WO2015198311A1 - Compositions comprenant des anticorps anti-ceacam -1 et kir pour le traitement du cancer - Google Patents

Compositions comprenant des anticorps anti-ceacam -1 et kir pour le traitement du cancer Download PDF

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WO2015198311A1
WO2015198311A1 PCT/IL2015/050635 IL2015050635W WO2015198311A1 WO 2015198311 A1 WO2015198311 A1 WO 2015198311A1 IL 2015050635 W IL2015050635 W IL 2015050635W WO 2015198311 A1 WO2015198311 A1 WO 2015198311A1
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human
ceacam
cell
pharmaceutical composition
kir
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PCT/IL2015/050635
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English (en)
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Tehila Ben-Moshe
Edna MEILIN
Yair SAPIR
Ilana MANDEL
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Ccam Therapeutics Ltd.
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Publication of WO2015198311A1 publication Critical patent/WO2015198311A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—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
    • 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
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/75—Agonist effect on antigen

Definitions

  • the present invention relates to pharmaceutical compositions comprising antibodies to human CEACAM-1 and KIR molecules, and methods for their use in treating cancer and activating lymphocytes.
  • CEACAM-1 The transmembrane protein carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1, also known as biliary glycoprotein (BGP), CD66a and C-CAM1), is a member of the carcinoembryonic antigen family (CEA) that also belongs to the immunoglobulin superfamily.
  • CEACAM-1 is known to interact with other known CEACAM proteins, including CD66a (CEACAM1), CD66c (CEACAM6) and CD66e (CEACAM5, CEA) proteins. It is expressed on a wide spectrum of cells, ranging from epithelial cells to those of hemopoietic origin (e.g. immune cells). Many different functions have been attributed to the CEACAM-1 protein.
  • CEACAM-1 protein is over expressed in some carcinomas of colon, prostate, as well as other types of cancer. Additional data support the central involvement of CEACAM-1 in angiogenesis and metastasis. CEACAM-1 also plays a role in the modulation of innate and adaptive immune responses. For example, CEACAM-1 was shown to be an inhibitory receptor for activated T cells contained within the human intestinal epithelium (WO 99/52552 and Morales et al. J. Immunol. 1999, 163, 1363-1370). Additional reports have indicated that CEACAM-1 engagement either by T cell receptor cross-linking with Monoclonal antibodies (mAbs) or by Neisseria gonorrhoeae Opa proteins inhibits T cell activation and proliferation. There are two different kinds of surface receptors which are responsible for triggering
  • NK-mediated natural cytotoxicity the NK KARs (meaning: Killer Activation Receptors) and the NK KIRs (meaning: Killer Inhibitory Receptors).
  • NK KARs are receptors expressed on the plasmatic membrane of Natural Killer cells (NK cells). KARs work with inhibitory Killer-cell immunoglobulin-like receptors (KIRs), which inactivate them in order to regulate the NK cells functions on hosted or transformed cells.
  • KAR Killer Activation Receptor
  • KIRs Killer Inhibition Receptors
  • KARs can detect a specific type of molecules: MICA (MHC class I polypeptide - related sequence A; MIC-A; PERB l l. l) and MICB (MHC class I polypeptide-related sequence B; PERB 11.2). These molecules are in MHC class I of human cells and they are related to cellular stress: this is why MICA and MICB appear in infected or transformed cells but are not common in healthy cells. KARs recognise MICA and MICB and get engaged. This engagement activates the natural killer cell to attack the transformed or infected cells. This action can be done in different ways. NK can directly kill the target cells, it can kill the target cells by producing cytokines, such as IFN- ⁇ and IFN-a, or it can do both.
  • NK cells are able to distinguish between normal and infected or transformed cells.
  • a KAR located on the surface of the NK cell binds to certain molecules which only appear on cells that are undergoing stress situations. In humans, this KAR is called NKG2D and the stress-related molecules are MICA and MICB. This binding provides a signal which induces the NK cell to kill the target cell.
  • KIRs examine the surface of the tumor cell in order to determine the levels of MHC class I molecules it has. If KIRs bind sufficiently to MHC class I molecules, the "killing signal" is overridden to prevent the killing of the cell. In contrast to this, if KIRs are not sufficiently engaged to MHC class I molecules, killing of the target cell proceeds.
  • KIR molecules are highly polymorphic, meaning their gene sequences differ greatly between individuals, so that different individuals possess different arrays/repertoires of KIR genes.
  • KIR genes are grouped as encoding receptors having (1) two domains, long cytoplasmic tail (KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL4, KIR2DL5A, KIR2DL5B), (2) two domains, short cytoplasmic tail (KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4, KIR2DS5), (3) three domains, long cytoplasmic tail (KIR3DL1, KIR3DL2, KIR3DL3), and (4) three domains, short cytoplasmic tail (KIR3DS1).
  • KIRs killer-cell immunoglobulin-like receptors
  • WO 2015/075725 to some of the present inventors relates to combinations of anti- CEACAMl and anti-PD-l/PD-Ligand antibodies, and their use in treating cancer.
  • WO 2015/075710 to some of the present inventors relates combinations of anti-CEACAMl antibodies, lymphocyte activating agent and activated lymphocytes, and their use in treating cancer.
  • International PCT application PCT/IL2015/050007 to some of the present inventors relates to combinations of kinase inhibitors and antibodies to CEACAMl, and to their use in treating cancer.
  • International PCT application PCT/IL2015/050433 to some of the present inventors relates to humanized antibodies, capable of specific binding to human CEACAMl molecules.
  • the present inventions provides novel combinations of monoclonal antibodies directed to human CEACAM-1 and human KIR proteins, as well as methods for their use in treating cancer and activating human lymphocytes.
  • the present invention stems in part from the surprising finding that a combination of anti-human-CEACAM-1 antibodies and anti-human-KIR antibodies has a synergistic anticancer effect, which is significantly better than the anti-cancer effect of each antibody alone.
  • the antibodies of the present invention allow cells of the human immune system to affect their cytotoxic activity towards cancerous cells. More specifically, it is speculated that these antibodies prevent cytotoxic cells of the human immune system from becoming deactivated by interaction with their target cancer cells, thus allowing them to destroy these target cells.
