WO2019185502A1 - Anticorps comprenant du sulfoxyde de méthionine au niveau de l'interface ch2-ch3 - Google Patents

Anticorps comprenant du sulfoxyde de méthionine au niveau de l'interface ch2-ch3 Download PDF

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Publication number
WO2019185502A1
WO2019185502A1 PCT/EP2019/057361 EP2019057361W WO2019185502A1 WO 2019185502 A1 WO2019185502 A1 WO 2019185502A1 EP 2019057361 W EP2019057361 W EP 2019057361W WO 2019185502 A1 WO2019185502 A1 WO 2019185502A1
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igg antibody
sap
oxidised
seq
antibody according
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Wasfi Abdel Karim AL-AZZAM
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GlaxoSmithKline Intellectual Property Development Ltd
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GlaxoSmithKline Intellectual Property Development Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/40—Immunoglobulins specific features characterized by post-translational modification
    • 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
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C07K2317/526—CH3 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

Definitions

  • the present invention relates to Fc regions with improved binding to the complement protein Clq.
  • the invention also provides pharmaceutical compositions and medical uses of antibodies and fusion proteins comprising these Fc regions.
  • the classical pathway of complement is activated by antibody-antigen complexes binding to Clq (the first subcomponent of Cl).
  • Clq has six identical subunits with globular heads and collage-like tails. The heads bind to the fragment crystal I isable (Fc) regions of the antibody classes IgM and IgG (except IgG4) or directly to the pathogen surface (Vidarsson et al.,"IgG Subclasses and
  • Fc regions with improved Clq binding may lead to improved activation of the classical pathway of complement and hence to improved therapies.
  • an Fc fusion protein or IgG antibody with improved Clq binding wherein one or more methionine residues at the CH2-CH3 interface are oxidised to form methionine sulfoxide.
  • a pharmaceutical composition comprising an Fc fusion protein or antibody comprising an Fc region with improved Clq binding, wherein one or more methionine residues at the CH2-CH3 interface are oxidised to form methionine sulfoxide.
  • Figure 1 is a graph showing the change in thermal stability of an oxidised anti-SAP antibody as measured by differential scanning calorimetry and described in Example 2.
  • Figure 2 is a graph showing the NMR profile of an oxidised anti-SAP antibody as described in Example 3.
  • Figure 3 is a graph showing the conformational change in an oxidised anti-SAP antibody as measured by HDX and described in Example 4.
  • Fc region is the antibody fragment generated by digestion of an antibody with papain and comprises the CH2 and CH3 domains of the heavy chain of an immunoglobulin such as an IgGl, IgG2, IgG3, IgG4 or IgG4PE.
  • the Fc region comprises the CH2 and CH3 antibody constant domains of an IgGl heavy chain.
  • the Fc region comprises the CH2 and CH3 antibody constant domains of an IgG3 heavy chain.
  • Fc fusion protein refers to an Fc region linked (genetically or chemically) to an Fc fused binding partner, which may comprise a peptide, protein or small molecule.
  • antibody is used herein in the broadest sense to refer to immunoglobulin-like molecules and includes monoclonal, recombinant, polyclonal, chimeric, humanised, bispecific, homopenta meric and hetero-conjugate antibodies.
  • Fc regions and CH constant domains can be defined using any of the known numbering conventions, for example IMGT, EU and Kabat. Unless otherwise specified EU numbering will be used throughout this specification to identify particular regions and amino acid residues of the Fc region.
  • improved Clq binding refers to an increase in the ability of the Fc region to bind to Clq.
  • Immunnoassays well known to those skilled in the art can be used to ascertain whether modified antibodies have the desired increase in Clq binding.
  • composition refers to a composition formulated in pharmaceutically- acceptable or physiologically-acceptable solutions for administration to a cell or animal (including humans).
  • compositions of the invention may be administered in combination with other agents as well, provided that the additional agents do not adversely affect the ability of the composition to deliver the intended therapy.
  • SAP serum amyloid P component
  • H 1L1 as described in W02011/107480 comprises a human IgGl Fc region.
  • SAP-E The H 1L1 variant (SAP-E) consists of the following sequences:
