WO2022057910A1 - Polythérapies ciblant des voies c5ar et pd-1/pd-l1 - Google Patents

Polythérapies ciblant des voies c5ar et pd-1/pd-l1 Download PDF

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WO2022057910A1
WO2022057910A1 PCT/CN2021/119170 CN2021119170W WO2022057910A1 WO 2022057910 A1 WO2022057910 A1 WO 2022057910A1 CN 2021119170 W CN2021119170 W CN 2021119170W WO 2022057910 A1 WO2022057910 A1 WO 2022057910A1
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seq
amino acid
acid sequence
antigen
binding fragment
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PCT/CN2021/119170
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Zhengyi WANG
Zhen MENG
Wei Cao
Chan CHEN
Julia Neugebauer
Barbara BACHLER
Yu PANG
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I-Mab Biopharma Co., Ltd
I-Mab Biopharma Us Limited
Morphosys Ag
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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
    • C07K16/2896—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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
    • A61K2039/507—Comprising a combination of two or more separate 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
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/71—Decreased effector function due to an Fc-modification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation

Definitions

  • C5a anaphylatoxin chemotactic receptor 1 (C5aR) is one of the two high-affinity receptors for the ligand, C5a, which is produced in serum as one of the core effector components of the complement response. Under physiological conditions, C5a acts as chemotactic agent for inflammatory cells, stimulates their respiratory burst as well as cytokine and chemokine release, and functions to increase vascular permeability.
  • C5aR The interaction of C5aR with C5a has been described in many different disease settings; most of them being involved in inflammatory and autoimmune diseases. It is also shown that C5a increases cancer cell proliferation, intra-tumor angiogenesis and enhances tumor invasiveness and metastasis. More recent data also implicates a role for C5a/C5aR in the generation of immunosuppressive environments in the context of solid tumors resulting in enhanced primary tumor growth by inhibiting antitumor responses (e.g. increased recruitment of C5aR-expressing myeloid cells such as myeloid-derived suppressor cell (MDSC) or M2 macrophages) .
  • MDSC myeloid-derived suppressor cell
  • Therapeutic antibodies targeting C5aR has been considered for clinical development.
  • the clinical development of the antagonistic C5aR specific antibody Neutrazumab, a humanized IgG4 mAb was stopped in Phase II clinical trials due to issues with immune cell depletion and immunogenicity (Daniluk S et al., Annals of the Rheumatic Diseases. 2014, 73: 684–685) .
  • C5aR appears constitutively expressed on a variety of cell types, it is important that an antagonistic antibody does not induce any depletion of the target cells.
  • Combination strategies of anti-tumor agents may also be useful, but have not been well studied.
  • the present disclosure provides combination therapies that target both C5aR and PD-1/PD-L1 pathway with synergistic effects.
  • a method for treating cancer in a subject in need thereof comprising administering to the subject an anti-C5aR antibody or antigen-binding fragment thereof and a PD-1/PD-L1 inhibitor, wherein the anti-C5aR antibody or antigen-binding fragment thereof comprises: (1) a heavy chain variable region (VH) , wherein the VH comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 17 (e.g., SEQ ID NO: 2 or 11) , and a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 18 (e.g., SEQ ID NO: 3 or 12) , and (2) a light chain variable region (VL) , wherein the VL comprises a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a VL
  • the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the SEQ ID NO: 1-6, respectively.
  • the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the SEQ ID NO: 1, 11, 12, 4-6, respectively.
  • the VH and the VL of the anti-C5aR antibody or antigen-binding fragment thereof comprise the amino acid sequences of SEQ ID NO: 7 and 8, respectively.
  • the anti-C5aR antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.
  • the VH and the VL of the anti-C5aR antibody or antigen-binding fragment thereof comprise the amino acid sequences of SEQ ID NO: 13 and 14, respectively.
  • the anti-C5aR antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 15 and a light chain comprising the amino acid sequence of SEQ ID NO: 16.
  • the PD-1/PD-L1 inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody or an antigen-binding fragment thereof.
  • the PD-1 inhibitor is selected from the group consisting of Pidilizumab, Cemiplimab, Sintilimab, Cetrelimab, Spartalizumab, Camrelizumab, Tislelizumab, Balstilimab, Dostarlimab, ABBV-181, Penpulimab, Pembrolizumab, Genolimzumab, Retifanlimab, Sasanlimab, AMP-224, AB122, F-520, MEDI-3387, MEDI-5771, MEDI-0680, SG-001, nivolumab, BCD-100, BAT-1306, BI-754091, CBT-501, GLS-010, LZM-009, Sym-021, CS-1003, HLX-10,
  • the PD-L1 inhibitor is selected from the group consisting of Manelimab, Atezolizumab, Avelumab, Cosibelimab, Durvalumab, Envafolimab, Socazolimab, AUNP12, BGB-A333, CK-301, CS-1001, FAZ-053, APL-502, MDX-1105, IMC-001, KD-005, Gensci-047, LY-3300054, SHR-1316, MSB-2311, AVA-004, CBT-502, JS-003, B12, KY-1003, CA-170, BMS-986189, B6 and B12-01.
  • the anti-C5aR antibody or antigen-binding fragment thereof is administrated to the subject in need thereof before, after or concurrently with the PD-1/PD-L1 inhibitor.
  • the anti-C5aR antibody or antigen-binding fragment thereof and the PD-1/PD-L1 inhibitor are administered at a molar ratio of 1.5: 1 to 6: 1.
  • the anti-C5aR antibody or antigen-binding fragment thereof and the PD-1/PD-L1 inhibitor are administered at a molar ratio of 2: 1 to 4: 1.
  • the cancer is selected from the group consisting of colorectal cancer, breast cancer, non-small cell lung cancer, renal cell carcinoma, pancreatic cancer, ovarian cancer, prostate cancer, liver cancer, gliosarcoma, malignant glioma, peritoneal cancer, fallopian tube cancer, rectal cancer, kidney cancer, Hodgkin's lymphoma, bladder cancer, uveal melanoma, gastric cancer, squamous cell carcinoma, cervical cancer, uterine cancer, chronic lymphocytic leukemia, lymphoma, myeloma, Kaposi's sarcoma, urothelial carcinoma, mesothelioma, malignant fibrous histiocytoma, colon cancer, solid tumor, multiple myeloma, gastrointestinal stromal tumor, head and neck cancer, melanoma, and leiomyosarcoma.
  • the cancer is a solid tumor.
  • the cancer is a
  • the anti-C5aR antibody or antigen-binding fragment thereof and the PD-1/PD-L1 inhibitor synergistically activate an immune response.
