WO2021168194A1 - Engineered anti-her2 bispecific proteins - Google Patents

Engineered anti-her2 bispecific proteins Download PDF

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Publication number
WO2021168194A1
WO2021168194A1 PCT/US2021/018705 US2021018705W WO2021168194A1 WO 2021168194 A1 WO2021168194 A1 WO 2021168194A1 US 2021018705 W US2021018705 W US 2021018705W WO 2021168194 A1 WO2021168194 A1 WO 2021168194A1
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WO
WIPO (PCT)
Prior art keywords
sequence
seq
identity
polypeptide
protein
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Ceased
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PCT/US2021/018705
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English (en)
French (fr)
Inventor
Gunasekaran Kannan
Do Jin Kim
Wanda KWAN
Raymond Ka Hang TONG
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Denali Therapeutics Inc
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Denali Therapeutics Inc
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Publication date
Priority to BR112022016232A priority Critical patent/BR112022016232A2/pt
Priority to AU2021224200A priority patent/AU2021224200A1/en
Priority to CN202180027050.7A priority patent/CN115361972A/zh
Priority to MX2022010161A priority patent/MX2022010161A/es
Priority to CA3170338A priority patent/CA3170338A1/en
Priority to JP2022549653A priority patent/JP2023514371A/ja
Priority to EP21756590.2A priority patent/EP4181950A4/en
Priority to IL295729A priority patent/IL295729A/en
Priority to KR1020227028989A priority patent/KR20220156526A/ko
Application filed by Denali Therapeutics Inc filed Critical Denali Therapeutics Inc
Publication of WO2021168194A1 publication Critical patent/WO2021168194A1/en
Priority to US17/819,182 priority patent/US20230192887A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • C07K16/32—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
    • 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
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A61K39/001102—Receptors, cell surface antigens or cell surface determinants
    • A61K39/001103—Receptors for growth factors
    • A61K39/001106—Her-2/neu/ErbB2, Her-3/ErbB3 or Her 4/ErbB4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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
    • C07K16/2881—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD71
    • 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
    • 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
    • C07K2317/50—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
    • C07K2317/52—Constant or Fc region; Isotype
    • C07K2317/526—CH3 domain
    • 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
    • C07K2317/53—Hinge
    • 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
    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
    • C07K2317/622—Single chain antibody (scFv)
    • 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
    • C07K2317/71—Decreased effector function due to an Fc-modification
    • 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
    • C07K2317/76—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
    • 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