  • the present invention provides, in one aspect, a pharmaceutical composition
  • a pharmaceutical composition comprising: (i) a monoclonal antibody to human carcinoembryonic antigen-related cell adhesion molecule- 1 (CEACAM-1) or an antigen-binding fragment thereof, and (ii) a monoclonal antibody to human killer-cell immunoglobulin-like receptor (KIR) or an antigen- binding fragment thereof, wherein the monoclonal antibody to human KIR or the antigen- binding fragment thereof prevents suppression of a lymphocyte cell or activates a lymphocyte cell.
  • CEACAM-1 human carcinoembryonic antigen-related cell adhesion molecule- 1
  • KIR human killer-cell immunoglobulin-like receptor
  • the present invention further provides, in another aspect, a method for treating cancer in a patient in need thereof, comprising administrating to the patient: (i) a pharmaceutical composition comprising a monoclonal antibody to human carcinoembryonic antigen-related cell adhesion molecule- 1 (CEACAM-1) or an antigen-binding fragment thereof, and (ii) a pharmaceutical composition comprising a monoclonal antibody to human killer-cell immunoglobulin-like receptor (KIR) or an antigen-binding fragment thereof, wherein the monoclonal antibody to human KIR or the antigen-binding fragment thereof prevents suppression of a lymphocyte cell or activates a lymphocyte cell.
  • a pharmaceutical composition comprising a monoclonal antibody to human carcinoembryonic antigen-related cell adhesion molecule- 1 (CEACAM-1) or an antigen-binding fragment thereof
  • a pharmaceutical composition comprising a monoclonal antibody to human killer-cell immunoglobulin-like receptor (KIR) or an antigen-bind
  • the present invention further provides methods for increasing the cytotoxicity of a lymphocyte cell, or for increasing the secretion of granzyme B or IFN- ⁇ from a lymphocyte cell, comprising contacting the lymphocyte cell with: (i) a monoclonal antibody to human carcinoembryonic antigen-related cell adhesion molecule- 1 (CEACAM-1) or an antigen-binding fragment thereof, and (ii) a monoclonal antibody to human killer-cell immunoglobulin-like receptor (KIR) or an antigen-binding fragment thereof, wherein the monoclonal antibody to human KIR or the antigen-binding fragment thereof prevents suppression of a lymphocyte cell or activates a lymphocyte cell.
  • a monoclonal antibody to human carcinoembryonic antigen-related cell adhesion molecule- 1 CEACAM-1
  • KIR human killer-cell immunoglobulin-like receptor
  • the present invention further provides, in yet another aspect, a kit comprising (i) a pharmaceutical composition comprising a monoclonal antibody to human CEACAM-1 or an antigen-binding fragment thereof, and (ii) a pharmaceutical composition comprising a monoclonal antibody to human KIR or an antigen-binding fragment thereof, wherein the monoclonal antibody to human KIR or the antigen-binding fragment thereof prevents suppression of a lymphocyte cell or activates a lymphocyte cell.
  • the monoclonal antibody to human CEACAM-1 or the monoclonal antibody to human KIR is a human antibody, a humanized antibody, or a chimeric antibody.
  • the monoclonal antibody to human CEACAM-1 is a human antibody, a humanized antibody, or a chimeric antibody. Each possibility represents a separate embodiment of the present invention.
  • the monoclonal antibody to human CEACAM-1 or the antigen-binding fragment thereof binds to a CEACAM-1 molecule on a lymphocyte cell and prevents suppression of the lymphocyte cell.
  • the monoclonal antibody to human CEACAM-1 binds to a CEACAM-1 molecule on a lymphocyte cell and prevents suppression of the lymphocyte cell.
  • the anti-CEACAM-1 antibody is selected from the group consisting of CM-24, CM-10, MRG-1, 26H7, 5F4, TEC-11, 12-140-4, 4/3/17, COL-4, F36- 54, 34B 1, YG-C28F2, D14HD11, bl8.7.7, D11-AD11, HEA81, B l. l, CLB-gran-10, F34- 187, T84.1, B6.2, B1.13, YG-C94G7, 12-140-5, TET-2, variants thereof, antigen-binding fragments thereof, and any combination thereof.
  • Each possibility represents a separate embodiment of the present invention.
  • the monoclonal antibody to human CEACAM-1 or the antigen-binding fragment thereof has a heavy-chain CDR1 comprising a sequence set forth in SEQ ID NO: 1, a heavy-chain CDR2 comprising a sequence set forth in SEQ ID NO: 2, a heavy-chain CDR3 comprising a sequence set forth in SEQ ID NO: 3, a light-chain CDR1 comprising a sequence set forth in SEQ ID NO: 4, a light-chain CDR2 comprising a sequence set forth in SEQ ID NO: 5 and a light-chain CDR3 comprising a sequence set forth in SEQ ID NO: 6.
  • a heavy-chain CDR1 comprising a sequence set forth in SEQ ID NO: 1
  • a heavy-chain CDR2 comprising a sequence set forth in SEQ ID NO: 2
  • a heavy-chain CDR3 comprising a sequence set forth in SEQ ID NO: 3
  • a light-chain CDR1 comprising a sequence set forth in SEQ ID NO: 4
  • the monoclonal antibody to human CEACAM-1 is CM-24 or the antigen-binding fragment thereof. In certain embodiments, the monoclonal antibody to human CEACAM-1 is CM-24.
  • the anti-KIR antibody capable of inhibiting or blocking lymphocyte cell suppression, is capable of binding to an inhibitory KIR molecule.
  • the monoclonal antibody to human KIR or the antigen-binding fragment thereof binds to an inhibitory KIR molecule on a lymphocyte cell and prevents suppression of the lymphocyte cell.
  • the anti-KIR antibody capable of activating the lymphocyte cell, is capable of binding to an activating KIR molecule.
  • the monoclonal antibody to human KIR or the antigen-binding fragment thereof binds to an activating KIR molecule on a lymphocyte cell and activates the lymphocyte cell.
  • anti- human-CEACAM-1 antibodies and/or anti-human-KIR antibodies may bind lymphocytes both in-vivo, e.g. bind a human subject's natural lymphocytes after being administered to the human subject, and/or bind lymphocytes in-vitro, i.e. bind lymphocytes in-vitro, e.g. outside the human subject's body.
  • the lymphocyte cell is found in the body of a patient, preferably a cancer patient.
