WO2023116770A1 - MOLÉCULES DE LIAISON POUR FCγRIIA ET LEUR UTILISATION - Google Patents

MOLÉCULES DE LIAISON POUR FCγRIIA ET LEUR UTILISATION Download PDF

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WO2023116770A1
WO2023116770A1 PCT/CN2022/140718 CN2022140718W WO2023116770A1 WO 2023116770 A1 WO2023116770 A1 WO 2023116770A1 CN 2022140718 W CN2022140718 W CN 2022140718W WO 2023116770 A1 WO2023116770 A1 WO 2023116770A1
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fcγriia
antigen
antibody
binding
cdrl1
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Chinese (zh)
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陈晓菁
陈波
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上海齐鲁制药研究中心有限公司
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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

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  • the present disclosure belongs to the field of immunology, and more specifically, the present disclosure relates to Fc ⁇ RIIA binding molecules or antigen-binding fragments thereof, nucleic acids encoding them, expression vectors and host cells, and related conjugates and compositions, as well as the above-mentioned substances in the treatment, Uses in detection and diagnosis.
  • FcyRs are a family of cell surface receptors that bind the Fc portion of antibodies of the immunoglobulin (IgG) subclass.
  • Human Fc ⁇ receptors Fc ⁇ Rs
  • Fc ⁇ Rs have diverse functions, binding affinities and cellular distributions.
  • Fc ⁇ R is a protein receptor present on the cell surface, widely expressed on various immune cells, such as B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, monocytes, neutrophils, Eosinophils, basophils, human platelets and mast cells, etc.
  • Fc ⁇ Rs In humans, there are five Fc ⁇ Rs: the high-affinity receptor Fc ⁇ RI (CD64), which can bind monomeric IgG; and the low-affinity receptors Fc ⁇ RIIA (CD32a), Fc ⁇ RIIB (CD32b), Fc ⁇ RIIIA (CD16a) and Fc ⁇ RIIIB (CD16b), It binds monomeric IgG weakly, but readily binds to immune complexes of IgG. FcyRI, FcyRIIA, FcyRIIIA and FcyRIIIB are believed to have activating properties, whereas FcyRIIB is primarily inhibitory.
  • FcyRIIB is primarily inhibitory.
  • Fc[gamma]RIIA is an activating Fc receptor that, in its intracellular tail, contains an ITAM motif, an immunoreceptor tyrosine-based activation motif (ITAM).
  • ITAM immunoreceptor tyrosine-based activation motif
  • Fc ⁇ RIIA131H also known as Fc ⁇ RIIAH or CD32a-H
  • Fc ⁇ RIIA131R also known as Fc ⁇ RIIAR or CD32a-R
  • FcyRIIA and FcyRIIB are the most closely related receptors, the extracellular regions of these receptors responsible for interaction with IgG share greater than 90% sequence identity. Sequence differences in the intracellular signaling regions of FcyRIIA and FcyRIIB mediate distinct cellular responses.
  • FcyRIIA is a low-affinity receptor for monomeric IgG that binds the Fc effector region of immunoglobulin G (IgG) as a ligand.
  • IgG immobilized on the cell surface or aggregated into immune complexes (ICs) can bind to Fc ⁇ RIIA to induce inflammatory responses in neutrophils, monocytes, platelets, and other immune cells, which is thought to lead to Heparin-induced thrombocytopenia (HIT), rheumatoid arthritis, systemic lupus erythematosus (SLE), immune thrombocytopenia (ITP) and autoimmune hemolytic anemia.
  • HIT Heparin-induced thrombocytopenia
  • SLE systemic lupus erythematosus
  • ITP immune thrombocytopenia
  • autoimmune hemolytic anemia The immune complex (IC) plays a very important role in the development of different autoimmune diseases.
  • IC is present in circulation and deposited in affected tissues and organs. Binding of ICs to immune cells bearing Fc receptors can trigger cell recruitment and activation, local inflammation, adaptive immunity, and histopathology. Immune complexes bind to activating Fc receptors (FcRs) and inhibitory FcRs expressed by innate immune effector cells such as basophils, mast cells, neutrophils, monocytes, and macrophages, thereby activating the corresponding effect response.
  • FcRs Fc receptors
  • inhibitory FcRs expressed by innate immune effector cells such as basophils, mast cells, neutrophils, monocytes, and macrophages
  • Fc ⁇ RIIA plays a critical role in IC-mediated Fc ⁇ R-dependent immune cell activation.
  • IC binding to Fc ⁇ RIIA on a type of dendritic cell called pDC drives IC-mediated type I interferon (IFN) production and is important for pathological development of SLE, psoriasis, type 1 diabetes .
  • IFN type I interferon
  • Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a systemic autoimmune disease characterized by inflammation of small vessels.
  • the pathogenesis of AAV is complex, including the pathogenic role of ANCA and neutrophils as mediators of injury, the dysregulation of the complement system, and the involvement of T cells.
  • Neutrophils are recognized to play an important role in the occurrence and development of AAV.
  • Fc ⁇ RIIA ANCA-immune complexes activate neutrophils, activate the downstream signaling pathway NADPH (reducing coenzyme), and release superoxide, thereby further activating neutrophils. So Fc ⁇ RIIA plays an important role in the occurrence and development of antineutrophil cytoplasmic antibody-associated vasculitis.
  • Fc ⁇ RIIA plays an important role in the development and pathogenesis of antibody-mediated autoimmune diseases, specifically blocking Fc ⁇ RIIA function is a potential key strategy for the treatment of these diseases.
