WO2015195163A1 - Anticorps totalement humain anti-pd-l1 - Google Patents

Anticorps totalement humain anti-pd-l1 Download PDF

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Publication number
WO2015195163A1
WO2015195163A1 PCT/US2015/010929 US2015010929W WO2015195163A1 WO 2015195163 A1 WO2015195163 A1 WO 2015195163A1 US 2015010929 W US2015010929 W US 2015010929W WO 2015195163 A1 WO2015195163 A1 WO 2015195163A1
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antibody
seq
acid sequence
polypeptide
nucleic acid
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PCT/US2015/010929
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English (en)
Inventor
Yan Lavrovsky
Ting Xu
Alexey REPIK
Mikhail Samsonov
Vasily IGNATIEV
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R-Pharm Overseas, Inc.
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Publication of WO2015195163A1 publication Critical patent/WO2015195163A1/fr

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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
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3053—Skin, nerves, brain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • 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
    • C07K16/2818—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 against CD28 or CD152
    • 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
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • 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
    • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
    • C07K2317/622—Single chain antibody (scFv)
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide

Definitions

  • the invention generally relates to the field of molecular biology, immunology, autoimmune and inflammatory diseases and oncology. More specifically, the invention relates to antibodies that bind to human receptors PD1 and B7-1.
  • the B7-H1 also known as PD-Ll, is a type I transmembrane protein approximately 53 kDa in size. It is a member of the costimulatory molecules belonging to B7 family of proteins.
  • B7-H1 (UniProt: Q9NZQ7) is mainly expressed on a number of immune cell types including activated and anergic/exhausted T cells, naive and activated B cells, as well as myeloid dendritic cells (DC), monocytes and mast cells. It is also found at increased levels on a number of tumors.
  • B7-H1 is known to bind two alternative ligands, the first of which, PD-1, is a type I transmembrane receptor. It is expressed on activated T cells, B cells, and monocytes, as well as on other cells of the immune system. It binds both, B7-H1 (PD-Ll), and the related B7-DC (PD-L2). The second is the B7 family member B7-1, which is expressed on activated T cells, B cells, monocytes and antigen presenting cells.
  • PD-1 is a type I transmembrane receptor. It is expressed on activated T cells, B cells, and monocytes, as well as on other cells of the immune system. It binds both, B7-H1 (PD-Ll), and the related B7-DC (PD-L2).
  • the second is the B7 family member B7-1, which is expressed on activated T cells, B cells, monocytes and antigen presenting cells.
  • Signaling via the PD-1/B7-H1 axis is believed to serve critical, non-redundant functions within the immune system, by negatively regulating T cell responses.
  • the antibodies if the present teachings are capable of specifically binding to B7-H1 and blocking PD-Ll binding to PD-1 as well as B7.1.
  • the antibodies can perform an important role in modulating immune response by manipulating the B7-H1/PD-1 pathway.
  • the antibodies of the present teachings were obtained from a Yeast Display scFv Antibody Library— a nonimmune Saccharomyces cerevisiae surface display library, by using PD-Ll (ECD)-Fc protein as bait.
  • a Yeast Display scFv Antibody Library a nonimmune Saccharomyces cerevisiae surface display library, by using PD-Ll (ECD)-Fc protein as bait.
  • the present invention provides for an isolated antibody that binds human PD1.
  • the antibody includes a VH chain of SEQ. ID NO. 1 and a VL chain of SEQ. ID NO. 2, or an antigen binding fragment of the antibody.
  • the antibody may contain amino acid sequence of SEQ. ID NO. 3.
  • the antibody may be a monoclonal antibody.
  • the present teachings provide for an isolated nucleic acid encoding a polypeptide containing amino acid sequence of SEQ ID NO. 3.
  • the nucleic acid may have its codon usage is optimized for high expression of the polypeptide in a mammalian cell.
  • the nucleic may have amino acid sequence containing the sequence of SEQ ID NO. 4.
  • the nucleic acid may further include an expression vector.
  • the present invention provides for a therapeutic composition.
  • the composition contains an antibody which includes amino acid sequence of SEQ. ID NO. 3.
  • the antibody of the therapeutic composition may exhibit a half-life in systemic circulation in a Cynomongus monkey after an intravenous administration at a dose of 6 mg/kg of at least 170 hours.
  • the present invention provides for a heterologous expression system.
