WO2014085808A1 - Méthodes destinées à améliorer la récupération thymique et à prévenir et à traiter la maladie du greffon contre l'hôte à l'aide d'antagonistes de ccr2 et ccr5 - Google Patents

Méthodes destinées à améliorer la récupération thymique et à prévenir et à traiter la maladie du greffon contre l'hôte à l'aide d'antagonistes de ccr2 et ccr5 Download PDF

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WO2014085808A1
WO2014085808A1 PCT/US2013/072613 US2013072613W WO2014085808A1 WO 2014085808 A1 WO2014085808 A1 WO 2014085808A1 US 2013072613 W US2013072613 W US 2013072613W WO 2014085808 A1 WO2014085808 A1 WO 2014085808A1
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ccr2
antagonist
ccr5
subject
thymic
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PCT/US2013/072613
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English (en)
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Ran RESHEF
Avinash Bhandoola
Shirley ZHANG
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The Trustees Of The University Of Pennsylvania
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies

Definitions

  • Allogeneic stem cell transplantation is performed in 28,000 patients annually as a curative procedure in a variety of blood cancers. Allogeneic SCT is primarily indicated in chemotherapy-resistant cancers of the blood or bone marrow, including multiple myeloma, lymphoma and leukemia, and is effective in part due to the graft-versus-tumor (GvT) potential of the donor graft. Transplantation of donor stem cells after ablation of the recipient's native blood and bone marrow progenitors can restore essential immune and hematopoietic tissue, and donor leukocytes also aid in destruction of cancerous cells or tumors in the recipient.
  • SCT Allogeneic stem cell transplantation
  • allogeneic SCT can be limited by poor immune recovery and graft versus host disease ("GVHD"), a serious complication in which the transplanted cells migrate to and are activated against the recipient's tissues, damaging in particular the gut, liver and skin. 20-50% of matched related transplant recipients and 50-70% of unrelated donor transplant recipients develop clinically significant GVHD in spite of standard prophylactic immunosuppression. Certain estimates show that 15% of deaths following allogeneic SCT are caused by GVHD, and another 15% of deaths following allogeneic SCT are the result of infections related to poor immune recovery (Pasquini M., Wang Z.
  • Autologous SCT is performed in 10,000 patients in the US alone each year. It is considered standard-of-care in certain malignancies such as myeloma, lymphoma and testicular cancer. Poor immune recovery contributes to morbidity and mortality after autologous SCT and faster and better recovery of the immune system can improve the outcome of patients after autologous SCT, including improved survival.
  • T-cell development in the thymus is dependent on a continuous supply of bone marrow-derived T-lineage progenitor cells. It has been shown that thymic recovery following SCT is highly dependent on progenitor T-cell chemotaxis. (Zlotoff D. et al. Blood 2010;115: 1897-905; Zlotoff D., et al. Blood 201 1 ; 1 18 : 1962- 1970). This migration is governed by sets of chemokines and chemokine receptors, each of which modulates discrete elements of immune cell function and activation.
  • CCR2 C-C Chemokine Receptor Type 2
  • CCR5 C-C Chemokine Receptor Type 2
  • RA rheumatoid arthritis
  • Crohn's disease rheumatoid arthritis
  • transplant rejection atherosclerosis
  • accelerated intimal hyperplasia rheumatoid arthritis
  • CCR2 alone or both CCR5 and CCR2 together improves thymic recovery and thymic immune function, and prevents graft versus host disease (GVHD) and organ transplant rejection.
  • GVHD graft versus host disease
  • the present subject matter provides an exemplary method for increasing thymic recovery or thymic function in a subject, e.g., a human, by administering to the subject an effective amount of a CCR2 antagonist alone, a CCR5 antagonist and a CCR2 antagonist, or a dual CCR2/CCR5 antagonist.
  • a CCR2 antagonist alone e.g., a CCR5 antagonist and a CCR2 antagonist, or a dual CCR2/CCR5 antagonist.
  • the CCR2 antagonist and the CCR5 antagonist are administered concurrently.
  • the CCR2 and/or CCR5 antagonists are antibodies. In certain embodiments, CCR2 and/or CCR5 antagonists are small molecules. In certain embodiments, the dual CCR2/CCR5 antagonist is a small molecule or peptide inhibitor.
  • the present subject matter provides method for treating or preventing graft versus host disease (GVHD) in a subject, e.g., a human, by administering to the subject an effective amount of a CCR2 antagonist alone, a CCR5 antagonist and a CCR2 antagonist, or a dual CCR2/CCR5 antagonist.
  • GVHD graft versus host disease
  • the present subject matter provides method for treating or preventing and organ transplant rejection in a subject, e.g., a human, by administering to the subject an effective amount of a CCR2 antagonist alone, a CCR5 antagonist and a CCR2 antagonist, or a dual CCR2/CCR5 antagonist.
  • the subject has undergone a solid organ transplant or a bone marrow transplant.
  • the CCR2 antagonist and the CCR5 antagonist are administered concurrently.
  • the subject is has undergone hematopoietic stem cell transplantation.
