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WO2025186043A1 - Formulation pharmaceutique pour anticorps anti-ccr8 - Google Patents

Formulation pharmaceutique pour anticorps anti-ccr8

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Publication number
WO2025186043A1
WO2025186043A1 PCT/EP2025/054952 EP2025054952W WO2025186043A1 WO 2025186043 A1 WO2025186043 A1 WO 2025186043A1 EP 2025054952 W EP2025054952 W EP 2025054952W WO 2025186043 A1 WO2025186043 A1 WO 2025186043A1
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WO
WIPO (PCT)
Prior art keywords
seq
antibody
heavy chain
light chain
approximately
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2025/054952
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English (en)
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WO2025186043A8 (fr
Inventor
Sheetal DMELLO
Jianjie NIU
Marc KUNZE
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer AG
Bayer Healthcare LLC
Original Assignee
Bayer AG
Bayer Healthcare LLC
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Filing date
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Application filed by Bayer AG, Bayer Healthcare LLC filed Critical Bayer AG
Publication of WO2025186043A1 publication Critical patent/WO2025186043A1/fr
Publication of WO2025186043A8 publication Critical patent/WO2025186043A8/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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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
    • C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
    • 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
    • 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

Definitions

  • the present invention relates to safe pharmaceutical formulations to stabilize a therapeutic anti-CCR8 antibody.
  • the pharmaceutical formulation is provided as a liquid, such as a frozen liquid, or in a lyophilized form and may be in a ready-to-use form or may be further diluted for intravenous infusion or for subcutaneous injection.
  • CCR8 is predominantly expressed by activated intra-tumoral regulatory T cells (Tregs), which are responsible for the immune escape of the tumor. Despite its role as a chemokine receptor, CCR8 is not required for the chemotaxis or immunosuppression of activated Tregs. Therefore, depletion of CCR8 positive tumor infiltrating Tregs rather than blocking the function of CCR8 seems to be the key for effective anti-tumor immunotherapy.
  • the underlying mode of action has first been disclosed by a team around George Plitas and Alexander Rudensky (Plitas, G., et al.
  • the pharmaceutical formulations according to the current invention were found to be safe in cynomolgus monkeys and did not substantially induce or increase the release of cytokines. Furthermore, they stabilize the anti-human CCR8 antibodies at convenient storage conditions, e.g. by preventing/reducing aggregation and degradation and in particular by preventing excessive formation of basic antibody species.
  • TPP-23411 is an afucosylated monoclonal anti-human CCR8 antibody of the IgGl type and was first disclosed in WO2021152186.
  • Antibodies disclosed in WO2021152186 efficiently deplete CCR8 expressing target cells via antibody dependent cellular cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP).
  • ADCC antibody dependent cellular cytotoxicity
  • ADCP antibody dependent cellular phagocytosis
  • TPP- 23411 triggers potent and dose dependent depletion of human primary CCR8+ Tregs or ectopic human CCR8 expressing HEK293 target cells by engaging either human NK92V cells or human primary M2c macrophages as effector cells. Afucosylation significantly enhances the ADCC potency of TPP-23411 while maintaining its ADCP potency.
  • a pharmaceutical formulation is provided for anti-CCR8 antibodies to enable their stable and safe pharmaceutical use in the clinics.
  • Monoclonal antibodies are heterogeneous in their biochemical and biophysical properties due to multiple posttranslational modification and degradation events. Different variants can be observed when mAbs are analyzed by charge based-separation techniques including isoelectric focusing (IEF), capillary isoelectric focusing (clEF), cation exchange chromatography (CEX) and anion exchange chromatography (AEX).
  • IEF isoelectric focusing
  • clEF capillary isoelectric focusing
  • CEX cation exchange chromatography
  • AEX anion exchange chromatography
  • the different variants are generally referred to as acidic or basic species in comparison with the main species. Acidic species are variants with lower apparent pl and basic species are variants with higher apparent pl relative to the main variant, when analyzed using IEF based methods.
  • acidic species and basic species are defined based on their retention times relative to the main peak. Acidic species are the variants that elute earlier than the main peak from CEX or later then than the main peak from AEX, while basic species are the variants that elute later than the main peak from CEX or earlier than the main peak from AEX, see Du, Yi et al. "Chromatographic analysis of the acidic and basic species of recombinant monoclonal antibodies.” mAbs vol. 4,5 (2012): 578-85. doi:10.4161/mabs.21328.
  • Charge variants may substantially affect the in vitro and in vivo properties of antibodies. It has been demonstrated using chemically-modified antibodies that charge variation can alter binding to proteins or cell membrane targets, thus affecting the tissue penetration, tissue distribution and pharmacokinetics (PK) of the antibodies. Depending on the respective antibody it is therefore important to stabilize the "right" variants.
  • WO2024/240224 Al discloses formulations which do not comprise methionine and are not specifically suited for afucosylated anti-human CCR8 antibodies.
  • Anti-CCR8 antibodies that can be formulated using the pharmaceutical formulation of the current invention are disclosed e.g. in WO2020/138489, W02021/142002, WO2021/163064, WO2021/178749, WO2021/194942, WO2021152186, W02022/003156, and W02022/042690.
  • anti-CCR8 antibodies are disclosed in WO2021/178749 Al, WO2020/138489 Al, WO2023/219147 Al, WO2021/194942 Al, WO2023/230473 Al, W02021/142002 Al, WO2021/163064 Al, W02022/042690 Al, WO2022/256563 Al, WO2022/081718 Al, WO2023/288241 Al, W02023/010054 Al, WO2022/078277 Al, WO2023/137466 Al, WO2023/098888 Al, WO2023/174396 Al, WO2023/206938 Al, WO2023/201812 Al, W02023/206350 Al, WO2023/193732 Al, WO2021/178749 Al, WO2022/216965 Al, WO2022/241034 Al, WO2022/136647 Al and WO2022/136650 Al.
  • a pharmaceutical formulation comprising an anti-human CCR8 antibody
  • the pharmaceutical formulation comprises a. 2.5 - 15 mM histidine; b. 50 - 200 ppm polysorbate, preferably 50 - 100 ppm polysorbate, preferably polysorbate 80; c. 5 % - 8 % sucrose; d. 10 - 50 mM arginine; e. 2.5 - 50 mM methionine; and f. 25 mg/mL - 150 mg/mL of the anti-human CCR8 IgG antibody, and wherein the formulation is characterized by a pH of 6.3 ⁇ 0.5.
  • the pharmaceutical formulation is provided as a liquid, such as a frozen liquid, or in a lyophilized from, and may be in a ready-to-use form or may be further diluted for administration, e.g. intravenous infusion or subcutaneous injection.
  • the pharmaceutical formulation is particularly suited for afucosylated antihuman CCR8 antibodies, e.g. of the human IgGl type.
  • • is a liquid or lyophilized formulation • is suited for high anti-CCR8 antibody concentrations, such that an acceptable overall volume can be reached for appropriate medical dosages and administration schemes,
  • the provided pharmaceutical formulation therefore solves the problem to find an advantageous pharmaceutical formulation for anti-CCR8 antibodies.
  • SEQ. ID NO:1 to SEQ ID NO:800 relate to antibodies than can be formulated using the pharmaceutical formulation disclosed herein.
  • the term “approximately” may refer to a range above and/or below of up to 10 %.
  • peptide As used herein, the terms “peptide”, “polypeptide”, and “protein” are used interchangeably, and refer to a compound comprised of amino acid residues covalently linked by peptide bonds.
  • a protein or peptide must contain at least two amino acids, and no limitation is placed on the maximum number of amino acids.
  • Polypeptides include any peptide or protein comprising two or more amino acids joined to each other by peptide bonds.
  • the term refers to both short chains, which also commonly are referred to in the art as peptides, oligopeptides and oligomers, for example, and to longer chains, which generally are referred to in the art as proteins, of which there are many types.
  • Polypeptides include, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, fusion proteins, among others.
  • the polypeptides include natural peptides, recombinant peptides, synthetic peptides, or a combination thereof.
  • nucleic acid, polypeptide, protein or antibody denotes that the nucleic acid, polypeptide, protein or antibody is essentially free of other cellular components with which it is associated in the natural state. It is preferably in a homogeneous state. It can be in either a dry or aqueous solution. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high-performance liquid chromatography. A protein, polypeptide or antibody that is the predominant species present in a preparation is substantially purified. In particular, an isolated gene is separated from open reading frames that flank the gene and encode a protein other than the gene of interest. An isolated polypeptide may however be immobilized, e.g. on beads or particles, e.g. via a suitable linker.
  • nucleic acid or protein gives rise to essentially one band in an electrophoretic gel. Particularly, it means that the nucleic acid or protein is at least 85% pure, more preferably at least 95% pure, and most preferably at least 99% pure.
  • synthetic with reference to, for example, a synthetic nucleic acid molecule or a synthetic gene or a synthetic peptide refers to a nucleic acid molecule or polypeptide molecule that is produced by recombinant methods and/or by chemical synthesis methods.
  • production by recombinant means by using recombinant DNA methods means the use of the well-known methods of molecular biology for expressing proteins encoded by cloned DNA.
  • Post-translational modification(s) refer to the covalent modification(s) of peptides or proteins, which are introduced following protein biosynthesis under natural conditions.
  • the term includes without limitation glycosylation, phosphorylation, acylation, adenylation, farnesylation, ubiquitination, and sulfation.
  • Post-translational modifications may influence the activity of peptides or proteins.
  • Gutierrez et al. have described the sulfation and glycosylation state of the murine CCR8 chemokine receptor, and the way in which these post-translational modifications affect CCR8 activity.
  • Sequence identity or “percent identity” is a number that describes how similar a query sequence is to a target sequence, more precisely how many characters in each sequence are identical after alignment.
  • the most popular tool to calculate sequence identity is BLAST (basic local alignment search tool, https://blast.ncbi.nlm.nih.gov/), which performs comparisons between pairs of sequences, searching for regions of local similarity.
  • BLAST basic local alignment search tool, https://blast.ncbi.nlm.nih.gov/
  • Suitable alignment methods are known in the art, e.g. Needleman-Wunsch algorithm for global-global alignment, using BLOSUM62 matrix, with gap opening penalty of 11 and a gap extension penalty of 1. Afterwards, the pairs of aligned identical residues can be counted and then divided by the total length of the alignment (including gaps, internal as well as external) to arrive at the percent identity value.
  • percent similarity or “sequence similarity” values, the same approach as for percent identity values can be used, except that what is counted, instead of pairs of identical residues, is the aligned residue pairs with BLOSUM62 values that are not negative (i.e., >0).
  • 7-TM receptors are integral membrane proteins that contain seven membrane-spanning helices. As used herein, 7-TM receptors are G protein-coupled receptors.
  • Cyclookine receptors are seven transmembrane receptors.
  • the chemokine receptor family contains 24 members in humans and can be subdivided, based on the class of chemokines they bind, into four subfamilies: CX3CR, CXCR, CCR, and XCR, all of them activating G proteins, and ACKR, containing 6 atypical receptors, unable to activate G proteins upon ligand binding.
  • CXC chemokine receptors are integral membrane proteins that specifically bind and respond to cytokines of the CXC chemokine family. They represent one subfamily of chemokine receptors, a large family of G protein-linked receptors that are known as seven transmembrane (7-TM) proteins, since they span the cell membrane seven times. There are currently seven known CXC chemokine receptors in mammals, named CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, and CXCR6. CXCR6 is more closely related in structure to CC chemokine receptors than to other CXC chemokine receptors.
  • CCR CC chemokine receptors
  • CCR also beta chemokine receptors
  • CC chemokine receptors are integral membrane proteins that specifically bind and respond to cytokines of the CC chemokine family. They represent one subfamily of chemokine receptors, a large family of G protein-linked receptors that are known as seven transmembrane (7-TM) proteins since they span the cell membrane seven times.
  • the subfamily of the CC chemokine receptors comprises CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9 and CCR10.
  • CCR8 refers to the C-C chemokine receptor type 8.
  • the CCR8 protein is encoded by the gene CCR8 (NCBI gene ID 1237).
  • CCR8 is inter alia CC-CKR-8, CCR-8, CDwl98, CKRL1, CMKBR8, CMKBRL2, GPRCY6, CY6, TERI.
  • the CCR8 protein comprises human, murine, rat, rhesus macaque and further mammalian and non-mammalian homologues. Sequence(s) for human CCR8 are accessible via UniProt Identifier P51685 (CCR8_HUI ⁇ /IAN), for instance human isoform P51685-1 or P51685-2 (UniProt, November 29, 2019). Sequence(s) for murine CCR8 are accessible via UniProt Identifier P56484 (CCR8_MOUSE).
  • CCR8_M ACM U UniProt Identifier 097665
  • CCR8_M ACM U UniProt Identifier 097665
  • CCR8 molecules before and after maturation i.e., independent of cleavage of one or more pro-domains.
  • synthetic variants of the CCR8 protein may be generated and are comprised by the term CCR8.
  • the protein CCR8 may furthermore be subject to various modifications, e.g, synthetic or naturally occurring modifications, such as post translational modifications.
  • Recombinant human CCR8 is commercially available or can be manufactured as known in the art.
  • CCR8 is a receptor for the chemokine CCL1/SCYA1/I-309.
  • Barington et al. have reported the importance of conserved extracellular disulfide bridges and aromatic residues in extracellular loop 2 (ECL-2) for ligand binding and activation in the chemokine receptor CCR8 (Barington, Line, et al. "Role of conserved disulfide bridges and aromatic residues in extracellular loop 2 of chemokine receptor CCR8 for chemokine and small molecule binding.” Journal of Biological Chemistry 291.31 (2016): 16208- 16220.).
  • PD-1 Protein Determination-1
  • PD-1 is expressed predominantly on previously activated T cells in vivo and binds to two ligands, PD-L1 and PD-L2.
  • the term "PD-1” as used herein includes without limitation human PD-1 (hPD-1), variants, isoforms, and species homologs of hPD-1, and analogs having at least one common epitope with hPD-1.
  • the complete hPD-1 sequence can be found under GenBank Accession No. U64863 (November 29, 2019).
  • P-L1 Programmed Death Ligand-1
  • PD-L1 is one of two cell surface glycoprotein ligands for PD-1 (the other being PD-L2) that down regulate T cell activation and cytokine secretion upon binding to PD-1.
  • the term "PD-L1” as used herein includes without limitation human PD-L1 (hPDLl), variants, isoforms, and species homologs of hPD-Ll, and analogs having at least one common epitope with hPD-Ll.
  • the complete hPDLl sequence can be found under GenBank Accession No. Q9NZQ7 (November 29, 2019).
  • F0XP3 is a 50-55 kD transcription factor, also known as Forkhead box protein P3, Scurfin, JM2, or IPEX. It is proposed to be a master regulatory gene and more specific marker of T regulatory cells than most cell surface markers. Transduced expression of F0XP3 in CD4+/CD25- cells has been shown to induce GITR, CD103, and CTLA4 and impart a T regulatory cell phenotype. Biolegend antibody clones 206D and 259D recognize a human F0XP3 epitope in the region of amino acids 105-235. Poly6238 recognizes both human and mouse F0XP3 and was raised against the N-terminal portion of F0XP3.
  • modulation refers to any alteration of an existing process or behavior, such as blocking (antagonism) and induction (agonism).
  • modulation of G protein independent signaling refers to any significant alteration of G-protein independent signaling.
  • an antibody, fragment or conjugate refers to the uptake of the antibody, fragment or conjugate into a cell.
  • internalization is determined for a cell line with endogenous target expression, e.g. as described elsewhere herein for human or murine CCR8.
  • internalization is determined by measuring total internalized fluorescence intensity per cell and is quantified relative to an isotype control, e.g. as described in example 10.5.
  • the antibody, fragment or conjugate and a matching isotype control are labeled with a dye and internalized fluorescence is determined and quantified for the antibody, fragment or conjugate relative to the isotype control.
  • a “non-internalizing antibody” is defined as an antibody showing substantially the same internalization as a corresponding isotype control.
  • a “low internalizing antibody” is defined as an antibody showing an internalization which is equal to or lower than the 10-fold of the internalization of the isotype control, preferably lower than the 9-, 8-, 7-, 6-, 5-, 4-, 3-, 2-, 1.5-, 1.4-, 1.3-, 1.2-, or 1.1-fold of the internalization of the isotype control.
  • a “medium internalizing antibody” is defined as an antibody showing an internalization which is equal to or lower than the 21-fold of the internalization of the isotype control and higher than the 10-fold of the internalization of the isotype control.
  • a “high internalizing antibody” is defined as an antibody showing an internalization which is higher than the 21-fold of the internalization of the isotype control.
  • antibodies according to the current invention are characterized by a time until half of the amount of antibody, fragment or conjugate has been internalized which is > 2 hours, preferably > 4, > 5, > 6, > 7, > 8, > 9, > 10, > 11, > 12, > 13, > 14, > 15, > 16, > 17, > 18, > 19, > 20, > 21, > 22, > 23, > 24, > 26, > 28, > 30, or > 48 hours.
  • antibodies according to the current invention are not internalized at all, i.e., no time can be defined until which half of the amount of antibody, fragment or conjugate has been internalized.
  • An "isotype control" is an antibody or fragment that does not bind a target but has the same class and type as the reference antibody or fragment recognizing the target.
  • an antibody or fragment is termed “cross-reactive” or “cross reactive” if the antibody or fragment binds an antigen from two or more different species, e.g. with a KD value of 10-7 M or less, more preferably of less than 10-8 M, even more preferably in the range from 10-9 M to 10-11 M.
