EP3781595A1 - Autoanticorps hautement sialylés et leurs utilisations - Google Patents
Autoanticorps hautement sialylés et leurs utilisationsInfo
- Publication number
- EP3781595A1 EP3781595A1 EP19719487.1A EP19719487A EP3781595A1 EP 3781595 A1 EP3781595 A1 EP 3781595A1 EP 19719487 A EP19719487 A EP 19719487A EP 3781595 A1 EP3781595 A1 EP 3781595A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- seq
- antibody
- fragment
- mog
- antibody according
- 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
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Classifications
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- 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
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
- C07K2317/524—CH2 domain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/72—Increased effector function due to an Fc-modification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]
Definitions
- the present invention relates to an isotype G antibody directed against an autoantigen, preferably against the native myelin oligodendrocyte glycoprotein (MOG), comprising:
- composition containing such an antibody, and to its uses in therapy, particularly in the prevention and / or treatment of multiple sclerosis.
- T and B lymphocytes are common to all autoimmune diseases, and leads to deleterious cellular and humoral inflammatory responses. Because of the presence of T cell and B cell receptors, these responses are antigen specific, which, in the case of autoimmunity, imposes targeted aggression on tissue-derived autoantigens. In fact, the antibodies and T cells isolated from the lesions react easily to the autoantigens present in the inflamed tissue.
- organ-specific autoimmune diseases are currently based on palliative approaches aimed at depleting immune cells, blocking their migration to tissue lesions, neutralizing effector cytokines, or the administration of intravenous immunoglobulins (IVIG). ).
- IVIG intravenous immunoglobulins
- MS Organ-specific autoimmune diseases include multiple sclerosis (MS).
- MS is a disease of the central nervous system (CNS).
- the CNS consists of the brain and spinal cord.
- the central nervous system is mainly composed of astrocytes, oligodendrocytes responsible for myelination, and neurons, each of which consists of a cell body and an extension (axon), surrounded by a myelin sheath. .
- This myelin sheath is used to isolate and protect nerve fibers, and also plays a role in the speed of propagation of nerve impulses carrying information along neurons.
- MS is characterized by focal lesions in the white matter in both the brain and the spinal cord.
- Pathological markers of the disease include demyelination, oligodendrocyte apoptosis, axonal scarring and finally neuronal loss. This tissue damage is caused by inflammation, as shown by the infiltration of lymphocytes and myeloid cells into the lesions. This physiopathology leads to a difficulty of conduction of nerve impulses within the axons, which causes motor, sensory and cognitive disturbances. In the more or less long term, these disorders can progress to irreversible disability.
- MS begins with a recurrence-remission phase, during which periods of active clinical deficits are followed by prolonged periods of remission.
- the inflammation disappears and repair mechanisms (remyelination) allow the patient to find a correct nerve conduction.
- repair mechanisms remyelination
- the mechanisms of remyelination are exceeded, and irreversible nerve impulse conduction disorders are established with corresponding neurological signs.
- MS is considered an autoimmune disease.
- the immune system attacks antigenic CNS targets, including myelin. All the components of the immune response participate: lymphocytes, myeloid cells, but also cytokines synthesized and released by the immune cells that sometimes favor the attack, sometimes moderate it.
- the immune response in MS is not static, it is composite and evolves over time, both in terms of antigenic specificity and in pathogenic mechanisms.
- the background treatments of MS used today act either directly on lymphocytes, either by depletion or by inhibiting their migration to the CNS, to limit the importance of inflammatory attack.
- autoimmune diseases including organ-specific autoimmune diseases.
- the present invention addresses this problem.
- an isotype G antibody directed against an autoantigen comprising:
- the inventors have identified a specific anti-MOG IgG antibody capable of curbing and / or reducing the progression of the disease.
- This antibody is derived from pathogenic clone 8-18C5 (commercially available as MAB5680 by Merck Millipore); it is able to bind to the native native human or murine MOG protein, but not to the MOG 35.55 linear fragment.
- this antibody has been modified with respect to pathogenic clone 8-18C5, in particular since it comprises a highly sialylated Fc fragment. More precisely, its Fc comprises a point deletion of glutamic acid at position 294 (the numbering being that of the EU index or equivalent in Kabat), which confers it an increased sialylation with respect to Fc which does not have this deletion .
- This deletion notably confers on the variant reduced binding affinities to Fc ⁇ RIII and Fc ⁇ RIIB, whereas the binding to FcRn is not affected; and anti-aging properties inflammatory.
- This antibody attenuates the severity of the disease in a mouse model of experimental autoimmune encephalomyelitis (EAE).
- Fc fragment or “Fc region” is meant the constant region of an immunoglobulin (antibody) of total length excluding the first immunoglobulin constant region domain (i.e. CH1-CL).
- the Fc fragment refers to a homodimer, each monomer comprising the last two constant domains of IgG (i.e. CH2 and CH3), and the flexible N-terminal hinge region of these domains.
- the Fc fragment of the antibody according to the invention is preferably a human Fc fragment and may be chosen from Fc fragments of IgG1, IgG2, IgG3 and IgG4.
- an Fc fragment of an IgG1 which consists of the N-terminal flexible hinge and CH2-CH3 domains, that is to say the portion from the amino acid, is used in the present invention.
- C226 to the C-terminus the numbering being indicated according to the EU index or equivalent in Kabat.
- an Fc fragment of a human IgG1 i.e. amino acids 226 to 447 according to the EU index or equivalent in Kabat
- the lower hinge refers to positions 226 to 230
- the CH2 domain refers to positions 231 to 340
- the CH3 domain refers to positions 341-447 according to the EU index or equivalent in Kabat.
- the Fc fragment used according to the invention may also comprise a part of the upper hinge region, upstream of the position 226.
- a Fc fragment of a human IgG1 comprising part of the region is used. located between positions 216 to 226 (according to the EU index).
- the Fc fragment of a human IgG1 refers to the portion from amino acid 216, 217, 218, 219, 220, 221, 222, 223, 224 or 225 to the C-terminus. - terminal.
- the Fc fragment of the antibody according to the invention is the Fc fragment of a IgG1.
- the Fc fragment of the antibody according to the invention is preferably human.
- Fc residues are that of the EU index or equivalent in Kabat (Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991) ). This numbering is only suitable for human Fc fragments.
- amino acid mutation is meant here a change in the amino acid sequence of a polypeptide.
- a mutation is chosen in particular from a substitution, an insertion and a deletion.