  • antibodies against Fc ⁇ RIIA have been reported in the prior art (such as CN109863174A)
  • the purpose of the present disclosure is to provide a binding molecule capable of specifically blocking Fc ⁇ RIIA while hardly binding to Fc ⁇ RIIB and an antigen-binding fragment thereof, the binding molecule or an antigen-binding fragment thereof capable of specifically binding Fc ⁇ RIIA while hardly binding to Fc ⁇ RIIB .
  • the present disclosure provides an Fc ⁇ RIIA binding molecule or an antigen-binding fragment thereof, comprising:
  • CDRH1 heavy chain complementarity determining region 1
  • CDRH2 heavy chain complementarity determining region 2
  • CDRH3 Heavy chain complementarity determining region 3
  • CDRL1 light chain complementarity determining region 1
  • CDRL1-L26 S-W and/or CDRL1-L27c L-P a) CDRL1-L26 S-W and/or CDRL1-L27c L-P;
  • CDRL1-L24 R-L and/or CDRL1-L27c L-P b) CDRL1-L24 R-L and/or CDRL1-L27c L-P
  • CDRL1-L24 R-L and/or CDRL1-L26 S-W CDRL1-L26 S-W
  • CDRL2 light chain complementarity determining region 2
  • CDRL3 Light chain complementarity determining region 3
  • CDRH2-H61 D-V means that the D at position 61 of the complementarity determining region 2 of the heavy chain is mutated to V
  • CDRL1-L24 R-L means that the R at position 24 of the light chain complementarity determining region 1 is mutated to L
  • the rest are analogous .
  • the amino acid sequence of the light chain complementarity determining region 1 (CDRL1) of the Fc ⁇ RIIA binding molecule or antigen-binding fragment thereof is shown in SEQ ID NO: 11.
  • the Fc ⁇ RIIA-binding molecule or antigen-binding fragment thereof comprises:
  • the heavy chain variable region as shown in SEQ ID NO: 9, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, A heavy chain variable region of 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% amino acid sequence identity; and/or;
  • the light chain variable region as shown in SEQ ID NO: 10, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, Light chain variable regions of 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% amino acid sequence identity.
  • the Fc ⁇ RIIA binding molecule of the present disclosure or an antigen-binding fragment thereof further comprises a heavy chain constant region and/or a light chain constant region; preferably, the heavy chain constant region comprises Fc; more preferably, the Fc is derived from a mouse or a human; more preferably Preferably, the sequence of the Fc is native or modified.
  • the heavy chain constant region is a human IgG1 heavy chain constant region, and the sequence is from the Uniprot database, and the number is P01857 (https://www.uniprot.org/uniprot/P01857); the light chain constant region is human kappa light
  • the chain constant region, the sequence is from the Uniprot database, the number is P01834 (https://www.uniprot.org/uniprot/P01834).
  • the Fc ⁇ RIIA binding molecules of the present disclosure or antigen-binding fragments thereof can be monoclonal antibodies, bispecific binding molecules, multispecific binding molecules, humanized antibodies, chimeric antibodies, modified antibodies, fully human antibodies, full-length antibodies , heavy chain antibody, Nanobody, Fab, Fv, scFv, F(ab') 2 , linear antibody or single domain antibody.
  • the present disclosure also provides a conjugate, which is formed by conjugating the Fc ⁇ RIIA binding molecule of the present disclosure or an antigen-binding fragment thereof with a capture label or a detection label or a biologically active molecule;
  • the detection markers include radionuclides, luminescent substances, colored substances or enzymes;
  • the bioactive molecule is a small molecule drug; more preferably, the Fc ⁇ RIIA binding molecule or an antigen-binding fragment thereof is connected to the bioactive molecule through a linker.
  • the present disclosure also provides a nucleic acid encoding an Fc ⁇ RIIA binding molecule of the present disclosure or an antigen-binding fragment thereof.
  • the present disclosure also provides an expression vector comprising the aforementioned nucleic acid.
  • the present disclosure also provides a host cell comprising the aforementioned nucleic acid or vector;
  • the host cell is a prokaryotic cell or a eukaryotic cell;
  • the prokaryotic cell is preferably Escherichia coli;
  • the eukaryotic cell is preferably a mammalian cell or yeast; more preferably, the mammalian cell is a CHO cell, an Expi293 cell or HEK293 cells.
  • the present disclosure also provides a composition comprising the aforementioned Fc ⁇ RIIA binding molecules or antigen-binding fragments thereof, conjugates, nucleic acids, expression vectors and/or host cells;
  • the composition is a pharmaceutical composition, which further comprises a pharmaceutically acceptable carrier; more preferably, the pharmaceutical composition further comprises one or more additional therapeutic agents;
  • the composition is a diagnostic reagent.
  • the present disclosure also provides a method for preparing the aforementioned Fc ⁇ RIIA-binding molecules or antigen-binding fragments thereof, the method comprising: culturing the aforementioned host cells under suitable conditions.
  • the present disclosure also provides the aforementioned Fc ⁇ RIIA binding molecules or antigen-binding fragments thereof, conjugates, nucleic acids, expression vectors, host cells and/or compositions in the preparation of treatment, alleviation and/or prevention of inflammatory diseases or autoimmune diseases or other Fc ⁇ RIIA Use in medicines for mediated diseases;
  • the inflammatory disease or autoimmune disease or other Fc ⁇ RIIA-mediated disease is selected from: primary immune thrombocytopenia (ITP) or antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV ).
  • the present disclosure also provides the use of the aforementioned Fc ⁇ RIIA binding molecules or antigen-binding fragments thereof, conjugates, nucleic acids, expression vectors, host cells and/or compositions in the preparation of detection reagents or diagnostic reagents, which are used for Detection or diagnosis of inflammatory diseases or autoimmune diseases or other Fc ⁇ RIIA mediated diseases.
