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NZ756507B2 - Immunoconjugates of an anti-pd-1 antibody with a mutant il-2 or with il-15 - Google Patents
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NZ756507B2 - Immunoconjugates of an anti-pd-1 antibody with a mutant il-2 or with il-15 - Google Patents

Immunoconjugates of an anti-pd-1 antibody with a mutant il-2 or with il-15

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Publication number
NZ756507B2
NZ756507B2 NZ756507A NZ75650718A NZ756507B2 NZ 756507 B2 NZ756507 B2 NZ 756507B2 NZ 756507 A NZ756507 A NZ 756507A NZ 75650718 A NZ75650718 A NZ 75650718A NZ 756507 B2 NZ756507 B2 NZ 756507B2
Authority
NZ
New Zealand
Prior art keywords
amino acid
immunoconjugate
seq
domain
polypeptide
Prior art date
Application number
NZ756507A
Other versions
NZ756507A (en
Inventor
Deak Laura Codarri
Christian Klein
Laura Lauener
Valeria G Nicolini
Stefan Seeber
Pablo Umana
Inja Waldhauer
Original Assignee
F Hoffmann La Roche Ag
Filing date
Publication date
Application filed by F Hoffmann La Roche Ag filed Critical F Hoffmann La Roche Ag
Priority claimed from PCT/EP2018/058034 external-priority patent/WO2018184964A1/en
Publication of NZ756507A publication Critical patent/NZ756507A/en
Publication of NZ756507B2 publication Critical patent/NZ756507B2/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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/2013—IL-2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/2086—IL-13 to IL-16
    • 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
    • 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
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
    • A61K47/6813—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin the drug being a peptidic cytokine, e.g. an interleukin or interferon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6891—Pre-targeting systems involving an antibody for targeting specific cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/54—Interleukins [IL]
    • C07K14/5443—IL-15
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/54—Interleukins [IL]
    • C07K14/55—IL-2
    • 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
    • C07K16/2818—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 CD28 or CD152
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
    • 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
    • C07K2319/00—Fusion polypeptide
    • C07K2319/70—Fusion polypeptide containing domain for protein-protein interaction
    • C07K2319/74—Fusion polypeptide containing domain for protein-protein interaction containing a fusion for binding to a cell surface receptor

Abstract

The present invention relates to immunoconjugates comprising a human mutant interleukin-2 polypeptide bearing F42A, Y45A and L72G mutations relative to human IL-2 and an antibody that binds to PD-1. In addition, the invention relates to polynucleotide molecules encoding the immunoconjugates, and vectors and host cells comprising such polynucleotide molecules. The invention further relates to methods for producing the mutant immunoconjugates, pharmaceutical compositions comprising the same, and uses thereof.

Claims (34)

