WO2024148208A1 - Anticorps reconnaissant spécifiquement tnfr2 et compositions et utilisations associées - Google Patents

Anticorps reconnaissant spécifiquement tnfr2 et compositions et utilisations associées Download PDF

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Publication number
WO2024148208A1
WO2024148208A1 PCT/US2024/010380 US2024010380W WO2024148208A1 WO 2024148208 A1 WO2024148208 A1 WO 2024148208A1 US 2024010380 W US2024010380 W US 2024010380W WO 2024148208 A1 WO2024148208 A1 WO 2024148208A1
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WIPO (PCT)
Prior art keywords
composition
amount
cancer
seq
amino acid
Prior art date
Application number
PCT/US2024/010380
Other languages
English (en)
Inventor
Zuoan YI
Wenwu Zhai
Chong HE
Original Assignee
Staidson Biopharma Inc.
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Publication date
Application filed by Staidson Biopharma Inc. filed Critical Staidson Biopharma Inc.
Publication of WO2024148208A1 publication Critical patent/WO2024148208A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2878—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • 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
    • A61K39/39591—Stabilisation, fragmentation
    • 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
    • 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
    • C07K2317/70—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
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

  • This application pertains to antibodies that specifically recognize tumor necrosis factor receptor 2 (TNFR2), and compositions, and methods of treating diseases or conditions mediated through TNFR2, such as cancer or infectious diseases.
  • TNFR2 tumor necrosis factor receptor 2
  • Tumor necrosis factor receptor 2 (TNFR2), also known as tumor necrosis factor receptor superfamily member IB (TNFRSF1B) and CD 120b, is a membrane receptor that binds with cognate ligand TNFa and also with lymphotoxin-a (LT ⁇ ).
  • TNFR1 which has a death domain (DD) in its cytoplasmic part and activates caspase-dependent pathway and NFKB pathway
  • TNFR2 lacks DD but can recruit the adapter protein TNF receptor associated factor 2 (TRAF2) and TRAF3 and activates the nonconical NFKB pathway and MAP kinase pathway (Brenner et al., 2015).
  • TNFR2 is expressed on the immune cells and some non-immune cells including endothelial cells, cardiomyocytes, astrocytes, etc. (Ward-Kavanagh et al., 2016). Although early studies showed that TNFR2 co-stimulates naive T cell function, it was later demonstrated that TNFR2 also limits CD8+ T-cell-mediated viral clearance and anti-tumor immunity by inducing rapid contraction of CD8+ T cells (Bertrand et al., 2015; DeBerge et al., 2015; Kim et al., 2009; Wortzman et al., 2013b).
  • TNFR2 expression is higher in regulatory T cells (Treg cells) than in naive T cells and TNFR2 signaling is important for the development, proliferation, and survival of Treg cells (Chen et al., 2013; Horwitz et al., 2013; Mahmud et al., 2014). Therefore, TNFR2 signaling plays critical roles in regulating immune response.
  • TNFR2 is highly expressed in Treg cells and myeloid-derived suppressive cells (MDSC) in tumor microenvironment, indicating the potential function of TNFR2 in tumor immunity (Chen et al., 2013; Hu et al., 2014).
  • composition comprises an isolated anti-TNFR2 antibody in an amount of from about Img/ml to about 300mg/ml, a stabilizer, a surfactant and a buffering agent.
  • the antibody is in an amount of from about 15 mg/ml to about 180 mg/ml, preferably, from about 40 mg/ml to about 60 mg/ml.
  • the antibody is in an amount of lmg/ml, lOmg/ml, 15 mg/ml ,20 mg/ml, 40 mg/ml, 45mg/ml, 50mg/ml, 55mg/ml, 60mg/ml, 80mg/ml, 100mg/ml, 120 mg/ml, 140 mg/ml, 160 mg/ml, 180 mg/ml, 200 mg/ml, 220 mg/ml, 250 mg/ml or 300 mg/ml.
  • the surfactant is polysorbitol and/or poloxam; preferably, the polysorbate is Tween-20 or Tween-80.
  • the composition has a pH of 4.5-6.5, preferably 4.8-6.2. hi some embodiments, the composition has a pH of 4.5, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2 or 6.5.
  • the buffering agent is histidine-histidine hydrochloride buffer, phosphate buffer and/or aceto-sodium acetate buffer in an amount of from about 10 mM to about 30 mM;
  • the composition has a pH of from about 4.8 to about 6.2;
  • the surfactant is Tween-20 and/or Tween-80 in an amount of from about 0.05mg/ml to about 0.2mg/ml;
  • the antibody is in amount of about 60 mg/ml
  • the stabilizer is sodium chloride in an amount of about 90mM and trehalose in an amount of about 30mg/ml
  • the buffering agent is histidine-histidine hydrochloride buffer in an amount of about 30 mM
  • the composition has a pH of about 4.8