  • the CCR2 and/or CCR5 antagonists are antibodies. In certain embodiments, CCR2 and/or CCR5 antagonists are small molecules. In certain embodiments, the dual CCR2/CCR5 antagonist is a small molecule or peptide inhibitor.
  • the dual CCR2/CCR5 antagonist is a small molecule, e.g., cenicriviroc.
  • FIG. 1 Absence of CCR2 or CCR5 improves thymic recovery. Mice conditioned with irradiation received bone marrow from congenic CCR2 "A mice or wild type mice. After two weeks the mice were sacrificed and their thymi and bone marrows analyzed. Mice transplanted with CCR2 ⁇ A bone marrow demonstrated better repopulation of the thymus with hematopoietic cells as opposed to mice transplanted with wild type bone marrow. There was no significant impact on bone marrow engraftment. Similar results were obtained with CCR5 V" bone marrow.
  • the presently disclosed subject matter provides that blockade of CCR2 alone or CCR2 and CCR5 together improve thymic recovery and thymic immune function and treats or prevents GVHD and organ transplant rejection.
  • the present disclosed subject matter is based, at least in part, on the identification that antagonism of certain chemokine receptors, i.e., CCR2 alone or CCR2 and CCR5 (either separately or as a dual antagonist), can increase trafficking of progenitor cells to the thymus to thereby increase thymic recovery and immune function.
  • the disclosed subject matter provides methods for increasing thymic recovery or thymic function in a subject, e.g., a human subject, by administering to the subject an effective amount of a CCR2 antagonist, a CCR5 antagonist and a CCR2 antagonist, or a dual CCR2/CCR5 antagonist.
  • a CCR5 antagonist alone for increasing thymic recovery or thymic function is not encompassed in the present disclosure.
  • the present disclosed subject matter is also based, at least in part, on the determination that antagonism of certain chemokine receptors, i.e., CCR2 alone or CCR2 and CCR5 together (either separately or as a dual antagonist), can decrease chemotaxis of T-cells to host organs following stem cell transplantation (or organ transplantation) and thereby prevent graft versus host disease (GVHD) or organ transplant rejection.
  • antagonism of certain chemokine receptors i.e., CCR2 alone or CCR2 and CCR5 together (either separately or as a dual antagonist
  • the disclosed subject matter provides methods for treating, inhibiting, or preventing GVHD or organ transplant rejection in a subject, e.g., a human subject, by administering to the subject an effective amount of a CCR2 antagonist alone, a CCR5 antagonist and a CCR2 antagonist, or a dual CCR2/CCR5 antagonist.
  • a CCR5 antagonist alone for treating, inhibiting, or preventing GVHD or organ transplant rejection is not encompassed in the present disclosure.
  • the antagonism of CCR2 and CCR5 at the same time has an additive effect on thymic recovery or thymic function and/or on treating, inhibiting, or preventing GVHD or organ transplant rejection. In certain embodiments, the antagonism of CCR2 and CCR5 at the same time has a synergistic effect on thymic recovery or thymic function and/or on treating, inhibiting, or preventing GVHD or organ transplant rejection.
  • the antagonists of the disclosed subject matter can be administered to a subject in need of improved thymic function, thymic recovery, or immune recovery for any reason (e.g., as a consequence of HIV or AIDS, during treatment for cancer, or as a result of suppression of the immune system related to immune-suppressing drugs or disease), to improve, increase or enhance thymic recovery and/or immune function.
  • thymic recovery e.g., as a consequence of HIV or AIDS, during treatment for cancer, or as a result of suppression of the immune system related to immune-suppressing drugs or disease
  • Improvement in T-cell number or function can be achieved by dual blockade of CCR5 and CCR2, or by blockade of CCR2, by improving the trafficking of progenitor T- cells to the thymus, leading to clinical benefit.
  • the methods of the disclosed subject matter can be used to treat a subject at risk for GVHD following hematopoietic stem cell transplantation (HSCT), and following destruction of the immune system by irradiation, e.g., total body irradiation, and/or chemotherapy.
  • HSCT hematopoietic stem cell transplantation
  • the methods of the disclosed subject matter can be used to treat a subject at risk for GVHD following allogeneic HSCT.
  • HSCT can be autologous (using haematopoietic stem cells (HSC) from the patient), or allogeneic (using HSC from a donor).
  • HSC haematopoietic stem cells
  • Conditions treated with HSCT include, for example, multiple myeloma, leukemia, pediatric cases where the subject has an inborn defect such as severe combined immunodeficiency or congenital neutropenia with defective stem cells, and also children or adults with aplastic anemia who have lost their stem cells after birth.
  • stem cell transplants include sickle-cell disease, myelodysplastic syndrome, neuroblastoma, lymphoma, Ewing's Sarcoma, Desmoplastic small round cell tumor, testicular cancer, germ cell tumors, chronic granulomatous disease and Hodgkin's disease.
  • the antagonists of the disclosed subject matter can be administered to a subject following organ transplant, e.g., solid organ transplant or bone marrow transplant, to treat or prevent rejection of the transplanted organ or cells in the subject.
  • organ transplant e.g., solid organ transplant or bone marrow transplant
  • CCR2 is a G protein-coupled receptor that binds multiple ligands, known as macrophage chemoattractant proteins, including CCL2 (MCP-1), CCL8 (MCP-2), CCL7 (MCP-3), and CCL13 (MCP-4).