  • SEP ID NO: 2 SAP-E humanised Vi variant LI amino acid sequence G351 DIQMTQSPSSLSASVGDRVTITCRASENIYSYLAWYQQKPGKAPKLLIHNAKTLAEGVPSRFSGSGSGTDFTL
  • the invention provides an Fc fusion protein or IgG antibody with improved Clq binding wherein one or more methionine residues at the CH2-CH3 interface of the Fc region are oxidised to form methionine sulfoxide.
  • the invention provides an Fc fusion protein or IgG antibody with improved Clq binding, wherein two methionine residues at the CH2-CH3 interface are oxidised to form methionine sulfoxide.
  • the invention provides an Fc fusion protein or IgG antibody with improved Clq binding, wherein a methionine residue located on each side of the CH2-CH3 interface is oxidised to form methionine sulfoxide.
  • the invention provides an Fc fusion protein or IgG antibody with improved Clq binding, wherein methionine residues in the AB-turn of the CH2 domain and the FG-loop of the CH3 interface are oxidised to form methionine sulfoxide.
  • the invention provides an Fc fusion protein or IgG antibody with improved Clq binding, wherein the methionine residue at location 252 in the CH2 AB-turn is oxidised to form methionine sulfoxide.
  • the invention provides an Fc fusion protein or IgG antibody with improved Clq binding, wherein the methionine residue at location 252 of SEQ ID NO: 3 in the CH2 AB-turn is oxidised to form methionine sulfoxide.
  • the invention provides an Fc fusion protein or IgG antibody with improved Clq binding, wherein the methionine residue at location 428 in the CH3 FG-Loop is oxidised to form methionine sulfoxide.
  • the invention provides an Fc fusion protein or IgG antibody with improved Clq binding, wherein the methionine residue at location 428 of SEQ ID NO: 3 in the CH3 FG-Loop is oxidised to form methionine sulfoxide.
  • the invention provides an Fc fusion protein or IgG antibody with improved Clq binding, wherein the methionine residues at locations 252 in the CH2 AB-turn and 428 in the CH3 FG-loop are both oxidised to form methionine sulfoxide.
  • the invention provides an Fc fusion protein or IgG antibody with improved Clq binding, wherein the methionine residues at locations 252 of SEQ ID NO: 3 in the CH2 AB-turn and 428 of SEQ ID NO: 3 in the CH3 FG-loop are both oxidised to form methionine sulfoxide.
  • an IgG antibody of the present invention may be IgGl or IgG3.
  • an IgG antibody of the present invention has the CH2 amino acid sequence of SEQ ID No: 7 and the CH3 amino acid sequence of SEQ ID NO: 8.
  • the invention provides an IgG antibody which is an anti-SAP antibody with improved Clq binding, wherein one or more methionine residues at the CH2-CH3 interface are oxidised to form methionine sulfoxide.
  • the anti-SAP antibody has the heavy chain variable region of SEQ ID NO: 1 and the variable light chain region of SEQ ID NO: 2.
  • the anti-SAP antibody has the heavy chain sequence of SEQ ID NO: 3 and the light chain sequence of SEQ ID NO: 4.
  • the invention provides a pharmaceutical composition comprising an Fc fusion protein or antibody with improved Clq binding, wherein one or more methionine residues at the CH2-CH3 interface are oxidised to form methionine sulfoxide.
  • binding protein of the invention may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising the binding protein together with a pharmaceutically acceptable excipient comprise a further aspect of the invention.
  • compositions can be administered to patients by any convenient route.
  • compositions adapted for intravenous or sub-cutaneous administration include aqueous and non-aqueous sterile injection solutions (which may contain anti-oxidants, buffers, bacteriostats and solutes which render the composition isotonic with the blood of the intended recipient) and aqueous and non-aqueous sterile suspensions (which may include suspending agents and thickening agents).
  • aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the composition isotonic with the blood of the intended recipient
  • aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze- dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • the pharmaceutical composition is administered fortnightly or monthly via intravenous injection. In another embodiment, the pharmaceutical composition is administered fortnightly or monthly via sub-cutaneous injection.
  • An expression vector may be produced by placing the polynucleotide coding sequences in operative association with conventional regulatory control sequences capable of controlling the replication and expression in, and/or secretion from, a host cell. Regulatory sequences include promoter sequences, e.g., CMV promoter, and signal sequences which can be derived from other known antibodies.