- substitution is meant the replacement of one or more amino acids at a particular position in a parent polypeptide sequence by the same number of other amino acids.
- the substitution is punctual, i.e. it concerns only one amino acid.
- the N434S substitution refers to a variant of a parent polypeptide, wherein the asparagine at position 434 of the Fc fragment according to the EU index or equivalent in Kabat is replaced by serine.
- insertion is meant the addition of at least one amino acid at a particular position in a parent polypeptide sequence.
- insertion G> 235-236 designates a glycine insertion between positions 235 and 236.
- deletion is meant the removal of at least one amino acid at a particular position in a parent polypeptide sequence.
- E294del refers to the removal of glutamic acid at position 294.
- parent polypeptide and “parent antibody” is meant respectively an unmodified polypeptide or antibody which is subsequently modified to generate a variant.
- the parent polypeptide or antibody may be of natural origin, a variant of a naturally occurring polypeptide or antibody, a modified version of a natural polypeptide or antibody, or a synthetic polypeptide or antibody.
- the parent polypeptide or antibody comprises an Fc fragment selected from wild type Fc fragments, fragments and mutants thereof. Therefore, the parent polypeptide or antibody may optionally include pre-existing amino acid modifications in the Fc fragment relative to wild-type Fc fragments.
- the Fc fragment of the parent polypeptide or antibody already comprises at least one additional mutation (ie pre-existing modification), preferably chosen from P230S, T256N, V259I, N315D, A330V, N361D, A378V, S383N, M428L. N434Y.
- the Fc fragment of the parent polypeptide or antibody is chosen from the sequences SEQ ID NO: 1, 2, 3, 4 and 5.
- the Fc fragment of the parent polypeptide or antibody has the sequence SEQ ID NO: 1.
- sequences shown in SEQ ID NOs: 1, 2, 3, 4 and 5 are free of an N-terminal hinge region.
- the sequences represented in SEQ ID NO: 6, 7, 8, 9 and 10 respectively correspond to the sequences represented in SEQ ID NOs: 1, 2, 3, 4 and 5 with their hinge regions at the N-terminal.
- the Fc fragment of the parent polypeptide or antibody is chosen from the sequences SEQ ID NO: 6, 7, 8, 9 and 10.
- the Fc fragment of the parent polypeptide or antibody has a sequence corresponding to the 1-232, 2-232, 3-232, 4-232, 5-232, 6-232, 7-232, 8-232, 9 positions. 232, 10-232 or 11-232 of the sequence SEQ ID NO: 6.
- variant is meant a polypeptide sequence which is different from the parent polypeptide sequence by at least one amino acid modification.
- the sequence of the variant has at least 80% identity with the sequence of the parent polypeptide, and more preferably at least 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%. , 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5% identity.
- percent identity between two amino acid sequences in the sense of the present invention is intended to denote a percentage of identical amino acid residues between the two sequences to be compared, obtained after the best alignment, this percentage being purely statistical and the differences between the two sequences being randomly distributed over their entire length.
- best alignment or “optimal alignment” is meant the alignment for which the percentage of identity determined as hereinafter is the highest.
- Sequence comparisons between two amino acid sequences are traditionally performed by comparing these sequences after optimally aligning them, said comparison being performed by segment or by "comparison window” to identify and compare the local regions of sequence similarity. .
- the optimal alignment of the sequences for comparison can be realized, besides manually, by means of the local homology algorithm of Smith and Waterman (1981, J. Mol Evol., 18: 38-46), by means of the local homology algorithm of Neddleman and Wunsch (1970), using the similarity search method of Pearson and Lipman (1988, PNAS, 85: 2444-2448), using computer programs using these algorithms (GAP, BESTFIT, BLAST P, BLAST N, FASTA and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, WI).
- the antibody according to the invention is chosen from IgG1, IgG2, IgG3 and IgG4, preferably IgG1.
- the antibody according to the invention can be chimeric, humanized or human.
- chimeric antibody an antibody which contains a naturally occurring variable (light chain and heavy chain) derived from an antibody of a given species in association with the constant light chain and heavy chain regions of an antibody of a heterologous species to said given species.
- the antibody is chimeric, it comprises human constant regions.
- a chimeric antibody can be prepared using genetic recombination techniques well known to those skilled in the art.
- the chimeric antibody may be made by cloning for the heavy chain and the light chain a recombinant DNA comprising a promoter and a sequence coding for the variable region of the non-human antibody, and a sequence coding for the constant region of the a human antibody.
- Verhoeyn et al Verhoeyn et al., BioEssays, 8:74, 1988.
- humanized antibody is meant an antibody which contains complementarity determining regions (CDRs) derived from an antibody of non-human origin, the other parts of the antibody molecule being derived from one or more ) human antibodies.
- CDRs complementarity determining regions
- FRs framework residues
- the humanized antibodies can be prepared by techniques known to those skilled in the art such as “CDR grafting”, “resurfacing”, “Human string content”, “FR libraries”, “Guided selection” technologies. ",” FR shuffling “and” Humaneering ", as summarized in the review by Almagro et al (Almagro et al Frontiers in Bioscience 13, 1619-1633, January 1, 2008).
- human antibody is understood to mean an antibody whose entire sequence is of human origin, that is to say whose coding sequences have been produced by recombination of human genes coding for the antibodies. Indeed, it is now possible to produce transgenic animals (for example mice) which are capable, upon immunization, of producing a complete repertoire of human antibodies in the absence of endogenous production of immunoglobulin (see Jakobovits et al. Proc Natl Acad Sci USA 90: 2551 (1993), Jakobovits et al., Nature, 362: 255-258 (1993), Bruggermann et al, Year in Immuno, 7:33 (1993), Duchosal et al.
- Human antibodies can also be obtained from phage display libraries (Hoogenboom et al., J. Mol Biol, 227: 381 (1991), Marks et al, J. Mol Biol, 222: 581-569 ( 1991), Vaughan et al Nature Biotech 14: 309 (1996).
- the antibody according to the invention is directed against an autoantigen.
- autoantigen is meant an antigen which, although a constituent of normal tissue, is the target of a humoral or cellular immune response, as in the case of an autoimmune disease (see definition in Miller-Keane encyclopedia).
- the antibody according to the invention is directed against an autoantigen chosen from the native myelin oligodendrocyte glycoprotein (MOG), the catalytic subunit 2 of glucose-6 phosphatase (IGRP, encoded by the G6PC2 gene, Q9NQR9 in Uniprot), collagen type 2 and aquaporin-4 (P55087 in Uniprot).