  • the anti-C5aR antibody or antigen-binding fragment thereof does not substantially induce effector function.
  • the anti-C5aR antibody or antigen-binding fragment thereof is not capable of inducing antibody-dependent cellular phagocytosis (ADCP) , antibody-dependent cell-mediated cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC) .
  • ADCP antibody-dependent cellular phagocytosis
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • CDC complement-dependent cytotoxicity
  • a pharmaceutical composition comprising an anti-C5aR antibody or antigen-binding fragment thereof and a PD-1/PD-L1 inhibitor, wherein the anti-C5aR antibody or antigen-binding fragment thereof comprises: (1) a heavy chain variable region (VH) , wherein the VH comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 17 (e.g., SEQ ID NO: 2 or 11) , and a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 18 (e.g., SEQ ID NO: 3 or 12) , and (2) a light chain variable region (VL) , wherein the VL comprises a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO
  • the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the SEQ ID NO: 1-6, respectively.
  • the VH and the VL of the anti-C5aR antibody or antigen-binding fragment thereof comprise the amino acid sequences of SEQ ID NO: 7 and 8, respectively.
  • the anti-C5aR antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.
  • the PD-1/PD-L1 inhibitor is an anti-PD-1, anti-PD-L1 antibody or an antigen-binding fragment thereof.
  • the PD-1 inhibitor is selected from the group consisting of Pidilizumab, Cemiplimab, Sintilimab, Cetrelimab, Spartalizumab, Camrelizumab, Tislelizumab, Balstilimab, Dostarlimab, ABBV-181, Penpulimab, Pembrolizumab, Genolimzumab, Retifanlimab, Sasanlimab, AMP-224, AB122, F-520, MEDI-3387, MEDI-5771, MEDI-0680, SG-001, nivolumab, BCD-100, BAT-1306, BI-754091, CBT-501, GLS-010, LZM-009, Sym-021, CS-1003, HLX-10, AK
  • the PD-L1 inhibitor is selected from the group consisting of Manelimab, Atezolizumab, Avelumab, Cosibelimab, Durvalumab, Envafolimab, Socazolimab, AUNP12, BGB-A333, CK-301, CS-1001, FAZ-053, APL-502, MDX-1105, IMC-001, KD-005, Gensci-047, LY-3300054, SHR-1316, MSB-2311, AVA-004, CBT-502, JS-003, B12, KY-1003, CA-170, BMS-986189, B6 and B12-01.
  • the anti-C5aR antibody or antigen-binding fragment thereof and the PD-1/PD-L1 inhibitor are present at a molar ratio of 1.5: 1 to 6: 1. In some embodiments, the anti-C5aR antibody or antigen-binding fragment thereof and the PD-1/PD-L1 inhibitor are present at a molar ratio of 2: 1 to 4: 1.
  • anti-C5aR antibody or antigen-binding fragment thereof and a PD-1/PD-L1 inhibitor in preparing a medicament for treating cancer in a subject in need thereof, wherein the anti-C5aR antibody or antigen-binding fragment thereof comprises: (1) a heavy chain variable region (VH) , wherein the VH comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 17 (e.g., SEQ ID NO: 2 or 11) , and a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 18 (e.g., SEQ ID NO: 3 or 12) , and (2) a light chain variable region (VL) , wherein the VL comprises a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a VL CDR3 compris
  • an article of manufacture comprises: (1) an anti-C5aR antibody or antigen-binding fragment thereof, and (2) a package insert, wherein the package insert provides instruction of administrating the anti-C5aR antibody or antigen-binding fragment thereof in combination with a PD-1/PD-L1 inhibitor for treating cancer in a subject in need thereof, wherein the anti-C5aR antibody or antigen-binding fragment thereof comprises: (i) a heavy chain variable region (VH) , wherein the VH comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 17 (e.g., SEQ ID NO: 2 or 11) , and a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 18 (e.g., SEQ ID NO: 3 or 12) , and (ii) a light chain variable region (VL) , wherein the VL comprises a VL CDR1 comprising the amino acid sequence
  • a pharmaceutical combination comprising an anti-C5aR antibody or antigen-binding fragment thereof and a PD-1/PD-L1 inhibitor, wherein the anti-C5aR antibody or antigen-binding fragment thereof comprises: (1) a heavy chain variable region (VH) , wherein the VH comprises: a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 17 (e.g., SEQ ID NO: 2 or 11) , and a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 18 (e.g., SEQ ID NO: 3 or 12) , and (2) a light chain variable region (VL) , wherein the VL comprises: a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a VL CDR3 comprising the amino acid sequence of SEQ
  • a pharmaceutical composition comprising an anti-C5aR antibody or antigen-binding fragment thereof and a PD-1/PD-L1 inhibitor for use in treating cancer in a subject in need thereof, wherein the anti-C5aR antibody or antigen-binding fragment thereof comprises: (1) a heavy chain variable region (VH) , wherein the VH comprises: a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 17 (e.g., SEQ ID NO: 2 or 11) , and a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 18 (e.g., SEQ ID NO: 3 or 12) , and (2) a light chain variable region (VL) , wherein the VL comprises: a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a VL C
  • FIG. 1 shows the impact of a mouse surrogate C5aR and PD-1 antibodies on tumor volume, along with a TGI (tumor growth inhibition) chart.
  • FIG. 2 shows the immunophenotyping (peripheral blood) results after treatment of combination of a mouse surrogate C5aR antibody and PD-1 antibody.
  • FIG. 3 shows the synergistic activation of immune response by the combination of the C5aR antibody MAB#1 and PD-1 antibody.
  • antibody refers to a protein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, which interacts with an antigen.
  • Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region.
  • the heavy chain constant region is comprised of three domains, CH1, CH2 and CH3.
  • Each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region.
  • the light chain constant region is comprised of one domain, CL.
  • VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR) , interspersed with regions that are more conserved, termed framework regions (FR) .
  • CDR complementarity determining regions
  • FR framework regions
  • Each VH and VL is composed of three CDRs and four FR’s arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the variable regions of the heavy and light chains contain a binding domain that interacts with an antigen.
  • the constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.
  • antibody includes for example, monoclonal antibodies, human antibodies, humanized antibodies, camelised antibodies and chimeric antibodies.
  • the antibodies can be of any isotype (e.g., IgG, IgE, IgM, IgD, IgA and IgY) , class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass. Both the light and heavy chains are divided into regions of structural and functional homology.
  • antibody fragment refers to one or more portions of an antibody that retain the ability to specifically interact with (e.g., by binding, steric hindrance, stabilizing spatial distribution) an antigen.
