WO2024251787A1 - Anticorps anti-ror1 et procédé d'utilisation - Google Patents

Anticorps anti-ror1 et procédé d'utilisation Download PDF

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WO2024251787A1
WO2024251787A1 PCT/EP2024/065428 EP2024065428W WO2024251787A1 WO 2024251787 A1 WO2024251787 A1 WO 2024251787A1 EP 2024065428 W EP2024065428 W EP 2024065428W WO 2024251787 A1 WO2024251787 A1 WO 2024251787A1
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antibody
target
derivative
binding
cells
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Anna KOSTYN
Petrus Johannes Louis Spee
Niina Veitonmaki
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Pure Biologics SA
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Pure Biologics SA
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Priority to AU2024285667A priority patent/AU2024285667A1/en
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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
    • C07K16/28—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
    • 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
    • A61P35/00—Antineoplastic agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/40—Immunoglobulins specific features characterized by post-translational modification
    • C07K2317/41—Glycosylation, sialylation, or fucosylation
    • 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
    • C07K2317/70—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
    • C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]
    • 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
    • C07K2317/734—Complement-dependent cytotoxicity [CDC]
    • 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

  • ROR1 Background Receptor tyrosine kinase-like orphan receptor 1
  • ROR1 is a member of the ROR family consisting of ROR1 and ROR2.
  • the ROR1 protein contains extracellular immunoglobulin-like (Ig) domain at the amino-terminus, followed by a cysteine-rich domain known as a Frizzled domain (FZD), and then a Kringle domain (KRD).
  • Ig immunoglobulin-like domain
  • FZD Frizzled domain
  • KRD Kringle domain
  • the intracellular part of ROR1 consists of a tyrosine kinase domain, two serine/threonine-rich domains and a proline-rich domain for cell signaling.
  • RORs have been discovered and massively studied in the context of embryogenesis and neurogenesis but lately a growing literature has established ROR1 as a marker for cancer, such as in CLL and in other blood malignancies. More importantly, ROR1 is shown to be critically involved in the progression of a number of blood and solid cancers. For example, ROR1 has been shown to inhibit apoptotic signals, potentiate EGFR signaling, and induce epithelial-mesenchymal transition (EMT). While ROR1 expression is present during normal embryonic and fetal development, the expression is absent in most of the mature tissues.
  • EMT epithelial-mesenchymal transition
  • ROR1 A low level of ROR1 expression is observed in the adipose tissue and to a lesser degree in the pancreas, lung, thyroid, stomach and a subset of intermediate B cells (Baskar et al., 2008; Hudecek et al., 2010; Bicocca et al., 2012 + others).
  • the expression of ROR1 has been seen reported be upregulated in numerous blood and solid malignancies.
  • a strong expression of ROR1 was initially identified in B-Cell chronic lymphocytic leukemia (CLL). Primary CLL cells express high levels of ROR1, but not ROR2 and the expression of ROR1 increases through the progression of CLL.
  • CLL B-Cell chronic lymphocytic leukemia
  • ROR1 is expressed on the surface of CLL cells from nearly all patients with CLL, 94% of them based on the flow cytometry analysis.
  • ROR1 is not only a biomarker for CLL, but it may serve as a potential prognostic indicator (Daneshmanesh et al., 2013).
  • the constitutive phosphorylation of STAT3, a hallmark of CLL, has been shown to bind multiple sites in the ROR1 promoter.
  • the expression of ROR1 could be induced by IL-6 in a STAT3-dependent and dose-dependent manner (Frank et al., 1997; Li et al., 2010).
  • ROR1 expression has been shown in Ovarian cancer, Breast cancer, especially triple negative breast cancer, and lung cancer.
  • Table 2 depicts kinetics parameters of interaction with recombinant extracellular hROR1 analyzed by BLI/SPR.
  • Apparent K D was evaluated from the 1:2 bivalent analyte model: binding EC50 to CHO cells transfected with hROR1 analyzed by flow cytometry, domain-binding analysis by BLI:cross-reactivity analysis to recombinant mouse ROR1, analysed by BLI/SPR and binding to human recombinant ROR-2 analyzed by BLI/SPR and flow cytometry analysis to CHO-ROR2 cells.
  • Figure 1A-1D depicts binding curves for EC50 assessment of tested antibodies for CHO cell lines overexpressing ROR1, ROR2 and control cell line CHO-EV.
  • A PB004.22.0357.aF afucosylated antibody binds only ROR1 overexpressing cell line with EC50 of 0.933 x 10-9 M.
  • B PB004.22.0372.aF afucosylated antibody binds only ROR1 overexpressing cell line with EC50 of 0.617 x 10-9 M
  • C PB004.22.0405.aF afucosylated antibody binds only ROR1 overexpressing cell line with EC50 of 0.557 x 10-9 M.
