WO2024251839A1 - Anticorps anti-garp et procédés d'utilisation - Google Patents

Anticorps anti-garp et procédés d'utilisation Download PDF

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WO2024251839A1
WO2024251839A1 PCT/EP2024/065505 EP2024065505W WO2024251839A1 WO 2024251839 A1 WO2024251839 A1 WO 2024251839A1 EP 2024065505 W EP2024065505 W EP 2024065505W WO 2024251839 A1 WO2024251839 A1 WO 2024251839A1
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binding
antibody
target
fragment
garp
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Sameer DESHMUKH
Monika Litwin
Marek ORLOWSKI
Petrus Johannes Louis Spee
Damian TROJANOWSKI
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Pure Biologics SA
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Pure Biologics SA
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Priority to KR1020257043910A priority Critical patent/KR20260022341A/ko
Priority to CN202480037499.5A priority patent/CN121241070A/zh
Priority to AU2024283789A priority patent/AU2024283789A1/en
Publication of WO2024251839A1 publication Critical patent/WO2024251839A1/fr
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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
    • 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
    • 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
    • C07K16/2851—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 lectin superfamily, e.g. CD23, CD72
    • 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
    • C07K2317/40—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
    • C07K2317/70—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
    • C07K2317/76—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
    • 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
    • C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/90—Fusion polypeptide containing a motif for post-translational modification
    • C07K2319/91—Fusion polypeptide containing a motif for post-translational modification containing a motif for glycosylation
    • C07K2319/912—Fusion polypeptide containing a motif for post-translational modification containing a motif for glycosylation containing a GPI (phosphatidyl-inositol glycane) anchor

Definitions

  • Anti-GARP antibodies and methods of use are provided.
  • the present invention relates to antibodies and fragments or derivatives thereof that bind to GARP and/or GARP/TGFP, and methods of using the same.
  • the tumor microenvironment is comprised of cancer cells, stromal tissue (e.g. blood vessels, fibroblasts, immune cells and signalling molecules) and extracellular matrix.
  • stromal tissue e.g. blood vessels, fibroblasts, immune cells and signalling molecules
  • extracellular matrix e.g. extracellular matrix.
  • the TME is a major determinant for tumor progression, tumor metastasis and response to therapy.
  • An important aspect of the TME that supports tumor progression, tumor metastasis and response to therapy is immunosuppression.
  • TME regulatory T cells
  • Figures 1 A-1G depict binding to GARP and GARP-TGFpi complex, as well as to NKG2D in case of bifunctional fusion proteins (BFPs) comprised of an IgG molecule fused to ULBP2.
  • the table in Fig. 1 A summarizes affinities (KD values) measured in molecular binding studies using surface plasmon resonance (SPR), and binding to cells evaluated by measuring EC50 with flow cytometry. All studied compounds showed affinities in a low nanomolar range for GARP, similar to DS-1055a, but in contrast to ABBV-151 which showed no binding to GARP.
  • Binding to cell-expressed targets showed as EC50 were in a comparable order of magnitude for most compounds (between studied compounds, and in comparison with DS-1055a and ABB V- 151), except for PB003G.23.0104.BFP which showed slightly lower binding affinity. Binding to NKG2D was confirmed for all BFPs (*N/D - not determined due to very low off-rate).
  • Figures 1B-1G show results of cell-based assays using HEK293 expressing GARP, GARP- TGFpbl orNKG2D.
  • FIGs 2A-2C depict comparison of Fc affinities to FcyRIIIA and ADCC potential between native (fucosylated) and afucosylated PB003G.21.0111 IgGl (PB003G.21.0111.aF).
  • the table in Fig. 2A shows affinities of Fc for the ADCC-inducing receptor FcyRIIIA, which is present in humans in 2 variants (176V and 176F).
  • Afucosylation of PB003G.21.0111 resulted in 12- and 10-fold increase of affinity for FcyRIIIA (176V) and FcyRIIIA (176F), respectively.
  • KD values were measured using surface plasmon resonance (SPR).
  • the afucosylated Fc domain of anti-GARP PB003G.21.0111.aF resulted in significant increase of ADCC induction potential of against GARP-expressing Raji cells (2B), and GARP-TGFpi- expressing Raji cells (2C) when compared to PB003G.21.0111 IgGl in its native (fucosylated) form.