  • binding fragments include, but are not limited to, a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; a F (ab) 2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; a Fd fragment consisting of the VH and CH1 domains; a Fv fragment consisting of the VL and VH domains of a single arm of an antibody; a dAb fragment (Ward et al., (1989) Nature 341: 544-546) , which consists of a VH domain; and an isolated complementarity determining region (CDR) .
  • CDR complementarity determining region
  • the two domains of the Fv fragment, VL and VH are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv) ; see e.g., Bird et al., (1988) Science 242: 423-426; and Huston et al., (1988) Proc. Natl. Acad. Sci. 85: 5879-5883) .
  • Such single chain antibodies are also intended to be encompassed within the term “antibody fragment” .
  • Antibody fragments are obtained using conventional techniques known to those of skill in the art, and the fragments are screened for utility in the same manner as are intact antibodies.
  • Antibody fragments can also be incorporated into single domain antibodies, maxibodies, minibodies, intrabodies, diabodies, triabodies, tetrabodies, v-NAR and bis-scFv (see, e.g., Hollinger and Hudson, (2005) Nature Biotechnology 23: 1126-1136) .
  • Antibody fragments can be grafted into scaffolds based on polypeptides such as Fibronectin type III (Fn3) (see U.S. Pat. No. 6,703,199, which describes fibronectin polypeptide monobodies) .
  • Fn3 Fibronectin type III
  • Antibody fragments can be incorporated into single chain molecules comprising a pair of tandem Fv segments (VH-CH1-VH-CH1) which, together with complementary light chain polypeptides, form a pair of antigen-binding sites (Zapata et al., (1995) Protein Eng. 8: 1057-1062; and U.S. Pat. No. 5,641,870) .
  • an antibody “binds specifically to” , “specifically binds to” , is “specific to/for” or “specifically recognizes” an antigen, such as human C5aR, if such antibody is able to discriminate between such antigen and one or more reference antigen (s) , since binding specificity is not an absolute, but a relative property.
  • an antigen such as human C5aR
  • a standard ELISA assay can be carried out.
  • the scoring may be carried out by standard color development (e.g. secondary antibody with horseradish peroxide and tetramethyl benzidine with hydrogen peroxide) .
  • the reaction in certain wells is scored by the optical density, for example, at 450 nm.
  • determination of binding specificity is performed by using not a single reference antigen, but a set of about three to five unrelated antigens, such as milk powder, BSA, transferrin or the like.
  • affinity refers to the strength of interaction between the polypeptide and its target at a single site. Within each site, the binding region of the polypeptide interacts through weak non-covalent forces with its target at numerous sites; the more interactions, the stronger the affinity.
  • K D refers to the dissociation constant, which is obtained from the ratio of k off to K on (i.e. k off /k on ) and is expressed as a molar concentration (M) .
  • K D values for antigen binding moieties like e.g. monoclonal antibodies can be determined using methods well established in the art. Methods for determining the K D of an antigen binding moiety like e.g. a monoclonal antibody are SET (solution equilibrium titration) or surface plasmon resonance using a biosensor system such as a system.
  • an antibody specific for C5aR typically has a dissociation rate constant (K D ) (k off /k on ) of less than 5x10 -2 M, less than 10 -2 M, less than 5x10 -3 M, less than 10 -3 M, less than 5x10 -4 M, less than 10 -4 M, less than 5x10 -5 M, less than 10 -5 M, less than 5x10 -6 M, less than 10 -6 M, less than 5x10 -7 M, less than 10 -7 M, less than 5x10 -8 M, less than 10 -8 M, less than 5x10 -9 M, less than 10 -9 M, less than 5x10 -10 M, less than 10 -10 M, less than 5x10 -11 M, less than 10 -11 M, less than 5x10 -12 M, less than 10 -12 M, less than 5x10 -13 M, less than 10 -13 M, less than 5x10 -14 M, less than 10 -14 M, less than 5x10 -15 M, or less than 5x
  • epitope includes any proteinacious region which is specifically recognized by an antibody or antibody fragment thereof or otherwise interacts with a molecule.
  • epitopes are of chemically active surface groupings of molecules such as amino acids or carbohydrate or sugar side chains and generally may have specific three-dimensional structural characteristics, as well as specific charge characteristics. As will be appreciated by one of skill in the art, practically anything to which an antibody can specifically bind could be an epitope.
  • compositions may be used for therapeutic or prophylactic applications.
  • the present disclosure therefore, includes a pharmaceutical composition containing an antibody or antibody fragment as disclosed herein, a PD-1/PD-L1 inhibitor and a pharmaceutically acceptable carrier or excipient therefor.
  • the present disclosure provides a method for treating cancer. Such method contains the steps of administering to a subject in need thereof an effective amount of the pharmaceutical composition that contains an antibody or antibody fragment as described herein.
  • the present disclosure provides therapeutic methods comprising the administration of a therapeutically effective amount of an antibody or antibody fragment as disclosed herein and a therapeutically effective amount of PD-1/PD-L1 inhibitor to a subject in need of such treatment.
  • a “therapeutically effective amount” or “effective amount” refers to the amount of a C5aR antibody necessary to elicit the desired biological response.
  • the therapeutic effective amount is the amount of a C5aR antibody necessary to treat and/or prevent a disease.
  • administering includes but is not limited to delivery of a drug by an injectable form, such as, for example, an intravenous, intramuscular, intradermal or subcutaneous route or mucosal route, for example, as a nasal spray or aerosol for inhalation or as an ingestible solution, capsule or tablet.
  • an injectable form such as, for example, an intravenous, intramuscular, intradermal or subcutaneous route or mucosal route, for example, as a nasal spray or aerosol for inhalation or as an ingestible solution, capsule or tablet.
  • the administration is by an injectable form.
  • treatment refers to clinical intervention in an attempt to alter the natural course of a disease in the subject being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis.
  • antibodies or antibody fragments according to the preset disclosure are used to delay development of a disease or to slow the progression of a disease.
  • effector function refers to those biological activities attributable to the Fc region of an antibody, which vary with the antibody isotype.
  • antibody effector functions include C1q binding and complement dependent cytotoxicity (CDC) ; Fc receptor binding and antibody-dependent cell-mediated cytotoxicity (ADCC) and/or antibody-dependent cellular phagocytosis (ADCP) ; down regulation of cell surface receptors (e.g. B cell receptor) ; and B cell activation.
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • cytotoxic cells e.g. NK cells, neutrophils, and macrophages
  • NK cells e.g. NK cells, neutrophils, and macrophages
  • “Complement-dependent cytotoxicity” or “CDC” refers to the lysis of a target cell in the presence of complement. Activation of the classical complement pathway is initiated by the binding of the first component of the complement system (C1q) to antibodies (of the appropriate subclass) of the present disclosure, which are bound to their cognate antigen.
