WO2015195163A1 - Pd-l1 antagonist fully human antibody - Google Patents
Pd-l1 antagonist fully human antibody Download PDFInfo
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- 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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- C—CHEMISTRY; METALLURGY
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
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- 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
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- 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
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- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
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- 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)
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- 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
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- 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
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- 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
A antibody is described that can be used for treating or prevention of an immunological or an oncological disease or condition. The antibody is a fully human single-chain variable fragment (scFv) antibody molecule which is capable of binding to human PDl receptor and inhibiting its interactions with its cognate ligand - human PD- Ll. DNA expression vectors and expression systems for overproducing the antibody in mammalian cells are also provided for.
Description
PD-Ll ANTAGONIST FULLY HUMAN ANTIBODY
FIELD
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.
BACKGROUND
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. In humans 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.
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.
Further discussion of PD-1 and its therapeutic utility can be found in the references
provided below:
McDermott, D.F. and Atkins, M.B., "PD-1 as a potential target in cancer therapy", Cancer Medicine 2013; 2(5): 662-673;
Shi, et al., "The role of PD-1 and PD-L1 in T-cell immune suppression in patients with hematological malignancies", Journal of Hematology & Oncology 2013, 6:74;
Topalian, S.L., et al., "Targeting the PD-1/B7-H1(PD-L1) pathway to activate antitumor immunity", Curr Opin Immunol. 2012 April ; 24(2): 207-212;
Podojil, J.R. and Miller, S.D., "Targeting the B7 Family of Co-Stimulatory
Molecules: Successes and Challenges", BioDrugs. 2013 February ; 27(1): 1-13;
Riella, L.V., et al., "Role of the PD-1 Pathway in the Immune Response", Am. J. Transplant. 2012 October ; 12(10): 2575-2587.
SUMMARY
This summary is provided to introduce a selection of concepts in a simplified form that are further described below in the Detailed Description. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used as an aid in determining the scope of the claimed subject matter.
In some aspects 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.
In some aspects 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.
In some aspects 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.
In some aspects 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.
In some aspects 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.
In some aspects 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 inclusing the sequence of SEQ ID NO. 3.
The following description and the drawings set forth in detail certain illustrative features of the one or more aspects. These features are indicative, however, of but a few of the various ways in which the principles of various aspects may be employed, and this description is intended to include such aspects and their equivalents.
BRIEF DESCRIPTION OF THE DRAWINGS
The present teachings illustratively shown and described in reference to the accompanying drawings, in which:
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 ΡΚΝ-ΟΟΓ-PDl-ABl-scFv-Fc plasmid of the present teachings;
FIG. 4 shows the sequence of the ΡΚΝ-ΟΟΓ-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-γ 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
DETAILED DESCRIPTION
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.
To enable recombinant production of the antibody, 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.
In certain aspects, 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. In an example embodiment, 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)
1 QVQLVQSGSE VKKSGSSVKV SCKTSGGTFS ITNYAINWVR QAPGQGLEWM GGILPIFGAA 61 KYAQKFQDRV TITADESTNT AYLELSSLTS EDTAMYYCAR GKRWLQSDLQ YWGQGTLVTV 121 SS
VL chain of PD1-AB1 antibody (SEQ ID NO. 2)
1 QPVLTQPASV SGSPGQSITI SCTGSSSDVG SYDLVSWYQQ SPGKVPKLLI YEGVKRPSGV 61 SNRFSGSKSG NTASLTISGL QAEDEADYYC SSYAGTRNFV FGGGTQLTVL
Amino acid sequence of PD1-AB1 antibody (SEQ ID NO. 3)
1 QVQLVQSGSE VKKSGSSVKV SCKTSGGTFS ITNYAINWVR QAPGQGLEWM GGILPIFGAA
61 KYAQKFQDRV TITADESTNT AYLELSSLTS EDTAMYYCAR GKRWLQSDLQ YWGQGTLVTV 121 SSGILGSGGG GSGGGGSGGG GSQPVLTQPA SVSGSPGQSI TISCTGSSSD VGSYDLVSWY
181 QQSPGKVPKL LIYEGVKRPS GVSNRFSGSK SGNTASLTIS GLQAEDEADY YCSSYAGTRN
241 FVFGGGTQLT VL
In certain aspects, 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. In an example embodiment, the recombinant DNA molecule of the present teachings comprises nucleotide sequence of SEQ ID NO. 4.
PD1-AB1 DNA (SEQ ID NO. 4)
1 CAGGTCCAGC TGGTGCAGTC TGGGTCTGAG GTGAAGAAGT CTGGGTCCTC GGTGAAGGTC 61 TCCTGCAAGA CTTCTGGAGG CACCTTCAGC ATCACCAACT ATGCTATCAA CTGGGTGCGG 121 CAGGCCCCTG GACAAGGGCT TGAGTGGATG GGAGGGATCC TCCCTATCTT TGGTGCAGCA 181 AAGTACGCAC AGAAGTTCCA GGACAGAGTC ACTATTACCG CGGACGAATC TACGAATACA 241 GCCTACCTGG AGCTGAGCAG CCTGACATCT GAGGACACGG CCATGTATTA CTGTGCGAGA 301 GGAAAGAGAT GGCTACAATC AGACTTACAA TACTGGGGCC AGGGTACCCT GGTCACCGTC 361 TCCTCAGGAA TTCTAGGATC CGGTGGCGGT GGCAGCGGCG GTGGTGGTTC CGGAGGCGGC 421 GGTTCTCAGC CTGTGCTGAC TCAGCCTGCC TCCGTGTCTG GGTCTCCTGG ACAGTCGATC 481 ACCATCTCCT GCACTGGATC CAGCAGTGAT GTTGGCAGTT ATGACCTTGT CTCCTGGTAC 541 CAACAGTCCC CAGGCAAAGT CCCCAAACTC CTGATTTATG AGGGCGTTAA GCGGCCCTCA 601 GGGGTTTCTA ATCGCTTCTC TGGCTCCAAG TCTGGCAACA CGGCCTCCCT GACAATCTCT 661 GGGCTCCAGG CTGAGGACGA GGCTGATTAT TACTGCTCCT CATATGCAGG TACTAGGAAT 721 TTTGTGTTCG GAGGAGGCAC CCAGCTGACC GTCCTC
In certain aspects, the present invention provides for a recombinant mammalian expression plasmid for high expression of 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 plasmid of the present invention is illustratively shown in FIG. 3 and its sequence is shown in FIG. 4.