  • an antibody which recognizes a specific antigen, but does not substantially recognize or bind other molecules in a sample: An antibody characterized by substantial unspecific binding would lack therapeutic applicability, such that these embodiments are excluded.
  • specific binding of an antibody or binder does not necessarily exclude an antibody or binder binding to further antigens/target molecules.
  • An antibody that specifically binds to an antigen from one species may also bind to that antigen from one or more further species. Such cross-species reactivity does not itself alter the classification of an antibody as specific.
  • the terms “specific binding” or “specifically binding” can be used in reference to the interaction of an antibody, a protein, or a peptide with a second chemical species, to mean that the interaction is dependent upon the presence of a particular structure (e.g., an antigenic determinant or epitope) on the chemical species; for example, an antibody recognizes and binds to a specific protein structure rather than to proteins generally. If an antibody is specific for epitope "A”, the presence of a molecule containing epitope A (or free, unlabeled A), in a reaction containing labeled "A” and the antibody, will reduce the amount of labeled A bound to the antibody.
  • a particular structure e.g., an antigenic determinant or epitope
  • specific binding of an antibody or binder preferably describes binding of an antibody, antibody fragment or binder to its antigen/target with an affinity of at least 10-7 M (as KD value; i.e. preferably those with KD values smaller than 10-7 M), with the antibody or binder having an at least two times lower affinity for a non-specific antigen which is not the predetermined antigen/target molecule or a closely related antigen/target molecule.
  • Polyspecificity also "polyreactivity” or “unspecific binding” refers to the binders' or antibodies' ability to bind a defined set of unrelated antigens. Unspecific binding is substantial, if the (therapeutic) applicability of the antibody is compromised.
  • Polyspecificity for non-protein structures including without limitation target negative cell lines or tissues, baculo virus particle (BVP), insulin or DNA, may be evaluated as known in the art and as described herein.
  • unspecific binding to target negative human cell lines can be determined e.g. by FACS analysis using mock transfected CHO or HEK cells.
  • unspecific binding to different tissues can be analyzed by FACS analysis of a cell line or panel of cell lines derived from the respective tissue.
  • unspecific binding to immune cell populations can be analyzed by FACS after sorting the immune cell populations as known in the art.
  • unspecific binding to BVP, insulin or DNA can be analyzed using ELISA, e.g. as described in Hbtzel, Isidro, et al. "A strategy for risk mitigation of antibodies with fast clearance.”
  • An antibody without substantial unspecific binding is preferably characterized by an unspecific binding that is lower than unspecific binding of reference antibody Gantenerumab (Roche) and most preferably lower than unspecific binding of reference antibody Remicade (Janssen Biotech).
  • off target binding refers to the ability of an antibody to bind individual proteins different from the intended target, for example proteins of the targets' protein family. Off target binding may be evaluated using commercial assays known in the art such as the Retrogenix off target profiling assay. In brief, antibodies are tested on microarrays containing HEK293 cells individually expressing several thousand human membrane proteins and secreted proteins. Binding of the antibody to a potential off target has to be confirmed by FACS using cells overexpressing the potential off target.
  • affinity is a term of the art and describes the strength of binding between a binder, antibody or antibody fragment and a target.
  • the "affinity" of antibodies and fragments thereof for a target can be determined using techniques well known in the art or described herein, for example by ELISA, isothermal titration calorimetry (ITC), surface plasmon resonance (SPR), flow cytometry or fluorescent polarization assays.
  • ITC isothermal titration calorimetry
  • SPR surface plasmon resonance
  • flow cytometry or fluorescent polarization assays.
  • the affinity is provided as dissociation constant KD.
  • the "dissociation constant" has molar units (M) and corresponds to the concentration of the binder/antibody at which half of the target proteins are occupied at equilibrium.
  • M molar units
  • the antibodies preferably have a target affinity of at least 10-7 M (as KD value), more preferably of at least 10-8 M, even more preferably in the range from 10-9 M to 10-11 M.
  • KD values can be preferably determined by means of surface plasmon resonance spectroscopy, e.g. as described elsewhere herein. Where assay conditions were found to influence the determined KD, the assay setup with the least standard deviation shall be used.
  • Half maximal effective concentration refers to the concentration of a drug, antibody, fragment, conjugate or molecule which induces a response halfway between the baseline and maximum after a specified incubation time. In the context of antibody binding, the EC50 thus reflects the antibody concentration needed for half-maximal binding.
  • An EC50 can be determined if an inflection point can be determined by mathematical modeling (e.g., non-linear regression) of the dose-response curve describing the relationship between applied drug, antibody, fragment, conjugate or molecule concentration and signal. For example, if the dose-response curve follows a sigmoidal curve, an EC50 can be determined. Where the response is an inhibition, the EC50 is termed half maximal inhibitory concentration (IC50).
  • EC80 can be determined mutatis mutandis.
  • the "isoelectric point” (pl) is the pH at which a molecule carries no net electrical charge or is electrically neutral.
  • antibody refers to an immunoglobulin molecule (e.g. without limitation human IgGl, lgG2, lgG3, lgG4, IgM, IgD, IgE, IgAl, lgA2, mouse IgGl, lgG2a, lgG2b, lgG2c, lgG3, IgA, IgD, IgE or IgM, rat IgGl, lgG2a, lgG2b, lgG2c, IgA, IgD, IgE or IgM, rabbit IgAl, lgA2, lgA3, IgE, IgG, IgM, goat IgA, IgE, IgGl, lgG2, IgE, IgM or chicken IgY) that specifically binds to, or is immunologically reactive with, a particular antigen.
  • immunoglobulin molecule e.g. without limitation human IgGl
  • Antibodies or antibody fragments comprise complementarity determining regions (CDRs), also known as hypervariable regions, in both the light chain and heavy chain variable domains.
  • CDRs complementarity determining regions
  • FR framework
  • the amino acid position/boundary delineating a hypervariable region of an antibody can vary, depending on the context and the various definitions known in the art.
  • numbering of immunoglobulin amino acid residues is done according to the immunoglobulin amino acid residue numbering system of Kabat et al..
  • the variable domains of native heavy and light chains each comprise four FR regions.
  • antibody as used herein also refers to antibody fragments, except where explicitly stated otherwise. Depending on the respective context, the term antibody may also refer to any proteinaceous binding molecule with immunoglobulin-like function.
  • CDR refers to the complementary determining region of the antibody.
  • complementarity-determining regions are part of the variable chains in antibodies and T cell receptors.
  • a set of CDRs constitutes a paratope.
  • CDRs are crucial to the diversity of antigen specificities.
  • There are three CDRs (CDR1, CDR2 and CDR3), arranged non-consecutively on the amino acid sequence of a variable domain of an antigen receptor. Since the antigen receptors are typically composed of two variable domains (on two different polypeptide chains, heavy and light chain), there are usually six CDRs for each antigen receptor that can collectively come into contact with the antigen.
  • the CDRs of the light chain are LCDR1, LCDR2 and LCDR3.
  • the CDRs of the heavy chain are termed HCDR1, HCDR2 and HCDR3.
  • HCDR3 is the most variable complementary determining region (see, e.g., Chothia, Cyrus, and Arthur M. Lesk. "Canonical structures for the hypervariable regions of immunoglobulins.” Journal of molecular biology 196.4 (1987): 901-917.; Kabat, E. A., et al. "Sequences of proteins of immunological interest. Bethesda, MD: US Department of Health and Human Services.” Public Health Service, National Institutes of Health (1991): 103-511.).
  • the "constant region” refers to the portion of the antibody molecule that confers effector functions.
  • the heavy chain constant region can be selected from any of the five isotypes: alpha (a), delta (6), epsilon (E), gamma (g), or mu (p).
  • Fc domain refers to a C-terminal region of an antibody heavy chain that contains at least a portion of the constant region.
  • the term includes native sequence Fc regions and variant Fc regions.
  • a human IgG heavy chain Fc region may extend from Cys226, or from Pro230, to the carboxyl-terminus of the heavy chain.
  • Antibodies or binding fragments according to the current invention may have been modified to alter at least one constant region-mediated biological effector function.
  • an antibody may be modified to reduce or enhance at least one constant region-mediated biological effector function relative to the unmodified antibody, e.g., reduced or improved binding to the Fc receptor (FcyR).
  • FcyR binding may be reduced, e.g. by mutating the immunoglobulin constant region segment of the antibody at particular regions necessary for FcyR interactions (see, e.g., Canfield, Stephen M., and Sherie L. Morrison.
  • FcyR binding may be enhanced, e.g. by afucosylation. Reducing FcyR binding may also reduce other effector functions which rely on FcyR interactions, such as opsonization, phagocytosis and antigen-dependent cellular cytotoxicity ("ADCC").
  • ADCC antigen-dependent cellular cytotoxicity
  • the antibody according to the current invention comprises mutation H435A or has otherwise been engineered for a reduced half-life.
  • antibodies comprising "YTE" mutations (M252Y/S254T/T256E) and/or equivalent mutations such as “LS” mutations (M428L/N434S) have been shown to significantly extend the half-life by more efficient recycling from endosomes in both pre-clincal species as well as humans (Dall'Acqua, William F., et al. "Increasing the affinity of a human IgGl for the neonatal Fc receptor: biological consequences.” The Journal of Immunology 169.9 (2002): 5171-5180.; Zalevsky, Jonathan, et al. "Enhanced antibody halflife improves in vivo activity.” Nature biotechnology 28.2 (2010): 157-159.).
  • the antibody according to the current invention comprises YTE mutations (M252Y/S254T/T256E) and/or equivalent mutations such as LS (M428L/N434S) or has otherwise been engineered for an improved half-life.
  • Suitable Fc engineering approaches for extension of half-life can be found in Haraya, Kenta, Tatsuhiko Tachibana, and Tomoyuki Igawa. "Improvement of pharmacokinetic properties of therapeutic antibodies by antibody engineering.”
  • Drug metabolism and pharmacokinetics 34.1 (2019): 25-41., and/or Lee, Chang-Han, et al. “An engineered human Fc domain that behaves like a pH-toggle switch for ultra-long circulation persistence.” Nature communications 10.1 (2019): 1-11., both incorporated herein by reference.
  • “Afucosylated” antibodies are antibodies engineered such that the oligosaccharides in the Fc region of the antibody do not have any fucose sugar units. Glycosylation of an antibody can alter its function. For example, if glycosylation at N297 in the CH2 domain of an IgG is completely eliminated, binding to FcyRs is lost. However, modulation of the specific carbohydrate composition at N297 can have the opposite effect and enhance the ADCC activity of the antibody. In brief, the affinity of an antibody for the activating FcyRs depends on the composition of the N297 N-linked oligosaccharide. There are 32 different possible combinations of oligosaccharides that can occur at this site.
  • Naturally occurring human IgG and those produced by hybridomas or other common expression systems are usually composed of N-acetylglucosamine (GIcNAc) and three mannose residues that form a core carbohydrate. This core is attached to two additional GIcNAc groups to form biantennary branches. The addition of galactose at each branch can occur as well as the terminal addition of sialic acid to these galactose molecules. Fucose is often part of the core GIcNAc. This fucose, through steric hindrance, obstructs the interaction of the antibody with the FcyRIIIA.
  • GIcNAc N-acetylglucosamine
  • fucose-less antibodies include growth in rat myeloma YB2/0 cells (ATCC CRL 1662). YB2/0 cells express low levels of FUT8 mRNA, which encodes a-l,6-fucosyltransferase, an enzyme necessary for fucosylation of polypeptides. Afucosylated antibodies are preferred for the current invention.
  • ADCC antibody-dependent cellular cytotoxicity
  • FcyRllla FcyRllla
  • FcyRlllb FcyRlllb
  • FcyRllla is expressed on monocytes, neutrophils, mast cells, macrophages, and natural killer cells as a transmembrane receptor
  • FcyRlllb is only expressed on neutrophils.
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • Different assay systems to determine ADCC induction in human subjects have been described in the literature and are suitable for characterization of the subject matter disclosed herein.
  • Yao- Te Hsieh et al. have studied different ADCC assay systems, namely assays based on (i) natural killer cells from human donors (FcyRIIIA + primary NK), (ii) FcyRIIIA engineered NK-92 cells and (iii) FcyRIIIA/NFAT- RE/luc2 engineered Jurkat T cells (Hsieh, Yao-Te, et al.
  • an antibody or antigen-binding fragment inducing ADCC is an antibody which may elicit a substantial amount of lysis of target cells in the presence of NK effector cells.
  • the ADCC induction results in the lysis of at least 2 %, 5 %, 10 %, 15 %, 20 %, 25 %, 30 %, 35 %, 40 %, 45 %, 50 %, 55 %, 60 %, 65 %, 70 %, 75 %, 80 %, 85 %, 90 %, 95 % or 99 % of the target cells.
  • ADCP antibody-dependent cellular phagocytosis
  • an antibody or antigen-binding fragment inducing ADCP is an antibody which may elicit a substantial amount of phagocytosis of target cells in the presence of macrophages.
  • the ADCP induction results in the phagocytosis of at least 2 %, 5 %, 10 %, 15 %, 20 %, 25 %, 30 %, 35 %, 40 %, 45 %, 50 %, 55 %, 60 %, 65 %, 70 %, 75 %, 80 %, 85 %, 90 %, 95 % or 99 % of the target cells.
  • CDC Complement-dependent cytotoxicity
  • MAC membrane attack complex
  • Complement system is efficiently activated by human IgGl, lgG3 and IgM antibodies, weakly by lgG2 antibodies and is not activated by lgG4 antibodies. It is one mechanism of action by which therapeutic antibodies - also specific embodiments of the antibodies according to the current invention - can achieve an antitumor effect.
  • An antibody or antigen-binding fragment inducing CDC is an antibody which may elicit a substantial amount of formation of a membrane attack complex and lysis of target cells.
  • the CDC induction results in the lysis of at least 2 %, 5 %, 10 %, 15 %, 20 %, 25 %, 30 %, 35 %, 40 %, 45 %, 50 %, 55 %, 60 %, 65 %, 70 %, 75 %, 80 %, 85 %, 90 %, 95 % or 99 % of the target cells.
  • Antibodies comprising an Fc region may or may not comprise a modification promoting the association of the first and the second subunit of the Fc domain.
  • a "modification promoting the association of the first and the second subunit of the Fc domain” is a manipulation of the peptide backbone or the post-translational modifications of an Fc domain subunit that reduces or prevents the association of a polypeptide comprising the Fc domain subunit with an identical polypeptide to form a homodimer.
  • Antibodies comprising an Fc region may or may not comprise a modification promoting the association of the first and the second subunit of the Fc domain.
  • a modification promoting association as used herein particularly includes separate modifications made to each of the two Fc domain subunits desired to associate (i.e. the first and the second subunit of the Fc domain), wherein the modifications are complementary to each other so as to promote association of the two Fc domain subunits.
  • a modification promoting association may alter the structure or charge of one or both of the Fc domain subunits so as to make their association sterically or electrostatically favorable.
  • (hetero)dimerization occurs between a polypeptide comprising the first Fc domain subunit and a polypeptide comprising the second Fc domain subunit, which might be nonidentical, e.g. in the sense that further components fused to each of the subunits (e.g. antigen binding moieties) are not the same.
  • the modification promoting association comprises an amino acid mutation in the Fc domain, specifically an amino acid substitution.
  • the modification promoting association comprises a separate amino acid mutation, specifically an amino acid substitution, in each of the two subunits of the Fc domain.
  • a "fragment" of an antibody as used herein is required to substantially retain the desired affinity of the full-length antibody.
  • suitable fragments of an anti-human CCR8 antibody will retain the ability to bind to the target chemokine receptor, e.g. to bind to human CCR8 receptor.
  • Fragments of an antibody comprise a portion of a full-length antibody, generally the antigen binding or variable region thereof. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments, single-chain antibody molecules, diabodies and domain antibodies, see Holt, Lucy J., et al. "Domain antibodies: proteins for therapy.” Trends in biotechnology 21.11 (2003): 484-490.
  • a “Fab fragment” contains the constant domain of the light chain and the first constant domain (CH2) of the heavy chain.
  • Fab' fragments differ from Fab fragments by the addition of a few residues at the carboxyl terminus of the heavy chain CH2 domain including one or more cysteines from the antibody hinge region.
  • F(ab') fragments are produced by cleavage of the disulfide bond at the hinge cysteines of the F(ab')2 pepsin digestion product. Additional chemical couplings of antibody fragments are known to those of ordinary skill in the art. Fab and F(ab')2 fragments lack the Fc fragment of intact antibody, clear more rapidly from the circulation of animals, and may have less non-specific tissue binding than an intact antibody, see, e.g., Wahl, Richard L., Charles W. Parker, and Gordon W. Philpott. "Improved radioimaging and tumor localization with monoclonal F (ab 1 ) 2.” Journal of nuclear medicine: official publication, Society of Nuclear Medicine 24.4 (1983): 316-325.
  • an “Fv fragment” is the minimum fragment of an antibody that contains a complete target recognition and binding site. This region consists of a dimer of one heavy and one light chain variable domain in a tight, non-covalent association (VH-VL dimer). It is in this configuration that the three CDRs of each variable domain interact to define an antigen binding site on the surface of the VH-VL dimer. Often, the six CDRs confer antigen binding specificity upon the antibody. However, in some instances even a single variable domain (or half of an Fv comprising only three CDRs specific for a target) may have the ability to recognize and bind the antigen, although at a lower affinity than the entire binding site.
  • Single-chain Fv or “scFv” antibody fragments comprise the VH and VL domains of an antibody in a single polypeptide chain.
  • the Fv polypeptide further comprises a polypeptide linker between the VH and VL domains which enables the scFv to form the desired structure for antigen binding.