  • ADCP antibody-dependent cellular phagocytosis
  • Preventing refers to a reduction in risk of acquiring or developing a disease (i.e. causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset) . “Prevention” also refers to methods which aim to prevent the onset of a disease or its symptoms or which delay the onset of a disease or its symptoms.
  • Subject or “species” or as used in this context refers to any mammal, including rodents, such as mouse or rat, and primates, such as cynomolgus monkey (Macaca fascicularis) , rhesus monkey (Macaca mulatta) or humans (Homo sapiens) .
  • rodents such as mouse or rat
  • primates such as cynomolgus monkey (Macaca fascicularis) , rhesus monkey (Macaca mulatta) or humans (Homo sapiens) .
  • the subject is a primate, most preferably a human.
  • inhibitors or “inhibit” or “reduction” or “reduce” or “neutralization” or “neutralize” refer to a decrease or cessation of any phenotypic characteristic (such as binding or a biological activity or function) or to the decrease or cessation in the incidence, degree, or likelihood of that characteristic.
  • the “inhibition” , “reduction” or “neutralization” needs not to be complete as long as it is detectable using an appropriate assay.
  • by “reduce” or “inhibit” or “neutralize” is meant the ability to cause a decrease of 20%or greater.
  • by “reduce” or “inhibit” or “neutralize” is meant the ability to cause a decrease of 50%or greater.
  • by “reduce” or “inhibit” or “neutralize” is meant the ability to cause an overall decrease of 75%, 85%, 90%, 95%, or greater.
  • antagonistic antibody refers to an antibody or antibody fragment that interacts with an antigen and partially or fully inhibits or neutralizes a biological activity or function or any other phenotypic characteristic of a target antigen.
  • the “Fc region” is used to define the C-terminal region of an immunoglobulin heavy chain.
  • the Fc region of an immunoglobulin generally comprises two constant domains, a CH2 domain and a CH3 domain.
  • the human IgG heavy chain Fc region is usually defined to extend from Cys226, or from Pro230, to the C-terminus of the heavy chain.
  • the C-terminal lysine (Lys447) of the Fc region may or may not be present.
  • EU numbering system also called the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.
  • Anti-C5aR antibodies and fragments thereof suitable for the combination therapy can be any known ones currently in development.
  • the anti-C5aR antibodies and fragments are those disclosed herein, such as MAB#1 and MAB#2.
  • the anti-C5aR antibody or antigen-binding fragment thereof includes a heavy chain variable region (VH) and a light chain variable region (VL) , wherein the VH includes a VH CDR1, VH CDR2, and VH CDR3, and the VL includes a VL CDR1, VL CDR2 and VL CDR3.
  • the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 have the corresponding CDR sequences of MAB#1 or MAB#2. Exemplary CDR sequences from MAB#1 and MAB#2 are provided in Tables 1 and 2.
  • the VH CDR1 includes the amino acid sequence of SEQ ID NO: 1
  • the VH CDR2 includes the amino acid sequence of SEQ ID NO: 17
  • the VH CDR3 includes the amino acid sequence of SEQ ID NO: 18
  • the VL CDR1 includes the amino acid sequence of SEQ ID NO: 4
  • the VL CDR2 includes the amino acid sequence of SEQ ID NO: 5
  • the VL CDR3 includes the amino acid sequence of SEQ ID NO: 6.
  • the VH CDR1 includes the amino acid sequence of SEQ ID NO: 1
  • the VH CDR2 includes the amino acid sequence of SEQ ID NO: 2 or 11
  • the VH CDR3 includes the amino acid sequence of SEQ ID NO: 3 or 12
  • the VL CDR1 includes the amino acid sequence of SEQ ID NO: 4
  • the VL CDR2 includes the amino acid sequence of SEQ ID NO: 5
  • the VL CDR3 includes the amino acid sequence of SEQ ID NO: 6.
  • the VH CDR1 includes the amino acid sequence of SEQ ID NO: 1
  • the VH CDR2 includes the amino acid sequence of SEQ ID NO: 2
  • the VH CDR3 includes the amino acid sequence of SEQ ID NO: 3
  • the VL CDR1 includes the amino acid sequence of SEQ ID NO: 4
  • the VL CDR2 includes the amino acid sequence of SEQ ID NO: 5
  • the VL CDR3 includes the amino acid sequence of SEQ ID NO: 6.
  • the anti-C5aR antibody or antigen-binding fragment thereof includes a VH including the amino acid sequence of SEQ ID NO: 7, and a VL including the amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-C5aR antibody or antigen-binding fragment thereof includes a heavy chain including the amino acid sequence of SEQ ID NO: 9, and a light chain including the amino acid sequence of SEQ ID NO: 10.
  • the VH CDR1 includes the amino acid sequence of SEQ ID NO: 1
  • the VH CDR2 includes the amino acid sequence of SEQ ID NO: 11
  • the VH CDR3 includes the amino acid sequence of SEQ ID NO: 12
  • the VL CDR1 includes the amino acid sequence of SEQ ID NO: 4
  • the VL CDR2 includes the amino acid sequence of SEQ ID NO: 5
  • the VL CDR3 includes the amino acid sequence of SEQ ID NO: 6.
  • the anti-C5aR antibody or antigen-binding fragment thereof includes a VH including the amino acid sequence of SEQ ID NO: 13, and a VL including the amino acid sequence of SEQ ID NO: 14. In some embodiments, the anti-C5aR antibody or antigen-binding fragment thereof includes a heavy chain including the amino acid sequence of SEQ ID NO: 15, and a light chain including the amino acid sequence of SEQ ID NO: 16.
  • the CDR sequences may also encompass sequence variants, such as through amino acid addition, deletion, or substitution.
  • each CDR may be mutated at one of the amino acids with a conservative mutation.
  • the anti-C5aR antibody or antigen-binding fragment thereof does not substantially induce effector function.
  • effector function may comprise ADCP, ADCC or CDC.
  • the anti-C5aR antibody or antigen-binding fragment thereof includes mutations of L234A, L235E, G237A, A330S and P331S in the human IgG1 Fc region, with numbering according to EU index.
  • a PD-1 inhibitor is a molecule that binds to and inhibits the biological activity of the PD-1 protein.
  • Programmed cell death protein 1 also known as PD-1 and CD279 (cluster of differentiation 279) , is a protein on the surface of cells that has a role in regulating the immune system's response to the cells of the human body by down-regulating the immune system and promoting self-tolerance by suppressing T cell inflammatory activity. Examples are anti-PD-1 antibodies and fragments thereof, such as those described below.
  • the PD-1 inhibitor is an anti-PD-1 antibody.