Example 1: Acquiring yeast clones with ability of binding to B7-H1
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.
Example 2: Expression and purification of antibodies in ScFv-Fc forms
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.
Essentially, PEI (polyethylenimine) (Polysicences cat# 24765) and the plasmid were mixed as 3: 1 in freestyle 293 media (Gibco: cat# 12338-026), vortexed for 10s and rested at room temperature (RT) for 5 min. Then the plasmid/PEI mixture was added to cells and incubated
for 4h at 37°C, 8% C02. Four hours later same volume of Ex Cell 293 media (Sigma: cat# 24571C ) was added to freestyle 293 media. The next day, cells were counted to make sure that the density was approximately 3xl06 cells/ml. Then 3.8 mM VPA (sodium valproate acid) (Sigma lot: 031M1798v) was added to the media. Five-to-six days later the supernatant was harvested. 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. In order to determine PDl-ABl binding specifically to PD-Ll rather than other antigens, 293 cells transiently transfected with huPD- 1-EGFP or huICOS-EGFP were stained in substantially the same way. 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 (ProteOn™ 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.
Table 1. Affinity and kinetic parameters analysis of PDl-ABl for binding to human B7-H1
Example 5: Inhibition of B7-H1/PD-1, B7-H1/B7.1 Receptor-Ligand Binding
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
concentrations of 100 ug/ml. 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. Further, 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.
Example 6: Determination of the effects of PDl-ABl on T-cell activation
Enhancement of T cell activation by PDl-ABl was determined in a PBMC
(Peripheral Blood Mononucleated Cell) assay. PBMCs isolated from a healthy donor were activated by a plate coated anti-CD3. Essentially, 3 ug/ml of a anti-CD3 antibody were added to a 96 well plate, the plate was placed at 4°C overnight, then PBMCs were added to the 96 well plate, at a concentration of 5xl05 PBMC/well, while PDl-ABl antibody was added at 10 ug/ml at the same time. Media alone were used as negative control. Five days later, supernatant was collected and IFN-γ was tested by ELISA. FIG. 8 shows a bar graph showing IFN-γ 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-
L1+) at a concentration of 5xl06 mixed with PBMC at a concentration of lxl 05. Mice were treated with PDl-ABl at a dose of lOmg/kg or PBS control once per week (totally 5 doses) from day 0, tumor volume was monitored every 3 days. 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. The data were analyzed with WinNonlin Software (Certara L.P., Princeton, NJ). 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.
Table 2: PD1-AB1 pharmacokinetics analysis results in a Cynomongus monkey model
Therefore, 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.
All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference.
While specific embodiments of the subject matter have been discussed, the above specification is illustrative and not restrictive. Many variations will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.
Claims
1. An isolated antibody that binds human PD 1 , the antibody comprising:
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.
2. The antibody of claim 1, wherein the antibody comprises amino acid sequence of SEQ.
ID NO. 3.
3. The antibody of claim 2, wherein the antibody is a monoclonal antibody.
4. An isolated nucleic acid encoding a polypeptide comprising amino acid sequence of SEQ ID NO. 3.
5. The nucleic acid of claim 4, wherein codon usage is optimized for high expression of said polypeptide in a mammalian cell.
6. The nucleic acid of claim 5, wherein the nucleic acid sequence comprises the sequence of SEQ ID NO. 4.
7. The nucleic acid of claim 6, wherein said nucleic acid comprises an expression vector.
8. A therapeutic composition, the composition comprising an antibody comprising amino acid sequence of SEQ. ID NO. 3.
9. The therapeutic composition of claim 8, wherein half-life of said antibody in systemic circulation in a Cynomongus monkey after an intravenous administration at a dose of 6 mg/kg is at least 170 hours.
10. A heterologous expression system, the expression system harboring an expression vector comprising a nucleic acid sequence encoding a polypeptide comprising the amino acid sequence of SEQ ID NO. 3.
11. The expression system of claim 8, wherein said expression vector is harbored in a
mammalian cell.
12. The expression system of claim 9, wherein said mammalian cell is a 293F cell.
13. The expression system of claim 10, wherein the level of said polypeptide expression is at least 100 mg per liter of cell culture.
14. 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 comprising a polypeptide comprising the amino acid sequence of SEQ ID NO. 3.
15. A method of treating or preventing an immunological or an oncological disease or
condition, the method comprising 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 comprising a polypeptide comprising the sequence of SEQ ID NO. 3.
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