Definitions

  • the disclosure provides a protein comprising:
  • the first Fc polypeptide and/or the second Fc polypeptide specifically binds to a transferrin receptor (e.g, contains any of sequence modifications described herein that create a TfR-binding site).
  • a transferrin receptor e.g, contains any of sequence modifications described herein that create a TfR-binding site.
  • the first Fc polypeptide and the second Fc polypeptide each comprises modifications that promote heterodimerization.
  • the first Fc polypeptide comprises a T366W substitution and the second Fc polypeptide comprises T366S, L368A, and Y407V substitutions, according to EU numbering.
  • the scFv that is fused to the first Fc polypeptide and/or the second Fc polypeptide comprises identical sequences.
  • the scFv that is fused to the Fd portion in (a) and/or (b) comprises identical sequences.
  • (i) (a) comprises a sequence having at least 90% (e.g, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the sequence of SEQ ID NO:27 or 28, (b) comprises a sequence having at least 90% (e.g, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the sequence of SEQ ID NO:4, and each of the two light chain polypeptides in (c) comprises a sequence having at least 90% (e.g, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the sequence of SEQ ID NO:25; or
  • (i) (a) comprises a sequence having at least 90% (e.g ., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the sequence of SEQ ID NO:l
  • (b) comprises a sequence having at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the sequence of SEQ ID NO:4
  • each of the two light chain polypeptides is fused at the C-terminus to the scFv and comprises a sequence having at least 90% (e.g, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the sequence of SEQ ID NO:55; or
  • the first Fc polypeptide is fused to the VH region of the Fv fragment and the second Fc polypeptide is fused to the VL region of the Fv fragment. In some embodiments, the first Fc polypeptide is fused to the VL region of the Fv fragment and the second Fc polypeptide is fused to the VH region of the Fv fragment. In some embodiments, the first Fc polypeptide and/or the second Fc polypeptide is fused at the C-terminus to the VH region or the VL region via a first linker.
  • bispecific proteins that can bind to both subdomain II of human HER2 and subdomain IV of human HER2 are provided.
  • the bispecific proteins can, in general, be generated without light chain mispairing or steering.
  • the bispecific proteins bind to each target subdomain of human HER2 monovalently.
  • the bispecific proteins bind to one target subdomain of human HER2 monovalently and the other target subdomain of human HER2 bivalently (e.g., to subdomain II monovalently and to subdomain IV bivalently, or to subdomain IV monovalently and to subdomain II bivalently).
  • the bispecific proteins bind to each target subdomain of human HER2 bivalently.
  • Various structures of the bispecific proteins are described in detail further herein.
  • the Fab is formed from the pairing of the Fd portion of the Fab, which is fused to the N-terminus of the first Fc polypeptide, with the light chain.
  • the Fab that specifically binds to the subdomain II of human HER2 comprises a VH region having at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the sequence of SEQ ID NO: 108.
  • an anti-HER2DII VH region can have a Gly to Cys substitution at position 44 of SEQ ID NO: 108.
  • the anti-HER2DII VH region containing the Cys substitution can have the sequence of SEQ ID NO: 112.
  • an anti-HER2DIV VH region can have a Gly to Cys substitution at position 44 of SEQ ID NO: 109.
  • the anti-HER2DIV VH region containing the Cys substitution can have the sequence of SEQ ID NO: 113.
  • (a) comprises a sequence having at least 90% (e.g, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the sequence of SEQ ID NO:3
  • (b) comprises a sequence having at least 90% (e.g, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the sequence of SEQ ID NO: 19
  • (c) comprises a sequence having at least 90% (e.g, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the sequence of SEQ ID NO:25.
  • the Fab that specifically binds to the subdomain IV of human HER2 comprises a VH region having at least 90% (e.g, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the sequence of SEQ ID NO: 109.
  • the bispecific protein comprises:
  • the bispecific protein comprises:
  • (a) comprises a sequence having at least 90% (e.g, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the sequence of SEQ ID NO:45 or 46
  • (b) comprises a sequence having at least 90% (e.g, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the sequence of SEQ ID NO:9 or 10
  • each of the two light chain polypeptides in (c) comprises a sequence having at least 90% (e.g, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the sequence of SEQ ID NO:26.
  • (a) comprises a sequence having at least 90% (e.g, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the sequence of SEQ ID NO:48
  • (b) comprises a sequence having at least 90% (e.g, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the sequence of SEQ ID NO:35
  • each of the two light chain polypeptides in (c) comprises a sequence having at least 90% (e.g, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the sequence of SEQ ID NO:26.
  • first Fc polypeptide can comprise T366S, L368A, and Y407V substitutions and the second Fc polypeptide can comprise a T366W substitution, according to EU numbering.
  • first Fc polypeptide and/or the second Fc polypeptide independently can comprise modifications that reduce effector function.
  • the modifications that reduce effector function are L234A and L235A substitutions, according to EU numbering.
  • (a) comprises a sequence having at least 90% (e.g ., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the sequence of SEQ ID NO:l
  • (b) comprises a sequence having at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the sequence of SEQ ID NO:4 or 5
  • each of the two light chain polypeptides is fused at the C-terminus to the scFv and comprises a sequence having at least 90% (e.g, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the sequence of SEQ ID NO:52.
  • (a) comprises a sequence having at least 90% (e.g, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the sequence of SEQ ID NO:2
  • (b) comprises a sequence having at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 91%, 98%, 99%, or 100%) identity to the sequence of SEQ ID NO:3
  • a first light chain polypeptide is fused at the N- terminus to the scFv and comprises a sequence having at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the sequence of SEQ ID NO:55
  • a second light chain polypeptide comprises a sequence having at least 90% (e.g, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to
  • the first Fc polypeptide (or the second Fc polypeptide) can comprise a sequence having at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the sequence of SEQ ID NO: 137
  • the second Fc polypeptide (or the first Fc polypeptide) can comprise a sequence having at least 90% (e.g, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the sequence of SEQ ID NO: 133).
  • the first Fc polypeptide and/or the second Fc polypeptide can specifically bind to a transferrin receptor (e.g, a TfR-binding Fc polypeptide).
  • a transferrin receptor e.g, a TfR-binding Fc polypeptide
  • the first Fc polypeptide and the second Fc polypeptide can each comprise modifications that promote heterodimerization.
  • the first Fc polypeptide can comprise a T366W substitution and the second Fc polypeptide can comprise T366S, L368A, and Y407V substitutions, according to EU numbering.
  • the first Fc polypeptide (or the second Fc polypeptide) can comprise a sequence having at least 90% (e.g 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the sequence of SEQ ID NO: 137
  • the second Fc polypeptide (or the first Fc polypeptide) can comprise a sequence having at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the sequence of SEQ ID NO: 133).
  • any bispecific protein described herein only one of the two Fc polypeptides (but not both Fc polypeptides) of the two Fc polypeptides in the bispecific protein is modified to both reduce effector function and bind TfR.
  • the other Fc polypeptide does not contain a TfR-binding site or any modifications that reduce effector function.
  • the Fc polypeptide dimer in the bispecific protein that has only one of the two Fc polypeptides containing both the TfR-binding site and modifications that reduce FcyR binding (e.g, LALA substitutions), while the other Fc polypeptide does not contain a TfR-binding site or any modifications that reduce FcyR binding, is referred to as having the cis-LALA configuration.

