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EP3383914A1 - Anticorps anti-ox40 et leurs procédés d'utilisation - Google Patents

Anticorps anti-ox40 et leurs procédés d'utilisation

Info

Publication number
EP3383914A1
EP3383914A1 EP16871651.2A EP16871651A EP3383914A1 EP 3383914 A1 EP3383914 A1 EP 3383914A1 EP 16871651 A EP16871651 A EP 16871651A EP 3383914 A1 EP3383914 A1 EP 3383914A1
Authority
EP
European Patent Office
Prior art keywords
antibody
human
antigen
heavy chain
seq
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.)
Withdrawn
Application number
EP16871651.2A
Other languages
German (de)
English (en)
Other versions
EP3383914A4 (fr
Inventor
Nicholas S. Wilson
Jeremy D. WAIGHT
Ekaterina V. Breous-Nystrom
Gerd Ritter
David SCHAER
Daniel HIRSCHHORN-CYMERMAN
Taha MERGHOUB
Volker Seibert
Marc VAN DIJK
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ludwig Institute for Cancer Research Ltd
Memorial Sloan Kettering Cancer Center
Agenus Inc
Original Assignee
Ludwig Institute for Cancer Research Ltd
Memorial Sloan Kettering Cancer Center
Agenus Inc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Ludwig Institute for Cancer Research Ltd, Memorial Sloan Kettering Cancer Center, Agenus Inc filed Critical Ludwig Institute for Cancer Research Ltd
Publication of EP3383914A1 publication Critical patent/EP3383914A1/fr
Publication of EP3383914A4 publication Critical patent/EP3383914A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2878—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 NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/35—Valency
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/70578—NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30 CD40 or CD95