  • NK cells were isolated from healthy donor peripheral blood mononuclear cells (PBMCs). Samples were incubated 4h with different concentrations of Zilovertamab, R12hIgG1 (humanized variant of rabbit monoclonal R12 described in Yang et al, 2011), the anti CD20 antibody Rituximab, afucosylated isotype control and selected antibodies (PB004.22.0357.aF, PB004.22.0372.aF, PB004.22.0405, PB004.22.0405.aF, PB004.22.0408.aF) with the target cells (Jeko-1, ratio NK:Jeko-1; Effector:Target 10:1).
  • PBMCs peripheral blood mononuclear cells
  • FIG. 1 Representative ADCC induction for PB004.22.0405 and PB004.22.0405.aF
  • B ADCC comparison PB004.22.0405.aF, Rituximab, Zilovertamab and R12hIgG1.
  • C Representative ADCC result for PB004.22.0357.aF
  • D Representative ADCC result for PB004.22.0372.aF
  • E Representative ADCC for PB004.22.0408.aF. Bars represent standard deviation calculated based on two technical replicates.
  • Figure 3 depicts the potent but safe ADCC induction by the tested antibodies. Either a whole cell PBMC or isolated NK cells isolated from healthy donor peripheral blood mononuclear cells (PBMCs) were used as effector cells.
  • PBMCs peripheral blood mononuclear cells
  • FIG. 5 depicts the Anti-tumor efficacy of the tested antibodies against subcutaneous JeKo-1 tumor.
  • Table 4 depicts the anti-tumor efficacy against JeKo-1 tumor.
  • CD34 + humanized NCG-hIL15 mice were inoculated subcutaneously with JeKo-1 tumor cells and were treated with 6 doses of different antibodies at 10 mg/kg twice weekly starting when the tumor volume was in average around 85 mm 3, At termination the tumor volumes were compared to vehicle. The table decapitates the tumor volume inhibition compared to vehicle treated group.
  • Figure 6 depicts anti-tumor efficacy in a leukemia model.
  • ANOVA analysis of variance
  • HuHSC-NCG-IL15 mice were inoculated with subcutaneous JeKo-1 cells and established tumor-bearing mice were treated intravenously biweekly with 6 injections at 10 mg/kg.
  • Safety of the antibodies was assessed by (A) weight measurements (B) GvHD score (measuring weight, posture, fur texture and skin integrity) (C). serum cytokines in plasma 6 h or 24 h after treatment.
  • the graph represents pooled 3 exemplary cytokines measured.
  • the graphs present mean ⁇ SEM for A and B and ⁇ SD for C. No statistical significance was observed in any parameters measured, (Kruskal-Wallis).
  • Figure 8 depict the pharmacokinetic profile of PB004.22.0405 measured by mouse serum in ELISA.
  • an antibody binding ROR1 or a target-binding fragment or derivative thereof retaining target binding capacities, is provided, which comprises the heavy chain/light chain variable domain (HCVD/LCVD) pairs set forth in the following: ⁇ 1 and 2, ⁇ 3 and 4, ⁇ 5 and 6, and/or ⁇ 7 and 8.
  • the antibody having the VH/VL sequences of SEQ ID NOs: 1 and 2 is called PB004.22.0357 herein.
  • the antibody having the VH/VL sequences of SEQ ID NOs: 3 and 4 is called PB004.22.0372 herein.
  • the antibody having the VH/VL sequences of SEQ ID NOs: 5 and 6 is called PBA0405, AF0405, PB0405 or PB004.22.0405 herein.
  • the antibody having the VH/VL sequences of SEQ ID NOs: 7 and 8 is called PB004.22.0408 herein.
  • Afucosylated variants of these antibodies carry the tag “af”.
  • Tyrosine-protein kinase transmembrane receptor ROR1 (UniProt: Q01973), also known as neurotrophic tyrosine kinase, receptor-related 1 (NTRKR1), is an enzyme that in humans is encoded by the ROR1 gene.
  • ROR1 is a member of the receptor tyrosine kinase-like orphan receptor (ROR) family.
  • the protein encoded by this gene is a receptor tyrosine kinase that modulates neurite growth in the central nervous system. It is a type I membrane protein and belongs to the ROR subfamily of cell surface receptors. ROR1 is currently under investigation for its role in the metastasis of cancer cells.
  • ROR1 has recently been shown to be expressed on ovarian cancer stem cell, on which it seems to play a functional role in promoting migration/invasion or spheroid formation in vitro and tumor engraftment in immune-deficient mice.
  • Human ROR1 consists of an immunoglobulin-like domain (IG), two cysteine-rich domain, frizzled (FZD) and kringle domain (KRD).
  • IG immunoglobulin-like domain
  • FZD frizzled
  • KRD kringle domain
  • ROR1 possesses a tyrosine kinase domain (TKD), two serine/threonine-rich domains (Ser/Thr), and a proline-rich domain (PRD).