Claims
1. An immunoconjugate comprising (i) an antibody that binds to PD-1 and (ii) an IL-2 polypetide, wherein the IL-2 polypeptide is a mutant IL-2 polypeptide, 5 wherein the mutant IL-2 polypeptide is a human IL-2 molecule comprising the amino acid substitutions F42A, Y45A and L72G (numbering relative to the human IL-2 sequence SEQ ID NO: 19).
2. An immunoconjugate according to claim 1, wherein the IL-2 polypeptide is a mutant IL-2 polypeptide, 10 wherein the mutant IL-2 polypeptide is a human IL-2 molecule comprising the amino acid substitutions F42A, Y45A and L72G, the numbering being relative to the human IL-2 sequence SEQ ID NO: 19; and wherein the antibody comprises (a) a heavy chain le region (VH) comprising a HVR-H1 comprising the amino acid sequence of SEQ ID NO:1, a HVR-H2 comprising the amino acid 15 sequence of SEQ ID NO:2, a HVR-H3 sing the amino acid sequence of SEQ ID NO:3, and a FR-H3 comprising the amino acid sequence of SEQ ID NO:7 at ons 71-73 according to Kabat numbering, and (b) a light chain variable region (VL) comprising a HVR-L1 sing the amino acid sequence of SEQ ID NO:4, a HVR-L2 comprising the amino acid sequence of SEQ ID NO:5, and a HVR-L3 sing the amino acid sequence of SEQ ID NO:6. 20
3. An immunoconjugate according to claim 1, wherein the IL-2 polypeptide is a mutant IL-2 polypeptide, n the mutant IL-2 polypeptide is a human IL-2 molecule comprising the amino acid substitutions F42A, Y45A and L72G, the numbering relative to the human IL-2 sequence SEQ ID NO: 19; and 25 wherein the antibody comprises (a) a heavy chain variable region (VH) comprising a HVR-H1 comprising the amino acid sequence of SEQ ID NO:8, a HVR-H2 comprising the amino acid sequence of SEQ ID NO:9, and a HVR-H3 comprising the amino acid sequence of SEQ ID NO:10, and (b) a light chain variable region (VL) comprising a HVR-L1 comprising the amino acid sequence of SEQ ID NO:11, a HVR-L2 comprising the amino acid ce of SEQ ID 30 NO:12, and a HVR-L3 comprising the amino acid sequence of SEQ ID NO:13.
4. An immunoconjugate ing to claim 1, wherein the IL-2 polypeptide is a mutant IL-2 polypeptide, wherein the mutant IL-2 polypeptide is a human IL-2 molecule comprising the amino acid substitutions F42A, Y45A and L72G, the ing relative to the human IL-2 sequence SEQ 5 ID NO: 19; and wherein the antibody comprises (a) a heavy chain variable region (VH) comprising an amino acid sequence that is at least about 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:14, and (b) a light chain variable region (VL) comprising an amino acid sequence that is at least about 95%, 96%, 97%, 98%, 99% or 100% identical to an amino 10 acid sequence ed from the group consisting of SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO: 17, and SEQ ID NO:18.
5. The immunoconjugate of any one of claims 1 to 4, wherein the mutant IL-2 polypeptide r comprises the amino acid substitution T3A and/or the amino acid substitution C125A.
6. The immunoconjugate of any one of claims 1 to 5, wherein the mutant IL-2 polypeptide 15 ses the sequence of SEQ ID NO: 20.
7. The immunoconjugate of any one of claims 1 to 6, wherein the immunoconjugate comprises not more than one mutant IL-2 polypeptide.
8. The immunoconjugate of any one of claims 1 to 7, wherein the antibody comprises an Fc domain composed of a first and a second subunit. 20
9. The conjugate of claim 8, wherein the Fc domain is an IgG class, particularly an IgG1 subclass, Fc domain.
10. The immunoconjugate of claim 8 or 9, wherein the Fc domain is a human Fc domain.
11. The immunoconjugate of any one of claims 1 to 10, n the antibody is an IgG class, particularly an IgG1 subclass immunoglobulin. 25
12. The immunoconjugate of any one of claims 8 to 11, wherein the Fc domain comprises a modification promoting the association of the first and the second subunit of the Fc domain.
13. The immunoconjugate of any one of claims 8 to 12, wherein in the CH3 domain of the first subunit of the Fc domain an amino acid residue is replaced with an amino acid residue having a larger side chain volume, thereby ting a protuberance within the CH3 domain of the first subunit which is positionable in a cavity within the CH3 domain of the second subunit, and in the CH3 domain of the second subunit of the Fc domain an amino acid e is replaced with an amino acid residue having a r side chain volume, thereby generating a cavity within the 5 CH3 domain of the second subunit within which the protuberance within the CH3 domain of the first subunit is positionable.
14. The immunoconjugate of any one of claims 8 to 13, wherein in the first subunit of the Fc domain the threonine residue at position 366 is ed with a tryptophan residue ), and in the second subunit of the Fc domain the tyrosine residue at on 407 is replaced with a 10 valine residue (Y407V) and optionally the threonine residue at position 366 is replaced with a serine residue (T366S) and the leucine residue at position 368 is replaced with an e residue (L368A), the numbering being according to Kabat EU index.
