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NZ779096B2 - Anti-LAG-3 Antibodies - Google Patents
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NZ779096B2 - Anti-LAG-3 Antibodies - Google Patents

Anti-LAG-3 Antibodies

Info

Publication number
NZ779096B2
NZ779096B2 NZ779096A NZ77909616A NZ779096B2 NZ 779096 B2 NZ779096 B2 NZ 779096B2 NZ 779096 A NZ779096 A NZ 779096A NZ 77909616 A NZ77909616 A NZ 77909616A NZ 779096 B2 NZ779096 B2 NZ 779096B2
Authority
NZ
New Zealand
Prior art keywords
amino acid
seq
acid sequence
antigen
sequence selected
Prior art date
Application number
NZ779096A
Other versions
NZ779096A (en
Inventor
Chrystelle Brignone
Frederic Triebel
Original Assignee
Immutep Sas
Filing date
Publication date
Priority claimed from GBGB1515572.4A external-priority patent/GB201515572D0/en
Priority claimed from GBGB1612437.2A external-priority patent/GB201612437D0/en
Application filed by Immutep Sas filed Critical Immutep Sas
Publication of NZ779096A publication Critical patent/NZ779096A/en
Publication of NZ779096B2 publication Critical patent/NZ779096B2/en

Links

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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • C07K16/2896—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/51—Complete heavy chain or Fd fragment, i.e. VH + CH1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/515—Complete light chain, i.e. VL + CL
    • 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
    • C07K2317/50—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
    • C07K2317/565—Complementarity determining region [CDR]
    • 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
    • C07K2317/567—Framework region [FR]
    • 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
    • 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
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • 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
    • C07K2317/90—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

Antibodies, or antigen-binding fragments thereof, that bind to Lymphocyte-activation gene-3 (LAG-3) are described, in particular antibodies, or antigen-binding fragments thereof, that are agonists of LAG-3. The antibodies bind to LAG-3 and inhibit antigen-induced CD4+ and/or CD8+ T cell proliferation, or antigen-induced CD4+ and/or CD8+ T cell activation. The antibodies may be used as medicaments, in particular for the treatment of conditions associated with proliferation and/or activation of CD4+ and/or CD8+ T cells, such as inflammatory and autoimmune disorders.

Claims (26)