  • the present disclosure also provides a method for treating, alleviating and/or preventing inflammatory diseases or autoimmune diseases or other Fc ⁇ RIIA-mediated diseases in a subject in need thereof, which comprises administering the aforementioned Fc ⁇ RIIA binding molecules to the subject or an antigen-binding fragment thereof, a conjugate, a nucleic acid, an expression vector, a host cell and/or a composition.
  • the present disclosure also provides a method for detecting Fc ⁇ RIIA in a sample, comprising:
  • the technical solution of the present disclosure has the following beneficial effects: (1) the antibody of the present disclosure has higher selectivity, and can specifically recognize CD32a but not CD32b; (2) Cell level tests show that the antibody of the present disclosure has stronger CD32a binding ability.
  • Figure 1A and Figure 1B show the distribution of mutation sites of positive clones after single-site mutation ELISA screening, wherein Figure 1A is the heavy chain CDR, and Figure 1B is the light chain CDR.
  • Figure 2A and Figure 2B show the ELISA experiment results of QLS0309-A, QLS0309-D, and QLS0309-G, and the antigen concentrations in Figure 2A and Figure 2B are 2 ⁇ g/ml and 0.4 ⁇ g/ml, respectively.
  • Figure 3A and Figure 3B show the dose-response curves of the binding activity of QLS0309-E to Fc ⁇ RIIA-CHO-K1 stably transfected cell lines of different species of non-human primates, wherein Figure 3A is for cynomolgus monkeys and Figure 3B is for rhesus monkeys.
  • Figure 4A and Figure 4B respectively show the secretion of human cell TNF- ⁇ and IL-6 caused by QLS0309-E blocking immune complexes
  • Figure 4C and Figure 4D respectively show the food-eating effects caused by QLS0309-E blocking immune complexes.
  • Figure 5A, Figure 5B, and Figure 5C show the results of the affinity between QLS0309-E and human monocytes, and Figure 5A, Figure 5B, and Figure 5C correspond to the results of donors Y376, 804F, and 405F, respectively.
  • Figure 6A, Figure 6B, Figure 6C, and Figure 6D show the results of the affinity between QLS0309-E and human B cells, and Figure 6A, Figure 6B, Figure 6C, and Figure 6D correspond to the results of donors Y376, 804F, 405F, and 304F, respectively.
  • Figure 7A, Figure 7B, Figure 7C, Figure 7D, and Figure 7E show the binding of QLS0309-E to different Fc ⁇ R subtypes, and the subtypes in Figure 7A, Figure 7B, Figure 7C, Figure 7D, and Figure 7E are Fc ⁇ RI, Fc ⁇ RIIA-131H, Fc ⁇ RIIB, Fc ⁇ RIII-158F, Fc ⁇ RIII-158V.
  • Figure 8A, Figure 8B, Figure 8C, and Figure 8D show the results of QLS0309-E-mediated Fc ⁇ RIIA endocytosis
  • Figure 8A, Figure 8B, Figure 8C, and Figure 8D correspond to the results of donors Y376, 804F, 405F, and 304F, respectively.
  • Figure 9A, Figure 9B, and Figure 9C are the dose-response curves for the detection of Fc ⁇ RIIB endocytosis on the surface of B cells in human whole blood induced by QLS0309-E.
  • H2B is an Fc ⁇ RIIIB-recognizing antibody.
  • Figure 9A, Figure 9B, and Figure 9C correspond to the results of donors Y376, 804F, and 304F, respectively.
  • Figure 10A, Figure 10B, and Figure 10C show the ability of QLS0309-E to block ANCA-induced neutrophil superoxide production, and Figure 10A, Figure 10B, and Figure 10C correspond to donors Z0231, Z0285, and Z0299, respectively.
  • the term “about” is meant to include ⁇ 20%, or in some cases ⁇ 10%, or in some cases ⁇ 5%, or within ⁇ 1% in some cases, or ⁇ 0.1% in some cases.
  • antibody herein may include whole antibodies (e.g., full-length monoclonal antibodies) and any antigen-binding fragments thereof (i.e., antigen-binding portions) or single chains thereof, and may also include whole antibodies or antigen-binding fragments thereof or single chains thereof.
  • a product with antigen-specific binding ability formed on the basis of chain modification such as linking other peptides, rearrangement of functional units, etc.).
  • an antibody typically refers to comprising two heavy (H) polypeptide chains (HC) and two light (L) polypeptide chains (LC) held together by covalent disulfide bonds and non-covalent interactions Y-tetrameric protein.
  • Natural IgG antibodies have such a structure. Each light chain consists of a variable domain (VL) and a constant domain (CL). Each heavy chain comprises a variable domain (VH) and constant region (CH).
  • IgA Five major classes of antibodies are known in the art: IgA, IgD, IgE, IgG, and IgM, and the corresponding heavy chain constant domains are called ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ , respectively.
  • IgG and IgA can be further divided into different For example, IgG can be divided into IgG1, IgG2, IgG3, IgG4, and IgA can be divided into IgA1 and IgA2.
  • the light chains of antibodies from any vertebrate species can be assigned to one of two distinct classes, called kappa and lambda, based on the amino acid sequence of their constant domains.
  • this constant region comprises three domains called CH1, CH2 and CH3 (IgM and IgE have a fourth domain, CH4).
  • CH1 and CH2 domains are separated by a flexible hinge region, which is a proline- and cysteine-rich segment of variable length.
  • Each class of antibodies further comprises interchain and intrachain disulfide bonds formed by paired cysteine residues.