  • the pharmaceutical composition described above further comprises a human lymphocyte cell, preferably of a cancer patient.
  • the lymphocyte cell described above expresses CEACAM-1, an inhibitory KIR molecule, an activating KIR molecule, or any combination thereof. Each possibility represents a separate embodiment of the present invention.
  • the lymphocyte cell expresses CEACAM-1 and an inhibitory KIR molecule.
  • the lymphocyte cell expresses CEACAM-1 and an activating KIR molecule.
  • the lymphocyte cell expresses CEACAM-1, an inhibitory KIR molecule and an activating KIR molecule.
  • the KIR proteins are classified by the number of extracellular immunoglobulin domains (2D or 3D) and by whether they have a long (L) or short (S) cytoplasmic domain.
  • KIR proteins with the long cytoplasmic domain transduce inhibitory signals upon ligand binding via an immune tyrosine-based inhibitory motif (ITIM), while KIR proteins with the short cytoplasmic domain lack the ITIM motif and instead associate with the TYRO protein tyrosine kinase binding protein to transduce activating signals.
  • the inhibitory KIR molecule has a long (L) cytoplasmic domain.
  • the activating KIR molecule has a short (S) cytoplasmic domain.
  • the inhibitory KIR molecule is selected from the group consisting of 2DL1, 2DL2, 2DL3, 3DL1, 3DL2, 2DL5A, 2DL5B, 3DL3, 2DL4 and any combination thereof. In certain embodiments, the inhibitory KIR molecule is selected from the group consisting of 2DL1, 2DL2, 2DL3, 3DL1, 3DL2, 2DL5A, 2DL5B and any combination thereof. In certain embodiments, the inhibitory KIR molecule is selected from the group consisting of 2DL, 2DS1, 2DS2, 2DS4 and any combination thereof. Each possibility represents a separate embodiment of the present invention. In certain embodiments, the inhibitory KIR molecule is comprises 2DL, 2DS1, 2DS2, and 2DS4.
  • the activating KIR molecule is selected from the group consisting of 2DS1, 2DS2, 2DS4, 3DS1, 2DS5, 2DS3, 2DL4 and any combination thereof. In certain embodiments, the activating KIR molecule is selected from the group consisting of 2DS1, 2DS2, 2DS4, 3DS1 and any combination thereof. Each possibility represents a separate embodiment of the present invention.
  • the lymphocyte cell is activated. In certain embodiments, the lymphocyte cell is cytotoxic to a cancer cell. In certain embodiments, the cancer cell is found ex-vivo, preferably in a sterile container. In certain embodiments, the cancer cell is found in- vivo, preferably in a body of a cancer patient. In certain embodiments, the cancer cell expresses CEACAM-1, an MHC class I complex, or both. In certain embodiments, the cancer cell expresses CEACAM-1 and MHC class I. In certain embodiments, the cancer cell expresses CEACAM-1 and/or MHC class I in a significantly higher level than a corresponding non-cancerous cell of the same or of a different tissue.
  • the cancer is selected from the group consisting of a melanoma, lung cancer, thyroid cancer, breast cancer, colon cancer, prostate cancer, hepatic cancer, bladder cancer, renal cancer, cervical cancer, pancreatic cancer, leukemia, lymphoma, myeloid cancer, ovarian cancer, uterus cancer, sarcoma, biliary cancer, and endometrial cells cancers.
  • the cancer is melanoma.
  • the pharmaceutical compositions described above are for use in treating cancer. In certain embodiments, the pharmaceutical compositions described above are for use in increasing the cytotoxicity of a lymphocyte cell in-vivo or in-vitro. In certain embodiments, the pharmaceutical compositions described above are for use in increasing the secretion of granzyme B from a lymphocyte cell in-vivo or in-vitro. In certain embodiments, the pharmaceutical compositions described above are for use in increasing the secretion of IFN- ⁇ from a lymphocyte cell in-vivo or in-vitro.
  • the lymphocyte cell described above is a natural killer (NK) cell or a T cell. In certain embodiments, the lymphocyte cell is an NK cell. In certain embodiments, the lymphocyte cell is a T cell. In certain embodiments, the T cell is a lymphokine-activated killer (LAK) cell. In certain embodiments of the method described above, the method further comprises administrating to the patient a pharmaceutical composition comprising a lymphocyte cell.
  • the cancer's cells express CEACAM-1, an MHC class I complex, or both. In certain embodiments of the method described above, the cancer's cells express CEACAM-1 and an MHC class I complex.
  • the lymphocyte cell is incubated with the monoclonal antibody to human CEACAM-1, with the monoclonal antibody to human KIR, or with at least one antigen-binding fragment thereof, prior to administration. In certain embodiments, the lymphocyte cell is incubated with the monoclonal antibody to human CEACAM-1 or with an antigen-binding fragment thereof, and with the monoclonal antibody to human KIR or with an antigen-binding fragment thereof, prior to administration.
  • Each possibility represents a separate embodiment of the present invention.
  • the lymphocyte cell is found in the body of a human subject.
  • the human subject is a cancer patient.
  • the kit described above is for use in treating cancer.
  • the present invention further provides the use of the pharmaceutical compositions described above in preparing a medicament for treating cancer.
  • the present invention further provides the use of the kit described above in preparing a medicament for treating cancer.
  • NK cells express CEACAM-1 and KIR.
  • NK92MI cells were analyzed by flow cytometry (Figure 1A) with a PE-conjugated anti-CEACAM-1 antibody (CM-24-ENG, black histogram) or isotype control matched antibody (gray histogram); or ( Figure IB) with a mouse anti-human-KIR antibody (Serotec cat# MCA2243EL) followed by FITC-conjugated anti-mouse antibody (Jackson cat# 115-115-162, black histogram) or a secondary antibody only (grey histogram).
  • Figure 1A PE-conjugated anti-CEACAM-1 antibody
  • FITC-conjugated anti-mouse antibody Jackson cat# 115-115-162, black histogram
  • secondary antibody only grey histogram
  • Lymphokine-activated killer (LAK) cells express CEACAM-1 and KIR.
  • LAK cells were isolated from a healthy donor followed by activation with IL-2 (500 units/ml) for 7 days to generate a population of lymphokine-activated killer (LAK) cells.