- MOG myelin oligodendrocyte glycoprotein
- IGRP glucose-6 phosphatase
- collagen type 2 and aquaporin-4
- autoantigens are particularly relevant for the prevention and / or treatment of an autoimmune disease chosen from:
- demyelinating diseases involving anti-MOG antibodies such as multiple sclerosis
- NMO / NMOSD Optical Neuromyelitis of Deviance
- AQP-4 aquaporin-4
- MOG Optical Neuromyelitis of Deviance
- IGRP glucose-6 phosphatase
- Oligodendrocyte Myelin Glycoprotein is one of several myelin antigens and neurons to which immune reactivity is detected in MS. This glycoprotein is a minor component of the myelin sheath that isolates CNS axons.
- the sequence of this native human protein is accessible in Uniprot with accession number Q16653.
- the mature (native) human protein contains 218 amino acids (i.e. after cleavage of the 29 amino acid signal peptide).
- the native mouse MOG sequence is accessible in Uniprot with the accession number Q61885.
- the mature (native) mouse protein contains 218 amino acids (i.e. after cleavage of the 28 amino acid signal peptide).
- the invention relates to an isotype G antibody directed against native MOG, comprising:
- the native MOG epitope consists of three loops located on the distal side of the MOG membrane, and in particular at the residues 101 -108 of sequence SEQ ID NO: 26 (R101 DHSYQEE108, corresponding to residues 101-108 of the 218 of mature human MOG); these residues contain a loop which forms the upper edge of the putative ligand binding site.
- the invention relates to an isotype G antibody directed against native MOG, comprising:
- an Fab fragment capable of binding to native MOG, in particular to residues 101 -108 of sequence SEQ ID NO: 26.
- the antibody according to the invention is directed against native MOG.
- it comprises the 6 CDRs of the murine antibody 8-18C5.
- it includes the following 6 CDRs:
- H-CDR1 SEQ ID NO: 1 1
- H-CDR2 SEQ ID NO: 12,
- H-CDR3 SEQ ID NO: 13
- L-CDR1 SEQ ID NO: 14
- L-CDR2 GAS
- L-CDR3 SEQ ID NO: 15.
- the antibody directed against native MOG according to the invention is chimeric and comprises as VH the sequence SEQ ID NO: 16, and as VL the sequence SEQ ID NO: 17.
- the antibody according to the invention is chimeric, and comprises as a heavy chain the sequence SEQ ID NO: 24 with the deletion of glutamic acid at position 294 in numbering of the EU index or equivalent in Kabat, and as a light chain the sequence SEQ ID NO: 25.
- the present application also describes a murine antibody directed against native MOG; typically, it comprises as a heavy chain the sequence SEQ ID NO: 19, this sequence comprising the deletion of glutamic acid at position 171, and as a light chain the sequence SEQ ID NO: 20.
- the position 171 on the murine Fc corresponds to position 294 on the human Fc with the numbering of the EU index or equivalent in Kabat.
- variable region of each of the light chains of the antibody directed against native MOG according to the invention is coded by a sequence having at least 80%, preferably at least 85%, preferably at least 90%, of preferably at least 95%, preferably at least 99% identity with the murine sequence SEQ ID NO: 17, and the variable region of each of the heavy chains of the native MOG antibody according to the invention is encoded by a sequence having at least 80%, preferably at least 85%, preferably at least 90%, preferably at least 95%, preferably at least 99%, identity with the murine nucleic acid sequence SEQ ID NO : 16.
- the antibodies of the invention also include any antibody directed against native MOG having the CDR (Complementary Determining Region) regions of the 8-18C5 antibody, associated with FR regions (framework, highly conserved regions of the variable regions, named also "frame”).
- CDR Complementary Determining Region
- FR regions frame, highly conserved regions of the variable regions, named also "frame”).
- Such antibodies have a very comparable affinity and specificity, preferably identical, to the murine 8-18C5 antibody.
- the antibody directed against native MOG according to the invention comprises the 6 CDRs of the murine 8-18C5 antibody.
- it includes the following 6 CDRs:
- H-CDR1 SEQ ID NO: 1 1
- H-CDR2 SEQ ID NO: 12,
- H-CDR3 SEQ ID NO: 13
- L-CDR1 SEQ ID NO: 14
- L-CDR2 GAS
- L-CDR3 SEQ ID NO: 15.
- the FR regions of the VL region of the antibody directed against native MOG according to the invention is coded by a sequence having at least 80%, preferably at least 85%, preferably at least 90%, preferably at least 95%, preferably at least 99% identity with the FR regions of the SEQ ID murine sequence NO: 17, and the FR regions of the VH region of the native MOG antibody according to the invention is encoded by a sequence having at least 80%, preferably at least 85%, preferably at least 90%, of preferably at least 95%, preferably at least 99% identity with the FR regions of the murine sequence SEQ ID NO: 16.
- the antibody directed against native MOG comprises, as Fc region, a human Fc region, preferably chosen from SEQ ID NO: 1 to 10, preferably the Fc region coded by SEQ ID NO: 1, and comprising the deletion of glutamic acid at position 294 in numbering of the EU index or equivalent in Kabat.
- the isotype G antibody directed against an autoantigen and in particular directed against the native myelin oligodendrocyte glycoprotein (MOG), according to the invention, can be obtained by selection on a phage library, such as in particular described in Nixon et al. , Drugs derived from phage display, From Candidate Identification to Practice, mAbs 6: 1, 73-85; January / February 2014.
- a phage library such as in particular described in Nixon et al. , Drugs derived from phage display, From Candidate Identification to Practice, mAbs 6: 1, 73-85; January / February 2014.
- the present invention also relates to an isotype G antibody composition as mentioned above, which comprises Fc fragments exhibiting high sialylation. This high sialylation on Fc is typically increased or improved over that of a parent antibody composition.
- sialylation of the Fc of the antibody composition obtained is increased by at least 10%, preferably at least 15%, preferably at least 20%, preferably at least 25%, preferably at least 30%, preferably at least 35%, preferably at least 40%, preferably at least 45%, preferably at least 50%, preferably at least 55%, preferably preferably at least 60%, preferably at least 65%, preferably at least 70%, preferably at least 75%, preferably at least 80%, preferably at least 85%, preferably at least 90%, preferably at least 95%, relative to the sialylation of Fc of said parent antibody composition.