  • CCR2 is considered to be the exclusive receptor for MCP-1.
  • CCR2 is expressed on the so-called "inflammatory" subset of blood monocytes. It is also expressed on, and functions in, other immune/inflammatory cell types such as dendritic cells and memory Thl cells (Zhao, Q. (2010) Journal of Leukocyte Biology, 88(41).
  • CCR5 is also a G protein-coupled receptor that binds multiple ligands, including CCL4 (MIP- ⁇ ), CCL5 (RANTES), CCL3 ( ⁇ - ⁇ ), CCL8 (MCP-2), and CCL3L1 ( ⁇ -1 ⁇ /LD78p).
  • CCL4 MIP- ⁇
  • CCL5 RANTES
  • CCL3 ⁇ - ⁇
  • CCL8 MCP-2
  • CCL3L1 ⁇ -1 ⁇ /LD78p
  • CCR5 is expressed predominantly on macrophages differentiated from blood monocytes and Thl cells activated in response to inflammatory stimuli. It is also expressed on non-immune cells such as osteoclasts and VSMCs (Zhao, Q. (2010) Journal of Leukocyte Biology, 88(41 ).
  • an “antagonist” to CCR2 or CCR5 refers to any agent that blocks, suppresses or reduces CCR2 or CCR5 biological activity.
  • a “CCR2/CCR5 dual antagonist” is an antagonist agent that blocks, suppresses or reduces both CCR2 and CCR5 biological activity.
  • Exemplary CCR2 and/or CCR5 antagonists include, but are not limited to, anti-CCR2 or anti-CCR5 antibodies, an anti-sense molecule directed to CCR2 or CCR5 (including an anti-sense molecule directed to a nucleic acid encoding CCR2 or CCR5), a CCR2 and/or CCR5 inhibitory compound, e.g., a small molecule, a CCR2 and/or CCR5 peptide antagonist, a CCR2 or CCR5 structural analog, and a mutation resulting in a decrease or inhibition of CCR2 or CCR5 activity.
  • a dual CCR2/CCR5 antagonist that can be used in the methods of the present subject matter is cenicriviroc (CVC or TBR- 652, formerly known as TAK-652; Tobira Therapeutics).
  • a CCR2 and/or CCR5 antagonist binds (physically interacts with) CCR2 or CCR5 (e.g., an antibody), and/or reduces (impedes and/or blocks) CCR2 and/or CCR5 receptor signaling. Examples of types of CCR2 and CCR5 antagonists are provided herein.
  • an “antibody” (interchangeably used in plural form) as used herein is an immunoglobulin molecule capable of specific binding to a target, such as a carbohydrate, polynucleotide, lipid, polypeptide, etc., through at least one antigen recognition site, located in the variable region of the immunoglobulin molecule.
  • a target such as a carbohydrate, polynucleotide, lipid, polypeptide, etc.
  • the term encompasses not only intact polyclonal or monoclonal antibodies, but also fragments thereof (such as Fab, Fab', F(ab')2, Fv), single chain (ScFv), mutants thereof, fusion proteins comprising an antibody portion, humanized antibodies, chimeric antibodies, diabodies linear antibodies, single chain antibodies, multispecific antibodies (e.g.
  • immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these can be further divided into subclasses (isotypes), e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2.
  • the heavy-chain constant domains that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively.
  • the subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.
  • a “monoclonal antibody” refers herein to a homogeneous antibody population wherein the monoclonal antibody includes amino acids (naturally occurring and non-naturally occurring) that are involved in the selective binding of an antigen. Monoclonal antibodies are highly specific, being directed against a single antigenic site.
  • the term "monoclonal antibody” encompasses not only intact monoclonal antibodies and full-length monoclonal antibodies, but also fragments thereof (such as Fab, Fab', F(ab')2, Fv), single chain (ScFv), mutants thereof, fusion proteins comprising an antibody portion, humanized monoclonal antibodies, chimeric monoclonal antibodies, and any other modified configuration of the immunoglobulin molecule that includes an antigen recognition site of the required specificity and the ability to bind to an antigen. It is not intended to be limited as regards to the source of the antibody or the manner in which it is made (e.g. , by hybridoma, phage selection, recombinant expression, transgenic animals, etc.).
  • Humanized antibodies refer herein to a molecule having an antigen binding site that is substantially derived from an immunoglobulin from a non-human species and the remaining immunoglobulin structure of the molecule based upon the structure and/or sequence of a human immunoglobulin.
  • the antigen binding site can include either complete variable domains fused onto constant domains or only the complementarity determining regions (CDRs) grafted onto appropriate framework regions in the variable domains.
  • Antigen binding sites can be wild type or modified by one or more amino acid substitutions, e.g., modified to resemble human immunoglobulin more closely.
  • Some forms of humanized antibodies preserve all CDR sequences (for example, a humanized mouse antibody which contains all six CDRs from the mouse antibodies).
  • humanized antibodies have one or more CDRs (one, two, three, four, five, six) which are altered with respect to the original antibody.