  • Exemplary PD-1 inhibitor that can be used in the present application includes but is not limited to Pidilizumab, Cemiplimab, Sintilimab, Cetrelimab, Spartalizumab, Camrelizumab, Tislelizumab, Balstilimab, Dostarlimab, ABBV-181, Penpulimab, Pembrolizumab, Genolimzumab, Retifanlimab, Sasanlimab, AMP-224, AB122, F-520, MEDI-3387, MEDI-5771, MEDI-0680, SG-001, nivolumab, BCD-100, BAT-1306, BI-754091, CBT-501, GLS-010, LZM-009, Sym-021, CS-1003, HLX-10, AK-103, AM-
  • Pembrolizumab (formerly MK-3475 or lambrolizumab, Keytruda) is an anti-PD-1 monoclonal antibody developed by Merck and first approved by the Food and Drug Administration in 2014 for the treatment of melanoma. It was later approved for metastatic non-small cell lung cancer and head and neck squamous cell carcinoma.
  • Nivolumab (Opdivo) is an anti-PD-1 monoclonal antibody developed by Bristol-Myers Squibb and first approved by the FDA in 2014 for the treatment of melanoma. It was later approved for squamous cell lung cancer, renal cell carcinoma, and Hodgkin’s lymphoma.
  • Cemiplimab (Libtayo) is an anti-PD-1 monoclonal antibody developed by Regeneron Pharmaceuticals and first approved by the FDA in 2018 for the treatment of cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC who are not candidates for curative surgery or curative radiation.
  • Spartalizumab (PDR001) is an anti-PD-1 monoclonal antibody developed by Novartis to treat both solid tumors and lymphomas.
  • Camrelizumab (SHR1210) is an anti-PD-1 monoclonal antibody introduced by Jiangsu HengRui Medicine Co., Ltd. that recently received conditional approval in China for the treatment of relapsed or refractory classical Hodgkin lymphoma.
  • Sintilimab (IBI308) is an anti-PD-1 monoclonal antibody developed by Innovent and Eli Lilly for patients with non-small cell lung cancer (NSCLC) .
  • Tislelizumab (BGB-A317) is a humanized IgG4 anti–PD-1 monoclonal antibody developed by BeiGene for solid tumors and hematologic cancers.
  • Dostarlimab (TSR-042, WBP-285) is a humanized monoclonal antibody against PD-1 under investigation by GlaxoSmithKline.
  • INCMGA00012 (MGA012) is a humanized IgG4 monoclonal antibody developed by Incyte and MacroGenics.
  • AMP-224 is an anti-PD-1 monoclonal antibody by AstraZeneca/MedImmune and GlaxoSmithKline.
  • AMP-514 (MEDI0680) is an anti-PD-1 monoclonal antibody by AstraZeneca.
  • a PD-L1 inhibitor is a molecule that binds to and inhibits the biological activity of the PD-L1 protein.
  • Programmed death-ligand 1 also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1) is a protein that in humans is encoded by the CD274 gene. Examples are anti-PD-L1 antibodies and fragments thereof, such as those described below.
  • the PD-L1 inhibitor is an anti-PD-L1 antibody.
  • Exemplary PD-L1 inhibitor that can be used in the present application includes but is not limited to Manelimab, Atezolizumab, Avelumab, Cosibelimab, Durvalumab, Envafolimab, Socazolimab, AUNP12, BGB-A333, CK- 301, CS-1001, FAZ-053, APL-502, MDX-1105, IMC-001, KD-005, Gensci-047, LY-3300054, SHR-1316, MSB-2311, AVA-004, CBT-502, JS-003, B12, KY-1003, CA-170, BMS-986189, B6 and B12-01.
  • Atezolizumab (Tecentriq) is a humanized anti-PD-L1 IgG1 antibody developed by Roche Genentech. It has been approved by the FDA for urothelial carcinoma and non-small cell lung cancer.
  • Avelumab (Bavencio) is a human anti-PD-L1 IgG1 antibody developed by Merck Serono and Pfizer. Avelumab has been approved by the FDA for the treatment of metastatic merkel-cell carcinoma.
  • Durvalumab (Imfinzi) is a human anti-PD-L1 IgG1 antibody developed by AstraZeneca. Durvalumab has been approved by the FDA for the treatment of urothelial carcinoma and unresectable non-small cell lung cancer after chemoradiation.
  • KN035 is an anti-PD-L1 antibody with subcutaneous formulation currently under clinical evaluations in the US, China, and Japan.
  • CK-301 is an anti-PD-L1 antibody being developed by Checkpoint Therapeutics.
  • B6 has the following VH and VL sequences.
  • PCT patent application PCT/CN2020/087019 discloses a human anti-PD-L1 antibody referred to as B12-01.
  • B12-01 has the following VH and VL sequences.
  • AUNP12 is a 29-mer peptide as the first peptic PD-1/PD-L1 inhibitor developed by Aurigene and Laboratoires Pierre Fabre that is being evaluated in clinical trial, following promising in vitro results.
  • CA-170 discovered by Aurigene/Curis as the PD-L1 and VISTA antagonist, was indicted as a potent small molecule inhibitor in vitro. The compound is currently under phase I clinical trial over mesothelioma patients.
  • BMS-986189 is a macrocyclic peptide discovered by Bristol-Myers Squibb of which the pharmacokinetics, safety and tolerability is currently being studied on healthy subjects.
  • a method for treating cancer in a subject in need thereof comprising administering to the subject an anti-C5aR antibody or antigen-binding fragment thereof and a PD-1/PD-L1 inhibitor.
  • a method for treating cancer in a subject in need thereof comprising administering to the subject an anti-C5aR antibody or antigen-binding fragment thereof and a PD-1/PD-L1 inhibitor, wherein the anti-C5aR antibody or antigen-binding fragment thereof comprises: (1) a heavy chain variable region (VH) , wherein the VH comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 2 or 11, and a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 3 or 12, and (2) a light chain variable region (VL) , wherein the VL comprises a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 6.
  • VH heavy chain variable region
  • VL light chain variable region
  • a method for treating cancer in a subject in need thereof comprising administering to the subject an anti-C5aR antibody or antigen-binding fragment thereof and a PD-1/PD-L1 inhibitor, wherein the anti-C5aR antibody or antigen-binding fragment thereof comprises: (1) a heavy chain variable region (VH) , wherein the VH comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 3, and (2) a light chain variable region (VL) , wherein the VL comprises a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 6.