- Sialylation of a protein is a well known glycosylation mechanism (see especially Essentials of Glycobiology, 2 nd edition, Varki et al, 2009). It corresponds to a covalent addition of at least one sialic acid (ie N-acetylneuraminic acid and its derivatives, such as N-glycosylneuraminic acid, N-acetylglycosylneuraminic acid) in the glycosylated chain of the protein.
- the sialylation on the Fc fragment is obtained by mutation of the latter.
- the Fc fragment in particular human, is modified relative to that of a parent antibody and comprises at least one amino acid mutation chosen from amino acids in position 240 to 243, 258 to 267 and 290 to 305 of said fragment Fc, the numbering being that of the EU index or equivalent in Kabat.
- the mutation is carried out on at least one amino acid of the Fc fragment located at position 240, 241, 242, 243, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 290, 291. , 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304 or 305, the numbering being that of the EU index or equivalent in Kabat.
- the mutation is selected from V262del, V263F, V263K, V263W, V264K, V264P, D265A, D265E, D265G, D265L, D265S, D265V, V266A, V266P, V266S, V266T, S267N, S267P, S267R, S267W, P291C. , P291V, P291Y, P291W, R292A, R292del,
- the Fc fragment of the antibody according to the invention is modified relative to that of a parent antibody and comprises at least the E294del mutation, the numbering being that of the EU index or equivalent in Kabat.
- the Fc fragment of the antibody according to the invention in particular human, is modified relative to that of a parent antibody and consists of the E294del mutation, the numbering being that of the EU index or equivalent in Kabat.
- the Fc fragment of the antibody according to the invention is a mouse Fc, it is modified with respect to that of a parent antibody, in particular of sequence SEQ ID NO: 18, and consists of the mutation E171 del.
- the Fc fragment of the antibody according to the invention in particular human, is modified relative to that of a parent antibody and consists of the Y300del mutation, the numbering being that of the EU index or equivalent in Kabat.
- such an antibody is produced in HEK cells.
- the antibody according to the invention has at least one effector activity mediated by said Fc fragment decreased relative to the effector activity of the parent antibody.
- Fc fragment-mediated effector activity is meant, in particular, antibody-dependent cellular cytotoxicity (ADCC), complement dependent cytotoxicity (CDC or complement dependent cytotoxicity), cell-dependent cellular phagocytosis. antibodies (ADCP), endocytosis activity or secretion of cytokines.
- ADCC antibody-dependent cellular cytotoxicity
- CDC complement dependent cytotoxicity
- ADCP antibody dependent cellular phagocytosis
- the effector activity mediated by the Fc fragment considered in the invention is selected from antibody dependent cellular cytotoxicity (ADCC), complement dependent cytotoxicity (CDC) and antibody dependent cellular phagocytosis (ADCP) and the secretion of cytokines.
- the antibody according to the invention may have at least one effector activity mediated by the abolished Fc fragment.
- the antibody according to the invention has an effector activity mediated by the Fc region decreased, relative to that of the parent antibody, by at least 10%, preferably by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.
- the antibody according to the invention is devoid of any effector activity mediated by said Fc fragment.
- the antibody according to the invention has an affinity mediated by the Fc fragment, decreased relative to the affinity of the parent antibody, for at least one of the Fc region receptors (FcR).
- FcR Fc region receptors
- Fc region receptor or “FcR” is meant in particular C1q and Fcy Receptors (FcyR).
- Fc ⁇ receptors or “Fc ⁇ R” refer to the IgG receptors, called CD64 (Fc ⁇ RIII), CD32 (Fc ⁇ RI1), and CD16 (Fc ⁇ RIII), in particular to the five expressed Fc ⁇ RIa, Fc ⁇ RIla, Fc ⁇ RIIb, Fc ⁇ RIIIa and Fc ⁇ RIIIb receptors. All are effector cell activating receptors, except for human Fc ⁇ RIIb which is an inhibitory receptor for the activation of immune cells (Muta T et al., Nature, 1994, 368: 70-73).
- the complement C1q is involved in the CDC activity.
- the FcgRIIIa receptor (CD16a) is involved in the ADCC; it has a V / F polymorphism at position 158.
- the FcgRIla receptor (CD32a) is involved in platelet activation and phagocytosis; it has an H / R polymorphism at position 131.
- FcgRIIb receptor (CD32b) is involved in the inhibition of cellular activity.
- the affinity is reduced, relative to that of the parent antibody comprising the Fc fragment, by at least 10%, preferably by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.
- the antibody according to the invention has an affinity mediated by said decreased Fc fragment relative to the affinity of the parent antibody, for at least one of the Fc region receptors (FcR) chosen from the complement C1 q and FcgRI 11a receptors (CD16a), FcgRIla (CD32a) and FcgRIIb (CD32b).
- FcR Fc region receptors
- the antibody according to the invention has an affinity mediated by said decreased Fc fragment relative to the affinity of the parent antibody, for the two C1q and CD16a receptors.
- the affinity of an antibody comprising an Fc fragment for a FcR can be evaluated by methods well known in the art. For example, one skilled in the art can determine affinity (Kd) using, for example, surface plasmon resonance (SPR), or Octet® technology (BLI technology "Bio-Layer Interferometry", Pall). Alternatively, one skilled in the art can perform an appropriate ELISA test. An appropriate ELISA assay compares the binding forces of the parent Fc and the mutated Fc. The detected signals specific for the mutated Fc and the parent Fc are compared. Binding affinity can be indifferently determined by evaluating whole antibodies or evaluating isolated Fc regions thereof.
- the IgG antibody according to the invention is directed against native MOG and comprises:
- H-CDR1 SEQ ID NO: 1 1
- H-CDR2 SEQ ID NO: 12,
- H-CDR3 SEQ ID NO: 13
- L-CDR1 SEQ ID NO: 14
- L-CDR2 GAS
- L-CDR3 SEQ ID NO: 15; and a modified human Fc fragment relative to that of a parent antibody, comprising at least one amino acid mutation chosen from amino acids at position 240 to 243, 258 to 267 and 290 to 305 of said Fc fragment, the numbering being that of the EU index or equivalent in Kabat; preferably a modified human Fc fragment relative to that of a parent antibody, comprising at least the E294del mutation (or at least the Y300del mutation), the numbering being that of the EU index or equivalent in Kabat.