  • framework region (FR) residues or other residues of the human immunoglobulin replaced by corresponding non-human residues.
  • humanized antibodies can include residues which are not found in the recipient antibody or in the donor antibody.
  • an “individual” or “subject” herein is a vertebrate, such as a human or a non- human animal.
  • Non-limiting examples of non-human animals include primates, farm animals, sport animals, rodents and pets.
  • an "effective amount” of a substance as that term is used herein is that amount sufficient to effect beneficial or desired results, including clinical results, and, as such, an "effective amount” depends upon the context in which it is being applied.
  • an effective amount of an agent which is an antagonist to CCR2 alone, or CCR5 and CCR2 is an amount sufficient to achieve such a modulation as compared to the thymic recovery obtained when there is no antagonist administered.
  • an effective amount of an agent which is an antagonist to CCR2 alone, or CCR5 and CCR2 is an amount sufficient to achieve such a modulation as compared to the GVHD that occurs when there is no antagonist administered.
  • An effective amount can be administered in one or more administrations.
  • a CCR2 antagonist and a CCR5 antagonist can be administered at the same time (e.g., concurrently), or at separate times.
  • one or more CCR2 antagonists, one or more dual CCR2/CCR5 antagonists or one or more CCR2 and CCR5 antagonists can be administered at the same time (e.g., concurrently), or at separate times.
  • a dual CCR2/CCR5 antagonist is administered. Administration of a CCR5 antagonist alone is not encompassed in the present disclosure.
  • treatment is an approach for obtaining beneficial or desired results, including clinical results.
  • beneficial or desired clinical results include, but are not limited to, alleviation or amelioration of one or more symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, prevention of disease, delay or slowing of disease progression, and/or amelioration or palliation of the disease state.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • a "pharmaceutical composition” as used herein is intended to include the combination of an active agent with a carrier, inert or active, making the composition suitable for therapeutic use in vitro, in vivo or ex vivo.
  • the term "pharmaceutically acceptable carrier” encompasses any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, and emulsions, such as an oil/water or water/oil emulsion, and various types of wetting agents.
  • the compositions also can include stabilizers and preservatives.
  • stabilizers and adjuvants see Martin, REMINGTON'S PHARM. SCI., 15th Ed. (Mack Publ. Co., Easton (1975)).
  • the methods for increasing thymic recovery and immune function and treating or preventing GVHD or organ transplant rejection include administering a CCR2 antagonist, a CCR5 antagonist and a CCR2 antagonist, or a dual CCR2/CCR5 antagonist.
  • a CCR2 antagonist a CCR5 antagonist and a CCR2 antagonist
  • a dual CCR2/CCR5 antagonist examples include, but are not limited to, antibodies and fragments thereof, small molecules, peptide inhibitors, and antisense RNA and RNA interference agents.
  • the methods include administering one or more antagonist that is capable of reducing or partially inhibiting or completely inhibiting the activity of CCR2 alone or CCR2 and CCR5.
  • Suitable CCR2 antagonists for use with the methods described herein include, but are not limited to, small molecule pharmaceutical compounds, peptide antagonists, and antibodies. Anti-CCR2 antibodies are discussed in detail below. Examples of small molecule CCR2 inhibitors include, without limitation, MK-0812, produced by Merck (Beaulieu, A., Hasler F., Mola E. M., et al. The efficacy and safety of a CCR2 receptor antagonist in the treatment of rheumatoid arthritis (RA). Ann. Rheum. Dis., 2006;65:175-176), INCB-8696, produced by Incyte (Sharrack B., Leach T., Jacobsen E., et al.
  • Additional small molecule inhibitors of CCR2 that are suitable for use with the subject matter disclosed herein include without limitation the compounds disclosed in US2009/0233946, spiropiperidine-based compounds such as those described in US2008/318990 and WO2009/061881, and biarylaminopiperidinyl amide compounds such as those disclosed in WO2009/043747, the contents of which are hereby expressly incorporated by reference.
  • peptidyl CCR2 antagonists examples include MCP-1 (9-76), also referred to as MCP-1 7-ND (Gong J. H., et al. J. Exp. Med., 1997;186(1): 131-137), and the engineered fusokine construct GMME1 (Rafei M., et al. J. Immunol.
  • Suitable CCR5 antagonists for use with the methods described herein include, but are not limited to, small molecule pharmaceutical compounds, peptidyl antagonists, and antibodies. Anti-CCR5 antibodies are discussed in detail below.
  • Non-limiting examples of small molecule CCR5 inhibitors include INCB009471, developed by Incyte (Stellbrink H. J. Antivir Chem Chemother.