What I (or we) claim is:
1. An isolated agonistic anti-Lymphocyte activation gene-3 (LAG-3) antibody, or antigen-binding fragment thereof, that binds to LAG-3 and inhibits antigen-induced CD4+ and/or CD8+ T cell proliferation, and/or antigen-induced CD4+ and/or CD8+ T cell activation, wherein the antibody or antigen-binding fragment thereof, comprises: i) a heavy chain variable (VH) region comprising: (a) a VH complementarity determining region 1 (CDR1) region comprising SEQ ID NO: 1, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions as compared to SEQ ID NO: 1; (b) a VH CDR2 region comprising SEQ ID NO: 2, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions as compared to SEQ ID NO: 2; and (c) a VH CDR3 region comprising SEQ ID NO: 3, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions as compared to SEQ ID NO: 3; and a light chain variable (VL) region comprising: (a) a VL CDR1 region comprising SEQ ID NO: 4, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions as compared to SEQ ID NO: 4; (b) a VL CDR2 region comprising SEQ ID NO: 5, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions as compared to SEQ ID NO: 5; and (c) a VL CDR3 region comprising SEQ ID NO: 6, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions as compared to SEQ ID NO: 6; or ii) a heavy chain variable region comprising: 129 (a) a VH CDR1 region comprising SEQ ID NO: 21, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions as compared to SEQ ID NO: 21; (b) a VH CDR2 region comprising SEQ ID NO: 22, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions as compared to SEQ ID NO: 22; and (c) a VH CDR3 region comprising SEQ ID NO: 23, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions as compared to SEQ ID NO: 23; and a light chain variable region comprising: (a) a VL CDR1 region comprising SEQ ID NO: 24, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions as compared to SEQ ID NO: 24; (b) a VL CDR2 region comprising SEQ ID NO: 25, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions as compared to SEQ ID NO: 25; and (c) a VL CDR3 region comprising SEQ ID NO: 26, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions as compared to SEQ ID NO: 26, wherein the isolated agonistic antibody or antigen binding fragment thereof is obtainable by immunisation with IMP321, without using Complete Freund's Adjuvant (CFA) or Incomplete Freund's Adjuvant (IFA) as adjuvant.
2. An isolated antibody, or antigen-binding fragment thereof, according to claim 1, which inhibits antigen-induced CD4+ and antigen-induced CD8+ T cell proliferation.
3. An isolated antibody, or antigen-binding fragment thereof, according to claim 1 or 2, which inhibits antigen-induced CD8+ T cell proliferation more than antigen-induced CD4+ T cell proliferation. 130
4. An isolated antibody, or antigen-binding fragment thereof, according to any one of the preceding claims, wherein the inhibition of antigen-induced CD8+ T cell proliferation is LAG-3 dependent, and IL-2 independent.
5. An isolated antibody, or antigen-binding fragment thereof, according to any one of the preceding claims, which inhibits antigen-induced CD4+ and/or CD8+ T cell proliferation, and antigen-induced CD4+ and/or CD8+ T cell activation.
6. An isolated antibody, or antigen-binding fragment thereof, according to any one of the preceding claims, that binds to Lymphocyte activation gene-3 (LAG-3) and inhibits antigen-induced CD4+ and CD8+ T cell activation.
7. An isolated antibody, or antigen-binding fragment thereof, according to any one of the preceding claims, which binds to LAG-3 with higher affinity than monoclonal antibody 17B4.
8. An isolated antibody, or antigen-binding fragment thereof, according to any one of the preceding claims, which inhibits binding of LAG-3 or IMP321 to MHC class II-positive cells.
9. An isolated antibody, or antigen-binding fragment thereof, according to any one of the preceding claims, which inhibits LAGinduced antigen-presenting cell (APC) activation, or IMP321-induced monocyte activation.
10. An isolated antibody, or antigen-binding fragment thereof, according to any one of the preceding claims which binds to an epitope of LAG-3 that overlaps with the MHC class II binding site of LAG-3.
11. An isolated antibody, or antigen-binding fragment thereof, according to any one of the preceding claims, which comprises one, two, or three complementarity determining regions (CDRs) of an antibody heavy chain variable (VH) region comprising amino acid sequence SEQ ID NO:7, and one, two, or three CDRs of an antibody light chain variable (VL) region comprising amino acid sequence SEQ ID NO:8.
12. An isolated antibody, or antigen-binding fragment thereof, according to claim 11, wherein the CDRs of the antibody VH region are selected from CDRs of amino acid sequence SEQ ID NO:1, 2, 3, 21, 22, and 23, and the CDRs of the antibody VL region are selected from CDRs of amino acid sequence SEQ ID NO:4, 5, 6, 24, 25, and 26. 131
13. An isolated antibody, or antigen-binding fragment thereof, according to claim 11 or 12, which comprises an antibody VH region comprising a VH CDR1, a VH CDR2, and a VH CDR3, wherein the VH CDR1 has an amino acid sequence selected from SEQ ID NO:1 and 21, and/or the VH CDR2 has an amino acid sequence selected from SEQ ID NO:2 and 22, and/or the VH CDR3 has an amino acid sequence selected from SEQ ID NO:3 and 23.