  • LAK cells were analyzed by flow cytometry ( Figure 2A) with a PE-conjugated anti-CEACAM-1 antibody (CM-24-ENG, black histogram) or isotype control matched antibody (grey histogram); or ( Figure 2B) with a mouse anti-human-KIR antibody (Serotec cat# MCA2243EL) followed by FITC-conjugated anti mouse antibody (Jackson cat# 115-115-162, black histogram) or a secondary antibody only (grey histogram).
  • Figure 3 Figure 3
  • NK cells NK92MI
  • IgG anti-CEACAM-1 antibody
  • CM-24 anti-CEACAM-1 antibody
  • Serotec cat# MCA2243EL O.
  • NK cells (NK92MI) were incubated with a control antibody (IgG) or with various concentrations (0.17 ⁇ g/ml, 0.34 ⁇ g/ml, 0.67 ⁇ g/ml, 1.25 ⁇ g/ml, 2 ⁇ g/ml) of an anti- CEACAM-1 antibody (CM-24), an anti-KIR antibody (Serotec cat# MCA2243EL) (0.17 ⁇ g/ml, 0.34 ⁇ g/ml, 0.67 ⁇ g/ml, 1.25 ⁇ g/ml, 2.5 ⁇ g/ml) or a combination of both antibodies (0.17 ⁇ g/ml each, 0.34 ⁇ g/ml each, 0.67 ⁇ g/ml each, 1.25 ⁇ g/ml each, 2.5 ⁇ g/ml each) for 30 minutes at 37°C.
  • a control antibody IgG
  • concentrations 0.17 ⁇ g/ml, 0.34 ⁇ g/ml, 0.67 ⁇ g/ml, 1.25 ⁇ g/ml, 2 ⁇ g/
  • CEACAM-1 positive melanoma cells (SKMEL28) were then added for an incubation of 5 hours.
  • Results represent (Figure 4A) Granzyme B levels +SE as determined by commercial Granzyme B ELISA kit from triplicate wells per treatment; or (Figure 4B) IFN- ⁇ levels +SE as determined by commercial Granzyme B ELISA kit from triplicate wells per treatment. * P ⁇ 0.05 paired T-test compared to CM-24 or a-KIR only.
  • Combination index (CI) was calculated to be ⁇ 0.6 for granzyme B secretion, and ⁇ 0.5 for IFN- ⁇ secretion according to the equation above.
  • Figure 5 Synergistic effects of anti-CEACAM-1 and anti-KIR antibodies on the cytotoxicity of lymphokine-activated killer (LAK) cells against human melanoma cells.
  • LAK cells were isolated from a healthy donor followed by activation with IL-2 (500 units/ml) for 7 days to generate a population of lymphokine-activated killer (LAK) cells.
  • LAK cells (NK92MI) were incubated with a control antibody (IgG) or with various concentrations (0.34 ⁇ , 0.67 ⁇ g/ml, 1.25 ⁇ g/ml, 2 ⁇ g/ml) of an anti-CEACAM-1 antibody (CM-24), an anti-KIR antibody (Serotec cat# MCA2243EL) (0.34 ⁇ g/ml, 0.67 ⁇ g/ml, l ⁇ g/ml, 2 ⁇ g/ml) or a combination of both antibodies (0.34 ⁇ g/ml each, 0.67 ⁇ g/ml each, 1.25 ⁇ g/ml each, 2 ⁇ g/ml each) for 30 minutes at 37°C.
  • CEACAM-1 positive melanoma cells (SKMEL28) were then added for an incubation of 5 hours.
  • Results represent an average of % cytotoxicity +SE as determined by classical LDH release assay from triplicate wells per treatment. * P ⁇ 0.05 paired T-test compared to CM-24 or a-KIR only.
  • Combination index (CI) was calculated to be ⁇ 0.6 according to the equation above.
  • the present invention generally provides novel combinations of immunotherapeutic agents having a surprisingly prominent anti-cancer effect, which is significantly stronger than the anti-cancer effect of each agent alone, and methods for the use of these agents and combinations in treating cancer. More specifically, the present invention provides combinations of antibodies against the human transmembrane proteins carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1) and killer inhibition receptors (KIRs), expressed by human lymphocytes, which surprisingly together act in synergy to promote the cytotoxic activity of the lymphocytes towards cancerous cells.
  • CEACAM-1 carcinoembryonic antigen-related cell adhesion molecule 1
  • KIRs killer inhibition receptors
  • the present invention stems, in part, from the surprising findings that combinations of antibodies against human CEACAM-1 and human KIR molecules have a synergistic effect on promoting anti-cancer cytotoxic activity of human lymphocytes, as well as synergistically promoting the expression and secretion of granzyme B and IFN- ⁇ from these lymphocytes.
  • Granzyme B is a serine protease commonly found in the granules of cytotoxic lymphocytes (CTLs), natural killer cells (NK cells) and cytotoxic T cells. It is secreted by these cells along with the pore forming protein perforin to mediate apoptosis in target cells.
  • IFN- ⁇ is a cytokine produced predominantly by natural killer (NK) and natural killer T (NKT) cells as part of the innate immune response, and by CD4 Thl and CD8 cytotoxic T lymphocyte (CTL) effector T cells.
  • the present invention provides, in one aspect, a pharmaceutical composition
  • a pharmaceutical composition comprising: (i) a monoclonal antibody to human carcinoembryonic antigen-related cell adhesion molecule- 1 (CEACAM-1) or an antigen-binding fragment thereof, and (ii) a monoclonal antibody to human killer-cell immunoglobulin-like receptor (KIR) or an antigenic) binding fragment thereof, wherein the monoclonal antibody to human KIR or the antigen- binding fragment thereof prevents suppression of a lymphocyte cell or activates a lymphocyte cell.
  • CEACAM-1 human carcinoembryonic antigen-related cell adhesion molecule- 1
  • KIR human killer-cell immunoglobulin-like receptor
  • the present invention further provides the pharmaceutical composition described above for use in treating cancer, or for use in preparing a medicament for treating cancer, or 15 for increasing the cytotoxicity of a lymphocyte cell, or for increasing the secretion of granzyme B or IFN- ⁇ from a lymphocyte cell.