  • GlaxoSmith line (Maeda K., et al. Journal of Virology 78:8654-8662), TAK-220 and TAK-652, developed by Takeda (Baba M, Nishimura O, Kanzaki N. PNAS, 1999;96:5698-5703, Iizawa Y, et. al. 10th Conference on Retroviruses and Opportunistic Infections. Boston, USA, 10-14 February 2003. Abstract 11), and SCH-351125, developed by Schering-Plough (Strizki J. M., et al. PNAS
  • a non-limiting example of a suitable peptide inhibitor of CCR5 for use with the disclosed subject matter includes the peptide with amino acid sequence AFDWTFVPSLIL (Wang F. Y., et al. Biosci Biotechnol Biochem. 2006
  • Suitable antibodies include, without limitation, PRO 140, developed by Progenies (Khatib N., Das S. Recent Pat Antiinfect Drug Discov. 2010 Jan;5(l): 18-22), ROAM3 and ROA 4, developed by Roche (Schanzer J., Jekle A., Nezu J., et al. Antimicrob Agents Chemother. 2011 May; 55(5): 2369- 2378, Ji C, et al. Antiviral Res. 2007 May;74(2): 125-37), and HGS004, produced by Human Genome Sciences (Roschke V., et al. 44th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, Abstract 2871; Washington, D C. October 30 - November 2, 2004).
  • small molecule dual CCR2/CCR5 antagonists include, without limitation, cenicriviroc (CVC or TBR-652, formerly known as TAK-652; Tobira Therapeutics) (USPN 8,183,273 and USPN 7,371,772), BMS-813160, produced by Bristol Myers Squibb (Norman P. Expert Opin Ther Pat. 2011 ;
  • TAK-779 produced by Takeda (Yang Y. F., et al. Eur. J. Immunol., 2002;32(8):2124-2132), LYSN 2238290, produced by Eli Lilly (Singh J. P. et al. 91st Annual Scientific Sessions of the American Heart Association.: 503 abstr. 3922, 8 Nov 2008), NIBR-803 and NIBR-177, produced by Novartis (Braddock, M. 1 1th annual Inflammatory and Immune Diseases Drug Discovery and Development Summit 12-13 March 2007, San Francisco, USA. Expert Opin. Investig. Drugs, 2007;16(6):909-917, Horuk, R. Nat. Rev.
  • WO2008/101905, WO2009/013211, and WO2008/014360 the contents of which are hereby expressly incorporated by reference.
  • An example of a suitable peptide compound for use with the disclosed subject matter includes, without limitation, RAP 103, produced by Rapid
  • anti-CCR2 or anti-CCR5 antibodies can be polyclonal or monoclonal; can be from any of a number of human, non-human eukaryotic, cellular, fungal or bacterial sources; can be encoded by genomic or vector-borne coding sequences; and can be elicited against native or recombinant CCR2 or CCR5 or fragments thereof with or without the use of an adjuvant, all according to a variety of methods and procedures well-known in the art for generating and producing antibodies.
  • neutralizing antibodies against CCR2 or CCR5 are suitable for therapeutic applications.
  • antibodies include, but are not limited to, polyclonal, monoclonal, chimeric, single-chain, and various human or humanized types of antibodies, as well as various fragments thereof, such as Fab fragments and fragments produced from specialized expression systems.
  • various host animals can be immunized by injection with a CCR2 or CCR5 product, or a portion thereof including, but not limited to, portions of the CCR2 or CCR5 in a recombinant protein.
  • host animals can include but are not limited to rabbits, mice, and rats.
  • adjuvants can be used to increase the immunological response, depending on the host species.
  • Such adjuvants include, but are not limited to, mineral gels such as aluminum hydroxide, surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanin, dinitrophenol, and can include useful human adjuvants such as BCG (bacille Calmette-Guerin) and Corynebacterium parvum.
  • mineral gels such as aluminum hydroxide
  • surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanin, dinitrophenol
  • BCG Bacille Calmette-Guerin
  • Corynebacterium parvum useful human adjuvants
  • monoclonal anti-CCR2 or -CCR5 antibodies can be prepared using any technique that provides for the production of antibody molecules by continuous cell lines in culture. Such techniques, include but are not limited to, the hybridoma technique originally described by Kohler and Milstein, 1975, Nature, 256:495-497, the human B-cell hybridoma technique (Kosbor et al, 1983,
  • compositions comprising antagonists can include more than one antibody.
  • a composition comprising an antibody that binds CCR2 and an antibody that binds to CCR5 is contemplated.
  • a method for assessing the neutralizing ability of an antibody to CCR2 or CCR5 is to use an in vivo model.
  • neutralization of CCR2 or CCR5 can be determined in vitro using a chemotaxis assay, for example.
  • Non-limiting examples of antibodies to CCR2 include MLN1202, produced by Millennium (Davidson M., et al. Circulation, 2007; 116(16):II-172), and ABN912, produced by Novartis (Haringman, J. et al. Arthritis Rheum., 2006;54(8):2387-2392).
  • Non-limiting examples of antibodies to CCR5 include PRO 140, developed by Progenies (Khatib N., Das S. PRO 140 ⁇ a novel CCR5 co-receptor inhibitor. Recent Pat Antiinfect Drug Discov. 2010 Jan;5(l):18-22), ROAM3 and ROAM 4, developed by Roche (Schanzer J. et al. Antimicrob Agents Chemother. 201 1 May; 55(5): 2369-2378; Ji C, et al. Antiviral Res. 2007 May;74(2): 125-37), and HGS004, produced by Human Genome Sciences (Roschke V., et al. 44th Annual
  • kits including a composition having a CCR2 antagonist, a CCR2 antagonist and a CCR5 antagonist, a dual CCR2/CCR5 antagonist.