  • ADCC assay was performed using NK cells as effector cells; cell lysis was measured using flow cytometry.
  • Figures 3A-3B depict PB003G.21.0091.BFP and PB003G.21.0111.aF potential to block GARP-TGFbl complex formation (3 A), and to inhibit downstream TGFpi signaling (3B).
  • the assay was performed using flow cytometry.
  • FIGS 4A-4H depict the potential of the compounds to induce antibody-dependent cellular cytotoxicity (ADCC) against cancer cells and Tregs.
  • ADCC assays were performed using NK cells isolated from healthy donors.
  • Half-effective concentrations (EC50) calculated for induction of ADCC by the compounds against cancer cells are summarized in the table ( Figure 4A).
  • Figures 4B-4E depict representative results showing dose-dependent NK-mediated killing of Raji-GARP cells (4B), Raji-GARP-TGFpi cells (4C), L428 cells with native expression of GARP-TGFpi complex (4D), and Tregs (4E) induced by PB003G.21.0111.aF, PB003G21.0111.BFP, PB003G21.0091.BFP, PB003G.23.0104.BFP and control DS1055a.
  • ADCC induction EC50 for PB003G.21.0091.BFP against Tregs was estimated at approximately 1 nM. The analysis was performed using flow cytometry.
  • FIGS 5A-5C depict anti-tumor efficacy of PB003G.21.0111.aF in models bearing human tumors in the humanized mice.
  • Mice were treated with PB003G.21.0111.aF (10 mg/kg i.v.) for 3 weeks, leading to statistically significant 39% inhibition of tumor growth in comparison to vehicle control in both models.
  • Raji-GARP-TGFpi tumor model the number of CD8+ cytotoxic T cells (CTLs) was estimated in tumor tissue using flow cytometry. It was observed that in PB003G.21.0111.aF-treated mice the frequency of CTLs was increased (5C).
  • Figures 6A-6B depict safety analysis of PB003G.21.0111.aF treatment in HT-29 tumor model in mice. Safety was assessed by monitoring of mice body weight (5 A), and graft vs. host disease (GvHD) symptoms (5B). There were no statistical differences between mice treated with PB003G.21.0111.aF compared to DS-1055a or vehicle control.
  • Figure 7 depicts analysis of binding to platelets. Platelets are the predominant cell population expressing GARP-TGFpi complex under physiological conditions. Therefore, platelets can potentially bind anti-GARP antibodies. Platelets were defined as alive CD41+CD42b+CD45- cells using flow cytometry. Data represents a fold increase of MdFI normalized to MdFI of isotype control.
  • PB003G compounds showed very low level of binding to platelets, while DS-1055a and ABBV-151 showed significantly higher binding. Bars represent mean with SD calculated based on the data from six independent platelets donors. Statistical analysis was done using two-way analysis of variance (ANOVA; *p ⁇ 0.05; **p ⁇ 0.01; ***p ⁇ 0.001; ****p ⁇ 0.0001).
  • Figure 8 depicts schematic structure of bifunctional fusion protein (BFP) that is an anti-cancer target antibody fused within both Fab' s arms with ULBP2, immunoligand for NKG2D receptor.
  • the anti cancer antibody is an anti GARP antibody.
  • the antibody has increased ADCC e.g. as being afucosylated, preferably in the IgGl format.
  • Figure 9 depicts the comparison of the potential to induce antibody-dependent cellular cytotoxicity (ADCC) against cancer cells (Raji-AVB8) between anti-AVB8 antibody in two formats: IgGl (ADWA) and bifunctional fusion protein with NKG2D binding domain (ADWA BFP).
  • BFP format enhanced the ADCC potential of the AVB8-binding antibody.
  • ADCC assays were performed using IL-15 stimulated NK cells isolated from healthy donors.
  • an antibody capable of binding GARP, or a targetbinding fragment or derivative thereof retaining target binding capacities which comprises the heavy chain/light chain variable domain (HCVD/LCVD) pairs set forth in the following:
  • the antibody having the VH/VL sequences of SEQ ID NOs: 3 and 4 is called PB003G.21.0091, PB003G.21.009 l.BFP, or 091. bfp herein.