  • each polynucleotide is cloned into a separate expression vector.
  • the expression vectors are identical except insofar as the coding sequences and selectable markers are concerned. The use of different selectable markers ensures, as far as possible, that each polypeptide chain is functionally expressed.
  • all coding sequences may reside on a single vector, for example in separate expression cassettes in the same vector.
  • Suitable host cells or cell lines for the expression of the antibodies of the invention include mammalian cells such as NSO, Sp2/0, CHO (e.g. DG44), COS, HEK, a fibroblast cell (e.g., 3T3), and myeloma cells, for example, it may be expressed in a CHO or a myeloma cell.
  • mammalian cells such as NSO, Sp2/0, CHO (e.g. DG44), COS, HEK, a fibroblast cell (e.g., 3T3), and myeloma cells, for example, it may be expressed in a CHO or a myeloma cell.
  • Human cells may be used, thus enabling the molecule to be modified with human glycosylation patterns.
  • other eukaryotic cell lines may be employed.
  • the selection of suitable mammalian host cells and methods for transformation, culture, amplification, screening and product production and purification are known in the art.
  • Bacterial cells may prove useful as host cells suitable for the expression of the antibodies of the present invention (see, e.g., Pluckthun, A., Immunol. Rev., 130: 151-188 (1992)).
  • strains of yeast cells known to those skilled in the art are also available as host cells, as well as insect cells, e.g. Drosophila and Lepidoptera and viral expression systems. See, e.g. Miller et al., Genetic Engineering, 8:277-298, Plenum Press (1986) and references cited therein.
  • One method for the production of any of the antibodies described herein comprises a step of culturing the host cell described herein and recovering the binding protein produced.
  • the culture method of the present invention is a serum-free culture method, usually by culturing cells serum-free in suspension.
  • the antigen binding constructs of the invention may be purified from the cell culture contents according to standard procedures of the art, including centrifugation, ammonium sulfate precipitation, affinity columns, column chromatography, gel electrophoresis and the like. Such techniques are well known in the art.
  • the methionine residues at locations 252 and 428 may be oxidised to sulfoxide methionine by using any appropriate oxidant.
  • oxidants that are known to attack methionine is long and includes chloramines, hydrogen peroxide and hypochlorous acid (Savige et al., 1977 "Interconversion of methionine and methionine sulfoxide " Methods in Enzymoloogy 47 453- 459).
  • Example 1 Antibody binding to Clq by Surface Plasmon Resonance Clq binding activity between oxidized SAP-E and control sample was determined by Surface Plasmon Resonance (SPR).
  • SPR Surface Plasmon Resonance
  • the oxidized and control SAP-E samples (diluted within the standard curve range) were injected over the surface of a Clq sensor chip.
  • the assay utilized a mix and inject instrument function where anti-SAP and SAP antigen were mixed in a microplate to form an immune complex and then immediately injected over the immobilized Clq surface.
  • the standard curve was generated using different concentrations of anti-SAP mixed with a fixed concentration of SAP antigen.
  • the concentration of anti-SAP: SAP complex bound to Clq was calculated from the reference standard curve and reported as the Clq binding concentration.
  • the Clq binding activity was calculated by dividing the Clq binding concentration by the total protein concentration.
  • SAP antigen binding to SAP-E was also determined by SPR.
  • the SAP-E samples (diluted within the standard curve range) were injected over the surface of a CM5 sensor chip onto which they were immobilized with Protein A. Diluted SAP protein at a fixed concentration was injected and bound to the captured SAP-E reference standard, control, or sample. The concentration of SAP- E sample bound to SAP was calculated from the corresponding SAP-E reference standard calibration curve. This result was reported as functional binding of SAP-E to SAP. The specific binding activity was calculated by dividing the concentration of SAP-E bound to SAP by the total protein concentration. As shown in the table below, SAP antigen binding decreased in oxidized SAP-E compared to the control sample, while Clq binding increased for oxidized SAP-E. The results were obtained consistently in two different batches of SAP-E. The results were obtained at two different time points for each batch.