  • VH heavy chain variable region
  • VL light chain variable region
  • a method for treating cancer in a subject in need thereof comprising administering to the subject an anti-C5aR antibody or antigen-binding fragment thereof and a PD-1/PD-L1 inhibitor, wherein the anti-C5aR antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising the amino acid sequences of SEQ ID NO: 7 and a light chain variable region (VL) comprising the amino acid sequences of SEQ ID NO: 8.
  • VH heavy chain variable region
  • VL light chain variable region
  • a method for treating cancer in a subject in need thereof comprising administering to the subject an anti-C5aR antibody or antigen-binding fragment thereof and a PD-1/PD-L1 inhibitor, wherein the anti-C5aR antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequences of SEQ ID NO: 9 and a light chain comprising the amino acid sequences of SEQ ID NO: 10.
  • the PD-1/PD-L1 inhibitor is an anti-PD-1, an anti-PD-L1 antibody or antigen-binding fragment thereof.
  • the PD-1 inhibitor is selected from the group consisting of Pidilizumab, Cemiplimab, Sintilimab, Cetrelimab, Spartalizumab, Camrelizumab, Tislelizumab, Balstilimab, Dostarlimab, ABBV-181, Penpulimab, Pembrolizumab, Genolimzumab, Retifanlimab, Sasanlimab, AMP-224, AB122, F-520, MEDI-3387, MEDI-5771, MEDI-0680, SG-001, nivolumab, BCD-100, BAT-1306, BI-754091, CBT-501, GLS-010, LZM-009, Sym-021, CS
  • the PD-L1 inhibitor is selected from the group consisting of Manelimab, Atezolizumab, Avelumab, Cosibelimab, Durvalumab, Envafolimab, Socazolimab, AUNP12, BGB-A333, CK-301, CS-1001, FAZ-053, APL-502, MDX-1105, IMC-001, KD-005, Gensci-047, LY-3300054, SHR-1316, MSB-2311, AVA-004, CBT-502, JS-003, B12, KY-1003, CA-170, BMS-986189, B6 and B12-01.
  • the anti-C5aR antibody or antigen-binding fragment thereof and the PD-1/PD-L1 inhibitor are administered at a molar ratio of 1.5: 1 to 6: 1.
  • the molar ratio is from 1.2: 1, 1.3: 1, 1.4: 1, 1.5: 1, 1.6: 1, 1.7: 1, 1.8: 1, 1.9: 1, 2: 1, 2.1: 1, 2.2: 1, 2.3: 1, 2.4: 1, 2.5: 1, 2.6: 1, 2.7: 1, 2.8: 1, 2.9: 1, or 3: 1 to 4: 1, 4.1: 1, 4.2: 1, 4.3: 1, 4.4: 1, 4.5: 1, 4.6: 1, 4.7: 1, 4.8: 1, 4.9: 1, 5: 1, 5.1: 1, 5.2: 1, 5.3: 1, 5.4: 1, 5.5: 1, 5.6: 1, 5.7: 1, 5.8: 1, 5.9: 1, 6: 1, 6.1: 1, 6.2: 1, 6.3: 1, 6.4: 1, 6.5: 1, 6.6: 1, 6.7: 1, 6.8: 1,
  • the anti-C5aR antibody or antigen-binding fragment thereof is administrated to the subject in need thereof before, after or concurrently with the PD-1/PD-L1 inhibitor.
  • the anti-C5aR antibody or antigen-binding fragment thereof and the PD-1/PD-L1 inhibitor are admixed together and administrated to the subject.
  • the anti-C5aR antibody or antigen-binding fragment thereof and the PD-1/PD-L1 inhibitor are separately administered within, for example, 1 minutes, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, or 20 minutes.
  • anti-C5aR antibody or antigen-binding fragment thereof and the PD-1/PD-L1 inhibitor are administered sequentially. In some embodiments, the anti-C5aR antibody or antigen-binding fragment thereof is administered before the PD-1/PD-L1 inhibitor. In some embodiments, the anti-C5aR antibody or antigen-binding fragment thereof is administered after the PD-1/PD-L1 inhibitor.
  • the anti-C5aR antibody or antigen-binding fragment thereof and the PD-1/PD-L1 inhibitor are separately administered within, for example, 30 minutes, 1 hour, 2 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 24 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, or 1 month.
  • the anti-C5aR antibody or antigen-binding fragment thereof and the PD-1/PD-L1 inhibitor are administered at the same frequency, such as once daily, once every other day, twice a week, once a week, once every two weeks, or once a month.
  • the anti-C5aR antibody or antigen-binding fragment thereof and the PD-1/PD-L1 inhibitor are administered at different frequencies.
  • the anti-C5aR antibody or antigen-binding fragment thereof cis administrated weekly and the PD-1/PD-L1 inhibitor is administrated monthly.
  • the anti-C5aR antibody or antigen-binding fragment thereof is administrated once every two weeks and the PD-1/PD-L1 inhibitor is administrated monthly. In some embodiments, the anti-C5aR antibody or antigen-binding fragment thereof is administrated weekly and the PD-1/PD-L1 inhibitor is administrated once every two weeks. In some embodiments, the anti-C5aR antibody or antigen-binding fragment thereof is administrated monthly and the PD-1/PD-L1 inhibitor is administrated once every two weeks. In some embodiments, the anti-C5aR antibody or antigen-binding fragment thereof is administrated monthly and the PD-1/PD-L1 inhibitor is administrated once every week.
  • the anti-C5aR antibody or antigen-binding fragment thereof and the PD-1/PD-L1 inhibitor are formulated together as a fixed dose combination.
  • the method can be used for treating cancer in a subject in need thereof.
  • the cancer is selected from the group consisting of colorectal cancer, breast cancer, non-small cell lung cancer, renal cell carcinoma, pancreatic cancer, ovarian cancer, prostate cancer, liver cancer, gliosarcoma, malignant glioma, peritoneal cancer, fallopian tube cancer, rectal cancer, kidney cancer, Hodgkin's lymphoma, bladder cancer, uveal melanoma, gastric cancer, squamous cell carcinoma, cervical cancer, uterine cancer, chronic lymphocytic leukemia, lymphoma, myeloma, Kaposi's sarcoma, urothelial carcinoma, mesothelioma, malignant fibrous histiocytoma, colon cancer, solid tumor, multiple myeloma, gastrointestinal stromal tumor, head and neck cancer, melanoma, and leiomyo
  • compositions that includes an anti-C5aR antibody or antigen-binding fragment thereof and a PD-1/PD-L1 inhibitor, such as an anti-PD-1 or anti-PD-L1 antibody or antigen-binding fragment thereof.
  • the anti-C5aR antibody or antigen-binding fragment thereof comprises: (1) a heavy chain variable region (VH) , wherein the VH comprises: a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 2 or 11, and a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 3 or 12, and (2) a light chain variable region (VL) , wherein the VL comprises a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 6.