  • said antibody is a monoclonal antibody.
  • the term “monoclonal antibody (mAb)” shall refer to an antibody composition having a homogenous antibody population, i.e., a homogeneous population consisting of a whole immunoglobulin, or a fragment or derivative thereof retaining target binding capacities. Particularly preferred, such antibody is selected from the group consisting of IgG, IgD, IgE, IgA and/or IgM, or a fragment or derivative thereof retaining target binding capacities.
  • fragment shall refer to fragments of such antibody retaining target binding capacities, e.g.
  • a CDR complementarity determining region
  • a hypervariable region • a variable domain (Fv) • an IgG or IgM heavy chain (consisting of VH, CH1, hinge, CH2 and CH3 regions) • an IgG or IgM light chain (consisting of VL and CL regions), and/or • a Fab and/or F(ab)2.
  • the term “derivative” shall refer to protein constructs being structurally different from, but still having some structural relationship to, the common antibody concept, e.g., scFv, Fab and/or F(ab)2, as well as bi-, tri- or higher specific antibody constructs, and further retaining target binding capacities. All these items are explained below.
  • antibody derivatives known to the skilled person are Diabodies, Camelid Antibodies, Nanobodies, Domain Antibodies, bivalent homodimers with two chains consisting of scFvs, IgAs (two IgG structures joined by a J chain and a secretory component), shark antibodies, antibodies consisting of new world primate framework plus non-new world primate CDR, dimerized constructs comprising CH3+VL+VH, and antibody conjugates (e.g. antibody or fragments or derivatives linked to a toxin, a cytokine, a radioisotope or a label).
  • antibody conjugates e.g. antibody or fragments or derivatives linked to a toxin, a cytokine, a radioisotope or a label.
  • Methods for the production of a hybridoma cell are disclosed in Köhler & Milstein (1975). Methods for the production and/or selection of chimeric or humanised mAbs are known in the art. For example, US6331415 by Genentech describes the production of chimeric antibodies, while US6548640 by Medical Research Council describes CDR grafting techniques and US5859205 by Celltech describes the production of humanised antibodies. Methods for the production and/or selection of fully human mAbs are known in the art.
  • transgenic animal which is immunized with the respective protein or peptide
  • a suitable display technique like yeast display, phage display, B-cell display or ribosome display, where antibodies from a library are screened against human iRhom2 in a stationary phase.
  • In vitro antibody libraries are, among others, disclosed in US6300064 by MorphoSys and US6248516 by MRC/Scripps/Stratagene.
  • Phage Display techniques are for example disclosed in US5223409 by Dyax.
  • Transgenic mammal platforms are for example described in EP1480515A2 by TaconicArtemis.
  • IgG, IgM, scFv, Fab and/or F(ab)2 are antibody formats well known to the skilled person. Related enabling techniques are available from the respective textbooks.
  • Fab relates to an IgG/IgM fragment comprising the antigen binding region, said fragment being composed of one constant and one variable domain from each heavy and light chain of the antibody.
  • F(ab)2 relates to an IgG/IgM fragment consisting of two Fab fragments connected to one another by disulfide bonds.
  • the term “scFv” relates to a single-chain variable fragment being a fusion of the variable regions of the heavy and light chains of immunoglobulins, linked together with a short linker, usually serine (S) or glycine (G).
  • S serine
  • G glycine
  • This chimeric molecule retains the specificity of the original immunoglobulin, despite removal of the constant regions and the introduction of a linker peptide.
  • the antibody or fragment or derivative thereof has an enhanced potential to induce ADCC, relative to a naturally occurring antibody or fragment or derivative.
  • the main strategy to enhance the capacity of an IgG to induce ADCC is to alter the Fc portion of the antibody to increase binding affinity to the activating Fc ⁇ RIIIA via site-directed mutagenesis, changing Fc domain glycosylation, and/or preventing Fc domain fucosylation.
  • Creation of IgG variants with improved binding to activating Fc ⁇ R by mutagenesis has been an effective strategy for increasing ADCC efficiency of IgG antibodies (Shields et al 2000, Tang et al 2007, Zahavi et al 2018, the contents of all of which are incorporated herein by reference for enablement purposes).
  • the antibody or fragment or derivative thereof comprises an afucosylated Fc domain.
  • Afucosylated antibodies are monoclonal antibodies engineered such that the oligosaccharides in the Fc region of the antibody do not have any fucose sugar units.
  • ADCC antibody-dependent cellular cytotoxicity
  • afucosylation can be accomplished by either ⁇ inhibiting addition of fucose to the already existing sugar chain, e.g., by overexpressing th enzyme GnTIII (see e.g. Davies et al 2001), or by knocking out FUT8 Y(Fucosyltransferase 8, Yamane ⁇ Ohnuki et al 2004)) ⁇ removing fucoses that has already been added to the existing sugar chain chemically or enzymatically, ⁇ redirecting fucose synthesis by a heterologous enzyme that depletes the fucose pool inside the cell (GlyMaxx technology by ProBioGen, see also Chung et al, 2012), and/or ⁇ using an expression system that does not add fucose residues into the sugar chains, like e.g.