  • the antibodies having the VH/VL sequences of SEQ ID NOs: 5 and 6 are called PB003G.21.0111, PB003G21.0111.aF, PB003G21.0111.BFP, or Olll.aF herein.
  • the antibody having the VH/VL sequences of SEQ ID NOs: 7 and 8 is called PB003G.23.0104, PB003G.23.104.BFP herein.
  • Afucosylated variants of these antibodies carry the tag “aF”, while bifunctional variants carry the tag “BFP”.
  • GARP glycoprotein A repetitions predominant.
  • GARP UniProt identifier: Q14392
  • Lrrc32 Lrrc32 gene
  • the antibodies according to the invention target the glycoprotein A repetitions predominant (GARP) or GARP -transforming growth factor beta 1 (TGFpi) complex, which either prevents release of active TGFpi, or directly kills the tumor cells or regulatory T cells expressing the target, potentially leading to antitumor activity.
  • GARP glycoprotein A repetitions predominant
  • TGFpi transforming growth factor beta 1
  • said antibody of fragment or derivative thereof is, or is derived from, a monoclonal antibody.
  • mAb monoclonal antibody
  • mAb monoclonal antibody
  • 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.
  • a homogenous antibody population i.e., a homogeneous population consisting of a whole immunoglobulin, or a fragment or derivative thereof retaining target binding capacities.
  • 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,
  • IgG or IgM heavy chain consisting of VH, CHI, hinge, CH2 and CH3 regions
  • 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 and/or selection of fully human mAbs are known in the art. These can involve the use of a transgenic animal which is immunized with the respective protein or peptide, or the use of 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.
  • 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 Taconic Artemis.
  • 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.
  • 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). 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 FcyRIIIA via site-directed mutagenesis, changing Fc domain glycosylation, and/or preventing Fc domain fucosylation.
  • Creation of IgG variants with improved binding to activating FcyR 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
  • 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.
  • a published anti-GARP antibody is ABBV-151 (Tolcher et al 2022) manufactured by Abb Vie.
  • Another commercially available anti-GARP antibody is DS-1055a (Satoh et al 2021) manufactured by Daiichi Sankyo.
  • the inventors have yet shown herein that the antibodies according to the invention have an improved functional profile relative to DS-1055 and ABBV-151, in particular regarding effector functions (e.g. ADCC) and/or the blocking of GARP-TGFpi complex formation and TGF pi downstream signalling.
  • the respective bifunctional molecules have the same improved functional profile relative to DS-1055 and ABBV-151, in particular regarding effector functions/ ADCC and/or the blocking of GARP-TGFpi complex formation.
  • a bifunctional molecule comprising
  • NKG2D (UniProt identifier: P26718) as used herein relates to an activating receptor (transmembrane protein) belonging to the NKG2 family of C-type lectin-like receptors.
  • NKG2D is encoded by KLRK1 (killer cell lectin like receptor KI) gene which is located in the NK-gene complex (NKC). In humans, it is expressed by NK cells, y5 T cells and CD8+ aP T cells.
  • the activating receptor NKG2D is peculiar in its capability to bind to numerous and highly diversified MHC class I-like self-molecules. These ligands are poorly expressed on normal cells but can be induced on damaged, transformed or infected cells, with the final NKG2D ligand expression resulting from multiple levels of regulation. Although redundant molecular mechanisms can converge in the regulation of all NKG2D ligands, different stimuli can induce specific cellular responses, leading to the expression of one or few ligands. A large body of evidence demonstrates that NK cell activation can be triggered by different NKG2D ligands, often expressed on the same cell, suggesting a functional redundancy of these molecules.
  • NKG2D ligands can differ in their ability to down-modulate NKG2D membrane expression in human NK cells supporting the idea that NKG2D transduces different signals upon binding various ligands.
  • proteolytically shed and exosome-associated soluble NKG2D ligands share with their membrane-bound counterparts the same ability to induce NKG2D-mediated signalling is still a matter of debate (Zingoni et al, 2018).
  • bifunctional molecules which comprise a binding domain that is capable of binding NKG2D provides the option to engage and activate respective immune cells, as to attack cancer cells which are bound by the respective other binder of the bifunctional molecule.
  • bifunctional molecules which comprise a binding domain that is capable of binding NKG2D offer advantages to the well- established bispecific T cell engagers (“biTEs”) which comprise an anti-CD3 binder that engages T cells only, and only those that express CD3.