  • VH heavy chain variable region
  • VL light chain variable region
  • the anti-C5aR antibody or antigen-binding fragment thereof comprises: (1) a heavy chain variable region (VH) , wherein the VH comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 3, and (2) a light chain variable region (VL) , wherein the VL comprises a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 6.
  • VH heavy chain variable region
  • VL light chain variable region
  • the anti-C5aR antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising the amino acid sequences of SEQ ID NO: 7 and a light chain variable region (VL) comprising the amino acid sequences of SEQ ID NO: 8.
  • VH heavy chain variable region
  • VL light chain variable region
  • the anti-C5aR antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequences of SEQ ID NO: 9 and a light chain comprising the amino acid sequences of SEQ ID NO: 10.
  • the PD-1/PD-L1 inhibitor is an anti-PD-1, an anti-PD-L1 antibody of antigen-binding fragment thereof.
  • the PD-1 inhibitor is selected from the group consisting of Pidilizumab, Cemiplimab, Sintilimab, Cetrelimab, Spartalizumab, Camrelizumab, Tislelizumab, Balstilimab, Dostarlimab, ABBV-181, Penpulimab, Pembrolizumab, Genolimzumab, Retifanlimab, Sasanlimab, AMP-224, AB122, F-520, MEDI-3387, MEDI-5771, MEDI-0680, SG-001, nivolumab, BCD-100, BAT-1306, BI-754091, CBT-501, GLS-010, LZM-009, Sym-021,
  • the PD-L1 inhibitor is selected from the group consisting of Manelimab, Atezolizumab, Avelumab, Cosibelimab, Durvalumab, Envafolimab, Socazolimab, AUNP12, BGB-A333, CK-301, CS-1001, FAZ-053, APL-502, MDX-1105, IMC-001, KD-005, Gensci-047, LY-3300054, SHR-1316, MSB-2311, AVA-004, CBT-502, JS-003, B12, KY-1003, CA-170, BMS-986189, B6 and B12-01.
  • compositions may be suitable for oral, parenteral, topical administration or for administration by inhalation.
  • a pharmaceutical composition comprising at least one antibody or antibody fragment according to the present disclosure may be administered parenterally, such as intravenously, or intramuscularly, or subcutaneously.
  • an antibody of the invention may be administered via a non-parenteral route, such as per-orally or topically.
  • a pharmaceutical composition comprising an antibody or antibody fragment according to the present disclosure is administered intravenously or subcutaneously.
  • a combination comprising an anti-C5aR antibody or antigen-binding fragment thereof and an anti-PD-1 or anti-PD-L1 antibody or antigen-binding fragment thereof for use in the treatment of cancer.
  • the anti-C5aR antibody or antigen-binding fragment thereof and anti-PD-1 or anti-PD-L1 antibody or antigen-binding fragment thereof are present at a molar ratio of 1.5: 1 to 6: 1.
  • the anti-C5aR antibody or antigen-binding fragment thereof comprises: (1) a heavy chain variable region (VH) , wherein the VH comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 2 or 11, and a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 3 or 12, and (2) a light chain variable region (VL) , wherein the VL comprises a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 6.
  • VH heavy chain variable region
  • VL light chain variable region
  • the two agents here may be combined into a single composition for use. Nevertheless, in some embodiments, they are administered separately to the same patient.
  • an article of manufacture comprising: (1) an anti-C5aR antibody or antigen-binding fragment thereof, wherein the anti-C5aR antibody or antigen-binding fragment thereof comprises: (i) a heavy chain variable region (VH) , wherein the VH comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 2 or 11, and a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 3 or 12; and (ii) a light chain variable region (VL) , wherein the VL comprises a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 6, and (2) a package insert, wherein the package insert provides instruction of administrating the anti-C5aR antibody or antigen-binding
  • kits or package comprising an anti-C5aR antibody or antigen-binding fragment thereof and a PD-1/PD-L1 inhibitor, such as an anti-PD-1 or anti-PD-L1 antibody or antigen-binding fragment thereof. They can be packaged individually or placed in separate compartment within the kit or package.
  • the anti-C5aR antibody or antigen-binding fragment thereof and the PD-1/PD-L1 inhibitor can be present at a molar ratio of 1.5: 1 to 6: 1.
  • the molar ratio is from 1.2: 1, 1.3: 1, 1.4: 1, 1.5: 1, 1.6: 1, 1.7: 1, 1.8: 1, 1.9: 1, 2: 1, 2.1: 1, 2.2: 1, 2.3: 1, 2.4: 1, 2.5: 1, 2.6: 1, 2.7: 1, 2.8: 1, 2.9: 1, or 3: 1 to 4: 1, 4.1: 1, 4.2: 1, 4.3: 1, 4.4: 1, 4.5: 1, 4.6: 1, 4.7: 1, 4.8: 1, 4.9: 1, 5: 1, 5.1: 1, 5.2: 1, 5.3: 1, 5.4: 1, 5.5: 1, 5.6: 1, 5.7: 1, 5.8: 1, 5.9: 1, 6: 1, 6.1: 1, 6.2: 1, 6.3: 1, 6.4: 1, 6.5: 1, 6.6: 1, 6.7: 1, 6.8: 1, 6.
  • the HuCAL library was used to select for antibodies with specificity for human C5aR.
  • the HuCAL library is a phagemid library based on the HuCAL concept (Knappik et al., (2000) J Mol Biol 296: 57-86) and employs the technology for displaying the Fab on the phage surface (Lohning et al., WO2001/05950) .
  • the clones were subjected to two consecutively conducted affinity maturation panning using CHO Flp-In cells engineered to overexpress either human or cynomolgus C5aR in order to further increase affinity and specificity for human and cynomolgus C5aR.
  • antibody engineering was conducted to further increase specificity, to remove potential posttranslational modification sites (PTM motifs) and for germlining purposes.
  • MAB#1 and MAB#2 were identified as potential therapeutic candidates. Since both candidates MAB#1 and MAB#2 are derived from the same ancestors, they share similar amino acid sequences and in vitro characteristics.
  • Both MAB#1 and MAB#2 are of the human IgG1f isotype but are engineered in the Fc region to abolish the ability of the antibodies to mediate immune effector function.
  • the Fc region comprises 5 amino acid substitutions compared to the wild-type human IgG1 Fc region, namely L234A, L235E, G237A, A330S and P331S (h_IgG1f_AEASS) with numbering according EU index.
  • the antibodies consist of the heavy chain framework VH3-15 and the antibody light chain framework lambda 1.