  • the present invention further provides, in another aspect, a method for treating cancer in a patient in need thereof, comprising administrating to the patient: (i) a pharmaceutical composition comprising a monoclonal antibody to human carcinoembryonic antigen-related 20 cell adhesion molecule- 1 (CEACAM-1) or an antigen-binding fragment thereof, and (ii) a pharmaceutical composition comprising a monoclonal antibody to human killer-cell immunoglobulin-like receptor (KIR) or an antigen-binding fragment thereof, wherein the monoclonal antibody to human KIR or the antigen-binding fragment thereof prevents suppression of a lymphocyte cell or activates a lymphocyte cell.
  • a pharmaceutical composition comprising a monoclonal antibody to human carcinoembryonic antigen-related 20 cell adhesion molecule- 1 (CEACAM-1) or an antigen-binding fragment thereof
  • a pharmaceutical composition comprising a monoclonal antibody to human killer-cell immunoglobulin-like receptor (KIR) or an antigen
  • the present invention further provides methods for increasing the cytotoxicity of a lymphocyte cell, or for increasing the secretion of granzyme B or IFN- ⁇ from a lymphocyte cell, comprising contacting the lymphocyte cell with: (i) a monoclonal antibody to human carcinoembryonic antigen-related cell adhesion molecule- 1 (CEACAM-1) or an antigen-binding fragment thereof, and (ii) a monoclonal antibody to human killer-cell
  • kits comprising (i) a pharmaceutical composition comprising a monoclonal antibody to human CEACAM- 1 or an antigen-binding fragment thereof, and (ii) a pharmaceutical composition comprising a monoclonal antibody to human KIR or an antigen-binding fragment thereof, wherein the monoclonal antibody to human KIR or the antigen-binding fragment thereof prevents suppression of a lymphocyte cell or activates a lymphocyte cell.
  • the present invention further provides the kit described above for use in treating cancer, or for use in preparing a medicament for treating cancer, or for increasing the cytotoxicity of a lymphocyte cell, or for increasing the secretion of granzyme B or IFN- ⁇ from a lymphocyte cell.
  • composition refers to any composition comprising at least one chemical or biological agent and a pharmaceutically acceptable carrier.
  • agents according to the present invention are antibodies to human CEACAM- 1 proteins, and/or antibodies to human KIR proteins.
  • antibody is used in the broadest sense and includes monoclonal antibodies
  • polyclonal antibodies including full length or intact monoclonal antibodies, polyclonal antibodies, multivalent antibodies, multi-specific antibodies (e.g., bi-specific antibodies), and antibody fragments long enough to exhibit the desired biological activity.
  • Antibodies, or immunoglobulins comprise two heavy chains linked together by disulfide bonds and two light chains, each light chain being linked to a respective heavy chain by disulfide bonds in a "Y" shaped configuration.
  • Proteolytic digestion of an antibody yields Fv (Fragment variable) and Fc (Fragment crystalline) domains.
  • the antigen binding domains, Fab include regions where the polypeptide sequence varies.
  • F(ab')2 represents two Fab' arms linked together by disulfide bonds.
  • the central axis of the antibody is termed the Fc fragment.
  • Each heavy chain has at one end a variable domain (VH) followed by a number of constant domains (CH).
  • Each light chain has a variable domain (VL) at one end and a constant domain (CL) at its other end, the light chain variable domain being aligned with the variable domain of the heavy chain and the light chain constant domain being aligned with the first constant domain of the heavy chain (CHI).
  • VL variable domain
  • CL constant domain
  • CHI first constant domain of the heavy chain
  • the variable domains of each pair of light and heavy chains form the antigen-binding site.
  • the domains on the light and heavy chains have the same general structure and each domain comprises four framework regions, whose sequences are relatively conserved, joined by three hyper-variable domains known as complementarity determining regions (CDRs 1 -3). These domains contribute specificity and affinity of the antigen-binding site.
  • the isotype of the heavy chain determines immunoglobulin class (IgG, IgA, IgD, IgE or IgM, respectively).
  • the light chain is either of two isotypes (kappa, ⁇ or lambda, ⁇ ) found in all antibody classes.
  • the antibody according to the present invention is a molecule comprising at least the antigen-binding portion of an antibody.
  • Antibody or antibodies according to the invention include intact antibodies, such as polyclonal antibodies or monoclonal antibodies (mAbs), as well as proteolytic fragments thereof, such as the Fab or F(ab')2 fragments. Single chain antibodies also fall within the scope of the present invention.
  • Antibody fragments comprise only a portion of an intact antibody, generally including an antigen binding site of the intact antibody and thus retaining the ability to bind antigen.
  • Examples of antibody fragments encompassed by the present definition include: (i) the Fab fragment, having VL, CL, VH and CHI domains; (ii) the Fab' fragment, which is a Fab fragment having one or more cysteine residues at the C-terminus of the CHI domain; (iii) the Fd fragment having VH and CHI domains; (iv) the Fd' fragment having VH and CHI domains and one or more cysteine residues at the C-terminus of the CHI domain; (v) the Fv fragment having the VL and VH domains of a single arm of an antibody; (vi) the dAb fragment (Ward et al., Nature 1989, 341, 544-546) which consists of a VH domain; (vii) isolated CDR regions; (viii) F(ab')2 fragments, a
  • Single chain antibodies can be single chain composite polypeptides having antigen binding capabilities and comprising amino acid sequences homologous or analogous to the variable regions of an immunoglobulin light and heavy chain i.e. linked VH-VL or single chain Fv (scFv).
  • neutralizing antibody refers to a molecule having an antigen-binding site to a specific receptor or ligand target capable of reducing or inhibiting (blocking) activity or signaling through a receptor, as determined by in-vivo or in-vitro assays, as per the specification.
  • the term "monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigen. Furthermore, in contrast to polyclonal antibody preparations that typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen.
  • the modifier "monoclonal” is not to be construed as requiring production of the antibody by any particular method. mAbs may be obtained by methods known to those skilled in the art.
  • the monoclonal antibodies to be used in accordance with the present invention may be made by the hybridoma method first described by Kohler et al., Nature 1975, 256, 495, or may be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567).
  • the "monoclonal antibodies” may also be isolated from phage antibody libraries using the techniques described in Clackson et al, Nature 1991, 352, 624-628 or Marks et al., J. Mol. Biol., 1991, 222:581- 597, for example.