  • the binding domain that is capable of binding a cancer antigen is an antibody or target-binding fragment or derivative thereof
  • the binding domain that is capable of binding NKG2D is a ligand of NKG2D, optionally ULBP2 or an active fragment thereof.
  • ULBP2 ULI 6 binding protein 2, which is a GPI-anchored cell surface glycoprotein encoded by the ULBP2 gene located on the chromosome 6.
  • ULBP2 is related to MHC class I molecules, but its gene maps outside the MHC locus.
  • the domain structure of ULBP2 differs significantly from those of conventional MHC class I molecules. It does not contain the a3 domain and the transmembrane segment. ULBP2 is thus composed of only the ala2 domain which is linked to the cell membrane by the GPI anchor.
  • Glycosylphosphatidylinositol in short, is a phosphoglyceride that can be attached to the C-terminus of a protein during posttranslational modification.
  • the resulting GPI-anchored proteins play key roles in a wide variety of biological processes.
  • GPI is composed of a phosphatidylinositol group linked through a carbohydrate-containing linker (glucosamine and mannose glycosidically bound to the inositol residue) and via an ethanolamine phosphate (EtNP) bridge to the C-terminal amino acid of a mature protein, he extracellular fragment of ULBP2 devoid of the GPI anchor.
  • a cancer antigen refers to any molecule (e.g., protein, polypeptide, peptide, lipid, carbohydrate, etc.) solely or predominantly expressed or overexpressed on the surface of a tumor cell or cancer cell, or cell in the tumor microenvironment, such that the antigen is associated with the tumor or cancer.
  • the cancer antigen can additionally be expressed by normal, non-tumor, or non-cancerous cells.
  • the expression of the cancer antigen by normal, non-tumor, or non-cancerous cells is not as robust as the expression by tumor or cancer cells.
  • the tumor or cancer cells can overexpress the antigen or express the antigen at a significantly higher level, as compared to the expression of the antigen by normal, non-tumor, or non-cancerous cells.
  • the cancer antigen can additionally be expressed by cells of a different state of development or maturation.
  • the cancer antigen can be additionally expressed by cells of the embryonic or fetal stage, which cells are not normally found in an adult host.
  • the cancer antigen can be additionally expressed by stem cells or precursor cells, which cells are not normally found in an adult host.
  • the binding domain that is capable of binding a cancer antigen binds to at least one target selected from the group shown in the following table: Table 2: Examples of cancer antigens that can be used in the bifunctional molecule as disclosed herein
  • Such bifunctional molecule can also be equipped with an enhanced potential to induce ADCC, relative to a naturally occurring antibody or fragment or derivative, as discussed elsewhere herein.
  • ADCC enhanced potential to induce ADCC
  • the Fc domain of the antibody that binds to a cancer antigen can be modified accordingly.
  • ADCC and immune cell engagement via NKG2D binding complement each other synergistically in their cancer cell-killing effector functions.
  • ULBP2 comprises, or consists of, the amino acid sequence according to SEQ ID NO: 1, and/or
  • the binding domain that is capable of binding a cancer antigen is the anti-GARP antibody or fragment or derivative according to the above description.
  • Such anti-GARP antibody or fragment or derivative according to the above description comprises the heavy chain/light chain variable domain (HCVD/LCVD) pairs set forth in the following:
  • An anti-AVB8 antibody or fragment or derivative according to the above description comprises the heavy chain/light chain variable domain (HCVD/LCVD) pairs according to SEQ ID NO: 9 and 10.
  • ULBP2 comprises, or consists of, the amino acid sequence according to SEQ ID NO: 1.
  • the active fragment of ULBP2 comprises, or consists of, the amino acid sequence according to SEQ ID NO: 2.
  • the binding domain that is capable of binding NKG2D is fused, directly or via flexible linker to the N- terminus of the VH or VL domain of the antibody capable of binding GARP is, or the targetbinding fragment or derivative thereof.
  • Such linker has, for example, following amino acid sequence: (GGGGS)4 (SEQ ID NO: 19)
  • the binding domain that is capable of binding NKG2D is fused to the N- terminus of the VL domain of the antibody capable of binding GARP, or the target-binding fragment or derivative thereof.