  • thermogram is normalized to protein concentration and then fitted to a non-two state model accounting for the number of the observed thermal transitions unfolding for SAP-E.
  • These measurements provide both quantitative and qualitative information, predominantly about the physical and chemical changes that are driven by endothermic and exothermic processes, and used to monitor the tertiary structure conformation, structural dynamic and flexibility, and thermal stability of SAP-E overall structure and its sub-domains.
  • the results shown in Figure 1 indicate that the first thermal transition which occurs in control SAP-E at 71 °C representing thermal unfolding of the CH2 domain, occurs at 64°C for oxi-SAP-E samples.
  • the second transition at 85°C representing the thermal transition for the Fab region was largely unaffected by oxidation.
  • the DSC results indicate the structural changes in SAP-E upon oxidation induce a reduced thermal transition temperature of the CH2 domain. This can be caused by increased structural flexibility and dynamics of the CH2 domain.
  • the product of the cross-correlation coefficients between the broad and the fine-featured components across two samples (R) is sensitive to changes in both components. Correlation coefficients are converted onto a log dB scale (S) to provide a metric that sensitively discriminates small spectral changes. Changes in protein higher order structure can ipmact chemical shifts, resonance line widths, and peak intensities in NMR spectra. All these factors are included in the correlation coefficient quantitative measurement between PROFILE NMR spectra and thus expressed structural similarity between two samples. In order to establish variability of NMR measurement and establish the threshold of significant changes in NMR spectra, repeat measurements are made for the samples to identify the measurement variability (reproducibility). Comparability between replicates on identical samples as well as samples made on separate days are calculated.
  • sample replicate statistics were compiled by averaging all possible pairwise similarity scores across six datasets for each condition consisting of two repeated measurements for each of three separate samples.
  • Samples for NMR were prepared for each mAb in the respective formulation buffers at 20 mg/mL with 7% D20 and were measured at 30° C for a duration of 22 minutes per spectrum. Spectra were additionally acquired for the formulation buffers and used for buffer subtraction according to the published PROFILE method. Measurements were performed on a 600 MHz Bruker NMR equipped with an Avance III HD console and a QCI cryoprobe.
  • Spectra were processed using the published methods using NMRPipe, and similarity metrics were calculated using the statistics package R.
  • Spectral similarity comparisons were calculated for the region of the J H NMR spectrum characteristic of resonances from amide protons and aromatic protons and nearly devoid of excipient signals (12.0 - 6.4 ppm). Residual formulation buffer signals were subtracted from the raw spectra before calculating similarity metrics, since two buffer resonances remained in the region between 12.0 and 6.4 ppm.
  • HDX protocol is as described in Anal. Chem. 2014, 86, 3468-3475: Aming Zhang, et al;
  • Figure 2 shows the differential plot of Heavy chain HDX between the oxidized and control antibody.
  • X-axis is the peptide aligned from the N-terminal to the C-terminal sequence.
  • Y-axis is the difference of deuterium incorporation between two states into the peptide.
  • the stick bars are the total difference from five time points.
  • the longer dashed lines are the criteria for significant difference at a 99% confidence interval. From the figure, it can be observed that there are two sets of segments standing out above the 99% confidence interval. The positive value indicates that there is more deuterium labeling in the oxidized state, suggesting an open solvent exposed conformation upon oxidation.
  • A Average chemical shift ranges for each type of proton are annotated above the spectrum. A spectral overlay for the region of the spectrum used in similarity calculations is show comparing the untreated 50L sample, the H2O2 treated sample, and the formulation buffer. Two regions denoted by dashed boxes enclose residual un-suppressed excipient peaks that were excised from similarity calculations.
  • B Selected spectral regions are enlarged to display notable differences upon treatment with H2O2.
  • C Similarity scores were calculated to compare intra sample reproducibility to the effect of H2O2 treatment showing the significant effect of oxidation on the higher order structure of two batches.