  • the mAbs of the present invention may be of any immunoglobulin class including
  • a hybridoma producing a mAb may be cultivated in-vitro or in-vivo. High titers of mAbs can be obtained by in-vivo production where cells from the individual hybridomas are injected intra-peritoneally into pristine -primed Balb/c mice to produce ascites fluid containing high concentrations of the desired mAbs.
  • mAbs of isotype IgM or IgG may be purified from such ascites fluids, or from culture supernatants, using column chromatography methods well known to those of skill in the art.
  • human antibody refers to an antibody which possesses an amino acid sequence which corresponds to that of an antibody produced by a human and/or has been made using any of the techniques for making human antibodies as disclosed herein. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen-binding residues. Human antibodies can be produced using various techniques known in the art.
  • humanized antibody refers to an antibody that has its CDRs (complementarily determining regions) derived from a non-human species immunoglobulin and the remainder of the antibody molecule derived mainly from a human immunoglobulin.
  • chimeric antibody refers to an antibody in which at least one of the antibody chains (heavy or light) comprises variable region sequences from one species (e.g., mouse) and constant region sequences from another species (e.g., human).
  • the term “chimeric antibody” is intended to encompass antibodies in which: (i) the heavy chain is chimeric but the light chain comprises variable and constant regions from only one species; (ii) the light chain is chimeric but the heavy chain comprises variable and constant regions from only one species; and (iii) both the heavy chain and the light chain are chimeric.
  • molecule having the antigen-binding portion of an antibody and "antigen- binding-fragments” as used herein is intended to include not only intact immunoglobulin molecules of any isotype and generated by any animal cell line or microorganism, but also the antigen-binding reactive fraction thereof, including, but not limited to, the Fab fragment, the Fab' fragment, the F(ab')2 fragment, the variable portion of the heavy and/or light chains thereof, Fab mini-antibodies (see WO 93/15210, US patent application 08/256,790, WO 96/13583, US patent application 08/817,788, WO 96/37621, US patent application 08/999,554, the entire contents of which are incorporated herein by reference), dimeric bispecific mini-antibodies (see Muller et al., 1998) and single-chain antibodies incorporating such reactive fraction, as well as any other type of molecule in which such antibody reactive fraction has been physically inserted.
  • Such molecules may be provided by any known technique, including, but not limited to
  • the invention also provides conservative amino acid variants of the antibody molecules according to the invention. Variants according to the invention also may be made that conserve the overall molecular structure of the encoded proteins. Given the properties of the individual amino acids comprising the disclosed protein products, some rational substitutions will be recognized by the skilled worker. Amino acid substitutions, i.e. "conservative substitutions,” may be made, for instance, on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity, and/or the amphipathic nature of the residues involved.
  • antibody analog refers to an antibody derived from another antibody by one or more conservative amino acid substitutions.
  • antibody variant refers to any molecule comprising the antibody of the present invention.
  • fusion proteins in which the antibody or an antigen-binding-fragment thereof is linked to another chemical entity is considered an antibody variant.
  • CDR and “Complementarity determining region” refer to one of the six hypervariable regions within the variable domains of an antibody that mainly contribute to antigen binding.
  • antibody framework refers to the part of the variable domain, either VL or VH, which serves as a scaffold for the antigen binding loops (CDRs) of this variable domain. In essence it is the variable domain without the CDRs.
  • antigen refers to a molecule or a portion of a molecule capable of eliciting antibody formation and being bound by an antibody.
  • An antigen may have one or more than one epitope.
  • the specific reaction referred to above is meant to indicate that the antigen will react, in a highly selective manner, with its corresponding antibody and not with the multitude of other antibodies which may be evoked by other antigens.
  • An antigen according to the present invention is a CEACAM-1 or a KIR protein or a fragment thereof.
  • antigenic determinant or "epitope” as used herein refers to the region of an antigen molecule that specifically reacts with a particular antibody.
  • Peptide sequences derived from an epitope can be used, alone or in conjunction with a carrier moiety, applying methods known in the art, to immunize animals and to produce additional polyclonal or monoclonal antibodies. Isolated peptides derived from an epitope may be used in diagnostic methods to detect antibodies and as therapeutic agents when inhibition of said antibodies is required.
  • CEACAM-1 is used to refer to the protein product of the CEACAM-1 gene e.g., NP_001020083.1, NP_001703.2. In humans, 11 different CEACAM-1 splice variants have been detected so far. Individual CEACAM-1 isoforms differ with respect to the number of extracellular immunoglobulin-like domains (for example, CEACAM-1 with four extracellular immunoglobulin-like domains is known as CEACAM-1-4), membrane anchorage and/or the length of their cytoplasmic tail (for example, CEACAM-1-4 with a long cytoplasmic tail is known as CEACAM-1 -4L and CEACAM-1-4 with a short cytoplasmic tail is known as CEACAM-1 -4S).
  • the N-terminal domain of CEACAM-1 starts immediately after the signal peptide and its structure is regarded as IgV-type.
  • the N-terminal IgV-type domain is comprised of 108 amino acids, from amino acid 35 to 142. This domain was identified as responsible for the homophilic binding activity (Watt et al., 2001, Blood. 98, 1469-79). All variants, including these splice variants are included within the term "CEACAM-1".
  • anti-CEACAM-1 antibody an antibody which recognizes CEACAM-1
  • an antibody against CEACAM-1 an antibody against CEACAM-1
  • an antibody to CEACAM-1 are interchangeable, known in the field of immunotherapy, and are generally used herein to refer to an antibody or to an antibody fragment that binds or is capable of binding to a CEACAM-1 protein with sufficient affinity and specificity to affect a biological activity or outcome.
  • anti-KIR antibody an antibody which recognizes KIR
  • an antibody against KIR an antibody against KIR
  • an antibody to KIR are interchangeable, known in the field of immunotherapy, and are generally used herein to refer to an antibody, or to an antibody fragment, that binds or is capable of binding to at least one of the killer-cell immunoglobulin- like receptors, preferably those expressed and presented by lymphocyte cells, with sufficient affinity and specificity to affect a biological activity or outcome.
