WO2019237042A1 - Ciblage d'interactions de jaml-car pour l'immunothérapie antitumorale - Google Patents

Ciblage d'interactions de jaml-car pour l'immunothérapie antitumorale Download PDF

Info

Publication number
WO2019237042A1
WO2019237042A1 PCT/US2019/036121 US2019036121W WO2019237042A1 WO 2019237042 A1 WO2019237042 A1 WO 2019237042A1 US 2019036121 W US2019036121 W US 2019036121W WO 2019237042 A1 WO2019237042 A1 WO 2019237042A1
Authority
WO
WIPO (PCT)
Prior art keywords
jaml
car
tumor
antibody
subject
Prior art date
Application number
PCT/US2019/036121
Other languages
English (en)
Inventor
Wendy HAVRAN
Joseph Michael McGRAW
Deborah WITHERDEN
Original Assignee
The Scripps Research Institute
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Scripps Research Institute filed Critical The Scripps Research Institute
Publication of WO2019237042A1 publication Critical patent/WO2019237042A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • 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

Definitions

  • NKT Natural killer T cells
  • gd T cells have been identified as critical components in cancer immune surveillance.
  • the initial success of preclinical trials in the last decades has evoked NKT or gd T cells based immunotherapeutic approaches for the treatment of cancer.
  • a significant proportion of patients do not have a sufficient number of NKT or gd T cells and/or lack sufficient cells with normal function.
  • the invention provides methods for promoting T cell tumor infiltration in a subject.
  • the methods entail administering to the subject a pharmaceutical composition that contains a therapeutically effective amount of an agent that enhances the specific binding between junctional adhesion molecule (JAML) on T cells and Coxsackie and adenovirus receptor (CAR) on tumor cells. This will lead to enhanced T cell tumor infiltration in the subject.
  • the subject is also treated with an immune checkpoint inhibitor.
  • the checkpoint inhibitor can be administered to the subject prior to, simultaneously with, or subsequent to treatment with the agent that enhances JAML-CAR interaction.
  • the employed checkpoint inhibitor is a CTLA inhibitor, a PD-l inhibitor or a PD-Ll inhibitor.
  • the employed agent for enhancing JAML-CAR interaction is a monoclonal antibody targeting JAML.
  • the employed monoclonal antibody targeting JAML does not block or interfere with JAML binding to CAR.
  • the monoclonal antibody targeting JAML has a binding specificity that is the same as that of an antibody that has HCDR1-3 and LCDR1-3 sequences respectively shown in SEQ ID NOs: l-6.
  • the employed monoclonal antibody targeting JAML has HCDR1-3 and LCDR1-3 sequences respectively shown in SEQ ID NOs: l-6.
  • the employed monoclonal antibody targeting JAML is Fab antibody HL4E10.
  • the employed monoclonal antibody targeting JAML is a humanized antibody or a chimeric antibody.
  • the methods can employ a humanized antibody that is derived from Fab antibody HL4E10.
  • the humanized antibody contains at least one CDR as shown in SEQ ID NOs: l-6.
  • the humanized antibody contains heavy chain CDR1-3 as shown in SEQ ID NOs: 1-3, respectively.
  • the humanized antibody contains heavy chain CDRs 1-3 and light chain CDRs 1-3 as shown in SEQ ID NOs: 1-6, respectively.
  • the employed agent that enhances JAML-CAR interaction contains a soluble CAR molecule.
  • the soluble CAR molecule is a CAR-Fc fusion.
  • the employed soluble CAR molecule is the extracellular domain of CAR.
  • the tumor afflicted by the subject in need of treatment is a skin tumor, a colorectal tumor, a lung tumor, or an ovarian tumor.
  • the invention provides methods for stimulating T cell killing of a tumor in a subject. These methods involve administering to a subject afflicted with a tumor a pharmaceutical composition that contains a therapeutically effective amount of an agent that enhances the specific interaction between junctional adhesion molecule (JAML) on T cells and Coxsackie and adenovirus receptor (CAR) on tumor cells. This will result in stimulated T cell killing of the tumor in the subject.
  • the subject is also treated with an immune checkpoint inhibitor.
  • the checkpoint inhibitor can be administered to the subject prior to, simultaneously with, or subsequent to treatment with the agent that enhances JAML-CAR interaction.
  • the employed agent that enhances JAML-CAR interaction is a monoclonal antibody targeting JAML.
  • the employed monoclonal antibody targeting JAML has a binding specificity that is the same as that of an antibody comprising HCDR1-3 and LCDR1-3 sequences respectively shown in SEQ ID NOs: l-6.
  • the employed monoclonal antibody targeting JAML is a humanized antibody that is derived from Fab antibody HL4E10.
  • the agent targeting JAML-CAR interaction contains a soluble CAR molecule.
  • the employed soluble CAR molecule is a CAR-Fc fusion.
  • the tumor afflicted by the subject is a skin tumor, a colorectal tumor, a lung tumor, or an ovarian tumor.
  • the invention provides humanized antibodies that are derived from Fab antibody HL4E10.
  • the humanized antibodies contain one or more CDR sequence as shown in SEQ ID NOs: 1-6.
  • the humanized antibodies of the invention can specifically recognize junctional adhesion molecule (JAML) but do not block JAML interaction with Coxsackie and adenovirus receptor (CAR).