  • variable region exhibits significant variation in amino acid composition from one antibody to another and is primarily responsible for antigen recognition and binding.
  • the variable regions of each light chain/heavy chain pair form the antibody combining site such that an intact IgG antibody has two binding sites (ie it is bivalent).
  • the variable region (VH) of the heavy chain and the variable region (VL) of the light chain each contain three regions of extreme variability known as hypervariable regions (HVR) or, more commonly, Complementarity determining region (CDR), VH and VL each have four framework regions FR, denoted by FR1, FR2, FR3, FR4 respectively.
  • the CDR and FR sequences typically appear in the following sequence of the heavy chain variable domain (or light chain variable domain): FR1-CDRH1(CDRL1)-FR2-CDRH2(CDRL2)-FR3-CDRH3(CDRL3)- FR4.
  • Fc is used to define the C-terminal region of an immunoglobulin heavy chain, which region comprises at least a portion of the constant region.
  • the term includes native sequence Fc regions and variant Fc regions.
  • Antibody may be used in the broadest sense herein and may include, for example, polyclonal antibodies, monoclonal antibodies, chimeric antibodies, humanized and primatized antibodies, CDR-grafted antibodies (CDR- grafted antibody), human antibody (including recombinantly produced human antibody), recombinantly produced antibody, intrabody, multispecific antibody, bispecific antibody, monovalent antibody, multivalent antibody, anti-idiotype antibody, synthetic antibody ( Including muteins and variants thereof) and the like.
  • monoclonal antibody refers to a substantially homogeneous antibody produced by a single cell clone that only targets a specific epitope.
  • Monoclonal antibodies can be prepared using various techniques known in the art, including hybridoma technology, recombinant technology, phage display technology, transgenic animals, synthetic technology or a combination of the above technologies, etc.
  • substitutions referred to in the present disclosure are preferably represented by the kabat numbering system, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Edition Public Health Service, National Institutes of Health, Bethesda, MD, 1991.
  • chimeric antibody refers to an antibody in which the variable regions are derived from one species and the constant regions are derived from another species, eg, antibodies in which the variable regions are derived from a mouse antibody and the constant regions are derived from a human antibody.
  • humanized antibody refers to an antibody in which all or part of the amino acids other than the CDRs of a non-human antibody (such as a mouse antibody) are replaced with corresponding amino acids derived from human immunoglobulins. Minor additions, deletions, insertions, substitutions or modifications of amino acids are permissible so long as they do not eliminate the ability of the antibody to bind a particular antigen.
  • a “humanized” antibody retains similar antigen specificity to the original antibody.
  • antibody fragment includes at least a portion of an intact antibody.
  • a "fragment" of an antibody molecule includes an "antigen-binding fragment” of an antibody, and the term “antigen-binding fragment” refers to a fragment of an immunoglobulin or antibody that specifically binds to a selected antigen or an immunogenic determining portion thereof. Or reacted polypeptide fragments, or fusion protein products further derived from such fragments, such as single-chain antibodies, extracellular binding regions in chimeric antigen receptors, etc.
  • Exemplary antibody fragments or antigen-binding fragments thereof include, but are not limited to: variable light chain fragments, variable heavy chain fragments, Fab fragments, F(ab') 2 fragments, Fd fragments, Fv fragments, single domain antibodies, linear Antibodies, single-chain antibodies (scFv), bispecific antibodies or multispecific antibodies formed from antibody fragments, etc.
  • an antigen refers to a substance that is recognized and specifically bound by an antibody or antibody-binding fragment.
  • an antigen can include any immunogenic fragment or determinant of a selected target, including single-epitope, multi-epitope, single-structure domains, multiple domains, complete extracellular domains (ECDs), or proteins.
  • ECDs extracellular domains
  • Peptides, proteins, glycoproteins, polysaccharides and lipids, parts thereof and combinations thereof can constitute antigens.
  • Non-limiting exemplary antigens include tumor antigens or pathogen antigens, among others.
  • Antigen can also refer to a molecule that elicits an immune response.
  • antigen or cells or preparations containing the antigen can be used to generate antibodies specific for an antigenic determinant.
  • the antigen can be an isolated full-length protein, a cell surface protein (e.g., immunized with a cell expressing at least a portion of the antigen on its surface), or a soluble protein (e.g., immunized with only the ECD portion of the protein) or protein Constructs (eg, Fc antigens).
  • the antigen can be produced in genetically modified cells. Any of the foregoing antigens may be used alone or in combination with one or more immunogenicity enhancing adjuvants known in the art.
  • the DNA encoding the antigen may be genomic or non-genomic (eg, cDNA), and may encode at least a portion of the ECD sufficient to elicit an immunogenic response.
  • Any vector may be used to transform the cells in which the antigen is expressed, including but not limited to adenoviral vectors, lentiviral vectors, plasmids, and non-viral vectors such as cationic lipids.
  • epitopes refers to a site on an antigen to which an immunoglobulin or antibody specifically binds.
  • Epitopes can be formed from contiguous amino acids, or non-contiguous amino acids that are juxtaposed by the tertiary folding of the protein. Epitopes formed from adjacent amino acids are generally maintained upon exposure to denaturing solvents, whereas epitopes formed by tertiary folding are generally lost upon denaturing solvent treatment.
  • Epitopes generally exist in a unique spatial conformation and comprise at least 3-15 amino acids.
  • Methods for determining the epitope bound by a given antibody are well known in the art, including immunoblotting and immunoprecipitation assays, among others. Methods for determining the spatial conformation of epitopes include techniques in the art, such as X-ray crystallography and two-dimensional nuclear magnetic resonance, among others.