  • the binding domain that is capable of binding GARP is in the format of an IgG antibody.
  • the bifunctional molecule comprises a pair of (i) an anti-GARP antibody heavy chain and (ii) an active fragment of ULBP2 fused to the N-terminus of an anti-GARP antibody light chain, which pair is selected from the group consisting of
  • the bifunctional molecule comprises a pair of (i) an anti-AVB8 antibody heavy chain and (ii) an active fragment of ULBP2 fused to the N-terminus of an anti- AVB8 antibody light chain as set firth in SEQ ID NO: 11 and 12.
  • a target binding molecule is provided that
  • said target binding molecule is an antibody or target-binding fragment or derivative thereof, or a bifunctional molecule, 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, or the bifunctional.
  • the efficiency (e.g., kinetics or thermodynamics) of binding the target 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, or the bifunctional molecule.
  • 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 use of the antibody or target-binding fragment or derivative thereof, or the bifunctional molecule, or the target binding molecule according to the above description is provided in the treatment of a human or animal subject
  • a pharmaceutical composition comprising the antibody or target-binding fragment or derivative thereof, or the bifunctional 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 bifunctional molecule, according to the above description, and (ii) one or more therapeutically active compounds, is provided.
  • 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, or the bifunctional molecule, or the target binding molecule, or the pharmaceutical composition, or the combination according to the above description, in a therapeutically sufficient dose is provided.
  • Affinities of antibodies to GARP, GARP-TGFpi, and NKG2D using surface plasmon resonance (SPR) The affinities of antibodies to GARP and GARP-TGFpi were determined using surface plasmon resonance in a BIACORE 8K instrument (Cytiva).
  • Anti human IgG (Fc) antibody was immobilized on a CM5 chip by direct amine coupling according to the supplier’s instruction to capture selected binders in BFP and afucosylated IgGl formats.
  • Human GARP or GARP- TGFpi complex were injected as analytes over the chip surface in serial dilutions. Sensor surfaces were regenerated after each binding cycle with 10 mM glycine-HCl, pH 2.1.
  • affinities of antibodies to NKG2D were determined using surface plasmon resonance in a BIACORE 8K instrument (Cytiva).
  • Anti human IgG (Fc) antibody was immobilized on a CM5 chip by direct amine coupling according to the supplier’s instruction to capture selected binders in BFP format.
  • Serial dilution (50 - 0.78 nM) of human NKG2D/His (Sino Biological) was injected as analyte.
  • Sensor surfaces were regenerated after each binding cycle with 10 mM glycine-HCl, pH 2.1. Generated data was analyzed as described above.
  • HEK239T cells were used transfected with GARP, GARP-TGFpi, NKG2D or empty vector (EV) as a control. Barcoding was performed to analyze two or more cell lines in one sample in flow cytometry. Different cell lines were barcoded with fluorescent labels using CellTraceTM system (Invitrogen). Following barcoding antibodies stainings were performed. For anti-GARP staining human LAP (TGF-beta 1) Alexa Fluor® 647-conjugated antibody (R&D Systems) and human LRRC32/GARP Alexa Fluor® 647-conjugated antibody (R&D Systems) were used (incubated for 30 min on ice).
  • TGF-beta 1 Alexa Fluor® 647-conjugated antibody
  • R&D Systems human LRRC32/GARP Alexa Fluor® 647-conjugated antibody
  • serial dilutions were prepared for final concentrations of 40, 20, 10, 5, 0.5, 0.05, 0.005 and 0.0005 pg/mL. Cells were incubated for 30 min on ice. For secondary antibody staining cells were washed and incubated with Allophycocyanin (APC) AffiniPure Goat Anti-Human IgG, Fey fragment specific (Jackson ImmunoResearch) antibody (0.4 pL per sample) for 30 min on ice.
  • API Allophycocyanin
  • NK cells were isolated from peripheral blood mononuclear cells (PBMCs) obtained from healthy donor buffy coats. PBMC were first isolated by density centrifugation with SepMateTM- 50 PBMC Isolation Tubes (StemcellTM). The layer of PBMCs was transferred to a fresh 50 mL conical tube and incubated with Red Blood Cell Lysis Buffer (Biolegend, 420302) at RT for 10 minutes. Tubes were filled up with DPBS and centrifuged (350g, 5 min). After washing PBMCs were subjected to NK cell isolation by immunomagnetic negative selection with NK Cell Isolation Kit (Miltenyi Biotec, 130-092-657) according to manufacturer’s protocol.