  • the humanized antibodies of the invention additionally contain one or more amino acid substitutions in its framework region relative to that of Fab antibody HL4E10.
  • the humanized antibody contains heavy chain CDR1-3 as shown in SEQ ID NOs: 1-3, respectively.
  • the humanized antibody contains heavy chain CDRs 1-3 and light chain CDRs 1-3 as shown in SEQ ID NOs: 1-6, respectively.
  • the invention provides soluble polypeptide fragments derived from Coxsackie and adenovirus receptor (CAR) that are capable of binding to the junctional adhesion molecule (JAML) on T cells.
  • CAR Coxsackie and adenovirus receptor
  • these soluble polypeptide fragments are protein fusions with a Fc domain.
  • Figure 1 shows that expression of JAML and CAR is associated with improved survival in many epithelial cancers.
  • Figure 2 shows that expression of JAML is a favorable prognostic factor in many epithelial cancers.
  • Figure 3 shows that high expression of JAML in tumors is associated with improved survival in melanoma and head and neck squamous cell carcinoma (TCGA).
  • Figure 4 shows that JAML-CAR interaction is a novel mechanism of T cell tumor infiltration and is required for antitumor immunity.
  • FIG. 5 shows that JAML is upregulated on activated T cells and is highly expressed on tumor-infiltrating lymphocytes (TILs).
  • TILs tumor-infiltrating lymphocytes
  • Figure 6 shows that increased expression of CAR turns“cold” tumors“hot” and improves antitumor immune response.
  • Figure 7 shows that human melanoma tissues with high CAR expression have increased T cell infiltration.
  • Figure 8 shows in vivo anti-JAML stimulation to induce T cell tumor infiltration.
  • Figure 9 is a schematic illustration of stimulating T cell tumor infiltration via intratumoral hydrogel injection of agents targeting JAML-CAR interaction.
  • Figure 10 a schematic illustration of stimulating T cell tumor infiltration via delivery of soluble CAR via hydrogel.
  • the term“agent” or“test agent” includes any substance, molecule, element, compound, entity, or a combination thereof. It includes, but is not limited to, e.g., protein, polypeptide, peptide or mimetic, small organic molecule, polysaccharide, polynucleotide, and the like. It can be a natural product, a synthetic compound, or a chemical compound, or a combination of two or more substances. Unless otherwise specified, the terms“agent”, “substance”, and“compound” are used interchangeably herein. In some screening methods of the invention, the employed test agents or candidate compounds are small organic molecules.
  • a checkpoint inhibitor or immune checkpoint inhibitor refers to a drug or compound that can block proteins that stop the immune system from attacking harmful cells (e.g., cancer cells). By eliciting or inducing an immune system attack on cancer cells, checkpoint inhibitors can overcome one of cancer’s main defenses against an immune system attack.
  • exemplary checkpoint inhibitors include CTLA-4 inhibitors, PD-1 inhibitors and PD-L1 inhibitors.
  • analog or“derivative” is used herein to refer to a molecule that structurally resembles a reference molecule (e.g., an JAML-targeting antibody exemplified herein) but which has been modified in a targeted and controlled manner, by replacing a specific substituent of the reference molecule with an alternate substituent.
  • a reference molecule e.g., an JAML-targeting antibody exemplified herein
  • an analog would be expected, by one skilled in the art, to exhibit the same, similar, or improved utility.
  • Synthesis and screening of analogs to identify variants of known compounds having improved traits is an approach that is well known in pharmaceutical chemistry.
  • Administration "in combination with" one or more other therapeutic agents includes simultaneous (concurrent) and consecutive administration in any order.
  • the term“contacting” has its normal meaning and refers to combining two or more agents (e.g., polypeptides or small molecule compounds) or combining agents and cells. Contacting can occur in vitro, e.g., combining two or more agents or combining an agent and a cell or a cell lysate in a test tube or other container. Contacting can also occur in a cell or in situ, e.g., contacting two polypeptides in a cell by coexpression in the cell of recombinant polynucleotides encoding the two polypeptides, or in a cell lysate. Contacting can also occur inside the body of a subject, e.g., by administering to the subject an agent which then interacts with the intended target (e.g., a tissue or a cell).
  • the intended target e.g., a tissue or a cell.
  • the Fc fragment or Fc domain of an immunoglobulin comprises the carboxy- terminal portions of both H chains held together by disulfides.
  • the effector functions of immunoglobulins are determined by sequences in the Fc region, which region is also the part recognized by Fc receptors (FcR) found on certain types of cells.
  • junctional adhesion molecule-like protein is expressed on the surface of several immune cells, including resting epithelial gd T cells, activated epithelial and lymphoid gd T cells, activated CD8 T cells, and monocytes and neutrophils.