  • bispecific binding molecule and “multispecific binding molecule” respectively refer to binding molecules (such as antibodies or molecules comprising antibody fragments) specific for two or more different antigens (or epitopes), preferably bispecific antibody.
  • variable regions in the present disclosure When using the variable regions in the present disclosure to produce antibodies, binding molecules, bispecific binding molecules or multispecific binding molecules, the constant regions are not particularly limited, and constant regions known to those skilled in the art or obtained by themselves can be used. Amino acid mutations (for example, mutations that increase or decrease binding to Fc ⁇ receptors or FcRn) can also be introduced into the constant region.
  • the method for obtaining the binding molecule, antigen-binding fragment, antibody, bispecific binding molecule or multispecific binding molecule of the present disclosure is not particularly limited, and can be obtained by any method, such as Cold Spring Harbor's Antibody Experimental Technical Guide, chapters 5-8 and 15 chapters.
  • the binding molecules, antigen-binding fragments, antibodies, bispecific binding molecules or multispecific binding molecules of the present disclosure can be prepared and purified using conventional methods. For example, cDNA sequences encoding heavy and light chains can be cloned and recombined into expression vectors.
  • the recombinant immunoglobulin expression vector can stably transfect CHO cells.
  • Stable clones are obtained by expressing antibodies that specifically bind to human antigens. Positive clones are expanded in serum-free medium in bioreactors for antibody production.
  • the culture fluid that secretes the antibody can be purified and collected using conventional techniques.
  • Antibodies can be concentrated by filtration using conventional methods. Soluble mixtures and aggregates can also be removed by conventional methods such as molecular sieves and ion exchange.
  • affinity refers to the strength of the sum of all non-covalent interactions between a single binding site of a molecule (eg, an antibody) and its binding partner (eg, an antigen).
  • KD refers to the dissociation constant for a particular antibody-antigen interaction. Binding affinity can be determined using various techniques known in the art, such as surface plasmon resonance, biolayer interferometry, dual polarization interferometry, static light scattering, dynamic light scattering, isothermal titration calorimetry, ELISA, analytical ultrafast centrifugation and flow cytometry, etc.
  • biological activity refers to the ability of an antibody to bind antigen and cause a measurable biological response, which can be measured in vitro or in vivo.
  • the pharmaceutical composition of the present disclosure can be prepared by mixing the binding molecules of the present disclosure with appropriate pharmaceutically acceptable carriers, media, etc. as needed.
  • binding molecules or antigen-binding fragments of the present disclosure can be used in combination with other drugs, and the active ingredients can be mixed together to form a single administration unit, or can be used independently as administration units.
  • an effective amount refers to the dose of a pharmaceutical formulation of an antibody or fragment of the present disclosure which, when administered to a patient in single or multiple doses, produces the desired effect in a treated patient.
  • An effective amount can be readily determined by the attending physician, who is skilled in the art, by considering various factors such as ethnic differences; body weight, age and health; the particular disease involved; the severity of the disease; the response of the individual patient; The specific antibody administered; the mode of administration; the bioavailability characteristics of the formulation administered; the chosen dosing regimen; and the use of any concomitant therapy.
  • kits or “kit” includes an effective amount of one or more pharmaceutical compositions of the present disclosure in unit dosage form.
  • a kit may contain sterile containers; such containers may be in the form of boxes, ampoules, bottles, vials, tubes, bags, blister packs, or other suitable container forms known in the art. Such containers may be made of plastic, glass, laminated paper, foil, or other materials suitable for holding medications.
  • the kit includes instructions for administering a pharmaceutical composition of the present disclosure to an individual. The instructions generally include methods of using the disclosed pharmaceutical compositions to treat diseases.
  • subject refers to any animal, such as a mammal or a marsupial.
  • Subjects of the present disclosure include, but are not limited to, humans, non-human primates (such as cynomolgus monkeys or rhesus monkeys or other types of cynomolgus monkeys), mice, pigs, horses, donkeys, cows, sheep, rats, and Any kind of poultry.
  • the term “disease” or “condition” or “disorder” and the like refers to any change or disorder that damages or interferes with the normal function of a cell, tissue or organ.
  • the “disease” includes but is not limited to: tumor, pathogenic infection, autoimmune disease, T cell dysfunction disease, or immune tolerance defect (such as transplant rejection).
  • treatment refers to clinical intervention in an attempt to alter the course of a disease caused by an individual or a cell, either for prevention or for intervention in the course of clinical pathology.
  • Therapeutic effects include, but are not limited to, preventing the occurrence or recurrence of the disease, relieving symptoms, reducing any direct or indirect pathological consequences of the disease, preventing metastasis, slowing down the progression of the disease, improving or relieving the disease, remission or improving the prognosis, etc.
  • the mutant library was divided into two parts and screened by ELISA method.
  • Fc ⁇ RIIAR, Fc ⁇ RIIB, and Fc ⁇ RIIAH antigens were used in sequence in libraries 1-23 for screening;
  • Fc ⁇ RIIB, Fc ⁇ RIIAR, and Fc ⁇ RIIAH antigens were used in sequence for screening in libraries 24-65.
  • OD450>2 were identified as positive clones; while for Fc ⁇ RIIB antigen screening, OD450 ⁇ 1 were identified as negative clones.
  • Table 2 and Table 3 The statistical results of all batch screening are shown in Table 2 and Table 3:
  • 7 double-site mutant antibody molecules were constructed by PCR site-directed mutagenesis.