  • the composition can include more than one antagonist. More than one antibody can be included in the kit, for example, an antibody that binds to CCR2 and an antibody that binds to CCR5.
  • more than one small molecule antagonist can be included in the kit (e.g., a CCR5 antagonist and a CCR2 antagonist).
  • the antagonist(s) can be in any state suitable for packing in a kit, such as lyophilized or resuspended in a pharmaceutically acceptable excipient.
  • the kit can further include instructions for use, such as dosing regimen, and/or adjuvants that can be used with the composition(s).
  • the disclosed subject matter provides methods for increasing thymic recovery and/or immune function in a subject, e.g., a human subject, by administering to the subject an effective amount of a CCR2 antagonist alone, a CCR5 antagonist and a CCR2 antagonist (e.g., concurrently), or a dual CCR2/CCR5 antagonist.
  • the disclosed subject matter also provides methods for treating, inhibiting, or preventing GVHD or organ transplant rejection in a subject, e.g., a human subject, by
  • a CCR2 antagonist alone, a CCR5 antagonist and a CCR2 antagonist (e.g., concurrently), or a dual CCR2/CCR5
  • the CCR2 antagonist and the CCR5 antagonist have an additive effect on thymic recovery and/or immune function, and/or on treating, inhibiting, or preventing GVHD or organ transplant rejection. In certain embodiments, the CCR2 antagonist and the CCR5 antagonist have a synergistic effect on thymic recovery and/or immune function, and/or on treating, inhibiting, or preventing GVHD or organ transplant rejection.
  • compositions comprising an effective amount of a CCR2 antagonist alone, a CCR5 antagonist and a CCR2 antagonist, or a dual CCR2/CCR5 antagonist (e.g., antibody or small molecule or peptide inhibitor) to inhibit or reduce CCR2 and/or CCR5 activity.
  • the antagonist can be, for example, but not by way of limitation, a small molecule, an antibody or antibody fragment, or an antisense RNA or RNA interference agent.
  • composition including an effective amount of a
  • CCR2 antagonist alone, a CCR5 antagonist and a CCR2 antagonist, or a dual
  • CCR2/CCR5 antagonist e.g., neutralizing antibody or small molecule
  • a pharmaceutical composition can be administered orally or parenterally (e.g., intravenous, subcutaneous, intramuscular, and
  • compositions are prepared with carriers that will protect the compound(s) against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid.
  • Examples of a dosage form for parenteral administration include injectable solution, infusion, suppository, etc.
  • the administration can be in a single dose or repeatedly over a period of time or as needed as dictated by the appearance of symptoms associated with, for example, GVHD or organ transplant rejection.
  • the administration is prior to HSCT or organ transplantation, immediately following HSCT or organ transplantation, or concurrently with HSCT or organ transplantation, and ongoing for a certain period of time to prevent the onset of GVHD or organ transplant rejection.
  • administration can be ongoing one or more days, weeks, months, or indefinitely.
  • administration can begin when the patient develops symptoms of GVHD or organ transplant rejection and can continue for one or more days, weeks, months, or indefinitely.
  • the administration can be prior to or following ablation of the immune system, or other depletion or suppression of immune function, or at the same time as ablation or other depletion or suppression of immune function, and can continue for a certain period of time.
  • administration can be ongoing one or more days, weeks, months, or indefinitely, to increase or maintain thymic recovery or immune function.
  • a physician or one of skill in the art can monitor the individual for progress during the course of the treatment and determine the appropriate dosage regime.
  • a daily dosage of the pharmaceutical composition can be varied according to the patient's condition, weight, and route of administration.
  • the dose in the case of oral administration of, for example, small molecule antagonist(s), can be about 5 to 1000 mg as an active ingredient, per adult patient of 50 kg, about 10 to 600 mg, about 10 to 300 mg, or about 15 to 150 mg.
  • the dosage can range from about 0.0001 to 100 mg/kg, and more usually 0.01 to 5 mg/kg, of the host body weight.
  • dosages can be 1 mg/kg body weight, 3 mg/kg body weight, or 10 mg/kg body weight or within the range of 1-10 mg/kg.
  • the present subject matter provides for methods of delaying development of GVHD or organ transplant rejection by administration of a composition including an effective amount of a CCR2 antagonist, a CCR5 antagonist and a CCR2 antagonist, or a dual CCR2/CCR5 antagonist.
  • a composition including an effective amount of a CCR2 antagonist, a CCR5 antagonist and a CCR2 antagonist, or a dual CCR2/CCR5 antagonist.
  • the GVHD or organ transplant rejection is prevented from occurring at all.
  • the CCR2 and CCR5 antagonist(s) can be co-administered in combination with other immunosuppressive or anti-inflammatory reagents as known in the art including, for example, cyclosporine, tacrolimus, rapamycin, steroids, azatguioprine, mycophenolate mophetil, mizoribine, etc.