  • Coxsackie and adenovirus receptor is widely expressed in epithelial tissues, including skin, lung, small intestine, colon, liver, pancreas, bladder and prostate. Its expression is dysregulated in many human cancers. Cancer immunotherapies are dependent on immune cell infiltration into tumors.
  • subject and “patient” are used interchangeably and refer to mammals such as human patients and non-human primates, as well as experimental animals such as rabbits, rats, and mice, and other animals.
  • Animals include all vertebrates, e.g., mammals and non-mammals, such as dogs, cats, sheeps, cows, pigs, rabbits, chickens, and etc.
  • Preferred subjects for practicing the therapeutic methods of the present invention are human.
  • inhibiting in the context of tumor growth or tumor cell growth, refers to delayed appearance of primary or secondary tumors, slowed development of primary or secondary tumors, decreased occurrence of primary or secondary tumors, slowed or decreased severity of secondary effects of disease, or arrested tumor growth and regression of tumors.
  • prevent or“prevention” refers to a complete or partial inhibition of development of primary or secondary tumors or any secondary effects of disease.
  • the term“treat” or“treatment” refers to arrested tumor growth, and to partial or complete regression of tumors.
  • the term“treating” includes the administration of compounds or agents to prevent or delay the onset of the symptoms, complications, or biochemical indicia of a disease (e.g., a cancer), alleviating the symptoms or arresting or inhibiting further development of the disease, condition, or disorder.
  • Treatment may be prophylactic (to prevent or delay the onset of the disease, or to prevent the manifestation of clinical or subclinical symptoms thereof) or therapeutic suppression or alleviation of symptoms after the manifestation of the disease.
  • a "variant" of a reference molecule refers to a molecule substantially similar in structure and biological activity to either the entire reference molecule, or to a fragment thereof. Thus, provided that two molecules possess a similar activity, they are considered variants as that term is used herein even if the composition or secondary, tertiary, or quaternary structure of one of the molecules is not identical to that found in the other, or if the sequence of amino acid residues is not identical.
  • the present invention is directed to promoting immune cell (e.g., T cells) infiltration into tumors, which is important for cancer immune therapies.
  • immune cell e.g., T cells
  • checkpoint blockade therapies are more successful in patients with pre-established T cell response within tumors (“hot” tumors) whereas tumors lacking immune cell infiltration (“cold” tumors) are unresponsive.
  • all cancer immunotherapies including tumor vaccines, CAR T cells, etc. are dependent on immune cell infiltration into tumors.
  • There are cancers that unresponsive to checkpoint blockade e.g., colorectal cancer, lung cancer, ovarian cancer and melanoma, indicating a need for additional therapeutic interventions.
  • the invention provides methods of promoting the interaction between JAML on T cells and CAR on various tumor cells (e.g., epithelial tumor cells).
  • methods of the invention provides a novel strategy to turn cold tumors into hot tumors.
  • the present invention provides methods of stimulating T cell killing of tumor cells via promoting the JAML-CAR interaction.
  • the methods of the invention use agents that can specifically target the JAML-CAR interaction and induce T cell migration into tumor cells. Any of the antibody agents targeting JAML or CAR-derived polypeptide agents detailed herein can be used in the methods of the invention.
  • the agent used in the methods of the invention is an antibody that can specifically bind to JAML on T cells in enhancing JAML-CAR interaction.
  • the antibodies utilized in the methods of the invention do not block or substantially affect JAML interaction with CAR.
  • Antibodies that specifically recognize JAML are known in the art. These include Fab antibody HL4E10 as described in Verdino et al, PLoS One 6:
  • JAML antibodies that are commercially available.
  • the latter include antibodies ab67843 and abl837l4 from Abeam (Cambridge, MA), monoclonal antibody MAB34491 from R&D Systems, Inc. (Minneapolis, MN), and monoclonal antibody MAB34491 from LifeSpan BioSciences, Inc. Impact of binding of any of these antibodies on JAML interaction with CAR can be readily assessed with routinely practiced biochemical or immunological techniques, e.g., competitive ELISA.
  • the agent that specifically targets the JAML- CAR interaction can be a soluble CAR agent that can specifically bind to JAML.
  • the soluble CAR agent can be directly delivered into tumors to promote T cell migration into tumors.
  • the soluble CAR agent can be a fragment or domain of CAR that is capable of binding to JAML (e.g., the extracellular domain of CAR). It can also be a fusion protein that contains such a fragment that is fused to a heterologous protein domain, e.g., an Fc domain. By fusing to an Fc domain, the delivered polypeptide agent will have a markedly improved plasma half-life and slowed renal clearance, which prolongs therapeutic activity.
  • a soluble CAR polypeptide can be coupled to a suitable carrier such as degradable hydrogels to facilitate its delivery into tumors. See, e.g., Kislukhin et al, J. Am. Chem. Soc., 134: 6491-6497, 2012; and