  • the antibodies according to the invention were produced by expression in FUT8-KO CHO (Chinese hamster ovary) cell line containing a knock-out of the FUT8 gene.
  • the antibodies thus produced lack fucose, and are, as such, afucosylated.
  • the afucosylated antibodies according to the invention were produced in that way. It should be noted, however, that similar effects are to be expected for antibodies according to the present invention afucosylated by other approaches, as e.g. described above.
  • the antibody or target-binding fragment or derivative thereof is in the IgG format, preferably having the heavy chain/light chain variable domain (HCVD/LCVD) pairs of SEQ ID NO: 1 and 2, SEQ ID NO: 3 and 4, SEQ ID NO: 5 and 6 and/or SEQ ID NO: 7 and 8,
  • the antibody or target-binding fragment or derivative thereof evokes increased ADCC relative to Zilovertamab.
  • Zilovertamab is an anti-ROR1 antibody supplied by Oncternal Therapeutics. Similar findings apply to the antibody R12hIgG1 (Yang et al (2021), which is currently used as scFv in CAR-T cells but not as a naked antibody.
  • Table 1 summary of some characteristics of the antibody according to the invention and prior art Feature PBA0405 Zilovertamab R12hIgG1 Binding to ROR1 Yes Yes Yes Binding to Frizzled Yes No No domain of ROR1 Binding to IgG-like No Yes Yes domain of ROR1 ADCC on cancer Strong No/weak No/weak cells ADCP-CDC Strong Moderate N/A in vivo efficacy - Strong Moderate N/A Leukemic cells in spleen and bone marrow
  • the antibody or target-binding fragment or derivative thereof is administered to the same or another subject under comparable conditions to demonstrate increased ADCC.
  • the term “administered to a subject under comparable conditions” shall refer to comparable subject parameters (size, weight, sex, age, disease history) as well as to comparable administration conditions (dosage, timing, intervals).
  • the antibody or target-binding fragment or derivative thereof is tested in vitro relative to Zilovertamab to demonstrate increased ADCC.
  • Suitable cell based ADCC assays are commercially available at commercial laboratory suppliers, Principles of such assays are described in Parekh et al (2012) or Alpert et al (2012), and also elsewhere herein.
  • a target binding molecule that (i) competes for binding to ROR1 with the antibody or target-binding fragment or derivative thereof, according to the above description, (ii) or binds to the same epitope of ROR1 as the antibody or target-binding fragment or derivative thereof, according to the above description.
  • said target binding molecule is an antibody or target-binding fragment or derivative thereof, as defined elsewhere herein.
  • the term "competes for binding” is used in reference to target binding molecule with an activity which binds to the same substrate as does the antibody or target-binding fragment or derivative thereof.
  • the efficiency (e.g., kinetics or thermodynamics) of binding the binding molecule may be the same as or greater than or less than the efficiency substrate binding by the antibody or target-binding fragment or derivative thereof.
  • the equilibrium binding constant (Kj)) for binding to the substrate may be different.
  • K m refers to the Michaelis-Menton constant for an enzyme and is defined as the concentration of the specific substrate at which a given enzyme yields one-half its maximum velocity in an enzyme catalysed reaction.
  • the term "binds to the same epitope" with reference to two or more binding molecules means that the molecules bind to the same segment of amino acid residues, as determined by a given method.
  • Techniques for determining whether an antibody binds to the same epitope as another antibody include, for example, epitope mapping methods, such as, x- ray analyses of crystals of antigen: antibody complexes which provides atomic resolution of the epitope and hydrogen/deuterium exchange mass spectrometry (HDX-MS). Other methods monitor the binding to antigen fragments or mutated variations of the antigen where loss of binding due to a modification of an amino acid residue within the antigen sequence is often considered an indication of an epitope component.
  • computational combinatorial methods for epitope mapping can also be used. These methods rely on the ability of the antibody of interest to affinity isolate specific short peptides from combinatorial phage display peptide libraries.
  • a pharmaceutical composition comprising the antibody or target-binding fragment or derivative thereof or the target binding molecule according to the above description, and optionally one or more pharmaceutically acceptable excipients, is provided.
  • a combination comprising (i) the antibody or target-binding fragment or derivative thereof or the target binding molecule according to the above description, and (ii) one or more further therapeutically active compounds, is provided.