  • Example 3 Monovalent affinity determination for MAB#1 and MAB#2 for C5aR N-terminal peptides using SPR
  • K D determination via IgG capture setup was performed at 25°C with a Biacore T200 instrument (Biacore, GE Healthcare) . Approx. 500 RU of IgG diluted in HBS-EP+, pH 7.4, were captured on a CM5 chip (Biacore, GE Healthcare) immobilized with anti-human-Fc antibody (GE Healthcare) using standard EDC-NHS amine coupling chemistry. The reference flow cell 1 was only activated and deactivated.
  • Table 3 Determination of association and dissociation rate constants for binding of MAB#1 and MAB#2 to human and cynomolgus C5aR N-terminal peptides.
  • Example 4 Anti-tumor effects of anti-C5aR antibody in combination with PD-1 antibody in mouse colon cancer cell MC38 allograft tumor model in vivo
  • This example measured the anti-tumor efficacy of a mouse surrogate anti-C5aR antibody (Anti-mC5aR) with or without the combination with an anti-mouse PD-1 antibody (Anti-mPD-1) on a mouse transplanted tumor model of MC38 cells.
  • MC38 mouse colon cancer cell, item number: HYC3401; source: Heyuan Bio
  • MC38 mouse colon cancer cell, item number: HYC3401; source: Heyuan Bio
  • the tumor volume of the PBS control group was 1779.32 ⁇ 314.27 mm 3 .
  • the Anti-mC5aR alone treatment group did not show obvious tumor suppression effect.
  • Anti-mPD-1 (1 mg/kg) treatment group and Anti-mPD-1 (5 mg/kg) treatment group both showed certain anti-tumor effects, with tumor volumes of 1251.27 ⁇ 223.43 mm 3 and 1375 ⁇ 271.95 mm 3 , respectively.
  • the combined administration of Anti-mC5aR and Anti-mPD-1 significantly improved the anti-tumor effect.
  • the Q value method was used to analyze the combined effect between the two. The results show that Anti-mC5aR and Anti-mPD-1 have synergistic effect (Q ⁇ 1.15) .
  • the data analysis results are shown in Tables 6-8.
  • P value is obtained by analyzing the relative tumor volume using one-way ANOVA. According to Levene Statistic, the variance of the data is uniform (the F value is not significantly different) , and the LSD method is used for analysis.
  • the mouse colon cancer MC38 cell mouse transplanted tumor model was used to evaluate the in vivo effects of Anti-mC5aR, different doses of Anti-mPD-1 (1 mg/kg and 5 mg/kg) , and Anti-mC5aR + Anti-mPD-1 combinations.
  • the results showed that, compared with the control group, the Anti-mPD-1 single-drug group had a slight anti-tumor effect, and its anti-tumor effect was significantly enhanced when combined with Anti-mC5aR.
  • the Anti-mPD-1 (5 mg/kg) and Anti-mC5aR combination therapy exhibited the strongest anti-tumor effect. According to the Q value result, Anti-mC5aR and Anti-mPD-1 have a synergistic effect.
  • This example further conducted immunophenotyping from peripheral blood samples. Using FACS, the example counted cells with different markers, including T cells, B cells, Treg, M1, M2, and MDSC expressing CD45/CD3/CD4/CD8/CD19/Foxp3, CD11b/Ly6C/Ly6G or F4/80/CD206/CD86. The results are shown in FIG. 2. Significant effects are labeled.
  • Example 5 Synergistic activation of immune response by C5aR antibody in combination with PD-1 antibody
  • CD14+ cells were isolated from PBMCs by CD14+ magnetic beads.
  • the isolated CD14+ cells were supplemented with GM-CSF (20 ng/ml) and IL-6 (20 ng/ml) and cultured for 7 days to induce differentiation of the cells into MDSC cells.
  • the differentiated MDSC cells were mixed with T cells isolated from PBMCs by T cell isolation kit (MDSCs: T cells in a ratio of 1: 2) , 10nM C5a, anti-CD3/CD28 activator beads, together with C5aR antibody MAB#1 (0.4) , PD-1 antibody (Pembrolizumab, 1 ⁇ g/ml) or the combination of C5aR antibody MAB#1 (0.4) and PD-1 antibody (Pembrolizumab, 1 ⁇ g/ml) . After 5 days, IFN- ⁇ level in the supernatant of each group was measured by ELISA.

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Abstract

L'invention concerne des compositions et des thérapies pour le traitement du cancer, par ciblage à la fois des protéines C5aR et PD-1/PD-L1 chez le patient. Il est démontré ici que de tels traitements combinés, lorsqu'ils sont administrés à des doses appropriées, permettent d'obtenir des résultats synergiques.
PCT/CN2021/119170 2020-09-17 2021-09-17 Polythérapies ciblant des voies c5ar et pd-1/pd-l1 WO2022057910A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170275375A1 (en) * 2012-08-14 2017-09-28 Ibc Pharmaceuticals, Inc. Combination therapy with t-cell redirecting bispecific antibodies and checkpoint inhibitors
US20170283446A1 (en) * 2016-04-04 2017-10-05 Chemocentryx, Inc. SOLUBLE C5aR ANTAGONISTS
US20170291946A1 (en) * 2014-09-28 2017-10-12 The Regents Of The University Of California Modulation of stimulatory and non-stimulatory myeloid cells
US20180250338A1 (en) * 2015-11-18 2018-09-06 Duke University Tumor infiltrating lymphocytes for treatment of cancer
WO2020182974A1 (fr) * 2019-03-14 2020-09-17 Morphosys Ag Anticorps ciblant c5ar
WO2021180063A1 (fr) * 2020-03-09 2021-09-16 I-Mab Biopharma Co., Ltd. Procédés de détection et de quantification de modifications biologiques dans des anticorps

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170275375A1 (en) * 2012-08-14 2017-09-28 Ibc Pharmaceuticals, Inc. Combination therapy with t-cell redirecting bispecific antibodies and checkpoint inhibitors
US20170291946A1 (en) * 2014-09-28 2017-10-12 The Regents Of The University Of California Modulation of stimulatory and non-stimulatory myeloid cells
US20180250338A1 (en) * 2015-11-18 2018-09-06 Duke University Tumor infiltrating lymphocytes for treatment of cancer
US20170283446A1 (en) * 2016-04-04 2017-10-05 Chemocentryx, Inc. SOLUBLE C5aR ANTAGONISTS
WO2020182974A1 (fr) * 2019-03-14 2020-09-17 Morphosys Ag Anticorps ciblant c5ar
WO2021180063A1 (fr) * 2020-03-09 2021-09-16 I-Mab Biopharma Co., Ltd. Procédés de détection et de quantification de modifications biologiques dans des anticorps

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