  • Single domain antibodies are composed of single VH or VL domains which exhibit sufficient affinity to the target.
  • the single domain antibody is a camelized antibody, see, e.g., Riechmann, Lutz, and Serge Muyldermans. "Single domain antibodies: comparison of camel VH and camelised human VH domains.” Journal of immunological methods 231.1-2 (1999): 25-38.
  • Bispecific antibodies are monoclonal antibodies that have binding specificities for at least two different epitopes on the same or different antigens.
  • one of the binding specificities can be directed towards the target chemokine receptor such as CCR8, the other can be for any other antigen, e.g., without limitation for a cell-surface protein, receptor, receptor subunit, tissuespecific antigen, viral ly derived protein, virally encoded envelope protein, bacterial ly derived protein, or bacterial surface protein.
  • Bispecific antibody constructs according to the invention also encompass multispecific antibody constructs comprising multiple binding domains/binding sites, such as trispecific antibody constructs, where the construct comprises three binding domains.
  • “Derivatized antibodies” are typically modified by glycosylation, acetylation, pegylation, phosphorylation, sulfation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, linkage to a cellular ligand or other protein. Any of numerous chemical modifications may be carried out by known techniques, including, but not limited to, specific chemical cleavage, acetylation, formylation, metabolic synthesis of tunicamycin, etc. Additionally, the derivative may contain one or more non-natural amino acids, e.g., using ambrx technology, see, e.g., Wolfson, Wendy.
  • Antibodies according to the current invention may be derivatized, e.g. glycosylated or sulfated.
  • Monoclonal antibodies are substantially homogenous populations of antibodies binding a particular antigen.
  • Monoclonal immunoglobulins may be obtained by methods well known to those skilled in the art (see for example, Kohler, Georges, and Cesar Milstein. "Continuous cultures of fused cells secreting antibody of predefined specificity.” nature 256.5517 (1975): 495-497., and U.S. Patent No. 4,376,110).
  • An immunoglobulin or immunoglobulin fragment with specific binding affinity can be isolated, enriched, or purified from a prokaryotic or eukaryotic organism.
  • the antibodies according to the current invention are preferably monoclonal.
  • Humanized antibodies contain CDR regions derived from a non-human species, such as mouse, that have, for example, been engrafted, along with any necessary framework back-mutations, into human sequence-derived V regions.
  • humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a hypervariable region of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit or non-human primate having the desired specificity, affinity, and capacity. See, for example, U.S. Pat. Nos. 5,225,539; 5,585,089; 5,693,761; 5,693,762; 5,859,205, each herein incorporated by reference.
  • Fully human antibodies may comprise a low number of germline deviations compared with the closest human germline reference determined based on the IMGT database (http://www.imgt.org, November 29, 2019).
  • a fully human antibody according to the current invention may comprise up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14 or 15 germline deviations in the CDRs compared with the closest human germline reference.
  • Fully human antibodies can be developed from human derived B cells by cloning techniques in combination with a cell enrichment or immortalization step.
  • CAT Cambridge Antibody Technologies
  • Dyax have obtained antibody cDNA sequences from peripheral B cells isolated from immunized humans and devised phage display libraries for the identification of human variable region sequences of a particular specificity. Briefly, the antibody variable region sequences are fused either with the Gene III or Gene VIII structure of the M13 bacteriophage. These antibody variable region sequences are expressed either as Fab or single chain Fv (scFv) structures at the tip of the phage carrying the respective sequences.
  • scFv single chain Fv
  • an in vitro maturation process can be introduced, including a combinatorial association of different heavy and light chains, deletion/addition/mutation at the CDR3 of the heavy and light chains (to mimic V-J, and V- D-J recombination), and random mutations (to mimic somatic hypermutation).
  • An example of a "fully human" antibody generated by this method is the anti-tumor necrosis factor a antibody, Humira (adalimumab).
  • Atezolizumab refers to a further PD-L1 blocking antibody likewise indicated for the treatment of patients across a number of cancer indications. Dosage forms and strength are solutions for injection provided in a single-dose vial with 840 mg/14 mL (60 mg/mL) or 1200 mg/20 mL (60 mg/mL). Atezolizumab can be administered by intravenous infusion after dilution, e.g. at a dose of 840 mg every two weeks, 1200 mg every 3 weeks, or 1680 mg every 4 weeks.
  • Avelumab refers to a fully human monoclonal antibody targeting PD-L1. Avelumab was developed by Merck KGaA and is used as a cancer medication, e.g. for the treatment of Merkel cell carcinoma, urothelial carcinoma, and renal cell carcinoma.
  • the term “Durvalumab” (IMFINZI) is a PD-L1 blocking antibody indicated for various cancer types. Dosage forms and strength are solutions for injection provided in a single-dose vial with 500 mg/10 mL or 120 mg/2.4 mL (each 50 mg/mL). Durvalumab can be administered by intravenous infusion after dilution, e.g. at a dose of 10 mg/kg every two weeks or 1500 mg every 3 weeks as part of a combination scheme.
  • Pembrolizumab refers to a potent humanized lgG4 mAb with high specificity of binding to PD-1 receptor, thus inhibiting its interaction with PD-L1 and PD-L2. Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor blocking activity for PD-1. Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as an intravenous (IV) immunotherapy for advanced malignancies. Pembrolizumab is indicated for the treatment of patients across a number of cancer indications.
  • IV intravenous
  • Zimberelimab is a monoclonal antibody that binds PD-1 restoring the antitumor activity of T cells. Zimberelimab is in clinical studies for various cancer indications, e.g. for the treatment of first-line metastatic non-small cell lung cancer, e.g. in combination with domvanalimab, an anti-TIGIT monoclonal antibody, and etrumadenant, a dual A2a/A2b adenosine receptor antagonist. Zimberelimab can be administered by intravenous infusion after dilution, e.g. at a dose of 360 mg every 3 weeks.
  • Treating" a disease in a subject or “treating” a subject having a disease refers to subjecting the subject to a pharmaceutical treatment, e.g., the administration of a drug, such that at least one symptom of the disease is decreased or prevented from worsening.
  • a pharmaceutical treatment e.g., the administration of a drug
  • prevent preventing
  • prevention and the like refer to reducing the probability of developing a disease, disorder, or condition in a subject, who does not have, but is at risk of or susceptible to developing a disease, disorder, or condition.
  • CR Complete Response
  • PR Partial Response
  • PD Progressive Disease
  • ORR Objective Response Rate
  • PFS progression Free Survival
  • OS Overall Survival
  • DOR Duration of Overall Response
  • DpR Depth of Response
  • Clinical endpoints for both ORR and PFS can be determined based on RECIST 1.1 criteria described above.
  • Typical "subjects” according to the current invention include human and non-human subjects.
  • Subjects can be mammals such as mice, rats, cats, dogs, primates and/or humans.
  • pharmaceutical formulation refers to a mixture of active ingredients and inactive compounds that can be administered to a subject or patient.
  • a pharmaceutical formulation can be prepared by mixing an antibody, antibody fragment or conjugate having the desired degree of purity with physiologically acceptable carriers, excipients or stabilizers, e.g. according to Remington's Pharmaceutical Sciences (18th ed.; Mack Pub. Co.: Eaton, Pa., 1990). Acceptable carriers, excipients, or stabilizers for pharmaceutical formulations are nontoxic to recipients at the dosages and concentrations employed.
  • Enteral formulations comprise without limitation tablets, capsules or sustained release formulations.
  • Parenteral formulations comprise without limitation liquids or lyophilized formulations.
  • Topical formulations comprise without limitation creams, ointments, gels, pastes and powders.
  • a “liquid” or “liquid (pharmaceutical) formulation” comprises the active ingredient and usually further compounds to ensure a stable active medication following storage. These further compounds may be without limitation solubilizers, stabilizers, buffers, tonicity modifiers, bulking agents, viscosity enhancers/reducers, surfactants, chelating agents, and adjuvants. If concentrated by evaporation, the liquid formulation may be further diluted before administration. For IV administration, the liquid formulation may be transferred from a vial to an IV bag and may be mixed with other compounds or materials.
  • a "frozen liquid” is a liquid formulation in a solid state of matter, for example where a liquid formulation has been transferred into a solid state of matter by freezing.
  • a "lyophilized formulation” (also: lyophilizate) can be obtained by removing solvent (e.g. water) from a liquid drug or liquid formulation thereby creating a solid powder, or cake.
  • the lyophilized formulation is stable for extended periods of time and allows storage at higher temperatures. Stabilizers can be added to replace the water/solvent and preserve the structure of the antibody or fragment thereof.
  • a lyophilized formulation is usually reconstituted as a liquid. This can be achieved by combining a liquid diluent (with or without further ingredients) with the lyophilized formulation and mixing or otherwise resuspending it.
  • a lyophilizate is "arranged for dilution to further specified concentrations" of the ingredients, if dilution with a solvent results in a liquid characterized by these further specified ingredient concentrations.
  • histidine refers to the essential amino acid "histidine” or salts thereof, such as without limitation histidine basic component and histidine HCI monohydrate. Histidine contains an a- amino group (which may occur in the protonated -NH3+ form), a carboxylic acid group (which may occur in the deprotonated -COO- form), and an imidazole side chain (which may be partially protonated). Histidine may be used as part of a pharmaceutical formulation. "L-histidine” is the L-enantiomer of the amino acid histidine and refers e.g. to L-histidine basic component and L-histidine HCI monohydrate.
  • arginine refers to the amino acid "arginine” or salts thereof, such as arginine HCI. Arginine contains an a-amino group, a carboxylic acid group, and a guanidino group. Arginine may be used as part of a pharmaceutical formulation. "L-arginine” is the L-enantiomer of the amino acid arginine.
  • methionine refers to the essential amino acid “methionine” or salts thereof. Methionine contains an a-amino group, a carboxylic acid group, and a S-methyl thioether side chain. Methionine may be used as part of a pharmaceutical formulation. "L-methionine” is the L-enantiomer of the amino acid methionine.
  • Polysorbate 80 is derived from polyethoxylated sorbitan and oleic acid. It is sold inter alia under the brand name Tween 80.
  • the hydrophilic groups in this compound are polyethers also known as polyoxyethylene groups, which are polymers of ethylene oxide. In the nomenclature of polysorbates, the numeric designation following polysorbate refers to the lipophilic group, in this case, the oleic acid.
  • the full chemical names for polysorbate 80 are: Polyoxyethylene (20) sorbitan monooleate or (x)- sorbitan mono-9-octadecenoate poly(oxy-l,2-ethanediyl).
  • sucrose (also “(2R,3R,4S,5S,6R)-2- ⁇ [(2S,3S,4S,5R)-3,4-Dihydroxy-2,5-bis(hydroxymethyl)oxolan-2- yl]oxy ⁇ -6-(hydroxymethyl)oxane-3,4,5-triol)" or "P-D-Fructofuranosyl a-D-glucopyranoside”) is a disaccharide sugar.
  • sucrose the monomers glucose and fructose are linked via an ether bond between Cl on the glucosyl subunit and C2 on the fructosyl unit.
  • a pharmaceutical solution comprising 6 % sucrose comprises approximately 175 mM sucrose, while a pharmaceutical solution comprising 8 % sucrose comprises approximately 234 mM sucrose.
  • intravenous administration or “intravenous infusion” refers to a method of putting fluids, including pharmaceutical compositions or drugs, into the bloodstream.
  • subcutaneous administration refers to a method of the insertion of medications, pharmaceutical compositions or drugs beneath the skin either by injection or infusion.
  • aqueous dextrose solution refers to a solution of dextrose (glucose) in aqueous solution such as water or normal saline (0.9% w/v of NaCI).
  • the solution may come in a number of strengths including 5% (D5W), 10%, and 50% dextrose.
  • the percentage can for example be a mass-volume percentage, such that a 5% solution contains 50 g/L of glucose/dextrose, which equals 278 mmol/L dextrose.
  • a "host cell” is a cell that is used to receive, maintain, reproduce and amplify a vector.
  • a host cell also can be used to express the polypeptide, e.g. an antibody or fragment thereof encoded by the vector.
  • the nucleic acid contained in the vector is replicated when the host cell divides, thereby amplifying the nucleic acids.
  • Preferred host cells are mammalian cells, such as CHO cells or HEK cells. Further preferred host cells are rat myeloma YB2/0 cell.
  • a "cell with endogenous target expression” is a cell which expresses a target protein at a level which is comparable to the physiological or diseased situation. Typically, cells which have been engineered for overexpression express a target protein at much higher levels.
  • intra-tumoral in the context of cells, structures, proteins, antibodies, or markers refers to their localization within the tumor tissue.
  • Cells which are "positive” or “+” for a certain marker or protein are cells characterized by substantial expression of that marker or protein.
  • Marker or protein expression can be determined and quantified as known in the art, e.g. to define different cell populations. For the characterization of (immune) cell populations, the marker expression can be determined by FACS or using any other technique described herein.
  • T cells are immune cells expressing TCRaP, CD3, and CD8 or CD4.
  • the term includes naive T cells, CD4+ T cells, CD8+ T cells, regulatory T cells, memory T cells, activated T cells, anergic T cells, tolerant T cells, chimeric B cells, and antigen- specific T cells and further T cell populations known in the art.
  • TCR T cell receptor
  • CD8+ T cells are T cells expressing CD3, CD45 and CD8.
  • CD8+ T cells can kill cancer cells, cells that are infected (particularly with viruses), or otherwise damaged cells.
  • CD4+ T cells are immune cells expressing CD3, CD4 and CD45.
  • T helper cells There are several subsets of T helper cells, such as, without limitation, Thl, Th2, and Thl7.
  • CD4+ T cells help suppress or regulate immune responses. They are essential in B cell antibody class switching, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages.
  • Treg cells refers to immune cells expressing CD3, CD4, CD45, and FoxP3, and furthermore expressing high levels of CD25 and low levels of CD127. Identification of Treg cells may be performed as described elsewhere herein. Treg cells typically also express high levels of CTLA-4, GITR, and LAG-3. In the literature, Tregs have furthermore been classified based on memory marker CD45RO. Under physiological conditions, Treg cells maintain immunological tolerance. During an immune response, Treg cells stop T cell-mediated immunity and suppress auto-reactive T cells that have escaped negative selection within the thymus. Treg cells can also suppress other types of immune cells such as NK cells and B cells. Adaptive Treg cells (called Th3 or Tri cells) are thought to be generated during an immune response.
  • Th3 or Tri cells are thought to be generated during an immune response.
  • Treg cells furthermore play an important role in immune escape by suppressing antitumor immunity, thereby providing an environment of immune tolerance.
  • T cells that recognize cancer cells are often present in large numbers in tumors, but their cytotoxic function is suppressed by nearby immune- suppressor cells.
  • Tregs are abundant in many different cancers, are highly enriched in the tumor microenvironment, and are well known for their role in tumor progression.
  • Activated Treg cells express CD4, CD45, FoxP3, CD69 and CCR8, and furthermore have a high expression of CD25, and have a low expression of CD127.
  • CD69 is a T cell activation marker.
  • CCR8 positive regulatory T cells or “CCR8+ regulatory T cells” are Tregs expressing CCR8.
  • CD4conv cells are conventional CD4+, CD25- T cells.
  • B cells are immune cells expressing CD19, and mature B cells express CD20 and CD22. B cells upon activation via CD40 undergo differentiation where somatic hypermutation and enhanced immunoglobulin class switch occur resulting in mature B cells or plasma cells (capable of secreting Abs). B cells are involved in humoral immunity of the adaptive immune system, and are antigen presenting cells.
  • Macrophages are immune cells expressing low CD14, high CD16, CDllb, CD68, CD163, and CD206. Macrophages engulf and digest cellular debris, foreign substances, microbes or cancer cells by phagocytosis. Besides phagocytosis, macrophages play a critical role in innate immunity and also help initiate adaptive immunity by recruiting other immune cells. For example, macrophages are important as antigen presenters to T cells. Macrophages that encourage inflammation are called Ml macrophages, whereas those that decrease inflammation and encourage tissue repair are called M2 macrophages.
  • Ml macrophages are a subset of macrophages expressing ACOD1. Ml macrophages have pro-inflammatory, bactericidal, and phagocytic functions.
  • M2 macrophages are a subset of macrophages expressing MRC1 (CD206). M2 macrophages secrete anti-inflammatory interleukins, play a role in wound healing and are needed for revascularization and reepithelialization. Tumor-associated macrophages are mainly of the M2 phenotype and seem to actively promote tumor growth.
  • DCs are bone marrow derived leukocytes and are the most potent type of antigen- presenting cells. DCs are specialized to capture and process antigens, converting proteins to peptides that are presented on major histocompatibility complex (MHC) molecules recognized by T cells. As defined herein, DCs are characterized by expression of CDlc, CD14, CD16, CD141, CDllc and CD123. Different subpopulations of Dendritic cells exist. In human, DC1 are immunogenic while DC2 cells are tolerogenic. Mature DC express CD83, while plasmacytoid DC express CD123.
  • MHC major histocompatibility complex
  • NK cells also natural killer cells
  • NK cells are immune cells which express CD45, CD16, CD56, NKG2D, but are CD3 negative. NK cells do not require activation to kill cells that are missing "self” markers of MHC class 1.
  • NCR1 also referred to as CD335 or NKp46
  • CD335 or NKp46 is expressed on NK cells and on a subset of NKT cells.
  • NKT Natural killer T cells
  • effector cells are immune cells that actively support immune response after stimulation.
  • effector cells refer to immune cells expressing Fey receptors and are therefore able to mediate ADCC or ADCP.
  • Non-limiting examples of effector cells are monocytes, neutrophils, mast cells, and, preferably, macrophages, and natural killer cells.