- the IgG antibody according to the invention is directed against native MOG and comprises:
- H-CDR1 SEQ ID NO: 1 1
- H-CDR2 SEQ ID NO: 12,
- H-CDR3 SEQ ID NO: 13
- L-CDR1 SEQ ID NO: 14
- L-CDR2 GAS
- L-CDR3 SEQ ID NO: 15;
- mouse Fc fragment modified with respect to that of a parent antibody, comprising at least the E171 del mutation (which corresponds to E294del on the human Fc fragment with the numbering of the EU index or equivalent in Kabat).
- the mouse Fc fragment has the sequence SEQ ID NO: 18 and comprises the E171 del mutation.
- the IgG antibody as defined above is directed against native MOG and comprises:
- variable domain of the heavy chain comprising or consisting of a sequence selected from the group consisting of the sequence SEQ ID NO: 29, SEQ ID NO: 31, SEQ ID NO: 33, SEQ ID NO: 35, SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 41, SEQ ID NO: 43, SEQ ID NO: 45,
- SEQ ID NO: 47 SEQ ID NO: 49, SEQ ID NO: 51, SEQ ID NO: 53,
- SEQ ID NO: 55 SEQ ID NO: 57, SEQ ID NO: 59, SEQ ID NO: 61, SEQ ID NO: 63, SEQ ID NO: 65, SEQ ID NO: 67, SEQ ID NO: 69,
- SEQ ID NO: 58 SEQ ID NO: 6, 0SEQ ID NO: 62, SEQ ID NO: 64,
- SEQ ID NO: 66 SEQ ID NO: 68, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 74, SEQ ID NO: 76, SEQ ID NO: 78, SEQ ID NO: 80,
- the IgG antibody as defined above is directed against native MOG and comprises a variable domain of the heavy chain and a variable domain of the light chain of sequences:
- SEQ ID NO: 27 Sequence of the heavy chain of the recombinant murine 8-18C5 murine antibody of sequence SEQ ID NO: 19:
- the present invention also relates to a process for obtaining an antibody according to the invention, comprising the following steps:
- the nucleic sequence (polynucleotide or nucleotide sequence) encoding the IgG heavy chain comprises a Fc fragment having a mutation.
- the nucleic acid coding sequence for the IgG heavy chain can be synthesized chemically (Young L and Dong, 2004, Nucleic Acids Res., Apr. 15, 32 (7), Hoover, DM and Lubkowski, J. 2002). , Nucleic Acids Res., 30, Villalobos A, et al., 2006. BMC Bioinformatics, Jun 6; 7: 285).
- the nucleotide sequence encoding the IgG heavy chain can also be amplified by PCR using suitable primers.
- the nucleotide sequence encoding the IgG heavy chain can also be cloned into an expression vector.
- nucleic sequence SEQ ID NO: 27 (coding for the heavy chain SEQ ID NO: 19).
- nucleic sequence provided in i) (polynucleotide), which encodes the parent polypeptide, is then modified to obtain a nucleic sequence encoding the variant.
- This step is the actual mutation stage. It can be carried out by any method known from the prior art, in particular by directed mutagenesis.
- amino acid substitutions and deletions are made by site-directed mutagenesis, using the assembly PCR technique using oligonucleotides corresponding to the inserted modifications (see, for example, Zoller and Smith, 1982, Nucl Acids Res. : 6487-6500, Kunkel, 1985, Proc Natl Acad Sci USA 82: 488).
- step ii) a nucleic sequence coding for an IgG light chain is provided, said light chain comprising in the variable domain, the 3 binding CDRs of the same autoantigen as that targeted in i).
- nucleic acid sequence SEQ ID NO: 28 (encoding the light chain SEQ ID NO: 20) can be used.
- step iii) the nucleic sequences obtained in i) and ii) are expressed in a host cell, and the antibody thus obtained is recovered.
- nucleic sequences obtained in i) and ii) can be inserted into a bicistronic vector.
- the cellular host may be chosen from prokaryotic or eukaryotic systems, for example bacterial cells, but also yeast cells or cells animals, especially mammalian cells. Insect cells or plant cells can also be used.
- the preferred host cells are the YB2 / 0 rat line, the CHO hamster line, in particular the CHO dhfr- and CHO Lec13 lines, the PER.C6 TM (Crucell) line and the HEK line in particular HEK293 (ATCC # CRL1573). , EB66, K562, NSO, SP2 / 0, BHK, HeLa, NIH / 3T3 or COS lines. More preferably, the YB2 / 0 rat line is used.
- These host cells for example CHO cells, may be transfected with at least one gene coding for a sialyltransferase.
- the Fc fragment of the antibody according to the invention in particular human, is modified relative to that of a parent antibody and consists of the Y300del mutation, it is produced in HEK cells such as HEK293 cells.
- the polynucleotides encoding the heavy and light chains may also comprise optimized codons, in particular for its expression in certain cells (step iii)). Codon optimization aims to replace natural codons by codons whose transfer RNA (tRNA) carrying the amino acids are most common in the cell type considered. The mobilization of frequently encountered tRNAs has the major advantage of increasing the translation speed of the messenger RNAs (mRNA) and therefore of increasing the final titre (JM Carton et al., Protein Expr Purif, 2007). Codon optimization also plays on the prediction of mRNA secondary structures that could slow down reading by the ribosomal complex. Codon optimization also has an impact on the percentage of G / C that is directly related to the half-life of the mRNAs and therefore to their translation potential (Chechetkin, J. of Theoretical Biology 242, 2006 922-934).
- Codon optimization can be done by substitution of natural codons using codon frequency (codon reading table) codons for mammals and more particularly for Homo sapiens.
- codon frequency codon reading table
- the polynucleotides encoding the heavy and light chains comprise codons optimized for expression in HEK cells, such as HEK293 cells, CHO cells, or YB2 / 0 cells. More preferably, the polynucleotides encoding the heavy and light chains comprise codons optimized for their expression in YB2 / 0 cells.
- the subject of the invention is also a composition comprising, in a physiologically acceptable medium, monoclonal antibodies according to the invention.
- monoclonal antibody or “monoclonal antibody composition”, or “mAb” for monoclonal Antibody, is meant a composition comprising antibody molecules having identical and unique antigenic specificity.
- the antibody molecules present in the composition are all encoded by the same heavy and light chain sequences and therefore have the same protein sequence.
- the subject of the invention is also the use of an antibody according to the invention, or the use of a composition as mentioned above, as a medicament.
