein the Fc region further comprises a S228P amino acid substitution according to the EU numbering system; or vi. the isolated antibody has a hybrid IgG
NZ729157A 2015-08-08 Anti-trem2 antibodies and methods of use thereof NZ729157B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
NZ766877A NZ766877B2 (en) 2015-08-08 Anti-trem2 antibodies and methods of use thereof

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201462035336P 2014-08-08 2014-08-08
US201562135122P 2015-03-18 2015-03-18
US201562135110P 2015-03-18 2015-03-18
PCT/US2015/044396 WO2016023019A2 (en) 2014-08-08 2015-08-08 Anti-trem2 antibodies and methods of use thereof

Publications (2)

Publication Number Publication Date
NZ729157A NZ729157A (en) 2024-08-30
NZ729157B2 true NZ729157B2 (en) 2024-12-03

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