  • Dosing schemes are abbreviated as known in the art, e.g. every day (QD), every 2 days (Q2D), or every 3 days (Q3D).
  • clEF Capillary isoelectric focusing
  • cGE capillary gel electrophoresis
  • electrophoresis is a separation technique based on the migration of charged molecules in response to an electric field, toward the electrode of opposite charge.
  • a pH gradient inside the gel is established by ampholyte mixtures. The molecule of interest migrates along the electrical field until it reaches the pH corresponding to its pl, where it has a net charge of zero and stops migrating.
  • clEF can be used for monitoring charge heterogeneity as well as oxidation and deamidation analysis of therapeutic (glyco)proteins or antibodies, and in the context of product characterization or comparability studies.
  • SE-HPLC Size exclusion HPLC
  • SE-HPLC is a chromatographic technique that employs porous particles in the column to separate molecules by virtue of their size in solution. SE-HPLC can be used to separate aggregates, monomers, and fragments in the analysis of monoclonal antibodies.
  • Osmolality is defined as the number of osmoles (Osm) of solute per kilogram of solvent (osmol/kg or Osm/kg). As such, larger numbers indicate a greater concentration of solutes in the plasma. Osmolality is a critical attribute for injectable formulations. It is desirable to have products match physiological osmotic conditions. Furthermore, osmolality provides confirmation of soluble content in solution. Preventing injection of hypo- or hyperosmotic solutions is a key element of parenteral formulation development. The osmolality of monoclonal antibody (mAb) formulations is typically determined using freezing point depression or vapor pressure osmometers.
  • mAb monoclonal antibody
  • a pharmaceutical formulation comprising an anti-human CCR8 antibody or antigen-binding fragment thereof having ADCC activity and/or ADCP activity
  • the pharmaceutical formulation comprises: a. 2.5 - 15 mM histidine; b. 50 - 200 ppm polysorbate, preferably 50 - 100 ppm polysorbate, preferably polysorbate 80; c. 5 % - 8 % sucrose; d. 10 - 50 mM arginine; e. 2.5 - 50 mM methionine; and f. 25 mg/mL - 150 mg/mL of the anti-human CCR8 IgG antibody, and wherein the formulation is characterized by a pH of 6.3 ⁇ 0.5.
  • the pharmaceutical formulation may be provided as a liquid, such as a frozen liquid.
  • the pharmaceutical formulation is a liquid or a frozen liquid.
  • the pharmaceutical formulation may also be provided as a lyophilizate arranged for dilution to the provided concentrations.
  • the pharmaceutical formulation is provided as a liquid.
  • the liquid can be stored in a freezer e.g. at 4°C or below, e.g. for at least 3 or 6 months or at 5 °C or 6 °C for at least 6 months preferably at least 36 months.
  • the pharmaceutical formulation is provided as a frozen liquid.
  • the frozen liquid can be stored in a freezer or in liquid nitrogen, at -20°C, - 30°C or below, for at least 3 months, at least 6 months, at least 12 months, or at least 36 months.
  • the pharmaceutical formulation is provided in lyophilized form for dilution to the specified concentrations.
  • Lyophilization also: freeze-drying
  • the lyophilized formulation can subsequently be regenerated by dissolving it with water or an alternative pharmaceutically acceptable solution.
  • the pharmaceutical formulation may be in a ready-to-use form, e.g. for subcutaneous administration, or may be further diluted for intravenous infusion. It may also be further diluted for subcutaneous administration. In a preferred embodiment the pharmaceutical formulation is provided ready-to-use for immediate administration to a patient.
  • the pharmaceutical formulation is provided for further dilution in a pharmaceutically acceptable solution.
  • a pharmaceutically acceptable solution can be for example an aqueous dextrose solution.
  • the pharmaceutical formulation is a solution for intravenous (i.v.) injection. In some other preferred embodiments the pharmaceutical formulation is a solution for subcutaneous administration.
  • the pharmaceutical formulation needs to be sterile and have a low level of endotoxins / be substantially free of endotoxins. This can be achieved as known in the art, e.g. as described elsewhere herein.
  • the pharmaceutical formulation according to the current invention may be stored at -30°C or lower for extended periods of time.
  • the pharmaceutical formulation according to the current invention may be stored at -30°C for at least 6 months. Experiments to demonstrate the stability over several years are ongoing.
  • the formulation comprises 2.5 - 15 mM histidine, preferably 5 - 15 mM histidine, most preferably 7.5 - 12.5 mM histidine.
  • the amount of histidine as buffer agent, in particular in combination with sucrose may impact osmotic pressure and solution viscosity.
  • the histidine is composed of approximately equal amounts of L- histidine HCI monohydrate and L-histidine basic component for buffering the pharmaceutical formulation.
  • the pharmaceutical formulation comprises approximately 10 mM histidine and the histidine is composed of approximately 4.7 mM L-histidine HCI monohydrate and approximately 5.3 mM L-histidine basic component.
  • the formulation comprises 5 to 12.5 mM L- histidine, preferably approximately 10 mM L-histidine, most preferably wherein the 10 mM L-histidine is composed of approximately 5 mM L-histidine HCI monohydrate and approximately 5 mM L-histidine basic component or approximately 4.7 mM L-histidine HCI monohydrate and approximately 5.3 mM L-histidine basic component.
  • the formulation comprises 10 - 50 mM arginine, preferably 15 - 45 mM arginine, most preferably 20 - 40 mM arginine, such as 25 - 35 mM arginine.
  • the formulation may comprise 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, or 50 mM of arginine.
  • the pharmaceutical formulation comprises approximately 30 mM arginine.
  • the arginine is L-arginine, most preferably wherein the arginine is L- arginine HCI.
  • the formulation comprises 20 to 40 mM arginine, preferably approximately 30 mM arginine, most preferably wherein the arginine is L-arginine HCI.
  • the formulation comprises 2.5 - 50 mM methionine, preferably 5 - 40 mM methionine, most preferably 5 - 30 mM methionine, 5 - 20 mM methionine, 5 - 15 mM methionine or approximately 10 mM methionine.
  • the methionine is L-methionine.
  • the formulation comprises approximately 5 to 50 mM methionine, preferably 10 mM methionine, preferably wherein the methionine is L-methionine.
  • any of the above formulations may also comprise 50 - 200 ppm polysorbate 20 or 80, 50 - 100 ppm polysorbate 20 or 80, 55 - 95 ppm polysorbate 20 or 80, 60 - 90 ppm polysorbate 20 or 80, 65 - 85 ppm polysorbate 20 or 80, 70 - 80 ppm polysorbate 20 or 80, or approximately 75 ppm polysorbate 20 or 80.
  • the above formulation comprises 50 ppm, 52.5 ppm, 55 ppm, 57.5 ppm, 60 ppm, 62.5 ppm, 65 ppm, 67.5 ppm, 70 ppm, 72.5 ppm, 75 ppm, 77.5 ppm, 80 ppm, 82.5 ppm, 85 ppm, 87.5 ppm, 90 ppm, 92.5 ppm, 95 ppm, 97.5 ppm, 100 ppm , 150 ppm, 200 ppm polysorbate 20 or 80.
  • the formulation comprises polysorbate 80, most preferably 75 ppm polysorbate 80.
  • the formulation comprises 100 to 200 ppm polysorbate 80, preferably approximately 150 ppm polysorbate 80.
  • the formulation comprises 70 to 80 ppm polysorbate 80, preferably approximately 75 ppm polysorbate 80.
  • the formulation comprises 5 % - 8 % (w/v) sucrose, preferably 5.5 % - 7.5 % sucrose, 5.5 % - 7 % sucrose, and most preferably approximately 6 % (w/v) sucrose.
  • 6 % sucrose corresponds to 175 mM sucrose and to 8 % sucrose corresponds to 234 mM sucrose. The skilled person can easily calculate the amount in mM for each percentage provided.
  • the pharmaceutical formulation according to the current invention is particularly useful to formulate comparably high amounts of an anti-human CCR8 antibody or antigen-binding fragment thereof having ADCC activity and/or ADCP activity.
  • the anti-human CCR8 IgG antibody or antigen-binding fragment thereof can be formulated in the pharmaceutical formulation according to the current invention.
  • the pharmaceutical formulation comprises 25 mg/mL to 100 mg/mL, 30 mg/mL to 95 mg/m, 35 mg/mL to 90 mg/mL, 40 mg/mL to 85 mg/mL, 45 mg/mL to 80 mg/mL, 45 mg/mL to 75 mg/mL, 45 mg/mL to 70 mg/mL, 45 mg/mL to 65 mg/mL, 45 mg/mL to 60 mg/mL, and most preferably 45 to 55 of the anti-human CCR8 IgG antibody or antigen-binding fragment thereof having ADCC activity and/or ADCP activity.
  • the pharmaceutical formulation comprises 50 mg/mL of the antihuman CCR8 IgG antibody or antigen-binding fragment thereof having ADCC activity and/or ADCP activity. In another utmost preferred embodiment, the pharmaceutical formulation comprises 75 mg/mL of the anti-human CCR8 IgG antibody or antigen-binding fragment thereof having ADCC activity and/or ADCP activity. In a third utmost preferred embodiment, the pharmaceutical formulation comprises 100 mg/mL of the anti-human CCR8 IgG antibody or antigen-binding fragment thereof having ADCC activity and/or ADCP activity.
  • the pharmaceutical formulation comprises an anti-human CCR8 antibody or antigen-binding fragment thereof having ADCC activity and/or ADCP activity, wherein the anti-human CCR8 antibody or antigen-binding fragment thereof is a human IgGl antibody.
  • the pharmaceutical formulation comprises an anti-human CCR8 antibody or antigenbinding fragment thereof having ADCC activity and/or ADCP activity, wherein the anti-human CCR8 antibody or antigen-binding fragment thereof is afucosylated.
  • the pharmaceutical formulation is also suited for an anti-human CCR8 antibody or antigen-binding fragment thereof that is a low-internalizing or a non-internalizing antibody.
  • the anti-human CCR8 antibody or antigen-binding fragment thereof is a non-internalizing antibody.
  • the pharmaceutical formulation is also suited for an anti-human CCR8 antibody or antigen-binding fragment thereof which has an isoelectric point of 7.5 to 9, preferably 8.3.
  • the anti-human CCR8 antibody or antigen-binding fragment thereof comprises a HCDR3 sequence that is at least 90 %, 95 %, 98 % or 100 % identical to SEQ ID NO:8, SEQ ID NO:22, SEQ ID NO:36, SEQ ID NO:50, SEQ ID NO:68, SEQ ID NO:86, SEQ ID NQ:104, SEQ ID NO:122, SEQ ID NQ:140, SEQ ID NO:158, SEQ ID NO:176, SEQ ID NO:194, SEQ ID NO:212, SEQ ID NO:232, SEQ ID NQ:250, SEQ ID NQ:270, SEQ ID NQ:290, SEQ ID NQ:310, SEQ ID NQ:330, SEQ ID NQ:350, SEQ ID NO:368, SEQ ID NO:388, SEQ ID NQ:406, SEQ ID NO:424, SEQ ID NO:442, SEQ ID NQ:460, SEQ ID NO:478, SEQ ID NO:496,
  • the anti-human CCR8 IgG antibody or antigen-binding fragment thereof comprised in the pharmaceutical formulation comprises a HCDR3 sequence that is at least 90 %, 95 %, 98 % or 100 % identical to SEQ ID NO:554.
  • the anti-human CCR8 antibody or antigen-binding fragment thereof may be characterized by six CDR sequences, a. wherein each of the six CDR sequences is at least 90%, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NQ:10, SEQ ID NO:11 or SEQ ID NO:12, b. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NQ:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:25 or SEQ ID NO:25, c.
  • each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:39 or SEQ ID NQ:40, d. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:48, SEQ ID NO:49, SEQ ID NQ:50, SEQ ID NO:52, SEQ ID NO:53 or SEQ ID NO:54, e.
  • each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NQ:70, SEQ ID NO:71 or SEQ ID NO:72, f. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:84, SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:88, SEQ ID NO:89 or SEQ ID NO:90, g.
  • each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:102, SEQ ID NQ:103, SEQ ID NQ:104, SEQ ID NQ:106, SEQ ID NQ:107 or SEQ ID NQ:108, h. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NQ:120, SEQ ID NO:121, SEQ ID NO:122, SEQ ID NO:124, SEQ ID NO:125 or SEQ ID NO:126, i.
  • each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:138, SEQ ID NO:139, SEQ ID NQ:140, SEQ ID NO:142, SEQ ID NO:143 or SEQ ID NO:144, j. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NQ:160, SEQ ID NO:161 or SEQ ID NO:162, k.
  • each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:178, SEQ ID NO:179 or SEQ ID NQ:180, l. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:192, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:196, SEQ ID NO:197 or SEQ ID NO:198, m.
  • each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NQ:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:214, SEQ ID NO:215 or SEQ ID NO:216, n. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NQ:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:234, SEQ ID NO:235 or SEQ ID NO:236, o.
  • each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:248, SEQ ID NO:249, SEQ ID NQ:250, SEQ ID NO:252, SEQ ID NO:253, or SEQ ID NO:254, p. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:268, SEQ ID NO:269, SEQ ID NQ:270, SEQ ID NO:272, SEQ ID NO:273 or SEQ ID NO:274, q.
  • each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:288, SEQ ID NO:289, SEQ ID NQ:290, SEQ ID NO:292, SEQ ID NO:293 or SEQ ID NO:294, r. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:308, SEQ ID NO:309, SEQ ID NO:310, SEQ ID NO:312, SEQ ID NO:313 or SEQ ID NO:314, s.
  • each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:328, SEQ ID NO:329, SEQ ID NQ:330, SEQ ID NO:332, SEQ ID NO:333 or SEQ ID NO:334, t. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:348, SEQ ID NO:349, SEQ ID NQ:350, SEQ ID NO:352, SEQ ID NO:353 or SEQ ID NO:354, u.
  • each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:366, SEQ ID NO:367, SEQ ID NO:368, SEQ ID NQ:370, SEQ ID NO:371 or SEQ ID NO:372, v. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:386, SEQ ID NO:387, SEQ ID NO:388, SEQ ID NQ:390, SEQ ID NO:391 or SEQ ID NO:392, w.
  • each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NQ:404, SEQ ID NQ:405, SEQ ID NQ:406, SEQ ID NQ:408, SEQ ID NQ:409 or SEQ ID NQ:410, x. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:422, SEQ ID NO:423, SEQ ID NO:424, SEQ ID NO:426, SEQ ID NO:427 or SEQ ID NO:428, y.
  • each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NQ:440, SEQ ID NO:441, SEQ ID NO:442, SEQ ID NO:444, SEQ ID NO:445 or SEQ ID NO:446, z. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:458, SEQ ID NO:459, SEQ ID NQ:460, SEQ ID NO:462, SEQ ID NO:463 or SEQ ID NO:464, aa.
  • each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:476, SEQ ID NO:477, SEQ ID NO:478, SEQ ID NQ:480, SEQ ID NO:481 or SEQ ID NO:482, bb. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:494, SEQ ID NO:495, SEQ ID NO:496, SEQ ID NO:498, SEQ ID NO:499 or SEQ ID NQ:500, cc.
  • each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:512, SEQ ID NO:513, SEQ ID NO:514, SEQ ID NO:516, SEQ ID NO:517 or SEQ ID NO:518, dd. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:532, SEQ ID NO:533, SEQ ID NO:534, SEQ ID NO:, 536 SEQ ID NO:537 or SEQ ID NO:538, ee.
  • each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:552, SEQ ID NO:553, SEQ ID NO:554, SEQ ID NO:556, SEQ ID NO:557 or SEQ ID NO:558, ff. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:563, SEQ ID NO:564, SEQ ID NO:565, SEQ ID NO:567, SEQ ID NO:568 or SEQ ID NO:569, gg.
  • each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:584, SEQ ID NO:585, SEQ ID NO:586, SEQ ID NO:588, SEQ ID NO:589 or SEQ ID NQ:590, hh. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NQ:604, SEQ ID NQ:605, SEQ ID NQ:606, SEQ ID NQ:608, SEQ ID NQ:609 or SEQ ID NQ:610, ii. ii.
  • each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:624, SEQ ID NO:625, SEQ ID NO:626, SEQ ID NO:628, SEQ ID NO:629 or SEQ ID NQ:630, jj. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:644, SEQ ID NO:645, SEQ ID NO:646, SEQ ID NO:648, SEQ ID NO:649 or SEQ ID NQ:650, kk.
  • each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:664, SEQ ID NO:665, SEQ ID NO:666, SEQ ID NO:668, SEQ ID NO:669 or SEQ ID NQ:670,
  • each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:684, SEQ ID NO:685, SEQ ID NO:686, SEQ ID NO:688, SEQ ID NO:689 or SEQ ID NQ:690, mm. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NQ:704, SEQ ID NQ:705, SEQ ID NQ:706, SEQ ID NQ:708, SEQ ID NQ:709 or SEQ ID NQ:710, nn.
  • each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:724, SEQ ID NO:725, SEQ ID NO:726, SEQ ID NO:728, SEQ ID NO:729 or SEQ ID NQ:730, oo. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:744, SEQ ID NO:745, SEQ ID NO:746, SEQ ID NO:748, SEQ ID NO:749 or SEQ ID NQ:750, pp.
  • each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:755, SEQ ID NO:756, SEQ ID NO:757, SEQ ID NO:759, SEQ ID NQ:760 or SEQ ID NO:761, qq. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:767, SEQ ID NO:768, SEQ ID NO:769, SEQ ID NO:771, SEQ ID NO:772 or SEQ ID NO:773, rr.