  • prevents suppression of a lymphocyte cell and “capable of inhibiting or blocking lymphocyte cell suppression” as used herein refer to the capability of an antibody to interact with a KIR molecule presented by a lymphocyte cell in such a way that the cell becomes less responsive, preferably insensitive, to signals otherwise preventing the cell from becoming cytotoxic toward a target cell, for example by initiating cytokine or granzyme B release, and/or by causing lysis or apoptosis.
  • signals may be, for example, interactions with MHC class I molecules or complexes, which are known to suppress the cytotoxic activity of lymphocyte cells by interacting with certain suppressive KIR molecules.
  • activates a lymphocyte cell and “capable of activating a lymphocyte cell” as used herein refer to the capability of an antibody to interact with a KIR molecule presented by a lymphocyte cell in such a way that the cell becomes more cytotoxic toward a target cell, for example by initiating cytokine or granzyme B release, and/or by causing lysis or apoptosis.
  • inhibitory KIR molecule refers to any KIR molecule, presented on the cell surface of an immune cell, which is capable of suppressing or blocking the cytotoxic activity and/or cytokine or granzyme B secretion of said immune cell.
  • activating KIR molecule refers to any KIR molecule, presented on the cell surface of an immune cell, which is capable of initiating or promoting the cytotoxic activity and/or cytokine or granzyme B secretion of said immune cell.
  • activated lymphocyte cell refers to any cell of the immune system, having a cytotoxic effect towards a target cell, for example by releasing cytokine(s) or granzyme B, causing lysis or apoptosis.
  • cytotoxic lymphocyte cell refers to any cell of the immune system which causes lysis or apoptosis of cancer cells by any mechanism.
  • cytotoxicity means the quality of being toxic to cells.
  • cytotoxicity refers to the degree to which a lymphocyte cell is able to induce the death, lysis or otherwise destruction of cancer cells.
  • treating cancer refers to administering therapeutic effective amounts of agents such as antibodies and/or lymphocyte cells to a patient diagnosed with cancer, to inhibit the further growth of malignant cells in the patient, to inhibit the spread of the malignant cells in the patient, and/or to cause the death of malignant cells in the patient.
  • treating further means to ameliorate one or more symptoms associated with the referenced disorder.
  • therapeutically effective amount refers to an amount of a drug effective to treat a disease or disorder in a mammal.
  • the therapeutically effective amount of the drug may reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and/or relieve to some extent one or more of the symptoms associated with the disorder.
  • the drug may prevent growth and/or kill existing cancer cells, it may be cytostatic and/or cytotoxic.
  • efficacy in vivo can, for example, be measured by assessing the duration of survival, time to disease progression (TTP), the response rates (RR), duration of response, and/or quality of life.
  • TTP time to disease progression
  • RR response rates
  • duration of response duration of response
  • quality of life the term "preventing" means to mitigate a symptom of the referenced disorder.
  • target cell refers to any cell exhibiting unregulated or abnormal cell growth.
  • cancer and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.
  • pre-incubated and “incubated” as used herein refers to the incubation of at least two chemical or biological agents, for example a cell and an antibody directed against an antigen presented by the cell, under conditions to allow and/or promote an interaction between the agents.
  • the interaction is a physical interaction.
  • the interaction is a high affinity physical interaction, such as between an antibody and its target antigen..
  • kit is used in reference to a combination of reagents and other materials. It is contemplated that the kit may include reagents such antibodies and/or storage vials or other containers. It is not intended that the term “kit” be limited to a particular combination of reagents and/or other materials.
  • Example 1 Human natural-killer (NK) cells express CEACAM-1 and KIR.
  • Human NK92MI cells were analyzed by flow cytometry with a PE-conjugated anti- CEACAM-1 antibody (CM-24-ENG, A, black histogram) or with an anti-KIR antibody (Serotec cat# MCA2243EL, clone NKVFS1, anti-KIR2DL, KIR2DS1, KIR2DS2 and KIR2DS4, B, black histogram).
  • CM-24-ENG PE-conjugated anti- CEACAM-1 antibody
  • an anti-KIR antibody Serotec cat# MCA2243EL, clone NKVFS1, anti-KIR2DL, KIR2DS1, KIR2DS2 and KIR2DS4, B, black histogram.
  • a similar assay was conducted for an isotype control or a secondary antibody only (grey histogram).
  • CM-24 developed by the present inventors, is a humanized antibody against CEACAM1, which has a heavy-chain CDRl comprising a sequence set forth in SEQ ID NO: 1, a heavy-chain CDR2 comprising a sequence set forth in SEQ ID NO: 2, a heavy-chain CDR3 comprising a sequence set forth in SEQ ID NO: 3, a light-chain CDRl comprising a sequence set forth in SEQ ID NO: 4, a light-chain CDR2 comprising a sequence set forth in SEQ ID NO: 5 and a light-chain CDR3 comprising a sequence set forth in SEQ ID NO: 6.
  • Figures 1A and IB demonstrate that the human NK cells used in the experiments express both CEACAM-1 + and KIR + .
  • Example 2 - Human lymphokine-activated killer (LAK) cells express CEACAM-1 and KIR.
  • LAK cells Human lymphokine-activated killer (LAK) cells, generated from PBMCs, were analyzed by flow cytometry with a PE-conjugated anti-CEACAM-1 antibody (CM-24-ENG, Figure 2A, black histogram) or with anti-KIR antibody antibody (Serotec cat# MCA2243EL, Figure 2B, black histogram). A similar assay was conducted for an isotype control or a secondary antibody only (grey histogram).
  • CM-24-ENG PE-conjugated anti-CEACAM-1 antibody
  • anti-KIR antibody antibody Serotec cat# MCA2243EL, Figure 2B, black histogram
  • Figures 2A and 2B demonstrate that the human LAK cells used in the experiments express both CEACAM-1 + and KIR + .
  • Example 3 Synergistic effects of an anti-CEACAM-1 antibody and anti-KIR on the cytotoxicity of human NK cells against human melanoma cells.
  • Human NK cells (NK92MI) were incubated with a control antibody (IgG) or with various concentrations (0.17 ⁇ g/ml, 0.34 ⁇ g/ml, 0.67 ⁇ g/ml, 1.25 ⁇ g/ml) of an anti-CEACAM-1 antibody (CM-24), an anti-KIR antibody (Serotec cat# MCA2243EL) (O. ⁇ g/ml, 0.34 ⁇ g/ml, 0.67 ⁇ g/ml, 1.25 ⁇ g/ml) or a combination of both antibodies (0.17 ⁇ g/ml each, 0.34 ⁇ g/ml each, 0.67 ⁇ g/ml each, 1.25 ⁇ g/ml each) for 30 minutes at 37°C.