- the antibody of the invention may be combined with pharmaceutically acceptable excipients, and optionally extended release matrices, such as biodegradable polymers, to form a therapeutic composition.
- the pharmaceutical composition may be administered orally, sublingually, subcutaneously, intramuscularly, intravenously, intraarterially, intrathecally, intraocularly, intracerebrally, transdermally, pulmonally, locally or rectally.
- the active ingredient can then be administered in unit dosage form, in admixture with conventional pharmaceutical carriers.
- Unit dosage forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and oral forms of administration, aerosols, subcutaneous implants, transdermal, topical, intraperitoneal, intramuscular, intravenous, subcutaneous, intrathecal, intranasal administration forms and rectal administration forms.
- the pharmaceutical composition contains a pharmaceutically acceptable carrier for a formulation that can be injected.
- a pharmaceutically acceptable carrier for a formulation that can be injected.
- It may be in particular isotonic, sterile, saline solutions (with monosodium or disodium phosphate, sodium chloride, potassium chloride, calcium or magnesium chloride and the like, or mixtures of such salts), or freeze-dried compositions which, when adding sterilized water or physiological saline as appropriate, allow the constitution of injectable solutions.
- Dosage forms suitable for injectable use include sterile aqueous solutions or dispersions, oily formulations, including sesame oil, peanut oil, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
- the form must be sterile and must be fluid to the extent that it must be injected by syringe. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
- the dispersions according to the invention can be prepared in glycerol, liquid polyethylene glycols or mixtures thereof, or in oils. Under normal conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
- the pharmaceutically acceptable carrier may be a solvent or dispersion medium containing, for example, water, ethanol, a polyol (eg, glycerine, propylene glycol, polyethylene glycol, and the like), suitable mixtures of these, and / or vegetable oils.
- a surfactant such as lecithin.
- Prevention of the action of microorganisms can be caused by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid or thimerosal. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride.
- Prolonged absorption of the injectable compositions may be caused by the use in the compositions of agents delaying absorption, for example, aluminum monostearate or gelatin.
- Sterile injectable solutions are prepared by incorporating the active ingredients in the required amount in the appropriate solvent with several of the other ingredients listed above, if appropriate, followed by sterilization by filtration.
- the dispersions are prepared by incorporating the sterilized active ingredients into a sterile vehicle that contains the basic dispersion medium and the other required ingredients from those enumerated above.
- the preferred methods of preparation are vacuum drying and lyophilization.
- the solutions will be administered in a manner compatible with the dosage formulation and in a therapeutically effective amount.
- the formulations are easily administered in a variety of dosage forms, such as the injectable solutions described above, but drug release capsules and the like can also be used.
- aqueous solutions For parenteral administration in an aqueous solution for example, the solution should be suitably buffered and the liquid diluent rendered isotonic with sufficient saline or glucose.
- aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
- sterile aqueous media that can be used are known to those skilled in the art.
- a dose may be dissolved in 1 ml of isotonic NaCl solution and then added to 1000 ml of appropriate liquid, or injected at the proposed site of the infusion. Certain dosage variations may be applied depending on the condition of the subject being treated.
- the pharmaceutical composition of the invention can be formulated in a therapeutic mixture comprising about 0.0001 to 1.0 milligrams, about 0.001 to 0.1 milligrams, about 0.1 to 1.0 milligrams, or about 10 milligrams per dose or more. Multiple doses may also be administered.
- the specific therapeutically effective dose level for a particular patient may depend on a variety of factors, including the disorder being treated and the severity of the disease, the activity of the specific compound employed, the specific composition used, the age the body weight, general health, sex and diet of the patient, the time of administration, the route of administration, the rate of excretion of the specific compound used, the duration of treatment, or the drugs used in parallel.
- the present invention relates to the use of an antibody according to the invention in the prevention and / or treatment of an autoimmune disease. It also relates to the use of a composition comprising monoclonal antibodies according to the invention for preventing and / or treating an autoimmune disease.
- the autoimmune disease is chosen from:
- demyelinating diseases involving anti-MOG antibodies such as multiple sclerosis
- NMO / NMOSD optic neuromyelitis
- AQP-4 aquaporin-4
- MOG metal-oxide-semiconductor
- Type 1 diabetes particularly by targeting the catalytic subunit 2 of glucose-6 phosphatase (IGRP).
- IGRP glucose-6 phosphatase
- the IGRP is specific to islets of Langerhans;
- the antibody or the composition according to the invention is used in the prevention and / or treatment of a demyelinating disease involving anti-MOG antibodies.
- Such a disease is preferably selected from acute disseminated encephalomyelitis (ADEM), deviant optic neuromyelitis (NMO / NMOSD) and multiple sclerosis (MS).
- ADAM acute disseminated encephalomyelitis
- NMO / NMOSD deviant optic neuromyelitis
- MS multiple sclerosis
- Figure 1 Pilot experiment of variants treated with the 8-18C5 antibody in an EAE model with MOG35 55
- the data are represented on average + / - SEM.
- FIG. 4 Western blot using sialic acid-specific lectin (SNA) at A2.6 for the different antibodies: antibody 8-18C5-Del produced in YB2 / 0 cells ("Del (YB2 / 0)"), antibodies 8-18C5-WT produced in YB2 / 0 cells (“WT (YB2 / 0)”) and 8-18C5-WT antibody produced in HEK cells (“WT (HEK)”).
- SNA sialic acid-specific lectin
- Fc engineering was performed from a DNA vector encoding the IgGI recombinant mouse mAb 8-18C5 clone.
- the inventors have created the in silico cloning construct by associating the sequences coding for a consensus constant domain with the variable domain (Fab) of mAb 8-18C5.
- the crystallized structure of the Fab 8-18C5 fragment is available in PDB (Protein Data Bank) under accession number 1 PKQ.
- PDB Protein Data Bank
- the inventors have chosen a consensus sequence of a murine IgG1 (Mus musculus, IGHG1 * 01) listed in the IMGT online database (Immunogenetics).
- Sequences corresponding to the heavy and light chains were synthesized in vitro and cloned into separate pCDNA3 vectors (eg, Geneart). Both sequences were then subcloned into a single mammalian bicistronic vector, allowing the production of murine mAb 8-18C5 (8-18C5-WT).
- the inventors have created a deletion homologous to the human E294Del deletion (the numbering being that of the EU index or equivalent in Kabat): they have deleted the glutamic acid at position 171 of SEQ ID NO: 18 (constant region) of Recombinant mAb 8-18C5 to obtain the 8-18C5-Del variant.