  • each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:779, SEQ ID NQ:780, SEQ ID NO:781, SEQ ID NO:783, SEQ ID NO:784 or SEQ ID NO:785, ss. wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:791, SEQ ID NO:792, SEQ ID NO:793, SEQ ID NO:795, SEQ ID NO:796 or SEQ ID NO:797.
  • the anti-human CCR8 IgG antibody or antigen-binding fragment thereof comprised in the pharmaceutical formulation comprises six CDR sequences wherein each of the six CDR sequences is at least 90 %, 95 % or 100 % identical to an amino acid sequence set forth in one of SEQ ID NO:552, SEQ ID NO:553, SEQ ID NO:554, SEQ ID NO:556, SEQ ID NO:557 or SEQ ID NO:
  • the anti-human CCR8 antibody or antigen-binding fragment thereof is characterized by a. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:13 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:14, b. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO: 27 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:28, c.
  • variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO: 41 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:42, d. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:55 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:56, e. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:73 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:74, f.
  • variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:91 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:92, g. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NQ:109 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NQ:110, h. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:127 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:128, i.
  • variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:145 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:146
  • j. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:163 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:164
  • k. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:181 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:182, l.
  • variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:199 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NQ:200
  • m a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:217 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:218,
  • n a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:237 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:238, o.
  • variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:255 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:256, p. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:275 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:276, q. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:295 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:296, r.
  • variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:315 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:316, s. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:335 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:336, t. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:355 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:356, u.
  • variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:373 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:374, v. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:393 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:394, w. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:411 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:412, x.
  • variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:429 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NQ:430
  • y a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:447 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:448,
  • z a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:465 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:466, aa.
  • variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:483 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:484, bb. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NQ:501 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NQ:502, cc. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:519 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NQ:520, dd.
  • variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:539 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NQ:540, ee. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:559 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NQ:560, ff. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:571 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:572, gg.
  • variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:591 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:592, hh. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:611 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:612, ii. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:631 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:632, jj.
  • variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:651 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:652, kk. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:671 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:672,
  • variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:691 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:692, mm. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:711 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:712, nn. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:731 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:732, oo.
  • variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:751 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:752, pp. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:763 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:764, qq. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:775 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:776, rr.
  • variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:787 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NO:788, or ss.
  • a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:799 and/or a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NQ:800.
  • the anti-human CCR8 IgG antibody or antigen-binding fragment thereof comprised in the pharmaceutical formulation further comprises a. a variable heavy chain sequence at least 98 % or 100 % identical to SEQ ID NO:559 and b. a variable light chain sequence at least 98 % or 100 % identical to SEQ ID NQ:560.
  • the anti-human CCR8 antibody or antigen-binding fragment thereof is characterized by a. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:5 and a light chain at least 98 % or 100 % identical to SEQ ID NO:9, b. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:19 and a light chain at least 98 % or 100 % identical to SEQ ID NO:23, c. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:33 and a light chain at least 98 % or 100 % identical to SEQ ID NO:37, d.
  • a heavy chain at least 98 % or 100 % identical to SEQ ID NO:47 and a light chain at least 98 % or 100 % identical to SEQ ID NO:51 e. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:65 and a light chain at least 98 % or 100 % identical to SEQ ID NO:69, f. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:83 and a light chain at least 98 % or 100 % identical to SEQ ID NO:87, g.
  • a heavy chain at least 98 % or 100 % identical to SEQ ID NQ:101 and a light chain at least 98 % or 100 % identical to SEQ ID NQ:105 h. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:119 and a light chain at least 98 % or 100 % identical to SEQ ID NO:123, i. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:137 and a light chain at least 98 % or 100 % identical to SEQ ID NO:141, j.
  • a heavy chain at least 98 % or 100 % identical to SEQ ID NO:385 and a light chain at least 98 % or 100 % identical to SEQ ID NO:389 w. a heavy chain at least 98 % or 100 % identical to SEQ ID NQ:403 and a light chain at least 98 % or 100 % identical to SEQ ID NQ:407, x. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:421 and a light chain at least 98 % or 100 % identical to SEQ ID NO:425, y.
  • a heavy chain at least 98 % or 100 % identical to SEQ ID NO:493 and a light chain at least 98 % or 100 % identical to SEQ ID NO:497 cc. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:511 and a light chain at least 98 % or 100 % identical to SEQ ID NO:515, dd. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:531 and a light chain at least 98 % or 100 % identical to SEQ ID NO:535, ee.
  • a heavy chain at least 98 % or 100 % identical to SEQ ID NO:551 and a light chain at least 98 % or 100 % identical to SEQ ID NO:555 ff. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:566 and a light chain at least 98 % or 100 % identical to SEQ ID NQ:570, gg. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:583 and a light chain at least 98 % or 100 % identical to SEQ ID NO:587, hh.
  • a heavy chain at least 98 % or 100 % identical to SEQ ID NQ:603 and a light chain at least 98 % or 100 % identical to SEQ ID NQ:607 ii. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:623 and a light chain at least 98 % or 100 % identical to SEQ ID NO:627, jj. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:643 and a light chain at least 98 % or 100 % identical to SEQ ID NO:647, kk. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:663 and a light chain at least 98 % or 100 % identical to SEQ ID NO:667,
  • a heavy chain at least 98 % or 100 % identical to SEQ ID NO:743 and a light chain at least 98 % or 100 % identical to SEQ ID NO:747 pp. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:758 and a light chain at least 98 % or 100 % identical to SEQ ID NO:762, qq. a heavy chain at least 98 % or 100 % identical to SEQ ID NQ:770 and a light chain at least 98 % or 100 % identical to SEQ ID NO:774, rr.
  • a heavy chain at least 98 % or 100 % identical to SEQ ID NO:782 and a light chain at least 98 % or 100 % identical to SEQ ID NO:786, or ss.
  • a heavy chain at least 98 % or 100 % identical to SEQ ID NO:794 and a light chain at least 98 % or 100 % identical to SEQ ID NO:798.
  • the anti-human CCR8 IgG antibody or antigen-binding fragment thereof comprised in the pharmaceutical formulation further comprises a. a heavy chain at least 98 % or 100 % identical to SEQ ID NO:551 and b. a light chain at least 98 % or 100 % identical to SEQ ID NO:555.
  • the anti-CCR8 antibody is characterized by the CDRs of any of the antibodies disclosed in WO2021/178749 Al, WQ2020/138489 Al, WO2023/219147 Al, WO2021/194942 Al, WQ2023/230473 Al, WQ2021/142002 Al,
  • WO2023/174396 Al WQ2023/206938 Al, WQ2023/201812 Al, WQ2023/206350 Al, WO2023/193732 Al, WO2021/178749 Al, WO2022/216965 Al, WO2022/241034 Al, WO2022/136647 Al and WO2022/136650 Al.
  • the anti-CCR8 antibody is an antibody selected from the list of antibodies disclosed in any of WO2021/178749 Al, WO2020/138489 Al, WO2023/219147 Al, WO2021/194942 Al, WO2023/230473 Al, W02021/142002 Al, WO2021/163064 Al, W02022/042690 Al, WO2022/256563 Al, WO2022/081718 Al, WO2023/288241 Al, W02023/010054 Al, WO2022/078277 Al, WO2023/137466 Al, WO2023/098888 Al, WO2023/174396 Al, WO2023/206938 Al, WO2023/201812 Al, W02023/206350 Al, WO2023/193732 Al, WO2021/178749 Al, WO2022/216965 Al, WO2022/241034 Al, WO2022/136647 Al or WO2022/136650 Al.
  • the pharmaceutical formulation further comprises an anti-human PD(L)1 antibody, preferably wherein the anti-PD(L)l antibody is pembrolizumab, nivolumab, atezolizumab, avelumab, or durvalumab.
  • the total amount of antibodies should not exceed 100 mg/mL.
  • a pharmaceutical formulation for an anti-human CCR8 antibody or antigen-binding fragment thereof having ADCC activity and/or ADCP activity wherein the pharmaceutical formulation comprises a. Approximately 10 mM histidine; b. Approximately 50 - 200 ppm polysorbate 80; c. Approximately 6 % (175 mM) - 8 % (234 mM) sucrose; d. Approximately 30 mM arginine; e. Approximately 10 mM methionine; and f. Approximately 25 mg/mL - 100 mg/mL of the anti-human CCR8 IgG antibody, and wherein the formulation is characterized by a pH of 6.3 ⁇ 0.5.
  • a pharmaceutical formulation for an anti-human CCR8 antibody or antigen-binding fragment thereof having ADCC activity and/or ADCP activity wherein the pharmaceutical formulation comprises a. Approximately 10 mM histidine; b. Approximately 150 ppm polysorbate 80; c. Approximately 6 % (175 mM) - 8 % (234 mM) sucrose; d. Approximately 30 mM arginine; e. Approximately 10 mM methionine; and f. Approximately 25 mg/mL - 100 mg/mL of the anti-human CCR8 IgG antibody, and wherein the formulation is characterized by a pH of 6.3 ⁇ 0.5.
  • a pharmaceutical formulation for an anti-human CCR8 antibody or antigen-binding fragment thereof having ADCC activity and/or ADCP activity wherein the pharmaceutical formulation comprises a. Approximately 10 mM histidine; b. Approximately 75 ppm polysorbate 80; c. Approximately 6 % (175 mM) - 8 % (234 mM) sucrose; d. Approximately 30 mM arginine; e. Approximately 10 mM methionine; and f. Approximately 25 mg/mL - 100 mg/mL of the anti-human CCR8 IgG antibody, and wherein the formulation is characterized by a pH of 6.3 ⁇ 0.5.
  • the pharmaceutical formulation according to the current invention is characterized by a pH of 6.3 ⁇ 0.5.
  • this pH was found to be advantageous, because it avoided the formation of basic antibody species.
  • the pH of 6.3 +/- 0.5 ensures isotonicity and iso-osmolality of the pharmaceutical formulation.
  • a method for preparing a pharmaceutical formulation for intravenous or subcutaneous administration comprising diluting a pharmaceutical formulation according to the first aspect with aqueous dextrose solution, preferably with sterile 5 % aqueous dextrose solution.
  • the pharmaceutical formulation as described herein for use in a method of treatment.
  • a method of treatment comprising administering the pharmaceutical formulation as described herein to a patient in need of an anti-CCR8 antibody treatment.
  • the pharmaceutical formulation as described herein for the manufacture of a medicament comprising administering the pharmaceutical formulation as described herein to a patient in need of an anti-CCR8 antibody treatment.
  • the method of treatment comprises a. thawing a glass vial comprising the pharmaceutical formulation according to the first aspect, and b. diluting the pharmaceutical formulation according to the first aspect, e.g. with 5 % aqueous dextrose solution to obtain a solution for intravenous or subcutaneous administration, and c. administering intravenously or subcutaneously the solution to a patient in need thereof.
  • the method of treatment comprises a. thawing a glass vial comprising the pharmaceutical formulation according to the first aspect, and b. administering the undiluted pharmaceutical formulation subcutaneously to a patient in need thereof.
  • the method of treatment is a method of treating cancer, preferably wherein the cancer is non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), head and neck squamous cell carcinoma (HNSCC), melanoma, gastric cancer, renal cell carcinoma (RCC), HPV-driven urogenital cancer, hypermutated tumors, gastro-esophageal junction tumors, or a skin cancer other than melanoma.
  • the treatment is a treatment of a tumor or a disease characterized by CCR8 positive cells, such as CCR8 positive tumor cells or CCR8 positive regulatory T cells.
  • the treatment comprises administering the anti-CCR8 antibody, preferentially intravenously or subcutaneously, in a total amount of a. 1 to 250 mg once every week (QW), b. 10 to 750 mg once every two weeks (Q2W), or c. 16 to 1500 mg once every three weeks (Q3W).
  • the treatment comprises administering the anti-CCR8 antibody, preferentially intravenously or subcutaneously, in a total amount of a. Approximately 1, 2.5, 3, 10, 30, 50, 75, 100, 125, 175 or 250 mg once every week, b. Approximately 10, 25, 50, 75, 100, 125, 150, 175, 200, 250, 450, 500, 750 mg once every two weeks, or c. Approximately 16, 30, 50, 75, 100, 125, 150, 175, 200, 450, 500, 750, 1000 or 1500 mg once every three weeks.
  • the total amount of the anti-CCR8 antibody is approximately 75 mg once every three weeks. In a further highly preferred embodiment the total amount of the anti-CCR8 antibody is approximately 100 mg once every three weeks. In one highly preferred embodiment the total amount of the anti-CCR8 antibody is approximately 125 mg once every three weeks. In a further highly preferred embodiment the total amount of the anti-CCR8 antibody is approximately 150 mg once every three weeks. In a further highly preferred embodiment the total amount of the anti-CCR8 antibody is approximately 175 mg once every three weeks. In one preferred embodiment the total amount of the anti-CCR8 antibody is approximately 175 mg once every three weeks In a further highly preferred embodiment the total amount of the anti-CCR8 antibody is approximately 200 mg once every three weeks.
  • the total amount of the anti-CCR8 antibody is approximately 500 mg once every three weeks. In another embodiment the total amount of the anti-CCR8 antibody is approximately 750 mg once every three weeks. In one embodiment the total amount of the anti-CCR8 antibody is approximately 1000 mg once every three weeks. In another embodiment the total amount of the anti-CCR8 antibody is approximately 1500 mg once every three weeks. Data showing the successful mode of action for these dosing schedules (Treg depletion / CD8+ T cell induction) are available.
  • the suggested medical use with a QW dosing schedule is superior because the anti-CCR8 antibody is provided with pharmacologically relevant plasma exposure levels, and also because the medical use allows for plasma Ctrough concentrations of the anti-CCR8 antibody above the estimated EC80 values for CCR8+ cell killing, which the inventors derived from in vitro studies.
  • the medical use with a dosing schedule of Q3W comes with higher doses but is advantageous because these can be administered less frequently while still achieving the required plasma exposures during a dosing interval to produce the desired pharmacological response (CCR8+ Treg killing).
  • the suggested Q3W dosing schedule also provides convenience of dosing and alignment with infusion of other drugs.
  • the total amount in the embodiments described herein is designed for a patient with an average weight of 70 kg and can be scaled based on the actual weight of the patient, i.e. by using the appropriate mg/kg.
  • Administration of the anti-CCR8 infusion can occur intravenously over 15 to 120 minutes, preferably over 30 to 60 minutes, most preferably over 30, 45, 60 or 75 minutes.
  • Administration of the diluted solution can occur through an intravenous line, e.g. containing a sterile, non-pyrogenic, low-protein binding 0.2 micron to 5 micron in-line or add-on filter.
  • intravenous line e.g. containing a sterile, non-pyrogenic, low-protein binding 0.2 micron to 5 micron in-line or add-on filter.
  • the medical use or treatment according to the current aspect may further comprise administering intravenously to a patient in need thereof an anti-PD-(L)l antibody in a total amount of i.
  • an anti-PD-(L)l antibody in a total amount of i.
  • the anti-PD-(L)l antibody is nivolumab, or vi.
  • the medical use or the treatment according to the current aspect comprises administering to the patient an anti-PD-(L)l antibody in a total amount of approximately 200 mg once every three weeks, or approximately 400 mg once every six weeks, wherein the anti-PD-(L)l antibody is pembrolizumab.
  • the medical use or the treatment according to the current aspect comprises administering to the patient an anti-PD-(L)l antibody in a total amount of approximately 240 mg once every two weeks, or approximately 360 mg once every three weeks, or approximately 480 mg once every four weeks, wherein the anti-PD-(L)l antibody is nivolumab.
  • the medical use or the treatment according to the current aspect comprises administering to the patient an anti-PD-(L)l antibody in a total amount of approximately 840 mg every two weeks, approximately 1200 mg every three weeks, or approximately 1680 mg every four weeks, wherein the anti-PD-(L)l antibody is atezolizumab.
  • the medical use or the treatment according to the current aspect comprises administering to the patient an anti-PD-(L)l antibody in a total amount of approximately 360 mg every three weeks, wherein the anti-PD-(L)l antibody is Zimberelimab.
  • the medical use or the treatment according to the current aspect comprises administering to the patient an anti-PD-(L)l antibody in a total amount of approximately 3 mg/kg every two weeks, wherein the anti-PD-(L)l antibody is Toripalimab.
  • the medical use or the treatment according to the current aspect comprises administering to the patient an anti-PD-(L)l antibody in a total amount of approximately 10 mg/kg every two weeks, or approximately 1500 mg every 3 weeks, wherein the anti-PD-(L)l antibody is Durvalumab.
  • the medical use of treatment according to this aspect may comprise administering intravenously or subcutaneously to a patient in need thereof an anti-PD-(L)l antibody in a total amount of a. Approximately 200 mg once every three weeks, or b. Approximately 480 mg once every four weeks, or c. Approximately 480 mg once every six weeks.
  • the anti-PD-(L)l antibody is pembrolizumab, nivolumab, atezolizumab, avelumab, or durvalumab.
  • the anti-PD-(L)l antibody is preferably administered after the anti-CCR8 antibody.
  • the medical use or treatment a comprises administering to a patient in need thereof the anti-CCR8 antibody in a total amount of 10 mg to 250 mg once every week, b. and preferably further comprises administering to the patient an anti-PD-(L)l antibody in a total amount of i.
  • the anti-PD-(L)l antibody is nivolumab, or v.