  • the expression system harbors an expression vector containing a nucleic acid sequence encoding a polypeptide including amino acid sequence of SEQ ID NO. 3.
  • the expression system may be harbored in a mammalian cell.
  • the mammalian cell may be a 293F cell.
  • the expression system may attain the level of the polypeptide expression of at least 100 mg per liter of cell culture.
  • the present invention provides for use of a substance for manufacture of a medicament for the treatment or prevention of an immunological or an oncological disease or condition.
  • the substance contains a polypeptide including the amino acid sequence of SEQ ID NO. 3.
  • the present invention provides for use of a method of treating or preventing an immunological or an oncological disease or condition.
  • the method includes administering to a patient in need for treating or preventing an immunological or an oncological disease or condition, a therapeutically effective amount of a pharmaceutical composition containing a polypeptide comprising the sequence of SEQ ID NO. 3.
  • FIG. 1A illustrates FACS imaging showing the process of sorting the pool from yeast Library: yeast were stained by antigens, B7Hl-biotin and c-myc, PDl-biotin as negative control, yeasts in P3 area were sorted;
  • FIG. IB illustrates FACS imaging of one of high throughput screening experiments utilizing FACS
  • FIG. 2 illustrates the domain structure of the PD1-AB1 antibody of the present teachings
  • FIG. 3 illustrates the map of the ⁇ - ⁇ -PDl-ABl-scFv-Fc plasmid of the present teachings
  • FIG. 4 shows the sequence of the ⁇ - ⁇ -PDl-ABl-scFv-Fc plasmid of the present teachings
  • FIG. 5 illustrates the ability of PD1-AB1 antibody of the present teachings to bind to 293F cells trans fected with human B7-H1;
  • FIG. 6 Show the kinetic report of the affinity binding analysis of the PD1-AB1/ human B7- Hl biding utilizing a BIAcore Surface Plasmon Resonance instrument
  • FIG. 7 A shows the binding curve from the ELISA assay that was performed to evaluate the ability of PD1-AB1 antibody of the present teachings to inhibit B7-H1/PD-1 interactions;
  • FIG. 7B shows the binding curve from the ELISA assay that was performed to evaluate the ability of PD1-AB1 antibody of the present teachings to inhibit B7-H1/B7.1 interactions;
  • FIG. 8 shows a bar graph showing IFN- ⁇ release by PD1-AB1 antibody in the PBMC assay
  • FIG. 9 shows a graph of measured tumor volume against time in a murine tumor model: PD1-AB1 tumor growth inhibition curve data points are represented as squares, which PBS control data points are represented as spheres; and
  • the teachings disclosed herein are based, in part, upon discovering of a fully human single-chain variable fragment (scFv) antibody molecule which is capable of binding to human PD1 receptor and inhibiting its interactions with its cognate ligand - human PD-L1.
  • the antibody molecule of the present teachings is comprised of a variable region of the heavy chain (VH) and a variable region of the light chain (VL), linked via a linker peptide.
  • a DNA expression vector has been constructed for overproducing the antibody in a heterologous protein expression system, and mammalian cells have been prepared transiently expressing the antibody to a high expression level.
  • the present teachings provide for a polypeptide comprising the VH chain having amino acid sequence of SEQ. ID NO. 1, and the VL chain having amino acid sequence of SEQ. ID NO. 2.
  • the polypeptide is an antibody (PD1-AB1) comprising amino acid sequence of SEQ ID NO. 3.
  • VH chain of PD1-AB1 antibody (SEQ ID NO. 1)
  • VL chain of PD1-AB1 antibody (SEQ ID NO. 2)
  • the present invention provides for a recombinant DNA molecule having an open reading frame coding for a polypeptide comprising amino acid sequence of SEQ. ID NO. 1 and a polypeptide comprising amino acid sequence of SEQ. ID NO. 2, connected via a flexible linker.
  • the recombinant DNA molecule of the present teachings comprises nucleotide sequence of SEQ ID NO. 4.
  • B7-Hl-Fc biotinylated protein was used as antigen. After two rounds of MACS enrichment and two rounds of F ACS sorting with 1-100 nM antigen, a relatively small pool of antibodies was obtained. After the last round of FACS sorting, yeasts were spread on SD- CAA plates. Thousands of single yeast colonies were screened by high throughput FACS analysis; PDl-Fc-biotin protein was used as negative control. Finally, several yeast clones were obtained, which had the ability of binding to B7-H1 protein and 293F cells transiently expressing B7-H1, further a single best binding antibody was identified and named PD1-AB1 (SEQ. ID NO. 1). The results of the high throughput FCS analysis are illustrated in FIG. 1A and FIG. IB. The domain structure of the PD1-AB1 antibody of the present teachings is illustratively shown in FIG. 2.
  • the DNA of PD1-AB1 (SEQ. ID NO. 2) was cloned into the Age I and Asc I sites of PKN001 ' vector, and a plasmid named PKN-001 '-PDl-ABl-scFv-Fc was obtained.
  • the map of the plasmid is illustratively shown in FIG. 3, the sequence of the plasmid is shown in FIG. 4.