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  • Health & Medical Sciences (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
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PCT/US2021/018705 2020-02-19 2021-02-19 Engineered anti-her2 bispecific proteins Ceased WO2021168194A1 (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
IL295729A IL295729A (en) 2020-02-19 2021-02-19 Bispecific engineered anti-2her proteins, preparations containing them and their uses
AU2021224200A AU2021224200A1 (en) 2020-02-19 2021-02-19 Engineered anti-HER2 bispecific proteins
CN202180027050.7A CN115361972A (zh) 2020-02-19 2021-02-19 工程化抗her2双特异性蛋白
MX2022010161A MX2022010161A (es) 2020-02-19 2021-02-19 Proteínas biespecíficas anti-her2 diseñadas.
CA3170338A CA3170338A1 (en) 2020-02-19 2021-02-19 Engineered anti-her2 bispecific proteins
BR112022016232A BR112022016232A2 (pt) 2020-02-19 2021-02-19 Proteínas biespecíficas anti-her2 manipuladas
EP21756590.2A EP4181950A4 (en) 2020-02-19 2021-02-19 Engineered anti-her2 bispecific proteins
JP2022549653A JP2023514371A (ja) 2020-02-19 2021-02-19 操作された抗ｈｅｒ２二重特異性タンパク質
KR1020227028989A KR20220156526A (ko) 2020-02-19 2021-02-19 조작된 항-her2 이중특이성 단백질
US17/819,182 US20230192887A1 (en) 2020-02-19 2022-08-11 Engineered anti-her2 bispecific proteins

Applications Claiming Priority (2)

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US202062978758P 2020-02-19 2020-02-19
US62/978,758 2020-02-19

Related Child Applications (1)

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US17/819,182 Continuation US20230192887A1 (en) 2020-02-19 2022-08-11 Engineered anti-her2 bispecific proteins

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WO2021168194A1 true WO2021168194A1 (en) 2021-08-26

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PCT/US2021/018705 Ceased WO2021168194A1 (en) 2020-02-19 2021-02-19 Engineered anti-her2 bispecific proteins

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US (1) US20230192887A1 (https=)
EP (1) EP4181950A4 (https=)
JP (1) JP2023514371A (https=)
KR (1) KR20220156526A (https=)
CN (1) CN115361972A (https=)
AR (1) AR121384A1 (https=)
AU (1) AU2021224200A1 (https=)
BR (1) BR112022016232A2 (https=)
CA (1) CA3170338A1 (https=)
IL (1) IL295729A (https=)
MX (1) MX2022010161A (https=)
TW (1) TW202144431A (https=)
WO (1) WO2021168194A1 (https=)

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US11795232B2 (en) 2017-02-17 2023-10-24 Denali Therapeutics Inc. Engineered transferrin receptor binding polypeptides
US11884944B2 (en) 2020-10-14 2024-01-30 Denali Therapeutics Inc. Fusion proteins comprising sulfoglucosamine sulfohydrolase enzymes and methods thereof
WO2024028732A1 (en) * 2022-08-05 2024-02-08 Janssen Biotech, Inc. Cd98 binding constructs for treating brain tumors
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Cited By (9)

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