15. The immunoconjugate of claim 14, wherein in the first subunit of the Fc domain additionally the serine residue at position 354 is replaced with a cysteine residue ) or the glutamic 15 acid residue at position 356 is replaced with a cysteine residue (E356C), and in the second subunit of the Fc domain additionally the tyrosine residue at position 349 is replaced by a cysteine residue (Y349C), the numbering being according to Kabat EU index.
16. The immunoconjugate of any one of claims 8 to 15, wherein the mutant IL-2 polypeptide is fused at its amino-terminal amino acid to the carboxy-terminal amino acid of one of the ts 20 of the Fc domain, particularly the first subunit of the Fc domain, optionally h a linker peptide.
17. The immunoconjugate of claim 16, wherein the linker peptide has the amino acid ce of SEQ ID NO:21.
18. The immunoconjugate of any one of claims 8 to 16, wherein the Fc domain comprises one or 25 more amino acid substitution that reduces g to an Fc receptor, particularly an Fc? receptor, and/or effector function, particularly antibody-dependent cell-mediated cytotoxicity (ADCC).
19. The immunoconjugate of claim 18, wherein said one or more amino acid substitution is at one or more position selected from the group of L234, L235, and P329, the numbering being according to Kabat EU index.
20. The immunoconjugate of any one of claims 9 to 20, wherein each subunit of the Fc domain ses the amino acid substitutions L234A, L235A and P329G, the numbering being according to the Kabat EU index.
21. The immunoconjugate of any one of claims 1 to 20, comprising a polypeptide comprising an 5 amino acid sequence that is 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:22, a polypeptide comprising an amino acid sequence that is 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the ce of SEQ ID NO:23 or
22. SEQ ID NO:24, and a polypeptide comprising an amino acid sequence that is 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:25. 10 22. The immunoconjugate of any one of claims 1 to 21, consisting of a mutant IL-2 polypeptide and an IgG1 immunoglobulin molecule, joined by a linker sequence.
23. One or more isolated polynucleotide ng the immunoconjugate of any one of claims 1 to 22.
24. One or more vector, ularly expression vector, comprising the polynucleotide(s) of claim 15 23.
25. A host cell comprising the polynucleotide(s) of claim 23 or the vector(s) of claim 24, with the proviso that said host cell is not present in a human body.
26. A method of producing an immunoconjugate comprising a mutant IL-2 polypeptide and an antibody that binds to PD-1, comprising (a) culturing the host cell of claim 25 under conditions 20 suitable for the expression of the immunoconjugate, and optionally (b) recovering the immunoconjugate.
27. A pharmaceutical composition comprising the immunoconjugate of any one of claims 1 to 22 and a pharmaceutically acceptable carrier.
28. Use of the immunoconjugate of any one of claims 1 to 22 in the manufacture of a 25 medicament.
29. Use of the immunoconjugate of any one of claims 1 to 22 in the manufacture of a medicament for the ent of a disease.
30. The use of claim 29, n said disease is cancer.
31. A method of treating a disease in a non-human dual, comprising administering to said individual a therapeutically effective amount of a composition comprising the immunoconjugate of any one of claims 1 to 22 in a pharmaceutically acceptable form.
32. The method of claim 31, wherein said disease is cancer. 5
33. A method of stimulating the immune system of a non-human individual, sing administering to said individual an effective amount of a composition comprising the immunoconjugate of any one of claims 1 to 22 in a pharmaceutically acceptable form.
34. A immunoconjugate of any one of claims 1-22; one or more polynucleotides of claim 23; one or more vectors of claim 24; a host cell of claim 25; a method of any one of claims 26 and 10 31-33; a pharmaceutical composition of claim 27; or a use of any one of claims 28-30, substantially as bed herein and with reference to any example thereof.
NZ756507A 2018-03-29 Immunoconjugates of an anti-pd-1 antibody with a mutant il-2 or with il-15 NZ756507B2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP17164533 2017-04-03
PCT/EP2018/058034 WO2018184964A1 (en) 2017-04-03 2018-03-29 Immunoconjugates of an anti-pd-1 antibody with a mutant il-2 or with il-15

Publications (2)

Publication Number Publication Date
NZ756507A NZ756507A (en) 2025-06-27
NZ756507B2 true NZ756507B2 (en) 2025-09-30

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