  • the surfactant is Tween-20 in an amount of about 0.05mg/ml
  • the antibody is in amount of about 50 mg/ml
  • the stabilizer is arginine in an amount of about 135mM
  • the buffering agent is histidine-histidine hydrochloride buffer in an amount of about 20 mM
  • the composition has a pH of about 5.7
  • the surfactant is Tween-80 in an amount of about 0. Img/ml
  • the preservative is in an amount of from about 0 mg/ml to about 0.5 mg/ml; the antioxidant is in an amount of from about 0 mg/ml to about 2.5 mg/ml.
  • the anti- TNFR2 antibody comprises: a heavy chain variable domain (VH) comprising: a heavy chain complementarity determining region (HC-CDR)! comprising the amino acid of SEQ ID NO: 1, and an HC-CDR2 comprising the amino acid of SEQ ID NO: 2; and an HC-CDR3 comprising the amino acid of SEQ ID NO: 3; and a ligjit chain variable domain (VL) comprising: a light chain complementarity determining region (LC-CDR)! comprising the amino acid of SEQ ID NO: 4; a LC-CDR2 comprising the amino acid of SEQ ID NO: 5; and a LC-CDR3 comprising the amino acid of SEQ ID NO: 6.
  • VH heavy chain variable domain
  • HC-CDR heavy chain complementarity determining region
  • An antigen- binding fragment also includes a fusion protein comprising the antibody fragment described above.
  • An antigen-binding fragment is capable of binding to the same antigen to which the parent antibody or a parent antibody fragment (e.g., a parent scFv) binds.
  • an antigen-binding fragment may comprise one of more CDRs from a particular human antibody grafted to a framework region from one or more different human antibodies.
  • Mouse B cells were isolated by EasySep Mouse B cell isolation Kit (StemCell, cat# 19854A) and fused with myeloma cells SP2/0-Agl4 cells (ATCC, CRL 1581) using PEG. Following standard protocols, the fused cells were plated into six-well plates in semi- solid ClonalCell-HY Cloning-Medium D (StemCell, cat# 03804). Monoclonal hybridoma clones were picked into 96 well/plate using Clone Pix 2 Machine (Molecular Devices) and cultured in HT medium.
  • Binding affinities (monovalent Kd) of anti-TNFR2 antibodies were determined using Biolayer interferometry on the Octet RED96 instrument (ForteBio) at 30 °C and with 1200 rpm agitation. The following kinetic assay was performed using anti-human IgG Fc capture (AHC) biosensors (ForteBio) in kinetics buffer (PBS, 0.1% Tween-20 and 1% bovine serum albumin): (a) antibody (2 ⁇ g/mL) for 300 sec, (b) baseline for 120 sec, (c) association with His-tag-huTNFR2 (2.5, 0.5 and 0 ⁇ g/mL) for 420 sec and (d) dissociation for 1200 sec.
  • AHC anti-human IgG Fc capture
  • PBS 0.1% Tween-20 and 1% bovine serum albumin
  • Expi293 cells stably expressing huTNFR2 were used to perform FACS analysis.
  • huTNFR2 Uniprot, P20333
  • the coding sequence of huTNFR2 was cloned into a lentiviral vector and the virus was packaged according to the instruction of the virus packaging kit (Lenti-XTM Packaging Single Shots, Cat# 631275, Takada).
  • the Expi293 cells were transduced with the recombinant virus and selected by puromycin.
  • the cell line stably expressing huTNFR2 was incubated with anti-TNFR2 antibodies in PBS with 0.5% BSA, 1 mM EDTA, and 0.1% sodium azide (FACS buffer) for 30 minutes at 4oC.
  • the cells were washed, and then incubated with lOnM phycoerythrin (PE) conjugated anti-Human Fc Ab (Biolegend, cat# 409304) for 20 minutes at 4oC. Cells were washed and then isolated by flow cytometry with Attune (ThermoFisher Scientific).
  • PE lOnM phycoerythrin
  • Expi293 cells stably expressing huTNFR2 were incubated with anti-TNFR2 antibodies for 30 minutes at 4 °C. The cells were washed, and then incubated with 10 nM Alexa Fluor 647 conjugated (ThermoFisher Scientific, cat# A20186) human TNFa (SinoBiological, cat# 10602- HNAE) for 20 minutes at 4 °C . Cells were washed and acquired by flow cytometry with Attune. Data were analyzed with FlowJo software. TNFa binding is represented as MFI.
  • V0 Initial tumor volume (before the first dose).
  • Formulations of SB1901-72, SB1901-74(IgGl Fc mutant), SB190 -76, SB1901-78(IgGl Fc mutant), SB1901-80, SB1901-82(IgGl Fc mutant) 1-11 were prepared accordingto Table 5, wherein, SB1901-72, SB 1901-76, SB1901-80 comprise a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 14 and a lighit chain constant region comprising the amino acid sequence of SEQ ID NO: 16; SB1901-74(IgGl Fc mutant), SB1901-78(IgGl Fc mutant), SB1901-82(IgGl Fc mutant) comprise a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 15 and a light chain constant region comprising the amino acid sequence ofSEQ ID NO: 16.
  • Example 5 Stability study of anti-TNFR2 antibody formulations under various conditions