Definitions

  • an isolated antibody that specifically binds to human OX40 comprises:(A) an antigen-binding domain that specifically binds to human OX40 comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO:54, wherein the antigen-binding domain comprises a first heavy chain constant region comprising a F405L or a K409R mutation, numbered according to the EU numbering system; and (B) a heavy chain comprising a second heavy chain constant region comprising a F405L or a K409R mutation, or a fragment thereof comprising the F405L or K409R mutation, numbered according to the EU numbering system; wherein the first heavy chain constant region and the second heavy chain constant region contain different mutations.
  • the heavy chain comprising a second heavy chain constant region or fragment thereof is from an antigen-binding domain that specifically binds to a non-human antigen. In one aspect, the heavy chain comprising a second heavy chain constant region or fragment thereof is from an antigen-binding domain that specifically binds to a viral antigen. In one aspect, the viral antigen is a HIV antigen. In one aspect, the heavy chain comprising a second heavy chain constant region or fragment thereof is from an antigen-binding domain that specifically binds to chicken albumin or hen egg lysozyme.
  • antibodies described herein refer to polyclonal antibody populations.
  • Antibodies can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, or IgY), any class (e.g., IgGi, IgG 2 , IgG 3 , IgG 4 , IgAi, or IgA 2 ), or any subclass (e.g., IgG 2a or IgG 2b ) of immunoglobulin molecule.
  • antibodies described herein are IgG antibodies, or a class (e.g., human IgGi, IgG 2 , or IgG 4 ) or subclass thereof.
  • Binding affinity generally refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless indicated otherwise, as used herein, "binding affinity” refers to intrinsic binding affinity which reflects a 1 : 1 interaction between members of a binding pair (e.g., antibody and antigen).
  • the affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (K D ). Affinity can be measured and/or expressed in a number of ways known in the art, including, but not limited to, equilibrium dissociation constant (K D ), and equilibrium association constant (KA).
  • the term "host cell” can be any type of cell, e.g., a primary cell, a cell in culture, or a cell from a cell line.
  • the term “host cell” refers to a cell transfected with a nucleic acid molecule and the progeny or potential progeny of such a cell.
  • BLAST Gapped BLAST
  • PSI Blast programs the default parameters of the respective programs (e.g., of XBLAST and NBLAST) can be used (see, e.g., National Center for Biotechnology Information (NCBI) on the worldwide web, ncbi.nlm.nih.gov).
  • NCBI National Center for Biotechnology Information
  • Another specific, non-limiting example of a mathematical algorithm utilized for the comparison of sequences is the algorithm of Myers and Miller, 1988, CABIOS 4: 11 17. Such an algorithm is incorporated in the ALIGN program (version 2.0) which is part of the GCG sequence alignment software package.
  • ALIGN program version 2.0
  • an antigen-binding domain that binds to OX40 comprises the VH frameworks described herein.
  • the antigen-binding domain that binds to OX40 comprises the VH framework regions (FRs) set forth in Table 6.
  • an antigen-binding domain that binds to OX40 comprises the four VL FRs set forth in Table 4 and the four VH FRs set forth in Table 6.
  • an antigen-binding domain described herein which immunospecifically binds to OX40 (e.g., human OX40) comprises a VL domain and a VH domain comprising any amino acid sequences described herein, wherein the constant regions comprise the amino acid sequences of the constant regions of an IgG, IgE, IgM, IgD, IgA, or IgY immunoglobulin molecule, any class (e.g., IgGi, IgG 2 , IgG 3 , IgG 4 , IgAi, and IgA 2 ), or any subclass (e.g., IgG 2a and IgG 3 ⁇ 4 ) of immunoglobulin molecule.
  • OX40 e.g., human OX40
  • the second heavy chain comprises a mutation selected from the group consisting of: N297A, D265A, L234F, L235E, N297Q, P331 S, and a combination thereof, numbered according to the EU numbering system.
  • the mutation is N297A or D265A, numbered according to the EU numbering system.
  • the mutation is L234F and L235E, numbered according to the EU numbering system.
  • the mutation is L234F, L234E, and D265A, numbered according to the EU numbering system.
  • the mutation is L234F, L234E, and N297Q, numbered according to the EU numbering system.
  • the antigen-binding domain that specifically binds to OX40 can comprise any of the anti-OX40 sequences described herein.
  • the antigen-binding domain that specifically binds to OX40 comprises a VH comprising an amino acid sequence derived from a human IGHV3-73 germline sequence (e.g., IGHV3-73 *01, e.g., having the amino acid sequence of SEQ ID NO:57).
  • the antigen-binding domain that specifically binds to OX40 comprises a VL comprising an amino acid sequence that is at least 75%, 80%, 85%, 90%, 95%, or 99% identical to the amino acid sequence of SEQ ID NO:55 or SEQ ID NO:56.
  • an antibody provided herein that immunospecifically binds to OX40 contains a combination of a heavy chain and a light chain for the anti-OX40 antigen- binding domain as shown in a single row of Table 7 below.
  • an antagonistic antibody described herein which immunospecifically binds to OX40 (e.g., human OX40), inhibits, reduces, or deactivates cytokine production (e.g., IL-2, T F-a, IFN- ⁇ , IL-4, IL-10, and/or IL-13) by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%), or 99%, as assessed by methods described herein or known to one of skill in the art, relative to cytokine production in the presence or absence of OX40L (e.g., human OX40L) stimulation without any antibody or with an unrelated antibody (e.g., an antibody that does not immunospecifically bind to OX40).
  • OX40L e.g., human OX40L
  • an unrelated antibody e.g., an antibody that does not immunospecifically bind
  • T cells e.g., CD4 + or CD8 + effector T cells
  • a T cell mitogen or T cell receptor complex stimulating agent e.g., phytohaemagglutinin (PHA) and/or phorbol myristate acetate (PMA), or a TCR complex stimulating antibody, such as an anti-CD3 antibody and anti-CD28 antibody
  • PHA phytohaemagglutinin
  • PMA phorbol myristate acetate
  • a TCR complex stimulating antibody such as an anti-CD3 antibody and anti-CD28 antibody
  • OX40 e.g., human OX40
  • OX40 e.g., human OX40
  • cytokine production e.g., IL-2, TNF-a, IFN- ⁇ , IL-4, IL-10, and/or IL-13
  • cytokine production e.g., IL-2, TNF-a, IFN- ⁇ , IL-4, IL-10, and/or IL-13
  • a humanized antibody is capable of binding to a predetermined antigen and which comprises a framework region having substantially the amino acid sequence of a human immunoglobulin and CDRs having substantially the amino acid sequence of a non-human immunoglobulin ⁇ e.g., a murine immunoglobulin).
  • a humanized antibody also comprises at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.
  • the antibody also can include the CHI, hinge, CH2, CH3, and CH4 regions of the heavy chain.
  • human antibodies can be produced using mouse-human hybridomas.
  • human peripheral blood lymphocytes transformed with Epstein-Barr virus (EBV) can be fused with mouse myeloma cells to produce mouse-human hybridomas secreting human monoclonal antibodies, and these mouse-human hybridomas can be screened to determine ones which secrete human monoclonal antibodies that immunospecifically bind to a target antigen ⁇ e.g., OX40 ⁇ e.g., human OX40)).
  • EBV Epstein-Barr virus
  • OX40 ⁇ e.g., human OX40
  • Such methods are known and are described in the art, see, e.g., Shinmoto H et al, (2004) Cytotechnology 46: 19-23; Naganawa Y et al, (2005) Human Antibodies 14: 27-31.
  • a polynucleotide described herein comprises a nucleotide sequence encoding an antibody or antigen-binding domain provided herein comprising a heavy chain variable region comprising an amino acid sequence described herein (e.g., SEQ ID NO: 54), wherein the antibody or antigen-binding domain immunospecifically binds to OX40 (e.g., human OX40).
  • OX40 e.g., human OX40
  • Hybridization conditions have been described in the art and are known to one of skill in the art.
  • hybridization under stringent conditions can involve hybridization to filter-bound DNA in 6x sodium chloride/sodium citrate (SSC) at about 45°C followed by one or more washes in 0.2xSSC/0.1% SDS at about 50-65°C;
  • hybridization under highly stringent conditions can involve hybridization to filter-bound nucleic acid in 6xSSC at about 45 °C followed by one or more washes in O. lxSSC/0.2% SDS at about 68°C.
  • cells for expressing antibodies described herein are human cells, e.g., human cell lines.
  • a mammalian expression vector is pOptiVECTM or pcDNA3.3.
  • bacterial cells such as Escherichia coli, or eukaryotic cells (e.g., mammalian cells), especially for the expression of whole recombinant antibody molecule, are used for the expression of a recombinant antibody molecule.
  • the antibodies described herein have reduced fucose content or no fucose content.
  • Such antibodies can be produced using techniques known one skilled in the art.
  • the antibodies can be expressed in cells deficient or lacking the ability of to fucosylate.
  • cell lines with a knockout of both alleles of al,6- fucosyltransferase can be used to produce antibodies with reduced fucose content.
  • the Potelligent ® system (Lonza) is an example of such a system that can be used to produce antibodies with reduced fucose content.
  • an antibody molecule described herein can be purified by any method known in the art for purification of an immunoglobulin molecule, for example, by chromatography (e.g., ion exchange, affinity, particularly by affinity for the specific antigen after Protein A, and sizing column chromatography), centrifugation, differential solubility, or by any other standard technique for the purification of proteins. Further, the antibodies described herein can be fused to heterologous polypeptide sequences described herein or otherwise known in the art to facilitate purification.
  • An anti-OX40 antibody described herein can be used for prognostic, diagnostic, monitoring and screening applications, including in vitro and in vivo applications well known and standard to the skilled artisan and based on the present description.
  • Prognostic, diagnostic, monitoring and screening assays and kits for in vitro assessment and evaluation of immune system status and/or immune response may be utilized to predict, diagnose and monitor to evaluate patient samples including those known to have or suspected of having an immune system-dysfunction or with regard to an anticipated or desired immune system response, antigen response or vaccine response.
  • an anti-OX40 antibody can be used in immunohistochemistry of biopsy samples.
  • detection may be accomplished by any of the presently utilized colorimetric, spectrophotometric, fiuorospectrophotometric, amperometric or gasometric techniques as known in the art. This can be achieved by contacting a sample or a control sample with an anti-OX40 antibody under conditions that allow for the formation of a complex between the antibody and OX40. Any complexes formed between the antibody and OX40 are detected and compared in the sample and the control.
  • the antibodies described herein for OX40 the antibodies thereof can be used to specifically detect OX40 expression on the surface of cells.
  • the antibodies described herein can also be used to purify OX40 via immunoaffinity purification.
  • Antibody reactive or non-reactive cell pools were expanded again in tissue culture and, due to the stable expression phenotype of retrovirally transduced cells, cycles of antibody- directed cell sorting and tissue culture expansion were repeated, up to the point that a clearly detectable anti-OX40 antibody (pabl949w, pab2049, or pabl928) non-reactive cell population was obtained.
  • This anti-OX40 antibody non-reactive cell population was subjected to a final, single-cell sorting step. After several days of cell expansion, single cell sorted cells were again tested for binding to a polyclonal anti-OX40 antibody and non-binding to monoclonal antibody pabl949w, pab2049 or pabl928 using flow cytometry.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