  • the therapeutic methods of the invention can additionally include a therapy based on immune checkpoint inhibitors.
  • Immune checkpoints are molecules on certain immune cells that need to be activated (or inactivated) to start an immune response. Tumor cells can sometimes find ways to use these checkpoints to avoid being attacked by the immune system. Immune checkpoint inhibitors are drugs that target these checkpoints in the treatment of tumors.
  • the agent promoting JAML-CAR interactions and the checkpoint inhibitor can be administered to the subject simultaneously.
  • the subject can be treated with the agent promoting JAML-CAR interaction prior to or subsequent to treatment with the checkpoint inhibitor.
  • Any known immune checkpoint inhibitors can be employed in these methods of the invention. These include, e.g., drugs that target PD-l or PD-L1.
  • PD-1 is a checkpoint protein on T cells. It normally acts as a type of“off switch” that helps keep the T cells from attacking other cells in the body. This is achieved when PD-l attaches to PD-L1 , a protein present on some normal cells and cancer cells. Some cancer cells have large amounts of PD-L 1, which helps them evade immune attack. Suitable immune checkpoint inhibitors also include drugs also include that target CTLA-4. CTLA-4 is another protein on some T cells that acts as a type of“off switch” to keep the immune system in check.
  • Methods of the invention can employ any of the immune checkpoint inhibitors known in the art.
  • monoclonal antibodies that target either PD-l or PD-L1 can block this binding and boost the immune response against cancer cells.
  • These drugs have shown a great deal of promise in treating certain cancers.
  • Specifi c examples of drugs that target PD-l include: Pembrohzumab (Keytruda) and Nivolumab (Opdivo). These drugs have been shown to be helpful in treating several types of cancer, including melanoma of the skin, non-small ceil lung cancer, kidney cancer, bladder cancer, head and neck cancers, and Hodgkin lymphoma. They are also being studied for use against many other types of cancer.
  • drugs that target PD-L1 include Atezohzumab (Tecentriq), Avelumab (Bavencio) and Durvalumab (Imfsnzi) These drugs have also been shown to be helpful in treating different types of cancer, including bladder cancer, non-small cell lung cancer, and Merkel cell skin cancer (Merkel cell carcinoma). They are also being studied for use against other types of cancer.
  • Specific examples of immune checkpoint inhibitors targeting CTLA-4 includes Ipilimumab (Yervoy). This is a monoclonal antibody that attaches to CTLA-4 and stops it from working. This can boost the body’s immune response against cancer cells.
  • the combination therapies of the invention can further utilize many other immune checkpoint inhibitors or other drugs that are currently being evaluated in various clinical trials. See, e.g.,“What’s new' in cancer immunotherapy research?” at https : //www. cancer org/treatmen t.
  • the invention provides specific agents that are capable of promoting the specific binding betw een JAML on T cells and CAR on tumor cells.
  • These include monoclonal antibodies that target JAML, including antibodies that can be derived from any of the known JAML-targetmg antibodies noted above. Preferably, such antibody agents do not block or substantially interfere with JAML binding with CAR.
  • Antibody agents of the invention include a full-length antibody or an antibody fragment that specifically recognizes or binds to the extracellular domain of CAR, e.g., human CAR.
  • the antibody, antibody fragment or antibody-based binding protein can be polyclonal, monoclonal, recombinant, chimeric, or humanized.
  • the antibody can be of any isotype including without limitation IgA, IgD, IgE, IgG, or IgM.
  • the antibody can be any IgA such as IgAl or IgA2, or any IgG such as IgGl , IgG2, IgG3, IgG4, or synthetic IgG.
  • the antibody can also be any antibody fragment or antibody- based binding protein having specificity for the extracellular domain of CAR, such as F(ab)2, Fv, scFv, IgGACH2, F(ab')2, scFv2CH3, Fab, VL, VH, scFv4, scFv3, scFv2, dsFv, Fv, scFv-Fc, (scFv)2, a diabody, and a bivalent antibody.
  • the antibody can be any modified or synthetic antibody, including, but not limited to, non-depleting IgG antibodies, or other Fc or Fab variants of antibodies.
  • the antibody agents of the invention are derived from antibody HL4E10.
  • Antibody HL4E10 is a hamster Fab targeting JAML and is strongly costimulaiory for gd T cells. See, e.g., Verdino et al, PLoS ONE 6: el9828, 2011. Its heavy and light chain CDR sequences are shown in SEQ ID NOs: 1-6, respectively.
  • Some antibody agents of the invention are humanized or chimeric antibodies derived from Fab antibody HL4E10. For example, human chimeric antibodies are those in which at least one region of the antibody is from a human immunoglobulin.
  • a human chimeric antibody typically contain variable regions from a non-human animal, e.g. a rodent, with the constant regions from a human.
  • a humanized antibody uses CDRs from the non-human antibody with most or all of the variable framework regions from and all the constant regions from a human immunoglobulin.