  • the VH and VL sequences of the seven double-site mutations were respectively amplified, and then subcloned into the transient expression vector pCP-hCg1/ pCP-hCk (Shanghai Ruizhi Chemical Research Co., Ltd.).
  • the plasmid DNA is then extracted. Matched plasmid DNA containing heavy and light chains was transiently co-transfected into Expi293T cells, the supernatant was collected, and the expressed antibody was purified by protein A affinity chromatography.
  • the construction scheme of the double-site mutation antibody molecule is shown in Table 5.
  • the heavy chain constant region is derived from human IgG1, and the light chain constant region is derived from the human kappa light chain constant region.
  • Position numbers in the table above are expressed in the kabat numbering system.
  • FIG. 1 The 7 purified antibodies were tested by ELISA to identify their binding activity to CD32.
  • Figure 2A and Figure 2B show the results of ELISA experiments for QLS0309-A, QLS0309-D, and QLS0309-G. It can be seen that QLS0309-D and QLS0309-G have basically lost their binding properties.
  • the screening scope was narrowed down to 5 antibody molecules, QLS0309-A, QLS0309-B, QLS0309-C, QLS0309-E, QLS0309-F.
  • the ELISA data results of these five IgG molecules are shown in Table 6, among which the QLS0309-F molecule is more obvious, and the binding ability decreases the fastest after the antigen concentration decreases.
  • Example 4 Evaluation of the binding ability of candidate molecules to Fc ⁇ RIIA on the surface of human stably-transformed CD32a cells and to Fc ⁇ RIIB on the surface of human stably-transformed CD32b cells Binding evaluation
  • Table 7A is the FACS experimental data of QLS0309-A, QLS0309-B, QLS0309-C, QLS0309-D and QLS0309-G. It can be seen that the binding ability of QLS0309-D and QLS0309-G to CD32a is significantly weaker than that of other molecules. Among the remaining 3 molecules, QLS0309-B and QLS0309-C have certain binding ability to CD32b, and QLS0309-A has the weakest binding ability to CD32b.
  • Table 7B is the FACS experimental data of QLS0309-E (Note: Table 7A and Table 7B are two separate experiments), showing that QLS0309-E and VIB9600 have better binding to CD32a (decreased EC 50 ). In terms of binding ability to CD32b, among the candidate antibody molecules, QLS0309-E has significantly weaker binding ability than VIB9600. Therefore, in the next experiment, QLS0309-E was selected to continue testing.
  • QLS0309-E comprises a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:9 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO:10, wherein the amino acid sequence of CDRL1 is as shown in SEQ ID NO:11 Show.
  • Fc ⁇ RIIA In order to determine the relevant animal species for QLS0309-E pharmacokinetics and toxicology studies, according to literature research, Fc ⁇ RIIA only exists in primates, so this study limited the selection of relevant animal species to non-human primates ( In this study, cynomolgus monkeys and rhesus monkeys were selected as alternative species).
  • the Fc ⁇ RIIA amino acid sequences of humans and different animal species were checked on the uniprot website, and the homology of the amino acid sequences was compared by Clustal W. The results are shown in Table 8.
  • the Biacore 8K molecular interaction instrument was used to detect the affinity of QLS0309-E to recombinant Fc ⁇ RIIA in cynomolgus monkeys and rhesus monkeys.
  • the results showed that the affinity KD values of QLS0309-E to cynomolgus monkey and rhesus monkey Fc ⁇ RIIA were 1.43E-07M and 2.93E-07M.
  • Rhesus monkey Fc ⁇ RIIA reported on human
  • H9BMP0 named Rhesus monkey Fc ⁇ RIIA
  • CN109863174A selects the cynomolgus Fc ⁇ RIIA-V3 sequence (see CN109863174A, which is the most common variant in cynomolgus monkeys), gene synthesis and in vitro expression of these two macaque proteins to detect Fc ⁇ RIIA antibodies
  • the strength of its affinity was compared with two gene polymorphism variants (R131, H131) of human Fc ⁇ RIIA.
  • the affinity of QLS0309-E to Fc ⁇ RIIA protein of cynomolgus monkey and rhesus monkey was determined by SPR technology (Biacore 8K). As shown in Table 9, the KD value difference between QLS0309-E and human and cynomolgus monkey is within 100 times, and the KD value difference between human and rhesus monkey is more than 100 times. Therefore, cynomolgus monkeys are closer to humans than rhesus monkeys.
  • Immobilized Ligand (IgG) antigen KD(M) Cynomolgus monkey KD/human KD QLS0309-E Cynomolgus Fc ⁇ RIIA_v3 1.43E-07 the QLS0309-E Rhesus Fc ⁇ RIIA_v1 2.93E-07 the QLS0309-E Human Fc ⁇ RIIA 131H 1.94E-09 73.71134 QLS0309-E Human Fc ⁇ RIIA 131R 2.98E-09 47.98658
  • the immune complex can activate monocytes to produce TNF- ⁇ and IL-6, which are key cytokines involved in immune inflammation. By blocking the signaling pathway of Fc ⁇ RIIA, it can inhibit the growth of macrophages or monocytes. Production of pro-inflammatory factors.
  • IgIC biotin-labeled IgG-avidin immune complex
  • PBMC peripheral blood mononuclear cells
  • QLS0309-E can effectively block the secretion of TNF- ⁇ and IL-6 caused by immune complexes.
  • the EC50 of QLS0309-E in inhibiting immune complex-mediated cytokine release in cynomolgus monkey and human PBMCs was within 10-fold.
  • the related animal species of QLS0309-E is cynomolgus monkey.
  • Y376 corresponds to Y1376 in the figure
  • 804F corresponds to P121051804F in the figure
  • 405F corresponds to P121051405F in the figure, the same below.