  • such combination comprises at least one of ⁇ a Bcl-2 inhibitor, and/or ⁇ an inhibitor of Bruton’s tyrosine kinase (BTK)
  • Bcl-2 (B-cell lymphoma 2), encoded in humans by the BCL2 gene, is a member of the Bcl-2 family of regulator proteins that regulate cell death (apoptosis), by either inhibiting (anti- apoptotic) or inducing (pro-apoptotic) apoptosis.
  • BCL-2 is localized to the outer membrane of mitochondria, where it plays an important role in promoting cellular survival and inhibiting the actions of pro-apoptotic proteins.
  • BCL-2 is further known to regulate mitochondrial dynamics, and is involved in the regulation of mitochondrial fusion and fission. Damage to the Bcl-2 gene has been identified as a cause of a number of cancers, including melanoma, breast, prostate, chronic lymphocytic leukemia, and lung cancer. It is also a cause of resistance to cancer treatments.
  • Inhibitors of Bcl-2 are inter alia ⁇ Oblimersen (antisense oligonucleotide) (G3139) ⁇ ABT-737 ⁇ Navitoclax (ABT-263) ⁇ Venetoclax (ABT-199) ⁇ Sonrotoclax (BGB-11417) Bruton's tyrosine kinase (abbreviated Btk or BTK), also known as tyrosine-protein kinase BTK, is a tyrosine kinase that is encoded by the BTK gene in humans. BTK plays a crucial role in B cell development.
  • BTK plays a crucial role in B cell development as it is required for transmitting signals from the pre-B cell receptor that forms after successful immunoglobulin heavy chain rearrangement. It also has a role in mast cell activation through the high-affinity IgE receptor. Mutations in the BTK gene are implicated in the primary immunodeficiency disease X-linked agammaglobulinemia (Bruton's agammaglobulinemia); sometimes abbreviated to XLA and selective IgM deficiency. Patients with XLA have normal pre-B cell populations in their bone marrow but these cells fail to mature and enter the circulation. The Btk gene is located on the X chromosome (Xq21.3- q22).
  • Inhibitors of BTK are, inter alia, ⁇ Ibrutinib (Imbruvica) ⁇ Acalabrutinib (Calquence) ⁇ Zanubrutinib (Brukinsa) ⁇ Tirabrutinib (Velexbru) ⁇ Pirtobrutinib (Jaypirca) ⁇ Orelabrutinib ⁇ Evobrutinib ⁇ Tolebrutinib ⁇ Remibrutinib ⁇ Fenebrutinib (RG7845) ⁇ ABBV-105 ⁇ Fenebrutinib (GDC-0853) ⁇ Tirabrutinib (GS-4059) ⁇ Spebrutinib (AVL-292, CC-292) ⁇ HM71224, and/or ⁇ Luxeptinib According to embodiments of such combination, ⁇ the Bc
  • Venetoclax (Cas number 1257044-40-8) is a drug which attaches to a protein called Bcl-2. This protein is present in high amounts in CLL cancer cells, where it helps the cells survive for longer in the body and makes them resistant to cancer medicines. By attaching to Bcl-2 and blocking its actions, venetoclax causes the death of cancer cells and thereby slows down progression of the disease. Venetoclax is used, inter alia, to treat adults with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or acute myeloid leukemia.
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • acute myeloid leukemia acute myeloid leukemia
  • Ibrutinib (Cas number 936563-96-1 is a small molecule drug that inhibits B-cell proliferation and survival by irreversibly binding the protein Bruton's tyrosine kinase (BTK). Blocking BTK inhibits the B-cell receptor pathway, which is often aberrantly active in B cell cancers.
  • Ibrutinib is therefore used to treat such cancers, including mantle cell lymphoma, chronic lymphocytic leukemia, and Waldenström's macroglobulinemia.[6][7] Ibrutinib also binds to C-terminal Src Kinases. These are off-target receptors for the BTK inhibitor. Ibrutinib binds to these receptors and inhibits the kinase from promoting cell differentiation and growth. This leads to many different side effects like left atrial enlargement and atrial fibrillation during the treatment of Chronic Lymphocytic Leukemia.
  • Ibrutinib is indicated for the treatment of mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), Waldenström's macroglobulinemia (WM), marginal zone lymphoma (MZL), and chronic graft versus host disease (cGVHD).
  • MCL mantle cell lymphoma
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • WM Waldenström's macroglobulinemia
  • MZL marginal zone lymphoma
  • cGVHD chronic graft versus host disease
  • the use of the antibody or target-binding fragment or derivative thereof, the target binding molecule, the pharmaceutical composition according, or the combination according to the above description is provided in the treatment of a human or animal subject ⁇ being diagnosed for, ⁇ suffering from or ⁇ being at risk of developing a neoplastic disease, or for the prevention of such condition.
  • This language is deemed to encompass both the swiss type claim language accepted in some countries (in this case, brackets are deemed absent) and EPC2000 language (in this case, brackets and content within the brackets is deemed absent).