  • CM-24 anti-CEACAM-1 antibody
  • an anti-KIR antibody Serotec cat# MCA2243EL
  • Figure 3 demonstrates that anti-CEACAM-1 antibodies and anti-KIR antibodies are able to bind their respective targets on lymphocytes such as human NK cells, and that this binding synergistically increases the toxicity of the human NK cells against human cancer cells.
  • Example 4 Synergistic effects of CM-24 and anti-KIR on the secretion of granzyme B and IFN- ⁇ from human NK cells in the presence of human melanoma cells.
  • Human NK cells (NK92MI) were incubated with a control antibody (IgG) or with various concentrations (0.17 ⁇ g/ml, 0.34 ⁇ g/ml, 0.67 ⁇ g/ml, 1.25 ⁇ g/ml, 2 ⁇ g/ml) of an anti- CEACAM-1 antibody (CM-24), an anti-KIR antibody (Serotec cat# MCA2243EL) (0.17 ⁇ g/ml, 0.34 ⁇ g/ml, 0.67 ⁇ g/ml, 1.25 ⁇ g/ml, 2.5 ⁇ g/ml) or a combination of both antibodies (0.17 ⁇ g/ml each, 0.34 ⁇ g/ml each, 0.67 ⁇ g/ml each, 1.25 ⁇ g/ml each, 2.5 ⁇ g/ml each) for 30 minutes at 37°C.
  • a control antibody IgG
  • concentrations 0.17 ⁇ g/ml, 0.34 ⁇ g/ml, 0.67 ⁇ g/ml, 1.25 ⁇ g/ml, 2 ⁇ g
  • Figures 4A and 4B demonstrate that anti-CEACAM-1 antibodies and anti-KIR antibodies are able to bind their respective targets on human lymphocytes such as NK cells, and that this binding increases their granzyme B and IFN- ⁇ secretion, and thereby their toxicity towards the cancer cells.
  • Figures 4A and 4B further surprisingly demonstrate that the binding of these antibodies to human NK cells is interrelated, warranting a further study of their binding mechanism.
  • Example 5 Synergistic effect of an anti-CEACAM-1 antibody and anti-KIR on the cytotoxicity of human ymphokine-activated killer (LAK) cells against human melanoma cells.
  • LAK human ymphokine-activated killer
  • Human lymphokine-activated killer (LAK) cells generated by activation of PBMCs from a healthy donor with IL-2 (500 units/ml) for 7 days, were incubated with a control antibody (IgG) or with various concentrations (0.34 ⁇ g/ml, 0.67 ⁇ g/ml, 1.25 ⁇ g/ml, 2 ⁇ g/ml) of an anti-CEACAM-1 antibody (CM-24), an anti-KIR antibody (Serotec cat# MCA2243EL) (0.34 ⁇ g/ml, 0.67 ⁇ g/ml, 1.25 ⁇ g/ml, 2 ⁇ g/ml) or a combination of both antibodies (0.34 ⁇ g/ml each, 0.67 ⁇ g/ml each, 1.25 ⁇ g/ml each, 2.5 ⁇ g/ml each) for 30 minutes at 37°C.
  • a control antibody IgG
  • concentrations 0.34 ⁇ g/ml, 0.67 ⁇ g/ml, 1.25 ⁇ g/ml, 2 ⁇ g/m
  • Figure 5 demonstrates that anti-CEACAM-1 antibodies and anti-KIR antibodies are able to bind their respective targets on human activated lymphocytes such as LAK cells, and that this binding synergistically increases the toxicity of the LAK cells against human cancer cells.
  • Figure 5 further surprisingly demonstrates that the binding of these antibodies to human LAK cells is somehow interrelated, warranting a further study of their binding mechanism, and that this mechanism is present in variety of activated lymphocytes.

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Abstract

La présente invention concerne des compositions comprenant des anticorps dirigés contre le CEACAM1 humain et les KIR humains, des kits les comprenant, et des méthodes pour les utiliser dans l'atténuation ou le traitement du cancer.
PCT/IL2015/050635 2014-06-24 2015-06-23 Compositions comprenant des anticorps anti-ceacam -1 et kir pour le traitement du cancer WO2015198311A1 (fr)

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WO2014055648A1 (fr) * 2012-10-02 2014-04-10 Bristol-Myers Squibb Company Combinaison d'anticorps anti-kir et d'anticorps anti-pd-1 pour le traitement du cancer
WO2014066532A1 (fr) * 2012-10-23 2014-05-01 Bristol-Myers Squibb Company Association d'anticorps anti-kir et anti-ctla-4 pour le traitement du cancer

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Publication number Priority date Publication date Assignee Title
WO2014055648A1 (fr) * 2012-10-02 2014-04-10 Bristol-Myers Squibb Company Combinaison d'anticorps anti-kir et d'anticorps anti-pd-1 pour le traitement du cancer
WO2014066532A1 (fr) * 2012-10-23 2014-05-01 Bristol-Myers Squibb Company Association d'anticorps anti-kir et anti-ctla-4 pour le traitement du cancer

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"cCAM Biotherapeutics Receives FDA Approval to Initiate Phase 1 Trial for CM-24, a Novel", IMMUNE CHECKPOINT INHIBITOR FOR CANCER IMMUNOTHERAPY, vol. 9, no. 10, 16 September 2015 (2015-09-16), pages 1936 - 1965, XP029341860, ISSN: 1574-7891, Retrieved from the Internet <URL:http://www.businesswire.com/news/home/20150106005535/en/cCAM-Biotherapeutics-Receives-FDA-Approval-Initiate-Phas> [retrieved on 20150916] *
SAPOZNIK, SIVAN ET AL.: "Novel anti-melanoma immunotherapies: disarming tumor escape mechanisms.", CLINICAL AND DEVELOPMENTAL IMMUNOLOGY, vol. 24, no. 2, 2012, pages 207 - 209, XP055247432, ISSN: 1740-2522, Retrieved from the Internet <URL:http://www.hindawi.com/journals/jir/2012/818214> *
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