  • a“humanized antibody” refers to an antibody or antibody fragment, antigen-binding fragment, or antibody -based binding protein that contains antibody VH or VL domains with a homology to human VH or VL antibody framework sequences having a T20 score of greater than 80, as defined by defined by Gao et al. (2013) BMC Biotechnol. 13, pp. 55.
  • the antibodies of the invention contain one or more CDR sequences that are identical to that of antibody HLE410.
  • the antibodies of the invention may additionally contain various modifications in the CDR regions as well as the framework regions.
  • the antibodies can contain modifications (e.g., amino acid deletions as well as conservative or non-conservation substitutions) in one or more of the heavy chain CDRs and light chain CDRs.
  • the antibodies can additionally contain one or more modifications in its framework regions relative to that of Fab antibody HL4E10.
  • the humanized or chimeric antibody agents of the invention are all capable of enhancing interaction between junctional adhesion molecule (JAML) and the Coxsackie and adenovirus receptor (CAR).
  • the antibody agents of the invention do not block or interfere with JAML binding to CAR.
  • the antibody agents of the invention contain one, two or all three of its heavy chain CDRs 1-3 that are identical to DYGVH (SEQ ID NO: l), IIGHAGGTD YN SNLKS (SEQ ID NO:2), and HFYTYFDV (SEQ ID NO:3), respectively.
  • these antibody agents of the invention may contain one, two or all three of its light chain CDRs 1-3 respectively shown in
  • the antibodies contain heavy chain CDRs 1-3 and light chain CDRs 1-3 respectively shown in SEQ ID NOs:l-6.
  • the antibodies may further contain various modifications in the framework regions.
  • the humanized or chimeric antibodies of the invention are expected to have similar or better activities and/or immunogenic properties. For example, these antibodies should have similar or better binding specificity for human JAML, substantively reduced immunogenicity in human subjects, and equal or better properties in not interfering with JAML binding to CAR.
  • Such characteristics of the antibodies of the invention can be readily examined and confirmed via standard techniques of immunology that have been routinely practiced in the art.
  • properties of the antibody agents can be examined in animal models.
  • mouse models can be used to assess in vivo effect of the antibodies on T cell tumor infiltration, tumor-infiltrating lymphocyte (TIL) survival, and cytokine production.
  • TIL tumor-infiltrating lymphocyte
  • the various antibodies and antibody fragments (or“antigen-binding fragments”) thereof described herein can be produced by enzymatic or chemical modification of the intact antibodies, or synthesized de novo using recombinant DNA methodologies, or identified using phage display libraries. Methods for generating these antibodies, antibody- based binding proteins, and antibody fragments thereof are all well known in the art.
  • chimeric and humanized antibodies may be prepared by methods well known in the art including CDR grafting approaches (see, e.g., U.S. Patent Nos. 5,843,708; 6,180,370; 5,693,762; 5,585,089; 5,530,101), chain shuffling strategies (see e.g., U.S. Patent No.
  • anti human JAML antibody can be generated via by directed mutagenesis of a known JAML antibody described herein, e.g., the HL4E10 antibody.
  • single chain antibodies can be obtained with routinely practiced immunological methods, e.g., phage display libraries or ribosome display libraries, gene shuffled libraries (see, e.g., McCafferty et al, Nature 348:552-554, 1990; and U.S. Pat. No.
  • scFv antibodies can be obtained using methods described in, e.g., Bird et al, Science 242:423-426, 1988; and Huston et al., Proc. Natl. Acad. Sci. USA 85:5879-5883, 1988.
  • Fv antibody fragments can be generated as described in Skerra and Pluckthun, Science 240: 1038-41, 1988.
  • Disulfide- stabilized Fv fragments can be made using methods described in, e.g., Reiter et al, Int. J. Cancer 67: 113-23, 1996.
  • single domain antibodies can be produced by a variety of methods described in, e.g., Ward et al, Nature 341 :544-546, 1989; and Cai and Garen, Proc. Natl. Acad. Sci. USA 93:6280-85, 1996.
  • Camelid single domain antibodies can be produced using methods well known in the art, e.g., Dumoulin et al, Nat. Struct. Biol. 11:500-515, 2002; Ghahroudi et al, FEBS Letters 414:521-526, 1997; and Bond et al, J. Mol. Biol. 332:643-55, 2003.
  • antigen-binding fragments e.g., Fab, F(ab’) 2 or Fd fragments
  • Fab, F(ab’) 2 or Fd fragments can also be readily produced with routinely practiced immunology methods. See, e.g., Harlow & Lane, Using Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1998; Kohler & Milstein, Nature 256:495-497, 1975; Kozbor et al, Immunology Today 4:72, 1983; and Cole et al., pp. 77-96 in Monoclonal Antibodies and Cancer Therapy, 1985.
  • the invention provides soluble CAR derived polypeptide agents that are capable of promoting the specific binding between JAML on T cells and CAR on tumor cells. These include, e g., the extracellular domain of CAR or any JAML-binding fragments thereof. As described above, such polypeptide agents can be readily obtained via methods well known in the art.
  • the soluble CAR fragment can be further linked to a fusion partner or carrier protein.