  • EXAMPLE 1 Absence of CCR2 and CCR5 receptors improves thymic recovery. Materials and Methods As shown in Figure 1, wild-type C57B1/6 mice, 5 mice per group, were irradiated with a Cesium source at a rate of 42.5 rads/min for 21.2 minutes, which is a total dose of 900 rads, to destroy their native hematopoietic stem cells. After irradiation, mice were rested for 2 hours. Irradiated mice were transplanted
  • CCR2 "7” CD45.2 bone marrow cells CCR5 “ “ bone marrow cells, or with wild type bone marrow cells by retro-orbital injection using a size 27.5 gauge needle.
  • 100,000 CD45.1 wild type bone marrow cells were injected into both groups of recipients to provide competition.
  • CCR2 " " and CCR5 " " bone marrow cells were obtained from commercially available mice from Jackson Laboratories.
  • mice Two weeks after transplantation, the transplanted mice were sacrificed and analyzed. Their bone marrow and thymi were analyzed for CD45 chimerism. Briefly, single cell suspensions of thymus and bone marrow were prepared, RBCs were lysed in bone marrow, counted in a hematocytometer, and 10e6 cells were stained with optimal concentrations of monoclonal antibody to CD45.1, CD45.2, CD4 and CD8 before being analyzed using a flow cytometer. The numbers of recovered subsets were then determined. Statistic significance was determined using Student's t-test in Microsoft Excel.
  • mice transplanted with CCR2 "A or CCR5 "7" bone marrow cells demonstrated greater repopulation of the thymus with hematopoietic (CD45+) cells relative to the mice transplanted with wild-type bone marrow (p ⁇ 0.05, Student's T- test).
  • CD45+ hematopoietic
  • an average of 23% of CD4 +CD8+ DP were derived from CCR2 knockout donor cells compared to 0% of DP from wild type donor mice.
  • An average of 3% of DP were derived from CCR5 knockout cells compared to 1% of DP from wild type donor mice.
  • EXAMPLE 2 The in vitro effect of dual CCR2/CCR5 inhibition on lymphocyte and monocyte chemotaxis, T-cell function and growth, and hematopoietic stem cell differentiation.
  • Chemotaxis assays are conducted using either normal donor PBMC, mouse lymph node, or splenic T-cells using a chemotaxis chamber and a standard 5- um pore size polycarbonate membrane. For each experimental condition, 5x10 5 PBMC or isolated T-cells or monocytes are placed in the top compartment of a chemotaxis chamber and allowed to migrate to the lower compartment of the chamber. Discrete experiments are conducted with each of the CCR5 and CCR2 ligands CCL3, CCL4, CCL5 and CCL2 (MCP-1), as well as cenicriviroc or a control. The controls are mariviroc (a CCR5 inhibitor), RSI 02895 (a CCR2 inhibitor) and control media.
  • Preliminary experiments are first conducted with each experimental cell type and treatment chemokine to determine the optimal concentration of the chemokines and the optimal assay length. Based on the results of the preliminary experiments, further assays determine the relationship between cenicriviroc concentration and chemotaxis inhibition in lymphocytes and monocytes. After migration, the cells are counted by flow cytometry. Cenicriviroc and control experimental results are analyzed and compared.
  • PBMC normal donor PBMC are stimulated in vitro with cognate cytomegalovirus peptide in the presence of cenicriviroc or control.
  • PBMC stimulation intracellular staining for interferon- ⁇ , tumor necrosis factor-a and interleukin-2 is performed and measured by flow cytometry.
  • Cenicriviroc and control experimental results are analyzed and compared.
  • Colony forming assays are performed in methylcellulose medium enriched with recombinant human (rh) GM-CSF, rhIL-3, rhSCF, and rhEpo with or without cenicriviroc in various concentrations to study the effect of cenicriviroc on human hematopoietic stem cells.
  • CD34-positive cells are seeded in the medium and incubated for 7 or 14 days. After incubation, colonies are identified and counted. Cenicriviroc and control experimental results are analyzed and compared.
  • EXAMPLE 3 Effect of dual CCR2/CCR5 inhibitor on GVHD in a full MHC- rn is match mouse model.
  • This Example shows that treatment with cenicriviroc prevents GVHD by limiting the infiltration of donor cells into secondary lymphoid organs and GVHD target tissues (e.g., liver, gut, and skin).
  • GVHD target tissues e.g., liver, gut, and skin.
  • a six-arm study is conducted using a GVHD mouse model, wherein recipient mice receive cenicriviroc or no treatment.
  • Recipient BALB/c mice receive lethal irradiation (1000 rads) and subsequently undergo bone marrow transplantation from a C57BL/6 mouse donor.
  • Donor mice are CCR5 "7" , CCR2 "A or wild type.
  • a preliminary experiment is performed to determine the dose of donor cells required to generate severe GVHD in irradiated recipients in 2-4 weeks. All experimental groups will consist of 6 mice. Recipient mice will be studied to determine survival after transplantation or sacrificed at 10 days for histopathological assessment.
  • Serum levels of MCP-1, CCL3, CCL4 and CCL5 are assessed weekly. Additionally, PBMC is assessed to determine the number of CD4-positive T-cells, regulatory T-cells and T-cell receptor excision circles to indicate recent emigrants from the thymus.
  • secondary lymphoid organs and GVHD target tissues are assessed by morphological and histological analysis.