  • the anti-PD-(L)l antibody is Zimberelimab, or x. Approximately 3 mg/kg every two weeks, preferably wherein the anti-PD-(L)l antibody is Toripalimab, or xi. Approximately 10 mg/kg every two weeks, preferably wherein the anti-PD-(L)l antibody is Durvalumab, or xii. Approximately 1500 mg every 3 weeks, preferably wherein the anti-PD-(L)l antibody is Durvalumab.
  • the medical use or treatment a comprises administering to a patient in need thereof the anti-CCR8 antibody in a total amount of 10 mg to 750 mg once every two weeks, b. and preferably further comprises administering to the patient an anti-PD-(L)l antibody in a total amount of i.
  • the anti-PD-(L)l antibody is nivolumab, or v.
  • the medical use or treatment a comprises administering to a patient in need thereof the anti-CCR8 antibody in a total amount of 16 mg to 450 mg once every three weeks, b.
  • an anti-PD-(L)l antibody in a total amount of i. Approximately 200 mg once every three weeks, preferably wherein the anti-PD-(L)l antibody is pembrolizumab, or ii. Approximately 400 mg once every six weeks, preferably wherein the anti-PD-(L)l antibody is pembrolizumab, or ill. Approximately 240 mg once every two weeks, preferably wherein the anti-PD-(L)l antibody is nivolumab, or iv. Approximately 360 mg once every three weeks, preferably wherein the anti-PD-(L)l antibody is nivolumab, or v.
  • the anti-PD-(L)l antibody is nivolumab, or vi.
  • the anti-PD-(L)l antibody is Toripalimab, or xi.
  • the anti-PD-(L)l antibody is Durvalumab, or xii.
  • the required volume of the anti-PD-(L)l antibody solution can be withdrawn from one or more vial(s), which may or may not comprise a formulation according to the current invention, and transferred into an intravenous (IV) bag containing 0.9 % Sodium Chloride Injection, USP or 5% Dextrose Injection, USP.
  • the diluted solution can be mixed by gentle inversion without shaking.
  • the final concentration of the diluted solution can be for example between 1 mg/mL to 10 mg/mL.
  • the intravenous administration of the anti-PD-(L)l antibody may occur as a 15- to 60- minute intravenous infusion, and preferably as a 30-minute intravenous infusion.
  • Administration of the anti-PD-(L)l antibody may occur through an intravenous line containing a sterile, non-pyrogenic, low-protein binding 0.2 micron to 5 micron in-line or add-on filter. Given the variability of infusion pumps from site to site, a window between -5 min and +10 min is permitted (i.e., infusion time is 30 min [-5 min/+10 min]).
  • the intravenous administration of the anti-PD-(L)l antibody may occur using the same IV line that was previously used for the intravenous administration of the inventive formulation.
  • This setup is preferred and advantageous because the complexity of treatment administration is reduced and because this is highly convenient for both patients and medical professionals.
  • the IV line is flushed with saline prior to the intravenous administration of second antibody, i.e. the anti-human PD- (L)l antibody formulation.
  • the anti-PD-(L)l antibody is pembrolizumab and is administered in a total amount of approximately 200 mg once every three weeks, or approximately 400 mg once every six weeks.
  • the total amount of the anti-CCR8 antibody is approximately 10 mg once every week, and the anti-PD-(L)l antibody is pembrolizumab and is administered in a total amount of approximately 200 mg once every three weeks, or approximately 400 mg once every six weeks.
  • the total amount of the anti-CCR8 antibody is approximately 30 mg once every week, and the anti-PD-(L)l antibody is pembrolizumab and is administered in a total amount of approximately 200 mg once every three weeks, or approximately 400 mg once every six weeks.
  • the total amount of the anti-CCR8 antibody is approximately 50 mg once every week and the anti-PD-(L)l antibody is pembrolizumab and is administered in a total amount of approximately 200 mg once every three weeks, or approximately 400 mg once every six weeks.
  • the total amount of the anti-CCR8 antibody is approximately 75 mg once every week and the anti-PD-(L)l antibody is pembrolizumab and is administered in a total amount of approximately 200 mg once every three weeks, or approximately 400 mg once every six weeks.
  • the total amount of the anti-CCR8 antibody is approximately 100 mg once every week, and the anti-PD-(L)l antibody is pembrolizumab and is administered in a total amount of approximately 200 mg once every three weeks, or approximately 400 mg once every six weeks.
  • the total amount of the anti-CCR8 antibody is approximately 125 mg once every week and the anti-PD-(L)l antibody is pembrolizumab and is administered in a total amount of approximately 200 mg once every three weeks, or approximately 400 mg once every six weeks.
  • the total amount of the anti-CCR8 antibody is approximately 175 mg once every week and the anti-PD-(L)l antibody is pembrolizumab and is administered in a total amount of approximately 200 mg once every three weeks, or approximately 400 mg once every six weeks.
  • the total amount of the anti-CCR8 antibody is approximately 250 mg once every week and the anti-PD-(L)l antibody is pembrolizumab and is administered in a total amount of approximately 200 mg once every three weeks, or approximately 400 mg once every six weeks.
  • the total amount of the anti-CCR8 antibody is approximately 175 mg once every three weeks and the anti-PD-(L)l antibody is pembrolizumab and is administered in a total amount of approximately 200 mg once every three weeks, or approximately 400 mg once every six weeks.
  • the total amount of the anti-CCR8 antibody is approximately 500 mg once every three weeks and the anti-PD-(L)l antibody is pembrolizumab and is administered in a total amount of approximately 200 mg once every three weeks, or approximately 400 mg once every six weeks.
  • the total amount of the anti-CCR8 antibody is approximately 750 mg once every three weeks and the anti-PD-(L)l antibody is pembrolizumab and is administered in a total amount of approximately 200 mg once every three weeks, or approximately 400 mg once every six weeks.
  • the total amount of the anti-CCR8 antibody is approximately 1000 mg once every three week and the anti-PD-(L)l antibody is pembrolizumab and is administered in a total amount of approximately 200 mg once every three weeks, or approximately 400 mg once every six weeks.
  • the total amount of the anti-CCR8 antibody is approximately 1500 mg once every three week and the anti-PD-(L)l antibody is pembrolizumab and is administered in a total amount of approximately 200 mg once every three weeks, or approximately 400 mg once every six weeks.
  • the anti-PD-(L)l antibody is nivolumab and is administered in a total amount of approximately 240 mg once every two weeks, approximately 360 mg once every three weeks, approximately 480 mg once every four weeks, or approximately 480 mg once every six weeks.
  • the total amount of the anti-CCR8 antibody is approximately 10 mg once every week
  • the anti-PD-(L)l antibody is nivolumab and is administered in a total amount of approximately 240 mg once every two weeks, approximately 360 mg once every three weeks, approximately 480 mg once every four weeks, or approximately 480 mg once every six weeks.
  • the total amount of the anti-CCR8 antibody is approximately 30 mg once every week
  • the anti-PD-(L)l antibody is nivolumab and is administered in a total amount of approximately 240 mg once every two weeks, approximately 360 mg once every three weeks, approximately 480 mg once every four weeks, or approximately 480 mg once every six weeks.
  • the total amount of the anti-CCR8 antibody is approximately 50 mg once every week and the anti-PD-(L)l antibody is nivolumab and is administered in a total amount of approximately 240 mg once every two weeks, approximately 360 mg once every three weeks, approximately 480 mg once every four weeks, or approximately 480 mg once every six weeks.
  • the total amount of the anti-CCR8 antibody is approximately 75 mg once every week and the anti-PD-(L)l antibody is nivolumab and is administered in a total amount of approximately 240 mg once every two weeks, approximately 360 mg once every three weeks, approximately 480 mg once every four weeks, or approximately 480 mg once every six weeks.
  • the total amount of the anti-CCR8 antibody is approximately 100 mg once every week
  • the anti-PD-(L)l antibody is nivolumab and is administered in a total amount of approximately 240 mg once every two weeks, approximately 360 mg once every three weeks, approximately 480 mg once every four weeks, or approximately 480 mg once every six weeks.
  • the total amount of the anti-CCR8 antibody is approximately 125 mg once every week and the anti-PD-(L)l antibody is nivolumab and is administered in a total amount of approximately 240 mg once every two weeks, approximately 360 mg once every three weeks, approximately 480 mg once every four weeks, or approximately 480 mg once every six weeks.
  • the total amount of the anti-CCR8 antibody is approximately 175 mg once every week and the anti-PD-(L)l antibody is nivolumab and is administered in a total amount of approximately 240 mg once every two weeks, approximately 360 mg once every three weeks, approximately 480 mg once every four weeks, or approximately 480 mg once every six weeks.
  • the total amount of the anti-CCR8 antibody is approximately 250 mg once every week and the anti-PD-(L)l antibody is nivolumab and is administered in a total amount of approximately 240 mg once every two weeks, approximately 360 mg once every three weeks, approximately 480 mg once every four weeks, or approximately 480 mg once every six weeks.
  • the total amount of the anti-CCR8 antibody is approximately 175 mg once every three weeks and the anti-PD-(L)l antibody is nivolumab and is administered in a total amount of approximately 240 mg once every two weeks, approximately 360 mg once every three weeks, approximately 480 mg once every four weeks, or approximately 480 mg once every six weeks.
  • the total amount of the anti-CCR8 antibody is approximately 500 mg once every three weeks and the anti-PD-(L)l antibody is nivolumab and is administered in a total amount of approximately 240 mg once every two weeks, approximately 360 mg once every three weeks, approximately 480 mg once every four weeks, or approximately 480 mg once every six weeks.
  • the total amount of the anti-CCR8 antibody is approximately 750 mg once every three weeks and the anti-PD-(L)l antibody is nivolumab and is administered in a total amount of approximately 240 mg once every two weeks, approximately 360 mg once every three weeks, approximately 480 mg once every four weeks, or approximately 480 mg once every six weeks.
  • the total amount of the anti-CCR8 antibody is approximately 1000 mg once every three week and the anti-PD-(L)l antibody is nivolumab and is administered in a total amount of approximately 240 mg once every two weeks, approximately 360 mg once every three weeks, approximately 480 mg once every four weeks, or approximately 480 mg once every six weeks.
  • the total amount of the anti-CCR8 antibody is approximately 1500 mg once every three week and the anti-PD-(L)l antibody is nivolumab and is administered in a total amount of approximately 240 mg once every two weeks, approximately 360 mg once every three weeks, approximately 480 mg once every four weeks, or approximately 480 mg once every six weeks.
  • the anti-PD-(L)l antibody is atezolizumab and is administered in a total amount of approximately 840 mg once every two weeks, approximately 1200 mg once every three weeks, or approximately 1680 mg once every four weeks.
  • the total amount of the anti-CCR8 antibody is approximately 10 mg once every week
  • the anti-PD-(L)l antibody is atezolizumab and is administered in a total amount of approximately 840 mg once every two weeks, approximately 1200 mg once every three weeks, or approximately 1680 mg once every four weeks.
  • the total amount of the anti-CCR8 antibody is approximately 30 mg once every week, and the anti-PD-(L)l antibody is atezolizumab and is administered in a total amount of approximately 840 mg once every two weeks, approximately 1200 mg once every three weeks, or approximately 1680 mg once every four weeks.
  • the total amount of the anti-CCR8 antibody is approximately 50 mg once every week and the anti-PD-(L)l antibody is atezolizumab and is administered in a total amount of approximately 840 mg once every two weeks, approximately 1200 mg once every three weeks, or approximately 1680 mg once every four weeks.
  • the total amount of the anti-CCR8 antibody is approximately 75 mg once every week and the anti-PD-(L)l antibody is atezolizumab and is administered in a total amount of approximately 840 mg once every two weeks, approximately 1200 mg once every three weeks, or approximately 1680 mg once every four weeks.
  • the total amount of the anti-CCR8 antibody is approximately 100 mg once every week, and the anti-PD-(L)l antibody is atezolizumab and is administered in a total amount of approximately 840 mg once every two weeks, approximately 1200 mg once every three weeks, or approximately 1680 mg once every four weeks.
  • the total amount of the anti-CCR8 antibody is approximately 125 mg once every week and the anti-PD-(L)l antibody is atezolizumab and is administered in a total amount of approximately 840 mg once every two weeks, approximately 1200 mg once every three weeks, or approximately 1680 mg once every four weeks.
  • the total amount of the anti-CCR8 antibody is approximately 175 mg once every week and the anti-PD-(L)l antibody is atezolizumab and is administered in a total amount of approximately 840 mg once every two weeks, approximately 1200 mg once every three weeks, or approximately 1680 mg once every four weeks.
  • the total amount of the anti-CCR8 antibody is approximately 250 mg once every week and the anti-PD-(L)l antibody is atezolizumab and is administered in a total amount of approximately 840 mg once every two weeks, approximately 1200 mg once every three weeks, or approximately 1680 mg once every four weeks.
  • the total amount of the anti-CCR8 antibody is approximately 175 mg once every three weeks and the anti-PD-(L)l antibody is atezolizumab and is administered in a total amount of approximately 840 mg once every two weeks, approximately 1200 mg once every three weeks, or approximately 1680 mg once every four weeks.
  • the total amount of the anti-CCR8 antibody is approximately 500 mg once every three weeks and the anti-PD-(L)l antibody is atezolizumab and is administered in a total amount of approximately 840 mg once every two weeks, approximately 1200 mg once every three weeks, or approximately 1680 mg once every four weeks.
  • the total amount of the anti-CCR8 antibody is approximately 750 mg once every three weeks and the anti-PD-(L)l antibody is atezolizumab and is administered in a total amount of approximately 840 mg once every two weeks, approximately 1200 mg once every three weeks, or approximately 1680 mg once every four weeks.
  • the total amount of the anti-CCR8 antibody is approximately 1000 mg once every three week and the anti-PD-(L)l antibody is atezolizumab and is administered in a total amount of approximately 840 mg once every two weeks, approximately 1200 mg once every three weeks, or approximately 1680 mg once every four weeks.
  • the total amount of the anti-CCR8 antibody is approximately 1500 mg once every three week and the anti-PD-(L)l antibody is atezolizumab and is administered in a total amount of approximately 840 mg once every two weeks, approximately 1200 mg once every three weeks, or approximately 1680 mg once every four weeks.
  • the anti-PD-(L)l antibody is Zimberelimab and is administered in a total amount of approximately 360 mg once every three weeks.
  • the total amount of the anti-CCR8 antibody is approximately 10 mg once every week, and the anti-PD-(L)l antibody is Zimberelimab and is administered in a total amount of approximately 360 mg once every three weeks.
  • the total amount of the anti-CCR8 antibody is approximately 30 mg once every week, and the anti-PD-(L)l antibody is Zimberelimab and is administered in a total amount of approximately 360 mg once every three weeks. In a preferred example the total amount of the anti-CCR8 antibody is approximately 50 mg once every week and the anti-PD-(L)l antibody is Zimberelimab and is administered in a total amount of approximately 360 mg once every three weeks.
  • the total amount of the anti-CCR8 antibody is approximately 75 mg once every week and the anti-PD-(L)l antibody is Zimberelimab and is administered in a total amount of approximately 360 mg once every three weeks.
  • the total amount of the anti-CCR8 antibody is approximately 100 mg once every week, and the anti-PD-(L)l antibody is Zimberelimab and is administered in a total amount of approximately 360 mg once every three weeks.
  • the total amount of the anti-CCR8 antibody is approximately 125 mg once every week and the anti-PD-(L)l antibody is Zimberelimab and is administered in a total amount of approximately 360 mg once every three weeks.
  • the total amount of the anti-CCR8 antibody is approximately 175 mg once every week and the anti-PD-(L)l antibody is Zimberelimab and is administered in a total amount of approximately 360 mg once every three weeks.
  • the total amount of the anti-CCR8 antibody is approximately 250 mg once every week and the anti-PD-(L)l antibody is Zimberelimab and is administered in a total amount of approximately 360 mg once every three weeks.
  • the total amount of the anti-CCR8 antibody is approximately 175 mg once every three weeks and the anti-PD-(L)l antibody is Zimberelimab and is administered in a total amount of approximately 360 mg once every three weeks.
  • the total amount of the anti-CCR8 antibody is approximately 500 mg once every three weeks and the anti-PD-(L)l antibody is Zimberelimab and is administered in a total amount of approximately 360 mg once every three weeks.
  • the total amount of the anti-CCR8 antibody is approximately 750 mg once every three weeks and the anti-PD-(L)l antibody is Zimberelimab and is administered in a total amount of approximately 360 mg once every three weeks.
  • the total amount of the anti-CCR8 antibody is approximately 1000 mg once every three week and the anti-PD-(L)l antibody is Zimberelimab and is administered in a total amount of approximately 360 mg once every three weeks.
  • the total amount of the anti-CCR8 antibody is approximately 1500 mg once every three week and the anti-PD-(L)l antibody is Zimberelimab and is administered in a total amount of approximately 360 mg once every three weeks.
  • the anti-PD-(L)l antibody is Toripalimab and is administered in a total amount of approximately 3 mg/kg once every two weeks.
  • the total amount of the anti-CCR8 antibody is approximately 10 mg once every week, and the anti-PD-(L)l antibody is Toripalimab and is administered in a total amount of approximately 3 mg/kg once every two weeks.
  • the total amount of the anti-CCR8 antibody is approximately 30 mg once every week, and the anti-PD-(L)l antibody is Toripalimab and is administered in a total amount of approximately 3 mg/kg once every two weeks.
  • the total amount of the anti-CCR8 antibody is approximately 50 mg once every week and the anti-PD-(L)l antibody is Toripalimab and is administered in a total amount of approximately 3 mg/kg once every two weeks.
  • the total amount of the anti-CCR8 antibody is approximately 75 mg once every week and the anti-PD-(L)l antibody is Toripalimab and is administered in a total amount of approximately 3 mg/kg once every two weeks.