  • a method for treating or preventing a neoplastic disease comprises administration, to a human or animal subject, of the antibody or target-binding fragment or derivative thereof, the target binding molecule, the pharmaceutical composition according, or the combination according to the above description, in a therapeutically sufficient dose is provided.
  • CHO-EV empty vector
  • CHO-ROR1 in 90 mL of 0.05 ⁇ M CFSE solution
  • CHO-ROR2 in 90 mL of 0.005 ⁇ M CFSE solution.
  • Cells were incubated for 30 min at RT with agitation and protected from light. Following incubation 10 mL of cell culture medium with 10% FBS was added and cells were incubated for 10 min at RT with agitation.
  • CHO-ROR1, CHO-ROR2 and CHO-EV cell lines were mixed in 1:1:1 ratio (22 mL each). Mixed cells were aliquoted (150 ⁇ L - 0.6 million cells per well) to 96-well plates. For staining with tested antibodies serial dilutions in DPBS + 5% FBS were made to achieve final concentrations of: 50, 10, 1, 0.1, 0.01, 0.001, 0.0001 and 0.00001 ⁇ g/mL.
  • Molecules were injected over the chip surface to a capture level of ⁇ 70 RU.
  • Serial dilutions of antibodies as analytes were prepared in PBS-P + buffer (Cytiva) and injected at the flow rate of 30 ⁇ L/min.
  • Generated data with double reference subtraction (reference cell subtracted and blank subtracted) were analyzed using BIAevaluation software (Cytiva).
  • Epitope binning – BLI Epitope binning was performed using the Octet RED384 instrument (Sartorius).
  • Antibodies (5 ⁇ g/mL in 10 mM acetate buffer pH 6.0) were immobilized on AR2G sensors. The resulting antibody sensors were incubated in 1000 nM ROR1-His (100s) followed by 1000 nM ROR1- His premixed with 500 nM of a competing antibody (100s), and dissociation was measured for 200s. Sensorgrams were evaluated with the Octet Analysis Studio 12.2 software (Sartorius). Results and conclusion Lead compounds bind to distinguished epitopes (Frizzled domain) from Zilovertamab and R12hIgG1 (IgG domain).
  • Jeko-1 was cultured in RPMI 1640 medium with 20% Fetal Bovine Serum, 1% L-Glutamine and 1% Penicillin/Streptomycin.
  • MDA-MB-231 was cultured in Dulbecco’s Modified Eagle Medium (DMEM) (GibcoTM, 11965092) with 10% Fetal Bovine Serum. All cell lines were kept at 37°C, 5% CO2 and cultured up to 20 passages. Isolation of PBMC and enrichment of human NK cells Peripheral blood mononuclear cells (PBMCs) were obtained from healthy donor buffy coat samples derived by leukapheresis, described as HIV-, HCV- and HBV-.
  • PBMCs Peripheral blood mononuclear cells
  • the density centrifugation was performed with SepMateTM-50 PBMC Isolation Tubes (StemcellTM, #85460). Isolation tubes were filled with 15 mL of Lymphoprep (StemcellTM, #07811). Buffy coats were transferred to a sterile PETG media bottle (FisherbrandTM, PBMB125) and diluted with equal volume of DPBS (GibcoTM, 14190144). 17 mL of diluted buffy coat was gently layered on Lymphoprep and the SepMateTM tubes were centrifuged (1200g, 30 min, acc/brake on).
  • PBMCs were cultured overnight in Iscove’s Modified Dulbecco Medium (IMDM) (GibcoTM, 31980030) with 10% Fetal Bovine Serum at 37°C, 5% CO2 or subjected to NK cell isolation.
  • IMDM Modified Dulbecco Medium
  • NK cells were isolated from PBMCs by immunomagnetic negative selection with NK Cell Isolation Kit (Miltenyi Biotec, 130-092-657) according to manufacturer’s protocol.
  • NK cells were cultured overnight in IMDM (GibcoTM, 31980030) with 10% Fetal Bovine Serum at 37°C, 5% CO 2 and used the next day.
  • NK cells which were used as effector cells in ADCC assay, phenotyping and isolation purity characterization by flow cytometry (Cytek Northern Lights (NL-00020)) was performed. Following markers were used: viability (LIVE/DEAD TM Fixable Aqua Dead Cell Stain Kit, Invitrogen TM , L34966), CD3 (APC-H7 Mouse Anti-Human CD3, BD Bioscience, 560176), CD16 (Alexa Fluor® 647 Mouse Anti-Human CD16, BD Biosciences, 557710), CD56 (Brilliant Violet 605 TM anti-human CD56(NCAM), BioLegend®, 362538), CD69 (BV711 Mouse Anti-Human CD69, BD Biosciences, 563836), CD107a (PE Mouse Anti-Human CD107a, BD Pharmingen TM , 555801), NKG2D (BV421 Mouse Anti-Human CD314 (NKG2D), BD Biosciences, 743558
  • ADCC assay Target cells were collected, washed twice with DPBS and labeled with 0.1 ⁇ M of CellTraceTM CFSE Proliferation Kit (InvitrogenTM, C34554) at 37°C for 20 min. After incubation, cells were washed twice with assay medium (IMDM with 10% FBS) and resuspended in assay medium at 0.2 ⁇ 10 6 cells/mL. Target cells (10,000 cells per well) in 50 ⁇ L volume were seeded into conical bottom 96-well plate (Thermo ScientificTM, NuncTM, 249935). Afterwards, serial concentrations of antibodies in 50 ⁇ L of IMDM indicated for each experiment were added.