- Recombinant murine 8-18C5 murine antibody 8-18C5-WT was produced in HEK cells.
- the recombinant 8-18C5 murine 8-18C5-WT and 8-18C5-Del variant murine antibodies were produced in YB2 / 0 cells to optimize the level of sialylation (50-90%).
- the YB2 / 0 cell line makes it possible to obtain an 8-18C5-Del variant, with a very high level of sialylation.
- the 8-18C5-WT and 8-18C5-Del antibodies were purified on protein G and characterized by SDS-PAGE and SEC, for validate their purity (> 97%) and their integrity (aggregated rates ⁇ 2%).
- the binding of 8-18C5-WT and 8-18C5-Del antibodies to FcRn was measured by standard ELISA.
- Maxisorp immunoplates were coated with recombinant human or murine FcRn proteins.
- the 8-18C5-WT or 8-18C5-Del antibody solutions were added to each well at different concentrations (from 5ng / mL to 0.5pg / mL) and incubated. for 1 h 30 at 37 ° C.
- F (ab ') 2 goat anti-human HRP IgG (or anti-mouse) were then incubated in a 1/2500 th for 1 h30 at 37 ° C.
- the ELISA plates were then revealed with TMB (Pierce) and the absorbances read at 450 nm.
- FCYRS human or murine
- Table 1 Preliminary characterization of the 8-18C5-WT and 8-18C5-Del antibodies. Bonds were evaluated by ELISA on rMOG, and on FcRs of type I and FcRn murine. Since the murine IgGI isotype does not bind FcyRIA (CD64) and FcyRIV, this indicates that the 8-18C5-Del variant no longer binds any of the murine type I Fc (FcRs) receptors.
- the increase in sialylation induced by the introduction of the "Del" mutation was confirmed by Western Blot using a lectin (SNA) specific for sialic acid in A2,6 (FIG. 4). For this, after the SDS-PAGE electrophoresis step, the antibodies were transferred to a nitrocellulose membrane and then subjected to an SNA Western Blot: the conditions were as follows:
- An intact blood-brain barrier prevents the infiltration of antibodies into the CNS parenchyma. It is therefore essential to induce mild autoimmune inflammation in the CNS to "prime” the tissue. This allows the antibodies to enter the parenchyma and exert their immune function.
- the experimental model of choice is experimental autoimmune encephalomyelitis ("Experimental Autoimmune Encephalomyelitis” or EAE), a disabling inflammatory autoimmune disease of the central nervous system. Since its description in 1933, it has served as a prototypical model of hypersensitivity (especially type IV) and preclinical model of multiple sclerosis (MS) in which most of the current disease-modifying treatments have been validated.
- EAE Experimental autoimmune encephalomyelitis
- MS preclinical model of multiple sclerosis
- the most common form is active IAAE, in which a demyelinating disease is induced by immunization with the 35-55 linear peptide of the MOG protein in C57BI / 6 mice (Ramadan A, Lucca LE, Carrie N, Desbois S, Axisa PP).
- the mAb 8-18C5 is specific for a conformational epitope of MOG (Breitmaschine C, Schafer B, Pellkofer H, Huber R, Linington C, Jacob U. Demyelinating myelin oligodendrocyte glycoprotein-specific autoantibody response is focused on one dominant conformational epitope region.
- MAb 8-18C5 does not recognize the linear MOG35-55 peptide used for immunization, and only interacts with the intact native MOG protein present in the CNS.
- the immune-mediated effects induced by mAb 8-18C5 are therefore a consequence of locally native MOG binding within inflammatory lesions.
- each antibody was injected at a single dose of 50 ⁇ g / mouse.
- This dose of 2.5 mg / kg of the 8-18C5 antibody is deliberately lower than the dose of IglV to treat the same disease (4 g / kg in total: 4 x 1 g / kg).
- mice treated with the 8-18C5-WT (WT) antibody showed an aggravated EAE, which caused the death of all these mice 5-6 days after injection ( Figure 1B).
- the 8-18C5-Del variant provides the opposite result: this variant not only lost its inherent pathogenicity (in this case, the severity of the disease would have been similar to that of PBS-treated mice), but it attenuated the severity of the disease. None of the mice treated with the 8-18C5-Del variant died, compared to 2 out of 4 mice for PBS ( Figure 1B), the severity of I ⁇ AE stagnant at a clinical score of 2 which reflects a delay in lightening . The most severe stages of paralysis (> 3) have never been reached (Figure 1 A).
- the induction of moderate I ⁇ AE is carried out in C57BI / 6 mice by immunization with 100 ⁇ g of MOG35-55 in CFA (complete Freund's adjuvant) containing 100 ⁇ g of inactivated mycobacterium tuberculosis H37RA, followed by 2 injections of pertussis toxin at day 0 ( 200ng) and day 2 (200ng).
- CFA complete Freund's adjuvant
- pertussis toxin at day 0 ( 200ng) and day 2 (200ng).
- mice treated with the antibody 8-18C5-WT showed an aggravated EAE, which caused the death of 38% of the mice approximately 15 days after immunization ( Figure 5B and Table 2)
- the 8-18C5-Del (Del) variant lost its inherent pathogenicity (in this case, the severity of the disease would have been similar to that of the PBS-treated mice) and attenuated the severity of the disease.
- the severity of I ⁇ AE stagnates at a score of 2 and the most severe stages of paralysis are never achieved (Figure 5A).
- Table 2 Effects of treatments with PBS, 8-18C5WT 5YB2) and 8-18C5Del (Del) on mouse mortality and clinical recovery.
- the 8-18C5-Del variant enhances I ⁇ AE at a single dose, which is 400-fold lower than IgG, and 40-fold lower than recombinant sialyl variant F241A (described in Fiebiger BM, Maamary J, Pincetic A, Ravetch JV Protection in antibody and cell mediated autoimmune diseases by antiinflammatory IgG Fcs requires type II FcRs Proc Natl Acad Soi USA (2015) 12: E2385-E2394). The critical difference between these parameters is that the 8-18C5 antibody recognizes an autoantigen related to the disease.
- the inventors isolated the mononuclear cells infiltrating the brain using a Percoll gradient, and analyzed the cellular composition of the immune infiltrate by flow cytometry.
- the human scFv library (MG-UmAb) was expressed on the surface of bacteriophage M13 using standard procedures (Smith GP, Science 228: 1315 (1985)).