  • samples of the anticoagulated whole blood and sections of the livers, skin, thymi, Peyer's patches and intestines of recipient mice are fixed in zinc formalin and paraffin embedded for haematoxylin and eosin staining and immunohistochemistry and subsequent histological analysis.
  • GVHD is graded in the fixed samples using standard optical microscopy techniques and histological criteria.
  • the macroscopic appearance of target organs is also assessed, including the size of the thymus. Cellularity of the thymus is also measured.
  • Lymphocyte CCR5 and CCR2 expression is also determined by isolation of lymphocytes from the organs after sacrifice followed by flow cytometric analysis. Survival curves and GVHD scoring are used to compare the outcomes of treatment with CCR5 " _ , CCR2 " " or wild- type donor cells.
  • EXAMPLE 4 Effect of a dual CCR2/CCR5 inhibitor on thymic recovery. This Example shows that treatment with cenicriviroc enhances thymic recovery after lethal irradiation and bone marrow transplantation by improving the trafficking of T-cell progenitors into the thymus.
  • Stem cell engraftment is assessed by measuring donor chimerism in the bone marrow by flow cytometry and plating bone marrow in colony forming assays. Thymic homing will be assessed by measuring donor chimerism in the thymus by flow cytometry.
  • recipient mice are treated with cenicriviroc and long term immunologic outcomes are assessed.
  • thymic size and cellularity are assessed and splenic and circulating numbers of CD4-positive, CD-8 positive cells will be measured at 2, 4, and 8 weeks by flow cytometry.
  • CD4, CD8, and regulatory T-cell content of PBMC is also measured by flow cytometry, and T- cell receptor excision circles in blood are measured to assess recent thymic emigrants.

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Abstract

La présente invention concerne le blocage du CCR2 seul ou du CCR2 et du CCR5 ensemble pour améliorer la récupération thymique et la fonction immunitaire thymique et traiter ou prévenir la maladie du greffon contre l'hôte ("GVHD") et le rejet de greffe d'organe. Par conséquent, l'invention ci-décrite concerne des méthodes destinées à accroître la récupération thymique ou la fonction thymique chez un sujet, par ex., un sujet humain, par administration au sujet d'une quantité efficace d'un antagoniste de CCR2, d'un antagoniste de CCR5 et d'un antagoniste de CCR2, ou d'un antagoniste double de CCR2/CCR5. La présente invention concerne également des méthodes destinées à traiter, à inhiber, ou à prévenir la GVHD ou le rejet de greffe d'organe chez un sujet, par ex., un sujet humain, par administration au sujet d'une quantité efficace d'un antagoniste de CCR2 seul, d'un antagoniste de CCR5 et d'un antagoniste de CCR2, ou d'un double antagoniste de CRR2/CCR5.
PCT/US2013/072613 2012-11-30 2013-12-02 Méthodes destinées à améliorer la récupération thymique et à prévenir et à traiter la maladie du greffon contre l'hôte à l'aide d'antagonistes de ccr2 et ccr5 WO2014085808A1 (fr)

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CN107847514A (zh) * 2015-06-23 2018-03-27 西托戴恩股份有限公司 炎症、癌症、自身免疫和其它病症中ccl5配体结合ccr5受体的抑制作用和ccr5/ccl5轴信号传导的改变
US20190016810A1 (en) * 2017-05-11 2019-01-17 Cytodyn Inc. Methods for treating or preventing graft-versus-host disease involving the administration of anti-ccr5 receptor agents
CN110337446A (zh) * 2016-12-21 2019-10-15 佛罗里达大学研究基金会 过继细胞疗法中ccr2+造血干细胞介导的t细胞激活
CN112266392A (zh) * 2014-12-23 2021-01-26 妥必徕疗治公司 制备cenicriviroc及相关类似物的方法

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112266392A (zh) * 2014-12-23 2021-01-26 妥必徕疗治公司 制备cenicriviroc及相关类似物的方法
CN107847514A (zh) * 2015-06-23 2018-03-27 西托戴恩股份有限公司 炎症、癌症、自身免疫和其它病症中ccl5配体结合ccr5受体的抑制作用和ccr5/ccl5轴信号传导的改变
US20190002571A1 (en) * 2015-06-23 2019-01-03 Cytodyn Inc. Inhibition of ccl5 ligand binding to ccr5 receptor and alteration of ccr5/ccl5 axis signaling in inflammation, cancer, autoimmune, and other conditions
US11584797B2 (en) * 2015-06-23 2023-02-21 Cytodyn Inc. Inhibition of CCL5 ligand binding to CCR5 receptor and alteration of CCR5/CCL5 axis signaling in inflammation, cancer, autoimmune, and other conditions
CN110337446A (zh) * 2016-12-21 2019-10-15 佛罗里达大学研究基金会 过继细胞疗法中ccr2+造血干细胞介导的t细胞激活
US20190016810A1 (en) * 2017-05-11 2019-01-17 Cytodyn Inc. Methods for treating or preventing graft-versus-host disease involving the administration of anti-ccr5 receptor agents
CN111201034A (zh) * 2017-05-11 2020-05-26 西托戴恩股份有限公司 涉及施用抗ccr5受体试剂的治疗或预防移植物抗宿主病的方法

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