  • the PKN-001 '-PDl-ABl-scFv-Fc plasmid was transient transfected into 293F cells.
  • PEI polyethylenimine
  • plasmid plasmid/PEI mixture
  • RT room temperature
  • plasmid/PEI mixture was added to cells and incubated for 4h at 37°C, 8% C0 2 .
  • Ex Cell 293 media Sigma: cat# 24571C
  • cells were counted to make sure that the density was approximately 3xl0 6 cells/ml.
  • VPA sodium valproate acid
  • Sigma lot: 031M1798v sodium valproate acid
  • the supernatant was subsequently purified by affinity chromatography. In brief, the supernatant was loaded (1 ml/min) onto a HiTrap MabSelect SuRe column at a flow rate of 1 ml/min. After wash, the protein was eluted by pH 3.6 sodium citrate, and neutralized with 2M Tris-HCL (pH 9.5). The neutralized eluted protein was filtered and stored at 4°C. The protein yield of transient transfection was 100 mg/L.
  • Example 3 Tests of purified PDl-ABl antibody binding to Human B7-H1 and Mouse B7-H1
  • the ability of the purified PDl-ABl to bind to human B7-H1, mouse B7-H1 was determined by FACS analysis. Essentially, 293F cells were transiently transfected with either human B7-H1-EGFP or mouse B7-H1-EGFP. Cells were re-suspended in PBS containing 0.5% BSA (FACS buffer), PDl-ABl antibody was added at a final concentration of 5 ug/ml, incubate for 30 min at 4°C. After washing twice with FACS buffer, goat anti-human IgG PE (5 ug/ml) was added and further incubate for 30 min at 4°C. The cells were washed again with FACS buffer and analyzed by FACS.
  • FIG. 3 illustrates the ability of PDl-ABl antibody to bind to 293F cells transfected with human B7-H1. As is apparent from FIG. 5, the antibody did not exhibit binding to 293F cells transfected with mouse B7-H1, human PD-1 or human ICOS.
  • Example 4 Human B7-HlBinding Kinetics Analysis of PDl-ABl (scFv)
  • the binding affinity and kinetic parameters of PDl-ABl (scFv) to human B7-H1 were determined by Surface Plasmon Resonance using a BIAcore instrument (ProteOnTM XPR36, BIO-RAD). Essentially, experiments were performed at 25°C, using HBS-EP buffer (lOmM HEPES, 150nM NaCl, 3 mM EDTA, 0.05% v/v surface P20) as running buffer. B7- Hl-Fc protein was affinity captured on the surface of a sensor chip ⁇ BIO-RAD). Different dilutions of PDl-ABl antibody in the running buffer were injected at a constant flow rate of 100 ul/min, using running buffer alone as a negative control. Data were analyzed using the software from BIO-RAD. FIG. 6 shows the resulting kinetic report. Table 1 summarises the affinity and kinetic parameters.
  • the ability of the purified human anti-B7-Hl antibody of the present teachings to inhibit the binding of PD-l-Fc protein or B7.1-Fc to human B7-Hl-Fc was evaluated by an ELISA. Essentially, B7-Hl-Fc protein was coated on ELISA plates. Serially diluted PDl- ABl ScFv-Fc was allowed to compete with PD-1 or B7.1 biotinylated protein at
  • PDl-ABl could effectively inhibit B7-H1/PD-1 binding with an IC50 value of about 1.37 ug/ml.
  • the resulting binding curve is shown in FIG. 7A.
  • PDl-ABl could inhibit B7-H1/B7.1 binding with an IC50 value of about 0.52 ug/ml.
  • the resulting binding curve is shown in FIG. 7B.
  • FIG. 8 shows a bar graph showing IFN- ⁇ release by PDl-ABl antibody in the PBMC assay.
  • Example 7 Inhibition of tumor growth by PDl-ABl in a murine model NOD-Scid mice were implanted with A375 human melanoma tumor cells (PD-
  • FIG. 9 shows a graph of measured tumor volume against time in the murine model used. As is apparent from the graph, FPD1- AB1 exhibited significant inhibition of tumor growth.
  • Example 8 PDl-ABl pharmacokinetics analysis in a Cynomolgus monkey model PDl-ABl was administered i.v. into a male and a female Cynomongus monkeys at a single dose of about 6 mg/kg. The monkeys were bleeded one day prior to injection and at 13 time-points post injection, Serum PDl-ABl levels were determined by ELISA with hPD-Ll muFc (human PD1 -LI /Murine Fc fusion) at a concentration of 5ug/ml as capture protein, anti-hlgG-HRP (anti-human IgG-horse redish peroxidise) as detection antibody.
  • hPD-Ll muFc human PD1 -LI /Murine Fc fusion
  • FIG. 10 shows measured PD1-AB1 concentrations against time for the male and the female monkeys used.
  • the results of the pharmacokinetics data analysis are shown in Table 2.
  • the half life of PD1-AB1 was estimated to be at about 251 h for a male Cynomongus monkey and at about 177 h for a female Cynomongus monkeys.

Abstract

La présente invention concerne un anticorps qui peut être utilisé pour le traitement ou la prévention d'une maladie ou d'une condition immunologique ou oncologique. L'anticorps est une molécule d'anticorps totalement humain à fragment variable simple chaîne (scFv) qui est capable de se lier au récepteur de PDl humain et d'inhiber ses interactions avec son ligand parent, PD-L1 humain. L'invention concerne également des vecteurs d'expression à ADN et des systèmes d'expression permettant de surproduire l'anticorps dans des cellules de mammifères.
PCT/US2015/010929 2014-06-20 2015-01-10 Anticorps totalement humain anti-pd-l1 WO2015195163A1 (fr)

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