  • NK background control and target viability control were supplemented with 50 ⁇ L of assay medium.
  • Target cells were incubated with antibodies for 30 min at 37C°, 5% CO2 for pre- coating.
  • NK cells effector cells isolated on the previous day were centrifuged (350g, 5 min) and resuspended in fresh assay medium at 1 ⁇ 10 6 cells/mL. After pre-coating step, NK cells were added to each well in 100 ⁇ L giving 100,000 cells/well.
  • Wells selected for target viability control were supplemented with 100 ⁇ L of assay medium. Then, the plate was centrifuged at 100g for 1 min and incubated at 37C°, 5% CO2 for 4 hours.
  • the final ratio of effector cells to target cells was 10:1. After 4 hours, the plate was centrifuged (350g, 5 min) and supernatants were discarded by vigorous inverting of the plate. Cell pellets were washed with DPBS and centrifuged (350g, 5 min) and resuspended in 100 ⁇ L of Live/DeadTM Fixable Violet Dead Cell Stain Kit solution (1:1000 in DPBS, InvitrogenTM, L34964) followed by incubation at 4°C for 20 min. After that time, 100 ⁇ L of FACS buffer (DPBS with 2% of Fetal Bovine Serum) was added and the plate was centrifuged (350g, 5 min).
  • FACS buffer DPBS with 2% of Fetal Bovine Serum
  • PB004.22.0357.aF 500000 of Jeko-1 cells per well were preincubated 30min with 50nM of selected binders PB004.22.0357.aF, PB004.22.0372.aF, PB004.22.0405.aF, PB004.22.0408.aF, Zilovertamab, R12hIgG1 and Rituximab, washed, added to target cells and co-cultured for 4 hours at 1:1 (PBMC: target cells) ratio in the presence of APC-conjugated anti-CD107a antibody and protein transport inhibitors (BD GolgiStop and BD GolgiPlug).
  • PBMC target cells
  • APC-conjugated anti-CD107a antibody and protein transport inhibitors BD GolgiStop and BD GolgiPlug
  • cells were labelled with aqua viability dye, BV605 anti-CD56, BV421 anti-CD16, APC-H7 anti- CD3 (from BD Biosciences or Biolegend) for 25 minutes at 37°C, fixed with BD Cytofix/CytopermTM Kit for 15min at 4°C, followed by intracellular staining for IFN ⁇ (BB700 anti-IFN ⁇ ) and TNF ⁇ (BV750 anti-TNF ⁇ ) for 60min at RT. Isotype-matched antibodies from the same manufacturer were used to assess background fluorescence. Cells were run through a FACS Cytek® flow cytometer with standard equipment. Data were analyzed using FlowJo v10.
  • ADCP Monocyte-derived macrophages for phagocytosis assay – cell culture and preparation Monocytes were enriched from frozen samples of Peripheral blood mononuclear cells (PBMCs) using the human Pan Monocyte Isolation Kit (Miltenyi Biotech, 130-096-537) according to manufacture instructions. Purification was verified by phenotypic analysis of surface markers: anti-CD14 and anti- CD16.
  • the enriched monocyte from PBMCs were 7 days in culture in IMDM 10% FBS in the presence of 50 ng/ml M-CSF + 50ng/ml IL-4 + 10% human serum.
  • the adherent population of differentiated macrophages were stained with 0,1uM Violet Dye (CellTraceTM Violet Cell Proliferation Kit, for flow cytometry, C34557) and washed 2 times before ADCP experiment.
  • 0,1uM Violet Dye CellTraceTM Violet Cell Proliferation Kit, for flow cytometry, C34557
  • the following surface markers were used: anti-CD163, anti-CD16, anti-CD32, anti-CD64.
  • Target cell culture and preparation Jeko-1 cells were cultured as a suspension in 75 cm2 flasks at 37 °C in 5% CO2 and maintained between 0.5-1.0106 cells/mL by adding fresh complete growth medium every 3 days.
  • Jeko-1 cells were counted and stained with 0,1uM CFSE Dye (CellTraceTM CFSE Cell Proliferation Kit, for flow cytometry, C34554) and washed 2 times before the ADCP experiment.