  • the fusion partner can be any molecule or moiety that can improve or enhance the biological, pharmacokinetics, or pharmacodynamics properties of the soluble CAR polypeptide.
  • the soluble CAR polypeptide such as the extracellular domain of CAR or a JAML-binding fragment thereof can be fused to the Fc domain of an IgG. Fusion with an Fc-domain provides a number of beneficial biological and pharmacological properties. For example, the presence of the Fc domain can markedly increase the plasma half-life of the hybrid molecule, which prolongs therapeutic activity, owing to its interaction with the salvage neonatal Fc-receptor, as well as to the slower renal clearance for larger sized molecules.
  • the attached Fc domain also enables the molecules to interact with Fc- receptors (FcRs) found on immune cells, a feature that is particularly important for their use in oncological therapies and vaccines. As the Fc domain folds independently, it can improve the solubility and stability of the fused CAR polypeptide both in vitro and in vivo. Further, the Fc region allows for easy cost-effective purification by protein-G/A affinity
  • the soluble CAR polypeptide can be fused with an Fc domain at either its N-terminus or C-terminus.
  • Hybrid or fusion molecules containing a soluble CAR polypeptide of the invention and a fusion partner such as Fc domain can be readily generated in accordance with standard recombination techniques, routinely practiced protein synthesis methods or the protocols described herein.
  • the methods for promoting JAML-CAR interaction and the related agents as described herein can be employed in various therapeutic or prophylactic applications. In particle, they are suitable for treating cancers or preventing the development of tumors, esp. tumors that have CAR expression in their development.
  • the cancers and tumors suitable for treatment with compositions and methods of the present invention can be those present in a variety of tissues and organs. They also include cancer cells, tumor cells, which include malignant tumor cells, and the like that are found in the component cells of these tissues and/or organs.
  • Examples include brain tumors (glioblastoma multiforme and the like), spinal tumors, maxillary sinus cancer, cancer of the pancreatic gland, gum cancer, tongue cancer, lip cancer, nasopharyngeal cancer, mesopharyngeal cancer, hypopharyngeal cancer, laryngeal cancer, thyroid cancer, parathyroid cancer, lung cancer, pleural tumors, cancerous peritonitis, cancerous pleuritis, esophageal cancer, stomach cancer, colon cancer, bile duct cancer, gallbladder cancer, pancreatic cancer, hepatic cancer, kidney cancer, bladder cancer, prostate cancer, penile cancer, testicular tumors, cancer of the adrenal glands, uterocervical cancer, endometrial cancer, vaginal cancer, vulvar cancer, ovarian cancer, ciliated epithelial cancer, malignant bone tumors, soft-tissue sarcomas, breast cancer, skin cancer, malignant melanomas, basal cell tumors, leuk
  • therapeutic methods of the invention are directed to treating tumors which contain high or upregulated CAR expressions.
  • CAR upregulation was observed in cancers of the endometrium, ovary, cervix, breast and lung, as well as neuroblastomas and medulloblastomas. See, e.g , Martino et al, Virol. 271: 99-108, 2000; Martin et al, Clin. Exp. Med. 5: 122-128, 2005; Persson et al, J. Neurooncol. 78:1-6, 2006; Wang et al, J. Mol. Histol. 37: 153-160, 2006; Reimer et al, Int. J. Cancer.
  • the treatment should affect a subject, tissue or cell to obtain a desired pharmacologic and/or physiologic effect.
  • the effect may be prophylactic in terms of completely or partially preventing a disease or sign or symptom thereof. It can also be therapeutic in terms of a partial or complete cure for a disease or disorder (e.g., tumor growth) that is associated with or mediated by CAR expression or biochemical activities, or amelioration of adverse effect that is attributable to the disorder.
  • Suitable subjects include an invertebrate, a vertebrate, a mammal, particularly a human.
  • the therapies described in the present invention can be used alone or in combination with any of various drugs, including known antitumor drugs (antineoplastic drugs), tumor metastasis-inhibitors, analgesics, anti-inflammatory drugs, immunoregulators (or immunomodulators) and/or immunosuppressants, which can be employed as not being restricted to particular species as long as they serve effectively or advantageously.
  • the therapies can be employed in combination with treatments based on immune checkpoint inhibitors, as noted above.
  • the JAML-CAR targeting compounds can be administered alone to a subject in need of treatment. More preferably, they are administered in the form of a pharmaceutical composition or preparation in admixture with any of various pharmacologically-acceptable additives.
  • the compounds may be administered in the form of a convenient pharmaceutical composition or formulation suitable for oral, topical, parenteral application, or the like.
  • Pharmaceutical compositions of the invention can be prepared in accordance with methods well known and routinely practiced in the art. See, e.g., Remington: The Science and Practice of Pharmacy, Mack Publishing Co., 20 th ed., 2000; and Sustained and Controlled Release Drug Delivery Systems, J.R. Robinson, ed., Marcel Dekker, Inc., New York, 1978.