  • Figures 5A-5C and Table 11 show the affinity results of QLS0309-E and VIB9600 to monocytes.
  • the binding ability of QLS0309-E to Fc ⁇ RIIA antigen on the surface of monocytes is enhanced.
  • H2B is the hFc ⁇ RIIB control antibody, as a negative control, only Fc[gamma]RIIB is identified; NA fits a straight line and no EC50 can be obtained.
  • QLS0309-E does not bind to Fc ⁇ RIIB on the surface of human B cells.
  • B cells express Fc ⁇ RIIB but no Fc ⁇ RIIA expression, indicating that QLS0309-E has significantly lower affinity for human B cell Fc ⁇ RIIB than VIB9600.
  • QLS0309-E has better binding specificity to Fc ⁇ RIIA than VIB9600.
  • Fc ⁇ RI, Fc ⁇ RIIA-131H, FcyRIIB, FcyRIII-158F, or FcyRIII-158V was assessed by ELISA. 0.125 ⁇ g/ml Fc ⁇ Rs (Fc ⁇ RI, Fc ⁇ RIIA-131H, Fc ⁇ RIIB, Fc ⁇ RIII-158F or Fc ⁇ RIII-158V) were added to a 96-well plate and incubated overnight at 4°C (100 ⁇ l per well).
  • detection secondary antibody 0.2 ⁇ g/ml, 50 ⁇ l per well, Peroxidase AffiniPure Donkey Anti-Human IgG, Fc ⁇ fragment specific/Jackson ImmunoResearch/709-035-098 or Peroxidase AffiniPure Goat Anti-Mouse IgG ( subclasses 1+2a+2b+3), Fc ⁇ Fragment Specific/Jackson ImmunoResearch/115-035-164, select according to whether the primary antibody is human or mouse), incubate for 1 hour, wash with PBST 10 times, add 100 microliters of TMB bottom After reacting for a certain period of time, 100 microliters of 0.2M sulfuric acid solution was added to terminate the reaction (reaction times were 20 minutes, 2.5 minutes, 10 minutes, 15 minutes, and 15 minutes), and the OD450 absorbance was detected by a microplate reader (TECAN, SPARK).
  • Anti-human IgG1 antibody was used as QLS0309-E isotype control, while antibodies H2B, VIB9600, 16-115, 3G8 were used as positive controls for Fc ⁇ RII B, Fc ⁇ RIIA, Fc ⁇ RI and Fc ⁇ RIII, respectively.
  • 16-115 is a commercial anti-FC ⁇ RIA antibody (purchased from https://www.antibodies-online.com/antibody/515560/anti-Fc+Fragment+of+IgG,+High+Affinity+Ia,+Receptor+ CD64+FCGR1A+AA+16-115+antibody/);
  • 3G8 is a commercially available anti-FC ⁇ RIIIA antibody (purchased from https://www.abcam.cn/cd16-antibody-3g8-low-endotoxin-azide-free-ab176528. html).
  • Fc ⁇ RIIA antibody After Fc ⁇ RIIA antibody binds to Fc ⁇ RIIA, it can mediate the endocytosis of Fc ⁇ RIIA. Therefore, after antigen-antibody binding, we evaluate the efficacy of candidate antibody endocytosis by detecting the expression of Fc ⁇ RIIA on the surface of human immune cells. We evaluated the efficacy of Fc ⁇ RIIA antibodies using a human PBMC endocytosis assay.
  • cloneIV.3 (IgG, stemcell, 60012FI) has the strongest binding to the Fc ⁇ RII subtype, and can simultaneously recognize Fc ⁇ RII R131 and Fc ⁇ RII H131 ( Boruchov A M, Heller G, Veri M C, et al. Activating and inhibiting IgG Fc receptors on human DCs mediate opposing functions [J]. The Journal of clinical investigation, 2005, 115(10): 2914-2923.). H2B is hFc ⁇ RIIB control antibody, as a negative control, it only recognizes Fc ⁇ RIIB.
  • QLS0309-E is the same as VIB9600, both can promote the endocytosis of FC ⁇ RIIA on the surface of monocytes
  • QLS0309-E is the same as VIB9600, both can promote the endocytosis of Fc ⁇ RIIA on the surface of monocytes
  • QLS0309-E antibody The specific binding of QLS0309-E antibody to Fc ⁇ RIIA is further different from that of VIB9600, which is also reflected in the endocytosis ability of Fc ⁇ RIIB on the surface of immune cells. Therefore, we tested the ability of candidate antibodies to internalize Fc ⁇ RIIB on the surface of B cells. In this study, QLS0309-E induced endocytosis of Fc ⁇ RIIB on the surface of B cells.
  • the main research process is to extract peripheral blood mononuclear cells from healthy donors, and after incubation with antibodies and human PBMCs, use immune cell biomarker antibodies and anti-Fc ⁇ RIIA antibodies to stain B cells (anti-CD20), and then prepare samples in Detection was performed on a flow cytometer, and the mean fluorescence intensity (MFI for short) of each concentration was calculated by software, and the half effective concentration (EC 50 hereinafter) was calculated by GraphPad software.
  • MFI mean fluorescence intensity
  • QLS0309-E has a lower affinity for Fc ⁇ RIIB than VIB9600 (does not bind to Fc ⁇ RIIB), and does not mediate endocytosis of Fc ⁇ RIIB receptors.
  • QLS0309-E can specifically recognize Fc ⁇ RIIA antigen and does not bind to Fc ⁇ RIIB, so compared with VIB9600, it will not affect the endocytosis of Fc ⁇ RIIB on the surface of B cells, while VIB9600 can recognize Fc ⁇ RIIB antigen at high concentrations and promote the endocytosis of Fc ⁇ RIIB on the surface of B cells .