  • PBMCs peripheral blood mononuclear cells
  • NK cells phenotyping cells was performed by flow cytometry (Cytek Northern Lights (NL-00020)). Viability of NK cells were evaluated with LIVE/DEADTM Fixable Aqua Dead Cell Stain Kit (InvitrogenTM, L34966, 1 : 1000).
  • CD3 APC-H7 Mouse Anti-Human CD3, BD Biosciences, 560176
  • CD16 Alexa Fluor® 647 Mouse Anti-Human CD16, BD Biosciences, 557710
  • CD56 Brilliant Violet 605TM anti-human CD56 (NCAM), BioLegend®, 362538
  • CD69 BV711 Mouse AntiHuman CD69, BD Biosciences, 563836
  • CD107a PE Mouse Anti-Human CD107a, BD PharmingenTM, 555801
  • NKG2D BV421 Mouse Anti-Human CD314 (NKG2D), BD Biosciences, 743558
  • NK cells were incubated overnight with an addition of IL15 in culture medium (5 ng/ml).
  • Target cells (Raji-GARP and Raji-GARP-TGFpi, Raji-AVB8, or L428) were stained with CFSE for separation from effector cells on flow cytometry and their viability was assessed with LIVE/DEADTM Fixable Violet Dead Cell Stain Kit.
  • NK cells isolated on the previous day were mixed with target cells in tha ratio of 10: 1 (effector to target).
  • Treg cells were isolated from PBMCs from the same donor as NK cells by immunomagnetic two-step procedure with human CD4+CD25+ Regulatory T Cell Isolation Kit (Miltenyi Biotec, 130-091-301) according to the manufacturer’s protocol. Tregs cells were seeded in a density 200,000 cells/well on a 96-well plate, mixed with DynabeadsTM Human T-Activator CD3/CD28 for T Cell Expansion and Activation (Gibco, 1116 ID) in ratio 1 : 1 and cultured for two days in IMDM (GibcoTM, 31980030). Isolation purity and phenotyping of Tregs was performed by flow cytometry (Cytek Northern Lights (NL-00020)).
  • DynabeadsTM were separated from cells with a magnet (Miltenyi Biotec) and discarded. The cells were labeled with 0.1 pM of CellTraceTM CFSE Proliferation Kit (InvitrogenTM, C34554). Target cells (10,000 cells per well) were seeded into conical bottom 96-well plate, and incubated with serial dilutions of studied antibodies for 30 min at 37°C, 5% CO2 for precoating. NK cells isolated on the previous day were added to final ratio of effector cells to target cells 10: 1. After overnight incubation, LIVE/DEADTM Fixable Violet Dead Cell Stain Kit (1 : 1000 in DPBS, InvitrogenTM, L34964) was used to estimate cell lysis level.
  • Target cells were preincubated for 30 min with tested molecules at 50 nM. Then PBMCs were added to the E:T ratio 1 : 1. BD GolgiStopTM, BD GolgiPlugTM and anti-CD107a antibody were added to culture for 4 h. Analysis was done using flow cytometry as described below.
  • NK cells were analyzed by multi-parametric surface markers and intracellular cytokine staining. After the coincubation of PBMCs with target cells, all cells were washed with and stained with viability marker, anti-CD56 (Clone 5.1H11) anti- CD16 (Clone 3G8) anti-CD3 (Clone SK7) for 25 min at 37°C. Samples were fixed and permeabilized according to manufacturer's directions (Fixation/Permeabilization Kit, BD). After washing, cells were stained with intracellular anti-JFN-y (Clone B27) and anti-TNFa antibodies (Clone MAbl l) for an additional 60 min.
  • Raji-GARP cells were incubated with tested antibodies and controls in serial dilutions (final concentrations 0.2 ng/mL to 50 pg/mL), and latent TGFpi (15 pg/mL) in full RPMI medium. After incubation (37 °C, 5% CO2, 60 min), After washing cells were stained for 30 minutes at room temperature with anti -LAP -AF647 antibody for latent TGFpi detection on cells. Samples were acquired (20.000 events) using Attune NxT Flow Cytometer equipped with CytKick Max autosampler. Data analysis was performed with Attune Cytometric Software ver 4.3.002.1. MdFI vs. log concentrations were plotted. Non-linear curve fitting (inhibition vs log agonist, three parameters) was applied.