  • compositions are preferably manufactured under GMP conditions.
  • Formulations for parenteral administration may, for example, contain excipients, sterile water, or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated napthalenes.
  • Biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or poly oxy ethylene-poly oxypropylene copolymers may be used to control the release of the compounds.
  • Other potentially useful parenteral delivery systems for molecules of the invention include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes.
  • Formulations for inhalation may contain excipients, for example, lactose, or may be aqueous solutions containing, e.g., polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel.
  • excipients for example, lactose
  • aqueous solutions containing, e.g., polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate
  • composition containing a JAML-CAR targeting compound can be administered locally or systemically in a therapeutically effective amount or dose. They can be administered parenterally, enterically, by injection, rapid infusion, nasopharyngeal absorption, dermal absorption, rectally and orally.
  • the JAML-CAR targeting compound for use in the methods of the invention should be administered to a subject in an amount that is sufficient to achieve the desired therapeutic effect (e.g., eliminating or ameliorating symptoms associated with tumor development and growth) in a subject in need thereof.
  • a therapeutically effective amount or efficacious dose of the compound employed in the pharmaceutical compositions of the invention should inhibit, slow or suppress tumor growth in a subject.
  • actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention can be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response without being toxic to the subject.
  • the selected dosage level depends upon a variety of pharmacokinetic factors including the activity of the particular compositions of the present invention employed, the route of administration, the time of administration, and the rate of excretion of the particular compound being employed. It also depends on the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compositions employed, the age, gender, weight, condition, general health and prior medical history of the subject being treated, and like factors. Methods for determining optimal dosages are described in the art, e.g., Remington: The Science and Practice of Pharmacy, Mack Publishing Co., 20 th ed., 2000. For a given JAML-CAR targeting compound, one skilled in the art can easily identify the effective amount by using routinely practiced pharmaceutical methods. Dosages used in vitro or in situ studies may provide useful guidance in the amounts useful for in vivo administration of the pharmaceutical composition, and animal models may be used to determine effective dosages for treatment of particular disorders. Typically, a
  • pharmaceutically effective dosage would be between about 0.001 and 100 mg/kg body weight of the subject to be treated.
  • the JAML-CAR targeting compounds and other therapeutic regimens described herein are usually administered to the subjects on multiple occasions. Intervals between single dosages can be daily, weekly, monthly or yearly. Intervals can also be irregular as indicated by measuring blood levels of the compounds and the other therapeutic agents used in the subject. In some methods, dosage is adjusted to achieve a plasma compound concentration of 1-1000 pg/ml, and in some methods 25-300 pg/ml or 10-100 pg/ml. Alternatively, the therapeutic agents can be administered as a sustained release formulation, in which case less frequent administration is required. Dosage and frequency vary depending on the half-life of the JAML-CAR targeting compound and the other drugs in the subject.
  • the dosage and frequency of administration can vary depending on whether the treatment is prophylactic or therapeutic.
  • a relatively low dosage is administered at relatively infrequent intervals over a long period of time. Some subjects may continue to receive treatment for the rest of their lives.
  • a relatively high dosage at relatively short intervals is sometimes required until progression of the disease is reduced or terminated, and preferably until the subject shows partial or complete amelioration of symptoms of disease. Thereafter, the subject can be administered a prophylactic regime.
  • Example 1 Targeting JAML-CAR binding to promote tumor infiltration of T cells
  • a number of studies that were performed and that can be performed as described herein are able to show the effect of JAML and CAR expression on T cell tumor infiltration, as well as feasibility of targeting JAML-CAR in the treatment of cancer. Detailed description of these studies is provided in Figures 1-10.
  • the studies also include testing safety of anti-JAML stimulation, with or co-administration of immune checkpoint inhibitors, by quantifying aberrant T cell infiltration into non-tumor tissues (e.g. skin, gut, lung) compared to tumor tissues.
  • Such safety test can be performed with, e.g., flow-cytometry and histology analysis.
  • the test can also include assessment of inflammatory cytokines in serum.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