  • QLS0309-E has similar binding specificity to Fc ⁇ RIIA, and reduces the binding to Fc ⁇ RIIB, which enhances the specificity of the antibody. This makes the selectivity and functionality of QLS0309-E significantly enhanced compared with VIB9600.
  • ANCA antineutrophil cytoplasmic antibody
  • AAV antineutrophil cytoplasmic antibody
  • ANCA antineutrophil cytoplasmic antibodies
  • Tumor necrosis factor eg, tumor necrosis factor
  • Tumor necrosis factor leads to neutrophil activation and, at low doses, induces synthetic expression of myeloperoxidase (MPO) in neutrophils And released from the cytoplasm to the cell membrane, where it binds to autoantibodies, activates neutrophils through Fc ⁇ RIIA, ANCA, activates the downstream signaling pathway NADPH (reducing coenzyme), releases superoxide, and plays a role in the development of AAV diseases play an important role.
  • MPO myeloperoxidase
  • DH123 is an uncharged and non-fluorescent reactive oxygen species (ROS) indicator that passively diffuses across membranes, where it is oxidized to the cationic rhodamine 123, which localizes to mitochondria and displays green fluorescence.
  • ROS reactive oxygen species
  • the neutrophils were resuspended in RPMI 1640 buffer and the cell density was adjusted, and seeded into a 96-well plate, 45 ⁇ L per well.
  • TNF- ⁇ 5 ⁇ L of TNF- ⁇ (R&D, 210-TA-020) and 1 ⁇ g/mL of anti-myeloperoxidase (MPO) antibody (Abcam, ab134132) with a final concentration of 1 ng/mL were added to the cell culture incubator (37 °C/5% CO 2 ) for 30 minutes, add dihydrohodamine (dihydrohodamine, DHR) 123 (Thermofisher Scientific, D632) at a final concentration of 1 ⁇ g/mL and incubate for 20 minutes in a cell culture incubator (37 °C/5% CO 2 ) , take it out and place it on ice for 10 minutes, collect the cell pellet by centrifugation, and resuspend in ice-cold HBSS at a density of 2x10 6 cells/mL.
  • Mean fluorescence intensity MFI was measured by flow cytometry (BD Biosciences, LSR Fortessa), and statistical differences were calculated by
  • Blank control well there is only phosphate buffered saline (PBS) in the cell suspension.
  • Positive control wells Add TNF- ⁇ and MPO antibodies to the cell suspension.
  • Test wells TNF- ⁇ and anti-MPO antibodies and humanized antibodies were added to the cell suspension.
  • FIGS 10A-10C show that QLS0309-E can specifically block the ability of anti-neutrophil cytoplasmic antibody (ANCA)-induced neutrophil activation to produce superoxide.
  • the experimental results show that: QLS0309-E has a good inhibitory ability on neutrophil superoxide production induced by anti-neutrophil cytoplasmic antibody (ANCA).
  • ANCA anti-neutrophil cytoplasmic antibody

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Abstract

L'invention concerne une molécule de liaison pour FcγRIIa ou un fragment de liaison à l'antigène de celle-ci, un acide nucléique codant pour la molécule de liaison ou le fragment de liaison à l'antigène de celle-ci, un vecteur d'expression et une cellule hôte comprenant l'acide nucléique, et un conjugué et une composition associés. L'invention concerne en outre l'utilisation de la substance mentionnée ci-dessus dans le cadre du traitement, de la détection et du diagnostic.
PCT/CN2022/140718 2021-12-22 2022-12-21 MOLÉCULES DE LIAISON POUR FCγRIIA ET LEUR UTILISATION WO2023116770A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101052653A (zh) * 2004-09-02 2007-10-10 健泰科生物技术公司 抗FcγRⅡB受体抗体及其用途
CN109863174A (zh) * 2016-04-29 2019-06-07 维埃拉生物股份有限公司 对FcγRIIA具有特异性的结合分子及其使用
WO2020191441A1 (fr) * 2019-03-25 2020-10-01 Newsouth Innovations Pty Limited Traitement de troubles des plaquettes immunitaires à l'aide de fragments de liaison à l'antigène

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CN101052653A (zh) * 2004-09-02 2007-10-10 健泰科生物技术公司 抗FcγRⅡB受体抗体及其用途
CN109863174A (zh) * 2016-04-29 2019-06-07 维埃拉生物股份有限公司 对FcγRIIA具有特异性的结合分子及其使用
WO2020191441A1 (fr) * 2019-03-25 2020-10-01 Newsouth Innovations Pty Limited Traitement de troubles des plaquettes immunitaires à l'aide de fragments de liaison à l'antigène

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Title
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CHEN, X. ET AL.: "FcγR-Binding is an Important Functional Attribute for Immune Checkpoint Antibodies in Cancer Immunotherapy", FRONTIERS IN IMMUNOLOGY, vol. 10, 26 February 2019 (2019-02-26), XP055672861, DOI: 10.3389/fimmu.2019.00292 *
RICHARDS JOHN O ET AL: "Optimization of antibody binding to FcgammaRIIa enhances macrophage phagocytosis of tumor cells.", MOLECULAR CANCER THERAPEUTICS, AMERICAN ASSOCIATION FOR CANCER RESEARCH, US, vol. 7, no. 8, 1 August 2008 (2008-08-01), US , pages 2517 - 2527, XP002590014, ISSN: 1535-7163, DOI: 10.1158/1535-7163.mct-08-0201 *
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