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

La présente demande concerne une composition d'anticorps anti-TNFR2, la composition comprenant un anticorps anti-TNFR2 isolé en une quantité d'environ 1 mg/ml à environ 300 mg/ml, un stabilisant, un tensioactif et un agent tampon. Les compositions selon la présente demande ont une bonne stabilité dans diverses conditions, par exemple, la congélation-décongélation, des conditions à haute température et à long terme (2 à 8°C et 25°C), qui peuvent assurer que les compositions conservent une bonne stabilité pendant la préparation, le transport et le procédé de stockage, et assurent la sécurité et le contrôle de qualité de médicaments cliniques.
PCT/US2024/010380 2023-01-06 2024-01-05 Anticorps reconnaissant spécifiquement tnfr2 et compositions et utilisations associées WO2024148208A1 (fr)

Applications Claiming Priority (2)

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US202363478907P 2023-01-06 2023-01-06
US63/478,907 2023-01-06

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WO2024148208A1 true WO2024148208A1 (fr) 2024-07-11

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140120086A1 (en) * 2012-10-31 2014-05-01 Takeda Gmbh Method for preparation of a high concentration liquid formulation of an antibody
US20200270355A1 (en) * 2017-11-09 2020-08-27 The General Hospital Corporation Antagonistic anti-tumor necrosis factor receptor superfamily polypeptides

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140120086A1 (en) * 2012-10-31 2014-05-01 Takeda Gmbh Method for preparation of a high concentration liquid formulation of an antibody
US20200270355A1 (en) * 2017-11-09 2020-08-27 The General Hospital Corporation Antagonistic anti-tumor necrosis factor receptor superfamily polypeptides

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