La présente invention concerne des compositions et des procédés pour favoriser la liaison de JAML sur des lymphocytes T à CAR sur des cellules tumorales. L'invention concerne également des méthodes de traitement de divers types de tumeurs.
PCT/US2019/036121 2018-06-08 2019-06-07 Ciblage d'interactions de jaml-car pour l'immunothérapie antitumorale WO2019237042A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201862682698P 2018-06-08 2018-06-08
US62/682,698 2018-06-08

Publications (1)

Publication Number Publication Date
WO2019237042A1 true WO2019237042A1 (fr) 2019-12-12

Family

ID=68769466

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2019/036121 WO2019237042A1 (fr) 2018-06-08 2019-06-07 Ciblage d'interactions de jaml-car pour l'immunothérapie antitumorale

Country Status (1)

Country Link
WO (1) WO2019237042A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115436636A (zh) * 2022-11-08 2022-12-06 济南市中心医院 连接粘附分子样蛋白jaml在结直肠癌中的应用
WO2023076701A3 (fr) * 2021-10-29 2023-06-08 La Jolla Institute For Immunology Procédés de modulation d'une réponse immunitaire à des cellules cancéreuses ou tumorales

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7575893B2 (en) * 2003-01-23 2009-08-18 Genentech, Inc. Methods for producing humanized antibodies and improving yield of antibodies or antigen binding fragments in cell culture
WO2017040666A2 (fr) * 2015-08-31 2017-03-09 Oncomed Pharmaceuticals, Inc. Polythérapie pour le traitement d'une maladie

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7575893B2 (en) * 2003-01-23 2009-08-18 Genentech, Inc. Methods for producing humanized antibodies and improving yield of antibodies or antigen binding fragments in cell culture
WO2017040666A2 (fr) * 2015-08-31 2017-03-09 Oncomed Pharmaceuticals, Inc. Polythérapie pour le traitement d'une maladie

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
COHEN, CJ ET AL.: "The coxsackievirus and adenovirus receptor is a transmembrane component of the tight junction", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE U.S.A., vol. 98, no. 26, 18 December 2001 (2001-12-18), pages 15191 - 15196, XP055660765 *
VERDINO, P ET AL.: "cDNA Sequence and Fab Crystal Structure of HL4E10, a Hamster IgG Lambda Light Chain Antibody Stimulatory for [gamma-delta] T Cells", PLOS ONE, vol. 6, no. 5, 24 May 2011 (2011-05-24), pages 1 - 10, XP055241596 *
WITHERDEN, DA ET AL.: "The adhesion molecule JAML is a costimulatory receptor for epithelial gamma-delta T cell activation", SCIENCE, vol. 329, no. 5996, 3 September 2010 (2010-09-03), pages 1205 - 1210, XP055660750 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023076701A3 (fr) * 2021-10-29 2023-06-08 La Jolla Institute For Immunology Procédés de modulation d'une réponse immunitaire à des cellules cancéreuses ou tumorales
CN115436636A (zh) * 2022-11-08 2022-12-06 济南市中心医院 连接粘附分子样蛋白jaml在结直肠癌中的应用

Similar Documents

Publication Publication Date Title
JP6591428B2 (ja) 癌治療のためのｐｄ−１拮抗薬およびｖｅｇｆｒ阻害剤の組み合わせ
US20210069147A1 (en) Pharmaceutical combination and uses thereof
KR20200016899A (ko) 활성화가능 항-pdl1 항체, 및 이의 이용 방법
KR20210006405A (ko) 암의 치료를 위한 PD-1/PD-L1, TGFβ 및 DNA-PK의 조합 억제
CN110382532B (zh) 抗g-csf抗体及其用途
JP7304595B2 (ja) ｕＰＡＲＡＰを標的にする抗体薬物複合体
JP2023155262A (ja) プレクチン１結合抗体およびその使用
WO2019237042A1 (fr) Ciblage d'interactions de jaml-car pour l'immunothérapie antitumorale
CA3059542A1 (fr) Anticorps ayant une affinite conditionnelle et leurs procedes d'utilisation
CN113195541A (zh) 针对pmel17的抗体及其缀合物
JP2023510429A (ja) 抗ガレクチン－９抗体およびその使用
CN110945128B (zh) 用于治疗肺纤维化的组合物和方法
US20080069818A1 (en) Method of Increasing Efficacy of Tumor Cell Killing Using Combinations of Anti-Neoplastic Agents
CN115551549A (zh) 用于通过靶向igsf8来治疗自身免疫疾病和癌症的组合物和方法
JP2022531978A (ja) 癌治療
US20230086800A1 (en) Antibody fragments conjugated to peg-plga nanoparticles improve immunotherapy against cancer cells
WO2021209017A1 (fr) Préparation spécifiquement liée à cd137 et son utilisation
US20210214442A1 (en) Neoadjuvant cancer treatment with immunotoxin and checkpoint inhibitor combination
KR20230061499A (ko) Pd-1 저해제 투여에 의한 암 통증 치료 방법
JP2024529451A (ja) がんを治療するための方法及び組成物
JP2024517986A (ja) 抗－ＣＤ３００ｃ抗体を利用した併用療法
EA046745B1 (ru) Способ лечения рака активируемым антителом против pdl1
TW201711702A (zh) 使用針對纖維母細胞生長因子受體３（ｆｇｆｒ３）之化合物的療法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19815162

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19815162

Country of ref document: EP

Kind code of ref document: A1