  • the total amount of the anti-CCR8 antibody is approximately 100 mg once every week, and the anti-PD-(L)l antibody is Toripalimab and is administered in a total amount of approximately 3 mg/kg once every two weeks.
  • the total amount of the anti-CCR8 antibody is approximately 125 mg once every week and the anti-PD-(L)l antibody is Toripalimab and is administered in a total amount of approximately 3 mg/kg once every two weeks.
  • the total amount of the anti-CCR8 antibody is approximately 175 mg once every week and the anti-PD-(L)l antibody is Toripalimab and is administered in a total amount of approximately 3 mg/kg once every two weeks.
  • the total amount of the anti-CCR8 antibody is approximately 250 mg once every week and the anti-PD-(L)l antibody is Toripalimab and is administered in a total amount of approximately 3 mg/kg once every two weeks.
  • the total amount of the anti-CCR8 antibody is approximately 175 mg once every three weeks and the anti-PD-(L)l antibody is Toripalimab and is administered in a total amount of approximately 3 mg/kg once every two weeks.
  • the total amount of the anti-CCR8 antibody is approximately 500 mg once every three weeks and the anti-PD-(L)l antibody is Toripalimab and is administered in a total amount of approximately 3 mg/kg once every two weeks.
  • the total amount of the anti-CCR8 antibody is approximately 750 mg once every three weeks and the anti-PD-(L)l antibody is Toripalimab and is administered in a total amount of approximately 3 mg/kg once every two weeks.
  • the total amount of the anti-CCR8 antibody is approximately 1000 mg once every three week and the anti-PD-(L)l antibody is Toripalimab and is administered in a total amount of approximately 3 mg/kg once every two weeks. In a preferred example the total amount of the anti-CCR8 antibody is approximately 1500 mg once every three week and the anti-PD-(L)l antibody is Toripalimab and is administered in a total amount of approximately 3 mg/kg once every two weeks.
  • the anti-PD-(L)l antibody is Durvalumab and is administered in a total amount of approximately 10 mg/kg every two weeks, or approximately 1500 mg every 3 weeks.
  • the total amount of the anti-CCR8 antibody is approximately 10 mg once every week, and the anti-PD-(L)l antibody is Durvalumab and is administered in a total amount of approximately 10 mg/kg every two weeks, or approximately 1500 mg every 3 weeks.
  • the total amount of the anti-CCR8 antibody is approximately 30 mg once every week, and the anti-PD-(L)l antibody is Durvalumab and is administered in a total amount of approximately 10 mg/kg every two weeks, or approximately 1500 mg every 3 weeks.
  • the total amount of the anti-CCR8 antibody is approximately 50 mg once every week and the anti-PD-(L)l antibody is Durvalumab and is administered in a total amount of approximately 10 mg/kg every two weeks, or approximately 1500 mg every 3 weeks.
  • the total amount of the anti-CCR8 antibody is approximately 75 mg once every week and the anti-PD-(L)l antibody is Durvalumab and is administered in a total amount of approximately 10 mg/kg every two weeks, or approximately 1500 mg every 3 weeks.
  • the total amount of the anti-CCR8 antibody is approximately 100 mg once every week, and the anti-PD-(L)l antibody is Durvalumab and is administered in a total amount of approximately 10 mg/kg every two weeks, or approximately 1500 mg every 3 weeks.
  • the total amount of the anti-CCR8 antibody is approximately 125 mg once every week and the anti-PD-(L)l antibody is Durvalumab and is administered in a total amount of approximately 10 mg/kg every two weeks, or approximately 1500 mg every 3 weeks.
  • the total amount of the anti-CCR8 antibody is approximately 175 mg once every week and the anti-PD-(L)l antibody is Durvalumab and is administered in a total amount of approximately 10 mg/kg every two weeks, or approximately 1500 mg every 3 weeks.
  • the total amount of the anti-CCR8 antibody is approximately 250 mg once every week and the anti-PD-(L)l antibody is Durvalumab and is administered in a total amount of approximately 10 mg/kg every two weeks, or approximately 1500 mg every 3 weeks.
  • the total amount of the anti-CCR8 antibody is approximately 175 mg once every three weeks and the anti-PD-(L)l antibody is Durvalumab and is administered in a total amount of approximately 10 mg/kg every two weeks, or approximately 1500 mg every 3 weeks.
  • the total amount of the anti-CCR8 antibody is approximately 500 mg once every three weeks and the anti-PD-(L)l antibody is Durvalumab and is administered in a total amount of approximately 10 mg/kg every two weeks, or approximately 1500 mg every 3 weeks. In a preferred example the total amount of the anti-CCR8 antibody is approximately 750 mg once every three weeks and the anti-PD-(L)l antibody is Durvalumab and is administered in a total amount of approximately 10 mg/kg every two weeks, or approximately 1500 mg every 3 weeks.
  • the total amount of the anti-CCR8 antibody is approximately 1000 mg once every three week and the anti-PD-(L)l antibody is Durvalumab and is administered in a total amount of approximately 10 mg/kg every two weeks, or approximately 1500 mg every 3 weeks.
  • the total amount of the anti-CCR8 antibody is approximately 1500 mg once every three week and the anti-PD-(L)l antibody is Durvalumab and is administered in a total amount of approximately 10 mg/kg every two weeks, or approximately 1500 mg every 3 weeks.
  • the medical use according to the first aspect preferably comprises at least one 21-day dosing cycle.
  • the anti-CCR8 antibody and the anti-PD-(L)l antibody are both administered on day 1 of the 21-day dosing cycle.
  • the medical use or treatment according to the current aspect may furthermore comprises administration of an effective dose of antihistamines, acetaminophen, corticosteroids or a combination thereof, preferably
  • acetaminophen may be administered orally.
  • diphenhydramine may be administered orally.
  • kits of parts comprising the pharmaceutical formulation according to the first aspect and optionally instructions for use.
  • the pharmaceutical formulation according to the first aspect is contained in a container.
  • said container is a vial.
  • the pharmaceutical formulation according to the first aspect is contained in a prefilled syringe.
  • the kit furthermore comprises an anti-PD(L)l antibody, preferably wherein the anti- PD(L)1 antibody is pembrolizumab, nivolumab, atezolizumab, avelumab, toripalimab, zimberelimab or durvalumab.
  • the kit comprises one or more further therapeutically active compounds, preferably selected from a. an antibody or a small molecule targeting a checkpoint protein, such as PD1, PD-L1 or CTLA-4, b. an antibody targeting a further chemokine receptor, such as CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CX3CR1 or CXCR1, c. an antibody targeting a protein which is specifically expressed by tumor cells, d. an antibody or a small molecule targeting HER2 and/or EGFR, e.
  • a further chemokine receptor such as CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CX3CR1 or CXCR1,
  • chemotherapeutic agent preferably a taxane, paclitaxel, doxorubicin, cis-platin, carboplatin, oxaliplatin, or gemcitabine, and/or g. a targeted kinase inhibitor, such as Sorafenib, Regorafenib, or MEKi-1.
  • the instructions for use comprise a label describing a. at least one step for preparing the use of the pharmaceutical formulation in a method of treatment or b. at least one step for using the pharmaceutical formulation in a method of treatment.
  • the label may include a description with instructions to perform step a., b. and/or c. according to the third aspect of the current invention.
  • Cell Culture started with thawing the cell bank vial and recombinant protein expression was performed in a Chinese hamster ovary (CHO) cell line using a fed-batch cell culture process and harvest. The harvest was followed by three chromatography steps (Protein A Affinity chromatography, Ion Exchange chromatography), two viral reduction steps (low-pH hold after affinity chromatography and viral filtration), and an ultrafiltration/diafiltration step to obtain the appropriate bulk drug substance concentration and formulation for long-term frozen storage.
  • CHO Chinese hamster ovary
  • the anti-CCR8 antibody was formulated in the histidine buffer system according to Table 1.1.
  • the formulations were sterile filtered with Millipore 0.22 pm filter and then sterile filled in 10 ml type I plus glass tubing vials with 1 mL fill volume and stoppered with either gray bromobutyl or chlorobutyl rubber stoppers for liquid and lyophilized formulations, respectively.
  • the resulting Buffer Composition 1 was a clear to slightly opalescent and colorless to slightly yellow liquid. Where it is prepared for i.v. administration, it needs to be sterile and have a low level of endotoxins / be substantially free of endotoxins.
  • the nominal content of the Drug Product was 250 mg antibody per vial, equivalent to a 5.0 mL fill of sterile filtered antibody solution per vial. There is an overfill of 0.3 mL, resulting in a total fill of 5.3 mL.
  • the resulting Buffer Composition 1 was prepared as a frozen liquid in a glass vial or as a lyophilized formulation, such that the provided concentrations were reached after dilution.
  • the frozen liquid Buffer Composition 1 is ready for injection after thawing the glass vial followed by dilution with 5 % aqueous dextrose solution. After thawing it has a concentration of approximately 50 mg/mL active ingredient.
  • Example 2 Stability of anti-CCR8 antibody in liquid and lyophilized histidine buffer formulation
  • the liquid antibody formulation was prepared as specified elsewhere herein and was stored at 5°C for up to 3 months.
  • Table 2.1 shows the raw data for the stability of the liquid antibody formulation
  • Table 2.2 shows the rate of change for the liquid antibody formulation
  • Table 2.3 shows the raw data for the stability of the lyophilized antibody formulation
  • Table 2.4 shows the rate of change for the lyophilized antibody formulation. Both dosage forms, liquid and lyophilized, were found to be stable.
  • SE-HPLC size-exclusion high-performance liquid chromatography
  • icIEF imaged capillary isoelectric focusing
  • the density was measured to be 1.036 g/cm3.
  • the osmolality was measured to be 308 mOsm/kg.
  • the pH was measured at 20 - 25°C.
  • Table 2.1 Stability of the liquid antibody formulation (Raw Data). High molecular weight forms (HMW, aggregates), main peak (monomer), and low molecular weight forms (LMW) are listed for SE-HPLC.
  • Table 2.5 Stability of liquid antibody formulation at a specified temperature and relative humidity (Raw
  • Buffer Composition 1 is suited as a pharmaceutical formulation for anti-CCR8 antibodies such as TPP-23411.
  • the antibody is sufficiently stabilized and can be stored under convenient conditions while no substantial increase of basic charge variants was observed. This has been an issue for similar liquid formulations, where an increase in the basic charge variant from 11 % to 25 % had been observed after 30 months at 5°C.
  • Buffer Composition 1 While changing the amount of the excipients of Buffer Composition 1 is possible to a certain degree without substantial impact on the increase of the basic charge variant, lowering the pH (i.e., to pH 4 and 5) seems to promote the basic species formation.
  • a stable formulation was developed where the anti-CCR8 antibody is soluble at the required concentration (25-100 mg/mL), that is stable under the intended storage conditions (e.g. as a frozen liquid), where precipitation and aggregation is largely avoided, where formation of basic antibody species is largely avoided, and that is isosmotic for better patient compliance.
  • succinimide intermediate is stable at 25°C, while it is not stable at 40°C and rapidly converts back to Asp and iso-Asp.
  • the isomerization reaction is acid catalysed at a pH between 4 and 6.
  • Example 4 Formulation scouting studies for reducing the basic peaks
  • a high concentration antibody dosage form may present many challenges in formulation development.
  • the first challenge is antibody solubility.
  • phase separation will occur through several different mechanisms, including precipitation, gelation, and crystallization.
  • the second challenge is antibody stability.
  • the stability of antibody can be problematic because protein molecules would have high probability of collision and result in more protein-protein interactions, which would cause protein aggregation, including the formation of soluble and insoluble aggregates.
  • Example 5 Preparation of a Dilution for Injection from frozen liquid
  • Buffer Composition 1 was provided as a frozen liquid in a glass vial. After thawing, Buffer Composition 1 had a concentration of 50 mg/mL active ingredient. It was further diluted with 5 % aqueous dextrose solution to prepare a dilution for injection, i.e. for intravenous injection.
  • Example 6 Preparation of a Dilution for Injection from lyophilized formulation
  • Buffer Composition 1 was provided as a lyophilized formulation.
  • the lyophilized formulation was dissolved in water to reach a concentration of 50 mg/mL active ingredient. It was further diluted with 5 % aqueous dextrose solution to prepare a dilution for injection.
  • Example 7 Local tolerability in cynomolgus monkey
  • Buffer Composition 1 The local tolerability of Buffer Composition 1 in 5 % dextrose solution was evaluated as part of repeatdose toxicity studies in monkeys. There was no indication for enduring adverse effects at the sites of injection.
  • Example 8 Nonclinical pharmacokinetics and drug metabolism
  • TPP-23411 Pharmacokinetics of TPP-23411 was studied in vivo in male Cynomolgus monkeys after single i.v. and s.c. administration of TPP-23411.
  • TPP-23411 was measured in monkey plasma using an anti-human IgG generic assay (IgG-ELISA). Anti-TPP-23411 antibody formation was monitored with a validated TPP- 23411-based bridging ELISA method (described elsewhere).
  • Table 10.1 Overview of single dose pharmacokinetics, in vivo study, i.v.: intravenous; s.c.: subcutaneous; PK: pharmacokinetics; m: male. Observation intervals were 336 hours for the low and 504 hours for the high dose.
  • the exposure in terms of AUCnorm increased slightly more than dose-proportionally from 391 kg-h/L to 617 kg-h/L with no hints for target mediated drug disposition.
  • the plasma elimination was bi-phasic and the plasma clearance was 2.55 mL/(h-kg) for the 1 mg/kg and 1.62 mL/(h-kg) (mean values) for the 10 mg/kg dose.
  • the volume of distribution amounted to 0.154 and 0.110 L/kg (mean values) for the 1 and 10 mg/kg dose, respectively.
  • the effective half-lives were short with 41.9 and 46.8 hours reflecting a relatively fast elimination of the antibody and the pharmacologically less relevant terminal elimination half-lives were 108 and 148 hours.
  • TPP-23411 After single subcutaneous administration of 3 and 10 mg/kg TPP-23411 a dose-proportional increase of exposure in terms of AUCnorm from 331 kg-h/L to 403 kg-h/L and Cmax,norm from 2.22 kg/L to 2.95 kg/L was observed (mean values). Cmax was reached at 8 to 30 h hours (mean values) after administration. TPP-23411 was eliminated from plasma with terminal half-lives of 81 and 109 h (mean values) at dose levels of 3 and 10 mg/kg, respectively, with plasma concentrations running in parallel to the intravenous profile. Bioavailability in both dose groups was moderate to high and ranged from 54% to 103%.
  • Table 10.2 Pharmacokinetics of TPP-23411 after a single dose (non-rodent).
  • a bioavailability, calculated with the IV AUCnorm value of 1 mg/kg b.w. in case of 3 mg/kg s.c. and calculated with the IV AUCnorm value of 10 mg/kg b.w. in case of 10 mg/kg s.c;
  • b not calculated.
  • TPP-23411 Long term stability of TPP-23411 was tested with buffer composition 1. Standard techniques were used for characterization. As shown below this formulation was particularly suited to formulate an IgGl antihuman CCR8 antibody with a high pl, such as TPP-23411.
  • the liquid antibody formulation was prepared as specified elsewhere herein and was stored at 5 °C and -30 °C.
  • SE-HPLC size-exclusion high-performance liquid chromatography
  • icIEF imaged capillary isoelectric focusing

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Abstract

La présente invention concerne des formulations pharmaceutiques sûres pour stabiliser un anticorps thérapeutique anti-CCR8. La formulation pharmaceutique est fournie sous forme liquide, tel qu'un liquide congelé, ou sous forme lyophilisée, et peut être sous une forme prête à l'emploi ou peut en outre être diluée pour une administration intraveineuse ou sous-cutanée.