  • Jurkat and Jurkat P8-GARP cells P I O 6 cells/well were stimulated with anti-CD3 (OCT3 clone, BioLegend, final concentration 1 pg/mL) and soluble anti-CD28 (BD Biosciences, final concentration 1 pg/mL). Stimulations were done simultaneously to incubation with tested antibodies and controls: PB003G.21.0091.BFP, PB003G.21.0111.aF, DS-1055, ABBV-151, and IgGl isotype control. Cell lysates were collected after 24 h and prepared for Western blot. 4-20% Mini-Protean TGX Gel (BioRad) was used for SDS-PAGE electrophoresis.
  • PB003G.21.011 l.aF The anti-tumor efficacy, safety, and immune-activation by PB003G.21.011 l.aF was evaluated in Raji-GARP-TGFpi tumor-bearing CD34+ hematopoietic stem cell (HSC) humanized NSG- hIL15 mice at Jackson Laboratories (Bar Harbor, USA).
  • Raji-GARP-TGFpi cells (2xl0 6 ) were inoculated subcutaneously into the right flank/shoulder of CD34+ HSC humanized NSG-hILl 5 mice. When the average tumor volume reached around 150-180- mm 3 , the mice were randomized according to HSC donor, and tumor volume.
  • mice were treated with intravenous injections of vehicle, PB003G.21.011 l.aF , or DS-1055 at 10 mg/kg body weight (bw), biweekly for 6 doses.
  • vehicle PB003G.21.011 l.aF
  • DS-1055 body weight
  • the tumor volume and mice weights were measured 2-3 times a week.
  • 2-way ANOVA with Bonferroni’s multiple comparison was used for statistical analysis.
  • HSC hematopoietic stem cell
  • HT29 cells (5xl0 6 ) were inoculated subcutaneously into the right flank/shoulder of CD34+ HSC humanized NCG-hIL15 mice.
  • the mice were randomized according to HSC donor, humanization level, and tumor volume.
  • mice were treated with intravenous injections of vehicle, PB003G.21.0111.aF , or DS-1055 at 10 mg/kg body weight (bw), biweekly for 6 doses.
  • vehicle PB003G.21.0111.aF
  • DS-1055 10 mg/kg body weight (bw)
  • the tumor volume and mice weights were measured 2-3 times a week.
  • Platelets were isolated from the buffy coats obtained from healthy donors by density centrifugation. PBMC were first isolated by density centrifugation with SepMateTM-50 PBMC Isolation Tubes (StemcellTM). The layer of PBMCs was transferred to a fresh 50 mL conical tube and incubated with Red Blood Cell Lysis Buffer (Biolegend, 420302) at RT for 10 minutes. Tubes were filled up with DPBS and centrifuged (350g, 5 min). After washing and resuspension PBMCs were centrifuged (350 g, 5 min), and supernatant was kept as a platelet-rich fraction. Platelet-rich fraction was then centrifuged at 3200 g, 5 min. and resuspended in Tyrode's solution.
  • the signal peptides may be encompassed in the reproduced sequences.
  • 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.php7SignalP.
  • the signal peptide is underlined. The same applies for sequences that comprise a His tag, which shall be deemed disclosed with and without His tag.
  • BFP stands for bifunctional fusion protein
  • af stands for afucosylated

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Abstract

La présente invention concerne un anticorps capable de se lier à GARP, ou un fragment de liaison à une cible ou un dérivé de celui-ci conservant des capacités de liaison cibles.
PCT/EP2024/065505 2023-06-05 2024-06-05 Anticorps anti-garp et procédés d'utilisation Ceased WO2024251839A1 (fr)

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KR1020257043910A KR20260022341A (ko) 2023-06-05 2024-06-05 항 garp 항체 및 이의 사용 방법
CN202480037499.5A CN121241070A (zh) 2023-06-05 2024-06-05 抗garp抗体和使用方法
AU2024283789A AU2024283789A1 (en) 2023-06-05 2024-06-05 Anti-garp antibodies and methods of use

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