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
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  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

La présente invention concerne des protéines de fusion Fc ou des anticorps IgG présentant une liaison améliorée à la protéine du complément Clq, en raison d'un ou de plusieurs résidus de méthionine au niveau de l'interface CH2-CH3 qui sont oxydés pour former du sulfoxyde de méthionine. L'invention concerne également des compositions pharmaceutiques et des utilisations médicales desdits anticorps et protéines de fusion Fc.
PCT/EP2019/057361 2018-03-26 2019-03-25 Anticorps comprenant du sulfoxyde de méthionine au niveau de l'interface ch2-ch3 Ceased WO2019185502A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011030107A1 (fr) * 2009-09-10 2011-03-17 Ucb Pharma S.A. Anticorps multivalents
WO2011107480A1 (fr) 2010-03-03 2011-09-09 Glaxo Group Limited Protéines de liaison à un antigène spécifiques pour un composant p de substance amyloïde sérique

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011030107A1 (fr) * 2009-09-10 2011-03-17 Ucb Pharma S.A. Anticorps multivalents
WO2011107480A1 (fr) 2010-03-03 2011-09-09 Glaxo Group Limited Protéines de liaison à un antigène spécifiques pour un composant p de substance amyloïde sérique

Non-Patent Citations (15)

* Cited by examiner, † Cited by third party
Title
AMING ZHANG ET AL., UNDERSTANDING THE CONFORMATIONAL IMPACT OF CHEMICAL MODIFICATIONS ON MONOCLONAL ANTIBODIES WITH DIVERSE SEQUENCE VARIATION USING HYDROGEN/DEUTERIUM EXCHANGE MASS SPECTROMETRY AND STRUCTURAL MODELING
ANAL. CHEM., vol. 86, 2014, pages 3468 - 3475
AUSUBEL ET AL.: "Short Protocols in Molecular Biology", 1999, JOHN WILEY & SONS, INC.
DIEBOLDER ET AL.: "Complement is activated by IgG Hexamers assembled at the cell surface", SCIENCE, vol. 343, 2014, pages 1260, XP055268751, DOI: doi:10.1126/science.1248943
IZABELA SOKOLOWSKA ET AL: "Subunit mass analysis for monitoring antibody oxidation", MABS, vol. 9, no. 3, 3 April 2017 (2017-04-03), US, pages 498 - 505, XP055447287, ISSN: 1942-0862, DOI: 10.1080/19420862.2017.1279773 *
JINGJIE MO ET AL: "Understanding the Impact of Methionine Oxidation on the Biological Functions of IgG1 Antibodies Using Hydrogen/Deuterium Exchange Mass Spectrometry", ANALYTICAL CHEMISTRY, vol. 88, no. 19, 14 September 2016 (2016-09-14), US, pages 9495 - 9502, XP055589134, ISSN: 0003-2700, DOI: 10.1021/acs.analchem.6b01958 *
LIU H ET AL: "Mass Spectrometry Analysis of Photo-Induced Methionine Oxidation of a Recombinant Human Monoclonal Antibody", JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY, ELSEVIER SCIENCE INC, US, vol. 20, no. 3, 1 March 2009 (2009-03-01), pages 525 - 528, XP025990451, ISSN: 1044-0305, [retrieved on 20081127], DOI: 10.1016/J.JASMS.2008.11.011 *
MILLER ET AL.: "Genetic Engineering", vol. 8, 1986, PLENUM PRESS, pages: 277 - 298
PLUCKTHUN, A., IMMUNOL. REV., vol. 130, 1992, pages 151 - 188
POPPE, L.; JORDAN, J.; ROGERS, G.; SCHNIER, P., ANAL. CHEM., vol. 87, 2015, pages 5539 - 5545
RICHARDS ET AL., THERAPEUTIC CLEARANCE OF AMYLOID BY ANTIBODIES TO SERUM AMYLOID P COMPONENT, THE NEW ENGLAND JOURNAL OF MEDICINE, vol. 373, 2015, pages 1106
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SAVIGE ET AL.: "Interconversion of methionine and methionine sulfoxide", METHODS IN ENZYMOLOOGY, vol. 47, 1977, pages 453 - 459
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WEIRONG WANG ET AL: "Impact of methionine oxidation in human IgG1 Fc on serum half-life of monoclonal antibodies", MOLECULAR IMMUNOLOGY, PERGAMON, GB, vol. 48, no. 6, 11 December 2010 (2010-12-11), pages 860 - 866, XP028143840, ISSN: 0161-5890, [retrieved on 20101227], DOI: 10.1016/J.MOLIMM.2010.12.009 *

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