14. An isolated antibody, or antigen-binding fragment thereof, according to claim 13, wherein: the VH CDR1 has an amino acid sequence selected from SEQ ID NO:1 and 21, and the VH CDR2 has an amino acid sequence selected from SEQ ID NO:2 and 22; the VH CDR1 has an amino acid sequence selected from SEQ ID NO:1 and 21, and the VH CDR3 has an amino acid sequence selected from SEQ ID NO:3 and 23; the VH CDR2 has an amino acid sequence selected from SEQ ID NO:2 and 22, and the VH CDR3 has an amino acid sequence selected from SEQ ID NO:3 and 23; or the VH CDR1 has an amino acid sequence selected from SEQ ID NO:1 and 21, the VH CDR2 has an amino acid sequence selected from SEQ ID NO:2 and 22, and the VH CDR3 has an amino acid sequence selected from SEQ ID NO:3 and 23.
15. An isolated antibody, or antigen-binding fragment thereof, according to any one of claims 11 to 14, which comprises an antibody VL region comprising a VL CDR1, a VL CDR2, and a VL CDR3, wherein the VL CDR1 has an amino acid sequence selected from SEQ ID NO:4 and 24, and/or the VL CDR2 has an amino acid sequence selected from SEQ ID NO:5 and 25, and/or the VL CDR3 has an amino acid sequence selected from SEQ ID NO:6 and 26.
16. An isolated antibody, or antigen-binding fragment thereof, according to claim 15, wherein: the VL CDR1 has an amino acid sequence selected from SEQ ID NO:4 and 24, and the VL CDR2 has an amino acid sequence selected from SEQ ID NO:5 and 25; the VL CDR1 has an amino acid sequence selected from SEQ ID NO:4 and 24, and the VL CDR3 has an amino acid sequence selected from SEQ ID NO:6 and 26; 132 the VL CDR2 has an amino acid sequence selected from SEQ ID NO:5 and 25, and the VL CDR3 has an amino acid sequence selected from SEQ ID NO:6 and 26; or the VL CDR1 has an amino acid sequence selected from SEQ ID NO:4 and 24, the VL CDR2 has an amino acid sequence selected from SEQ ID NO:5 and 25, and the VL CDR3 has an amino acid sequence selected from SEQ ID NO:6 and 26.
17. An isolated antibody, or antigen-binding fragment thereof, according to any one of claims 13 to 16, wherein the VH CDR1 has an amino acid sequence selected from SEQ ID NO:1 and 21, the VH CDR2 has an amino acid sequence selected from SEQ ID NO:2 and 22, and the VH CDR3 has an amino acid sequence selected from SEQ ID NO:3 and 23; and/or the VL CDR1 has an amino acid sequence selected from SEQ ID NO:4 and 24, the VL CDR2 has an amino acid sequence selected from SEQ ID NO:5 and 25, and the VL CDR3 has an amino acid sequence selected from SEQ ID NO:6 and 26.
18. An isolated antibody, or antigen-binding fragment thereof, according to any one of the preceding claims, which comprises an antibody VH region with CDRs comprising amino acid sequences of SEQ ID NOs:1, 2, and 3, or an antibody VL region with CDRs comprising amino acid sequences of SEQ ID NOs:4, 5, and 6.
19. An isolated antibody, or antigen-binding fragment thereof, according to any one of claims 1 to 17, which comprises an antibody VH region with CDRs comprising amino acid sequences of SEQ ID NOs:21, 22, and 23, or an antibody VL region with CDRs comprising amino acid sequences of SEQ ID NOs:24, 25, and 26.
20. An isolated antibody, or antigen-binding fragment thereof, according to any one of the preceding claims, which comprises an antibody VH region comprising amino acid sequence SEQ ID NO:7 or amino acid sequence that is at least 60% identical to amino acid sequence SEQ ID NO:7, and an antibody VL region comprising amino acid sequence SEQ ID NO:8 or amino acid sequence that is at least 60% identical to amino acid sequence SEQ ID NO:8.
21. A nucleic acid comprising a nucleotide sequence encoding an antibody, or antigen binding fragment thereof, according to any one of the preceding claims.
22.
23. A recombinant vector comprising a nucleic acid of claim 21. An isolated recombinant cell comprising the nucleic acid of claim 21, or the recombinant vector of claim 22. 133
24. A pharmaceutical composition comprising an isolated antibody, or antigen-binding fragment thereof, according to any one of claims 1 to 20, and a pharmaceutically acceptable carrier, excipient, or diluent.
25. Use of an isolated antibody, or antigen-binding fragment thereof, according to any one of claims 1 to 20, in the manufacture of a medicament for the treatment of a T cell mediated immune disorder.
26. An isolated agonistic anti-Lymphocyte activation gene-3 (LAG-3) antibody, or antigen-binding fragment thereof, that binds to LAG-3 and inhibits antigen-induced CD4+ and/or CD8+ T cell proliferation, and/or antigen-induced CD4++ and/or CD8+ T cell activation, which comprises: an antibody VH region comprising: a VH CDR1 with an amino acid sequence selected from SEQ ID NO:1 and 21; a VH CDR2 with an amino acid sequence selected from SEQ ID NO:2 and 22; and a VH CDR3 with an amino acid sequence selected from SEQ ID NO:3 and 23; and an antibody VL region comprising: a VL CDR1 with an amino acid sequence selected from SEQ ID NO:4 and 24; a VL CDR2 with an amino acid sequence selected from SEQ ID NO:5 and 25; and a VL CDR3 with an amino acid sequence selected from SEQ ID NO:6 and 26; or a variant thereof in which no more than five amino acid residues are altered by amino acid substitution, addition, or deletion, within the CDR sequences.
NZ779096A 2016-09-01 Anti-LAG-3 Antibodies NZ779096B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GBGB1515572.4A GB201515572D0 (en) 2015-09-02 2015-09-02 Anti-LAG-3 antibodies
GBGB1612437.2A GB201612437D0 (en) 2016-07-18 2016-07-18 Anti-lag-3 antibodies
NZ740357A NZ740357B2 (en) 2016-09-01 Anti-LAG-3 Antibodies

Publications (2)

Publication Number Publication Date
NZ779096A NZ779096A (en) 2025-07-25
NZ779096B2 true NZ779096B2 (en) 2025-10-29

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