  • 3-Color flow-cytometric ADCP assay Stained target cells (Jeko-1, stock: 1M/ml, 50ul per well) were preincubated 30min with 50nM concentration of selected binders: Isotype ctrl, PB004.22.0357.aF, PB004.22.0372.aF, PB004.22.0405.aF, PB004.22.0408.aF, Zilovertamab, R12hIgG1 and Rituximab.
  • the fluorescently labeled effector monocyte-derived macrophages differentiated (Violet) from PBMCs were co-cultured with fluorescently labeled Jeko-1 cells (CFSE) and incubated at 2:1 (effector: target ratio) for 4 h at 37°, then stained 15min with viability dye (LIVE/DEAD Fixable Near-IR (780) stain) and analyzed using FACS Attune to measure phagocytosis. Percentage cell phagocytosis was calculated using the formula: number of dual-stain positive target cells (cells engulfed by macrophages; Violet+/CFSE+) divided by the total number of target cells (CFSE+). Data were analyzed using FlowJo v10.
  • huHSC-NCG-hIL15 JeKo-1 model Fifty-six (56) females + surplus huHSC-NCG-hIL15 mice were subcutaneously injected with Jeko-1 cells resuspended in DPBS.
  • the huHSC-NCG-hIL15 model was generated by reconstitution of CD34+ huHSC from 5 independent donors in irradiated female NCG-hIL15 mice.
  • the immune reconstitution level was confirmed by Flow cytometry and humanization of the mice model was identified as hCD45+/live single >25% in the peripheral blood before the inoculation of tumor cells.
  • mice were randomly grouped based on the table above.
  • HuHSC-NCG-hIL15 tumor bearing mice from different donors were evenly distributed into each experimental group, and each group contained mice from all the huHSC donors.
  • the mice were treated biweekly with intravenous injections with vehicle, the compounds, Zilovertamab or Rituximab at 10mg/kg/.
  • Blood was collected from mice 6 hours and 24 hours post dose, processed as serum for cytokine analysis using CBA detection using BD CBA Human Th1/Th2 kit.
  • PB004.22.0405.aF demonstrates safety as the activation was only in the tumor environment, and not systematically, as the activation was not seen in the blood or spleen NK cells.
  • the compounds were as safe as Rituximab and Zilovertamab as no weight loss, no GvDH score or increases in serum cytokines were observed.
  • MEC-ROR1 leukemia model CB-17/Icr-Prkdcscid/scid/Rj immunodeficient female mice were injected intravenously with MEC-1-ROR-1 cells (1X106) and the biweekly intravenous treatments were performed a week after inoculation for 6 injections at 10mg/kg, After four weeks of tumor cell inoculation, the spleens and bone marrows from femur and tibia of both hind legs were isolated from each transplanted mouse.
  • a cell suspension was prepared either from the homogenized spleen with a flat plunger end of a syringe or the flushed cells from BM after passing through a cell strainer (70mM) in a complete RPMI and red blood cells were lyzed and cells were counted.
  • Flow cytometry analysis was performed on splenic and BM derived cells (1X10 6 ) using commercially available anti-human ROR1 (ROR1-PE) and anti-human CD19 (CD19 APC) antibodies, as well as the corresponding isotype controls.
  • Cells were subjected for data acquisition and multiparametric FACS assessment by using a four-laser BD FACSMelody instrument.
  • Table 4 Anti-tumor efficacy against JeKo-1 tumor References ⁇ Parekh BS, Berger E, Sibley S, Cahya S, Xiao L, LaCerte MA, Vaillancourt P, Wooden S, Gately D. Development and validation of an antibody-dependent cell-mediated cytotoxicity-reporter gene assay. MAbs. 2012 May-Jun;4(3):310-8. doi: 10.4161/mabs.19873. Epub 2012 Apr 26. ⁇ Alpert MD, Heyer LN, Williams DE, Harvey JD, Greenough T, Allhorn M, Evans DT.
  • sequences in this table shall be deemed to be the correct ones.
  • the signal peptides may be encompassed in the reproduced sequences. In such case, the sequences shall be deemed disclosed with and without signal peptides.
  • a readily available tool to identify signal peptides in a given protein sequence is SignalP - 6.0 provided by Dansk Technical University under https://services.healthtech.dtu.dk/service.php?SignalP. The same applies for sequences that comprise a His tag, which shall be deemed disclosed with and without His tag.
  • Table 5 Sequences SEQ Name format chain/ AA Sequence NO domai n PB004.

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Abstract

La présente invention concerne des anticorps se liant à ROR1.
PCT/EP2024/065428 2023-06-05 2024-06-05 Anticorps anti-ror1 et procédé d'utilisation Ceased WO2024251787A1 (fr)

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CN202480037509.5A CN121240857A (zh) 2023-06-05 2024-06-05 抗ror1抗体和使用方法
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