PCT/EP2025/054952 2024-03-06 2025-02-25 Formulation pharmaceutique pour anticorps anti-ccr8 Pending WO2025186043A1 (fr)

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Citations (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4376110A (en) 1980-08-04 1983-03-08 Hybritech, Incorporated Immunometric assays using monoclonal antibodies
US5225539A (en) 1986-03-27 1993-07-06 Medical Research Council Recombinant altered antibodies and methods of making altered antibodies
US5585089A (en) 1988-12-28 1996-12-17 Protein Design Labs, Inc. Humanized immunoglobulins
US5859205A (en) 1989-12-21 1999-01-12 Celltech Limited Humanised antibodies
WO2008112640A2 (fr) 2007-03-09 2008-09-18 Sinomab Bioscience Limited Construction et utlisation d'une banque d'anticorps fonctionnellement humains a diversite de repertoire maximisee
US10087259B1 (en) 2014-04-28 2018-10-02 Memorial Sloan Kettering Cancer Center Depleting tumor-specific tregs
WO2020138489A1 (fr) 2018-12-27 2020-07-02 塩野義製薬株式会社 Nouvel anticorps anti-ccr8
WO2021142002A1 (fr) 2020-01-06 2021-07-15 Vaccinex, Inc. Anticorps anti-ccr8 et leurs utilisations
WO2021152186A2 (fr) 2020-06-26 2021-08-05 Bayer Aktiengesellschaft Anticorps ccr8 pour applications thérapeutiques
WO2021163064A2 (fr) 2020-02-14 2021-08-19 Jounce Therapeutics, Inc. Anticorps et protéines de fusion se liant à ccr8, et leurs utilisations
WO2021178749A2 (fr) 2020-03-05 2021-09-10 Memorial Sloan Kettering Cancer Center Agents anti-ccr8
WO2021194942A1 (fr) 2020-03-23 2021-09-30 Bristol-Myers Squibb Company Anticorps anti-ccr8 pour le traitement du cancer
WO2022003156A1 (fr) 2020-07-02 2022-01-06 Oncurious Nv Liants non bloquants ccr8
WO2022042690A1 (fr) 2020-08-28 2022-03-03 和铂医药(上海)有限责任公司 Anticorps anti-ccr8 et application correspondante
WO2022078277A1 (fr) 2020-10-16 2022-04-21 Lanova Medicines Limited Company Anticorps monoclonaux anti-ccr8 et leurs utilisations
WO2022081718A1 (fr) 2020-10-14 2022-04-21 Five Prime Therapeutics, Inc. Anticorps anti-récepteur de chimiokine c-c 8 (ccr8) et leurs procédés d'utilisation
WO2022136650A1 (fr) 2020-12-24 2022-06-30 Oncurious Nv Liants ccr8 humains à réactivité croisée
WO2022136647A1 (fr) 2020-12-24 2022-06-30 Oncurious Nv Liants ccr8 humains
WO2022216965A1 (fr) 2021-04-07 2022-10-13 Actinium Pharmaceuticals, Inc. Radioimmunothérapie dirigée contre ccr8 pour la réduction de lymphocytes t régulateurs infiltrant les tumeurs
WO2022241034A1 (fr) 2021-05-12 2022-11-17 BioLegend, Inc. Anticorps anti-ccr8, fragments de liaison à l'antigène de ceux-ci, et agents et compositions et leurs procédés de fabrication et d'utilisation
WO2022256563A1 (fr) 2021-06-04 2022-12-08 Amgen Inc. Anticorps anti-ccr8 et leurs utilisations
WO2023288241A1 (fr) 2021-07-14 2023-01-19 Genentech, Inc. Anticorps anti-récepteur de chimiokine à motif c-c 8 (ccr8) et méthodes d'utilisation
WO2023010054A1 (fr) 2021-07-27 2023-02-02 Abbvie Inc. Anticorps anti-ccr8
WO2023098888A1 (fr) 2021-12-02 2023-06-08 Zai Lab (Shanghai) Co., Ltd Unité de liaison à l'antigène ccr8 et ses utilisations
WO2023137466A2 (fr) 2022-01-14 2023-07-20 Qilu Puget Sound Biotherapeutics Corporation Anticorps anti-ccr8
WO2023174396A1 (fr) 2022-03-18 2023-09-21 北京天诺健成医药科技有限公司 Développement et utilisation d'un nouvel immunomodulateur
WO2023193732A1 (fr) 2022-04-07 2023-10-12 盛禾(中国)生物制药有限公司 Anticorps anti-ccr8 ou fragment de liaison à l'antigène de celui-ci
WO2023201812A1 (fr) 2022-04-18 2023-10-26 深圳市华星光电半导体显示技术有限公司 Procédé et appareil d'ajustement d'image d'affichage, et appareil d'affichage
WO2023206938A1 (fr) 2022-04-26 2023-11-02 深圳市体内生物医药科技有限公司 Cellules t porteurs de récepteur antigénique chimérique ciblant ccr8, leur procédé de préparation et leur utilisation
WO2023206350A1 (fr) 2022-04-29 2023-11-02 Analytical Biosciences Shanghai Limited Anticorps anti-ccr8 et leurs utilisations
WO2023219147A1 (fr) 2022-05-13 2023-11-16 塩野義製薬株式会社 Nouveaux anticorps anti-ccr8 pour la détection de ccr8
WO2023230473A1 (fr) 2022-05-24 2023-11-30 Bristol-Myers Squibb Company Anticorps se liant au ccr8 humain
WO2024240224A1 (fr) 2023-05-23 2024-11-28 再鼎医药(上海)有限公司 Formulation comprenant un anticorps anti-ccr8 et son utilisation
WO2025011439A1 (fr) 2023-07-07 2025-01-16 齐鲁制药有限公司 Préparation pharmaceutique d'anticorps monoclonal anti-ccr8 humain et son utilisation

Patent Citations (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4376110A (en) 1980-08-04 1983-03-08 Hybritech, Incorporated Immunometric assays using monoclonal antibodies
US5225539A (en) 1986-03-27 1993-07-06 Medical Research Council Recombinant altered antibodies and methods of making altered antibodies
US5585089A (en) 1988-12-28 1996-12-17 Protein Design Labs, Inc. Humanized immunoglobulins
US5693761A (en) 1988-12-28 1997-12-02 Protein Design Labs, Inc. Polynucleotides encoding improved humanized immunoglobulins
US5693762A (en) 1988-12-28 1997-12-02 Protein Design Labs, Inc. Humanized immunoglobulins
US5859205A (en) 1989-12-21 1999-01-12 Celltech Limited Humanised antibodies
WO2008112640A2 (fr) 2007-03-09 2008-09-18 Sinomab Bioscience Limited Construction et utlisation d'une banque d'anticorps fonctionnellement humains a diversite de repertoire maximisee
US10087259B1 (en) 2014-04-28 2018-10-02 Memorial Sloan Kettering Cancer Center Depleting tumor-specific tregs
WO2020138489A1 (fr) 2018-12-27 2020-07-02 塩野義製薬株式会社 Nouvel anticorps anti-ccr8
WO2021142002A1 (fr) 2020-01-06 2021-07-15 Vaccinex, Inc. Anticorps anti-ccr8 et leurs utilisations
WO2021163064A2 (fr) 2020-02-14 2021-08-19 Jounce Therapeutics, Inc. Anticorps et protéines de fusion se liant à ccr8, et leurs utilisations
WO2021178749A2 (fr) 2020-03-05 2021-09-10 Memorial Sloan Kettering Cancer Center Agents anti-ccr8
WO2021194942A1 (fr) 2020-03-23 2021-09-30 Bristol-Myers Squibb Company Anticorps anti-ccr8 pour le traitement du cancer
WO2021152186A2 (fr) 2020-06-26 2021-08-05 Bayer Aktiengesellschaft Anticorps ccr8 pour applications thérapeutiques
WO2022003156A1 (fr) 2020-07-02 2022-01-06 Oncurious Nv Liants non bloquants ccr8
WO2022042690A1 (fr) 2020-08-28 2022-03-03 和铂医药(上海)有限责任公司 Anticorps anti-ccr8 et application correspondante
WO2022081718A1 (fr) 2020-10-14 2022-04-21 Five Prime Therapeutics, Inc. Anticorps anti-récepteur de chimiokine c-c 8 (ccr8) et leurs procédés d'utilisation
WO2022078277A1 (fr) 2020-10-16 2022-04-21 Lanova Medicines Limited Company Anticorps monoclonaux anti-ccr8 et leurs utilisations
WO2022136650A1 (fr) 2020-12-24 2022-06-30 Oncurious Nv Liants ccr8 humains à réactivité croisée
WO2022136647A1 (fr) 2020-12-24 2022-06-30 Oncurious Nv Liants ccr8 humains
WO2022216965A1 (fr) 2021-04-07 2022-10-13 Actinium Pharmaceuticals, Inc. Radioimmunothérapie dirigée contre ccr8 pour la réduction de lymphocytes t régulateurs infiltrant les tumeurs
WO2022241034A1 (fr) 2021-05-12 2022-11-17 BioLegend, Inc. Anticorps anti-ccr8, fragments de liaison à l'antigène de ceux-ci, et agents et compositions et leurs procédés de fabrication et d'utilisation
WO2022256563A1 (fr) 2021-06-04 2022-12-08 Amgen Inc. Anticorps anti-ccr8 et leurs utilisations
WO2023288241A1 (fr) 2021-07-14 2023-01-19 Genentech, Inc. Anticorps anti-récepteur de chimiokine à motif c-c 8 (ccr8) et méthodes d'utilisation
WO2023010054A1 (fr) 2021-07-27 2023-02-02 Abbvie Inc. Anticorps anti-ccr8
WO2023098888A1 (fr) 2021-12-02 2023-06-08 Zai Lab (Shanghai) Co., Ltd Unité de liaison à l'antigène ccr8 et ses utilisations
WO2023137466A2 (fr) 2022-01-14 2023-07-20 Qilu Puget Sound Biotherapeutics Corporation Anticorps anti-ccr8
WO2023174396A1 (fr) 2022-03-18 2023-09-21 北京天诺健成医药科技有限公司 Développement et utilisation d'un nouvel immunomodulateur
WO2023193732A1 (fr) 2022-04-07 2023-10-12 盛禾(中国)生物制药有限公司 Anticorps anti-ccr8 ou fragment de liaison à l'antigène de celui-ci
WO2023201812A1 (fr) 2022-04-18 2023-10-26 深圳市华星光电半导体显示技术有限公司 Procédé et appareil d'ajustement d'image d'affichage, et appareil d'affichage
WO2023206938A1 (fr) 2022-04-26 2023-11-02 深圳市体内生物医药科技有限公司 Cellules t porteurs de récepteur antigénique chimérique ciblant ccr8, leur procédé de préparation et leur utilisation
WO2023206350A1 (fr) 2022-04-29 2023-11-02 Analytical Biosciences Shanghai Limited Anticorps anti-ccr8 et leurs utilisations
WO2023219147A1 (fr) 2022-05-13 2023-11-16 塩野義製薬株式会社 Nouveaux anticorps anti-ccr8 pour la détection de ccr8
WO2023230473A1 (fr) 2022-05-24 2023-11-30 Bristol-Myers Squibb Company Anticorps se liant au ccr8 humain
WO2024240224A1 (fr) 2023-05-23 2024-11-28 再鼎医药(上海)有限公司 Formulation comprenant un anticorps anti-ccr8 et son utilisation
WO2025011439A1 (fr) 2023-07-07 2025-01-16 齐鲁制药有限公司 Préparation pharmaceutique d'anticorps monoclonal anti-ccr8 humain et son utilisation

Non-Patent Citations (32)

* Cited by examiner, † Cited by third party
Title
"GenBank", Database accession no. Q9NZQ7
"Remington's Pharmaceutical Sciences", 1990, MACK PUB. CO
"Response Evaluation Criteria in Solid Tumors", 2000
ALMAGRO, JUAN C. ET AL.: "Progress and challenges in the design and clinical development of antibodies for cancer therapy.", FRONTIERS IN IMMUNOLOGY, vol. 8, 2018, pages 1751
BARINGTONLINE ET AL.: "Role of conserved disulfide bridges and aromatic residues in extracellular loop 2 of chemokine receptor CCR8 for chemokine and small molecule binding.", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 291, no. 31, 2016, pages 16208 - 16220, XP093167668, DOI: 10.1074/jbc.M115.706747
BRÜGGEMANNMARIANNE ET AL.: "Human antibody production in transgenic animals", ARCHIVUM IMMUNOLOGIAE ET THERAPIAE EXPERIMENTAL, vol. 63, no. 2, 2015, pages 101 - 108
CANFIELDSTEPHEN M.SHERIE L. MORRISON: "The binding affinity of human IgG for its high affinity Fc receptor is determined by multiple amino acids in the CH2 domain and is modulated by the hinge region.", THE JOURNAL OF EXPERIMENTAL MEDICINE, vol. 173, no. 6, 1991, pages 1483 - 1491
CARTERPAUL J: "Potent antibody therapeutics by design.", NATURE REVIEWS IMMUNOLOGY, vol. 6, no. 5, 2006, pages 343 - 357, XP007901440, DOI: 10.1038/nri1837
CHOTHIACYRUSARTHUR M. LESK: "Sequences of Proteins of Immunological Interest", vol. 196, 1987, NATL. INST. HEALTH, article "Canonical structures for the hypervariable regions of immunoglobulins.", pages: 901 - 917
DALL' ACQUAWILLIAM F. ET AL.: "Increasing the affinity of a human IgG1 for the neonatal Fc receptor: biological consequences.", THE JOURNAL OF IMMUNOLOGY, vol. 169, no. 9, 2002, pages 5171 - 5180
DU, YI ET AL.: "Chromatographic analysis of the acidic and basic species of recombinant monoclonal antibodies.", MABS, vol. 4, no. 5, 2012, pages 578 - 85, XP055077895, DOI: 10.4161/mabs.21328
FRENZELANDRETHOMAS SCHIRRMANNMICHAEL HUST: "MAbs", vol. 10, 2016, TAYLOR & FRANCIS, article "Establishing in vitro in vivo correlations to screen monoclonal antibodies for physicochemical properties related to favorable human pharmacokinetics."
GUTIÉRREZJULIO ET AL.: "Analysis of post-translational CCR8 modifications and their influence on receptor activity.", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 279, no. 15, 2004, pages 14726 - 14733, XP002459212, DOI: 10.1074/jbc.M309689200
HARAYAKENTATATSUHIKO TACHIBANATOMOYUKI IGAWA: "Improvement of pharmacokinetic properties of therapeutic antibodies by antibody engineering.", DRUG METABOLISM AND PHARMACOKINETICS, vol. 34, no. 1, 2019, pages 25 - 41, XP055813448, DOI: 10.1016/j.dmpk.2018.10.003
HOLTLUCY J. ET AL.: "Domain antibodies: proteins for therapy.", TRENDS IN BIOTECHNOLOGY, vol. 21, no. 11, 2003, pages 484 - 490, XP004467495, DOI: 10.1016/j.tibtech.2003.08.007
HSIEHYAO-TE ET AL.: "Characterization of FcyRIIIA effector cells used in in vitro ADCC bioassay: comparison of primary NK cells with engineered NK-92 and Jurkat T cells.", JOURNAL OF IMMUNOLOGICAL METHODS, vol. 441, 2017, pages 56 - 66
JAINTUSHAR ET AL.: "Biophysical properties of the clinical-stage antibody landscape.", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 114, no. 5, 2017, pages 944 - 949
JONES, PETER T. ET AL.: "Replacing the complementarity-determining regions in a human antibody with those from a mouse.", NATURE, vol. 321, no. 6069, 1986, pages 522 - 525
KOHLERGEORGESCESAR MILSTEIN: "Continuous cultures of fused cells secreting antibody of predefined specificity.", NATURE, vol. 256, no. 5517, 1975, pages 495 - 497
LEECHANG-HAN ET AL.: "An engineered human Fc domain that behaves like a pH-toggle switch for ultra-long circulation persistence.", NATURE COMMUNICATIONS, vol. 10, no. 1, 2019, pages 1 - 11
LUNDJOHN ET AL.: "Human Fc gamma RI and Fc gamma Rll interact with distinct but overlapping sites on human IgG.", THE JOURNAL OF IMMUNOLOGY, vol. 147, no. 8, 1991, pages 2657 - 2662, XP009546324, DOI: 10.4049/jimmunol.147.8.2657
NELSON, AARON L.EUGEN DHIMOLEAJANICE M. REICHERT: "Development trends for human monoclonal antibody therapeutics.", NATURE REVIEWS DRUG DISCOVERY, vol. 9, no. 10, 2010, pages 767 - 774, XP055161533, DOI: 10.1038/nrd3229
PLITAS, G. ET AL., ABSTRACT P4-04-11: PREFERENTIAL EXPRESSION OF THE CHEMOKINE RECEPTOR 8 (CCR8) ON REGULATORY T CELLS (TREG) INFILTRATING HUMAN BREAST CANCERS REPRESENTS A NOVEL IMMUNOTHERAPEUTIC TARGET., 2016
PLITASGEORGE ET AL.: "Regulatory T cells exhibit distinct features in human breast cancer.", IMMUNITY, vol. 45, no. 5, 2016, pages 1122 - 1134, XP029809259, DOI: 10.1016/j.immuni.2016.10.032
PRESTALEONARD G: "Antibody engineering.", CURRENT OPINION IN STRUCTURAL BIOLOGY, vol. 2, no. 4, 1992, pages 593 - 596
RIECHMANNLUTZ ET AL.: "Reshaping human antibodies for therapy.", NATURE, vol. 332, no. 6162, 1988, pages 323 - 327
RIECHMANNLUTZSERGE MUYLDERMANS: "Single domain antibodies: comparison of camel VH and camelised human VH domains.", JOURNAL OF IMMUNOLOGICAL METHODS, vol. 231, no. 1-2, 1999, pages 25 - 38
STRICKLEY ROBERT G. ET AL: "A review of formulations of commercially available antibodies", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 110, no. 7, 1 March 2021 (2021-03-01), United States, pages 2590 - 2608.e56, XP055799313, ISSN: 0022-3549, Retrieved from the Internet <URL:http://dx.doi.org/10.1016/j.xphs.2021.03.017> DOI: 10.1016/j.xphs.2021.03.017 *
WAHL, RICHARD L.CHARLES W. PARKERGORDON W. PHILPOTT: "Improved radioimaging and tumor localization with monoclonal F (ab') 2.", JOURNAL OF NUCLEAR MEDICINE: OFFICIAL PUBLICATION, SOCIETY OF NUCLEAR MEDICINE, vol. 24, no. 4, 1983, pages 316 - 325
WANG W ET AL: "ANTIBODY STRUCTURE, INSTABILITY, AND FORMULATION", JOURNAL OF PHARMACEUTICAL SCIENCES, ELSEVIER INC, UNITED STATES, vol. 96, no. 1, 1 January 2007 (2007-01-01), pages 1 - 26, XP009084505, ISSN: 0022-3549, DOI: 10.1002/JPS.20727 *
WOLFSONWENDY: "Amber codon flashing ambrx augments proteins with unnatural amino acids.", CHEMISTRY & BIOLOGY, vol. 13, no. 10, 2006, pages 1011 - 1012
ZALEVSKYJONATHAN ET AL.: "Enhanced antibody half-life improves in vivo activity.", NATURE BIOTECHNOLOGY, vol. 28, no. 2, 2010, pages 157 - 159

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