- E. coli XL1 -Blue bacteria containing the library to be expressed cloned into the vector pMG72, were cultured in 60 ml of 2YT medium supplemented with 100 ⁇ g / ml ampicillin, 15 ⁇ g / ml tetracycline and 1% (pg / ml).
- the phages were precipitated with PEG6000 using standard protocols, resuspended in 1 ml PBS buffer pH 7.4 and titrated by infecting XL1-Blue cells.
- phages-scFv diluted in PBS / 4% skim milk / 0.1% Tween 20 were incubated in 8 wells of Maxisorp plates (1 -2x10 11 phage / well in 100mI final) prior coated with the recombinant human protein MOG or Biotinylated MOG (on streptavidin plate) and blocked with 4% skimmed milk in PBS. After incubation for 2 hours at 37 ° C, the wells were washed 10 times with PBS / 0.1% Tween 20 and 2 times with PBS.
- the selected phages were then eluted by infection with XL1 -Blue bacteria in the exponential growth phase (2x150 ⁇ l / well, 20 min at 37 ° C without shaking). Infected bacteria were then plated on 2YT / ampicillin / glucose solid media. The next day, the cells were resuspended in 2YT medium with 15% glycerol, frozen and stored at -80 ° C until the next round of selection.
- phages were first incubated with biotinylated human MOG recombinant protein for 1 hour at room temperature with gentle shaking. Streptavidin-coated magnetic beads (Dynal) previously blocked with 4% skim milk in PBS were then added to the phages for 30 minutes at room temperature. The phage-bead complexes were washed 10 times with PBS / 0.1% Tween 20 and 2 times with PBS using a magnet. The phage-bead complexes were then used to infect 5 ml of exponentially growing XL1-Blue bacteria, which were plated on 2YT / ampicillin / glucose solid media.
- the binding characteristics of the scFvs expressed on the surface of isolated phages during screening were determined using an ELISA assay using the recombinant MOG (R & D System) protein.
- MOG R & D System
- the scFv-8-18C5 phage is expressed to serve as a positive control of the ELISA.
- scFv-phage were produced as isolated clones on a 96-well plate in 800 mI of 2YT / ampicillin / glucose cultures infected with helper phage M13K07 (as previously described). Phage produced overnight at 26 ° C were then recovered from the supernatants after 30 minutes of centrifugation at 3000g.
- the generated clones described above have a ratio greater than the ratio of the positive control 8-18C5; they therefore bind better to the MOG protein.
- the inventors isolated the mononuclear cells infiltrating the brain using a Percoll gradient, and analyzed the cellular composition of the immune infiltrate by flow cytometry.
- the amplitude of the responses of regulatory (Foxp3 +) and pathogenic (Th 1 / Th 17) T lymphocytes can be determined to formally show whether, in 8-18C5-Del treated mice, the contraction of the pathogenic response is correlated with the expansion of a response of regulatory T cells.
- MHC tetramers and T cells express a transgenic TCR specific for MOG35-55, the specificity of the regulatory and pathogenic T cell response can be established.
- the objective is to establish the central role of MOG autoantigen in mediating the therapeutic effect of monoclonal antibody 8-18C5.
- the m8-18C5-Del variant (not bound to type I receptors) will bind to type II FcRs that include, inter alia, the CD209 receptor of type C (SIGN-R1) and CD23.
- SIGN-R1 the CD209 receptor of type C
- CD23 the CD209 receptor of type C
- 8-18C5-Del and 8-18C5-WT are labeled with distinct fluorochromes, and flow cytometric cells infiltrating the brain that bind either or both antibodies are analyzed by flow cytometry.
- the profile of the type I or II Fc receptor on immune cells invading the brain is established using a flow cytometry approach.
- these approaches are performed at day 16 after immunization, by isolating the mononuclear cells infiltrating the brain using a Percoll gradient.
- the tolerogenic subsets are co-cultured with transgenic TCR T cells to demonstrate that the presentation of the MOG antigen results in the expansion of the regulatory T cells.
- neutralizing antibody approaches are used in vivo to delay the induction or function of the cells involved.
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FR1853485A FR3080376B1 (fr) | 2018-04-20 | 2018-04-20 | Autoanticorps hautement sialyles et leurs utilisations |
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CN117683131B (zh) * | 2024-01-24 | 2024-04-30 | 首都医科大学宣武医院 | 一种抗髓鞘少突胶质细胞糖蛋白(mog)抗体及其应用 |
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GB8823869D0 (en) | 1988-10-12 | 1988-11-16 | Medical Res Council | Production of antibodies |
US5175384A (en) | 1988-12-05 | 1992-12-29 | Genpharm International | Transgenic mice depleted in mature t-cells and methods for making transgenic mice |
US6150584A (en) | 1990-01-12 | 2000-11-21 | Abgenix, Inc. | Human antibodies derived from immunized xenomice |
US5545806A (en) | 1990-08-29 | 1996-08-13 | Genpharm International, Inc. | Ransgenic non-human animals for producing heterologous antibodies |
WO1995007096A1 (fr) * | 1993-09-06 | 1995-03-16 | La Trobe University | Traitement de maladies auto-immunes |
EP0690452A3 (fr) | 1994-06-28 | 1999-01-07 | Advanced Micro Devices, Inc. | Mémoire électriquement effaçable et procédé d'effacement |
EP2233502A1 (fr) * | 2009-03-27 | 2010-09-29 | Deutsches Rheuma-Forschungszentrum Berlin | Anticorps spécifiques à l'antigène syalilé pour le traitement ou prophylaxie des réactions immunitaires inflammatoires non désirables et leurs procédés de production |
AU2011258425B2 (en) * | 2010-05-27 | 2015-12-10 | Merck Sharp & Dohme Llc | Method for preparing antibodies having improved properties |
UY33492A (es) * | 2010-07-09 | 2012-01-31 | Abbott Lab | Inmunoglobulinas con dominio variable dual y usos de las mismas |
AR085302A1 (es) * | 2011-02-24 | 2013-09-18 | Sanofi Sa | Metodo de produccion de anticuerpos sialilados |
EP2771360A1 (fr) * | 2011-10-24 | 2014-09-03 | AbbVie Inc. | Agents de liaison immunologique dirigés contre la sclérostine |
FR3024453B1 (fr) * | 2014-08-01 | 2018-06-29 | Lab Francais Du Fractionnement | Procede de production de variants ayant un fc presentant une sialylation amelioree |
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