La présente invention concerne des anticorps qui se lient spécifiquement au récepteur OX40 d'origine humaine (OX40) et des compositions comprenant ces anticorps. Selon un aspect spécifique, les anticorps se lient spécifiquement à OX40 d'origine humaine et modulent l'activité d'OX40, par exemple ils réduisent, désactivent ou inhibent l'activité d'OX40.<i /> L'invention concerne également des méthodes de traitement de maladies ou d'affections auto-immunes ou inflammatoires, en administrant un anticorps qui se lie spécifiquement à OX40 d'origine humaine et module l'activité d'OX40, par exemple il réduit, désactive ou inhibe l'activité d'OX40.<i />.
EP16871651.2A 2015-12-02 2016-12-02 Anticorps anti-ox40 et leurs procédés d'utilisation Withdrawn EP3383914A4 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201562262371P 2015-12-02 2015-12-02
PCT/US2016/064794 WO2017096281A1 (fr) 2015-12-02 2016-12-02 Anticorps anti-ox40 et leurs procédés d'utilisation

Publications (2)

Publication Number Publication Date
EP3383914A1 true EP3383914A1 (fr) 2018-10-10
EP3383914A4 EP3383914A4 (fr) 2019-10-30

Family

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Family Applications (1)

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EP16871651.2A Withdrawn EP3383914A4 (fr) 2015-12-02 2016-12-02 Anticorps anti-ox40 et leurs procédés d'utilisation

Country Status (3)

Country Link
EP (1) EP3383914A4 (fr)
MA (1) MA43389A (fr)
WO (1) WO2017096281A1 (fr)

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