EP1187625A1 - Conception de composes a base de structure qui inhibe reponses prejudiciables de lymphocytes t cytotoxiques - Google Patents

Conception de composes a base de structure qui inhibe reponses prejudiciables de lymphocytes t cytotoxiques

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Publication number
EP1187625A1
EP1187625A1 EP00932013A EP00932013A EP1187625A1 EP 1187625 A1 EP1187625 A1 EP 1187625A1 EP 00932013 A EP00932013 A EP 00932013A EP 00932013 A EP00932013 A EP 00932013A EP 1187625 A1 EP1187625 A1 EP 1187625A1
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Prior art keywords
mhc
cells
analogs
compounds
analog
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EP00932013A
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German (de)
English (en)
Inventor
Bradford A. Jameson
Anna Tretiakova
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Philadelphia Health and Education Corp
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Philadelphia Health and Education Corp
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Publication of EP1187625A1 publication Critical patent/EP1187625A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/70517—CD8
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • Computational chemistry and molecular modeling can be used to study the surface contacts of receptor-mediated interactions as well as serve as a means to develop small molecule antagonists.
  • Contact regions of a protein's surface are comprised of a pattern of well-defined ridges and channels.
  • the ridges are relatively polar with high electropotential and flexibility in the unbound state.
  • the channels on the other hand, have a low electropotential and are relatively rigid. Recent biophysical studies suggest that these channels are protected by a shell of water molecules (Sidorova, N.Y. and Rau, D.C., Proc . Natl Acad. Sci. 1996 93 (22) :12272-12277; Vossen et al .
  • Synthetic mimicry of the ridge has been used to create molecules capable of blocking the initial handshake which occurs prior to the high affinity interaction.
  • analogs have been designed from the surface of blood coagulation factor XI to inhibit its binding to high molecular weight kininogen (Baglia et al . J. Biol. Chem. 1992 265:4247- 4252) .
  • Blood coagulation factor XIa has also been used as a template to design small analogs that potentially compete with its binding to activated platelets.
  • the IGF-1 protein surface has also been used to engineer analogs capable of inhibiting IGF-1 dependent growth of cells derived from a prostate carcinoma (Pietrzkowski et al . Cancer Research 1993 52:6447- 6451) .
  • the surface of CD4 was used to rationally design mimetics that were able to block CD4-independent T cell stimulation and to significantly inhibit both the severity and the incidence of EAE in rodents (Jameson et al . Nature 1994 368:744-746) .
  • IgE has also been used as a template to design effective inhibitors that are capable of blocking its binding to the high affinity Fc receptor so that IgE-induced degranulation of mast cells is inhibited (McDonnell et al . Nature Structural Biology 1996 3:419-425).
  • the domain 5 of kininostatin has also been used to engineer analogs that were able to block its binding to urokinase receptor and to block angiogenesis .
  • U.S. Patent 5,645,837 describes compounds which interfere with CD8 mediated activity by competing with CD8 in intermolecular interactions that involve CD8 which are associated with cytotoxic T lymphocyte (CTL) activation. These compounds comprise a molecular surface that corresponds to a molecular surface of human CD8 at amino acids 53-56, 60- 67 or 53-67 and are able to interact with the same molecules as the CD8 amino acids without producing the same biological effects as CD8 intermolecular interaction.
  • CTL cytotoxic T lymphocyte
  • Peptide analogues SC4 and SC7 which were engineered from CD8 and contain amino acids 54-59 or 63-71 of the CD8 sequence and terminal cysteines, have also been disclosed as capable of disrupting the activation and/or generation phase of CD8 CTLs (Choski et al . Nature Medicine 1998 4:309-314). Small synthetic peptide mimics of the CD8 DE loop have also been shown to possess inhibitory activity on in vi tro CD8 T cell function (Li et al . J. Biol. Chem. 1998 273 (26) : 16442-5) .
  • the present invention relates to compounds and methods of designing compounds which mimic or interact with surface structures of the CD8 activation complex specific to interaction with Major Histocompatibility Complex class I (MHC I) as a means of disrupting a primary signaling event of detrimental CTL responses .
  • MHC I Major Histocompatibility Complex class I
  • An object of the present invention is to provide a composition which inhibits a detrimental cytotoxic T lymphocyte response which comprises a compound which mimics or interacts with a surface feature of the CD8/MHC I complex.
  • Unique surface features include, but are not limited to the SHN, KIT, SSK, DEK and RDT surface feature.
  • Another object of the present invention is to provide a method of producing a compound which inhibits a detrimental cytotoxic T lymphocyte response which comprises identifying a surface feature of CD8 specific to the interaction of CD8 with MHC I; and synthesizing a compound which mimics or interacts with the identified surface feature.
  • Yet another object of the present invention is to provide a method of inhibiting a detrimental T lymphocyte response in a human by administering to the human a composition which comprises a compound which mimics or interacts with a surface feature of the human CD8/MHC I complex.
  • a pharmaceutical composition comprising a compound with a simple aromatic ring which fits into a hole in the surface of CD8, such as carbobenzoxy arginine, is administered to a human to inhibit a detrimental T lymphocyte response .
  • Figure 1 is a bargraph showing % cytotoxicity of compounds which mimic or interact with the surface of the CD8 ⁇ -chain. Compounds were tested at concentrations of 50, 100 and 200 ⁇ M .
  • the CD4 -positive helper T cells which recognize antigen in the context of the Major Histocompatibility Complex class II, while the other involves CD8-positive cytotoxic cells (CTLs) which recognize antigen in the context of Major Histocompatibility Complex class I (MHC I) .
  • CTLs cytotoxic cells
  • MHC I Major Histocompatibility Complex class I
  • the CD4 -positive T cells provide "helper" functions in mediating both the humoral as well as cellular immune responses. In healthy individuals, the CTL response is intended to kill cells infected with intracellular pathogens, such as viruses, parasites and bacteria.
  • helper T cells have been implicated in a variety of different pathological situations.
  • human gene therapy is rapidly on its way to becoming a medical reality.
  • Phase I clinical trials for gene therapy for treatment of a variety of diseases including cancer, cystic fibrosis, Gaucher's Disease and arthritis To successfully treat a patient, the engineered cell must be targeted and delivered to the appropriate cells.
  • An efficient gene delivery system has been found to be the adenoviral vector.
  • viral proteins are produced and presented to the host's immune system.
  • a powerful CTL response is generated that targets and destroys cells containing the newly delivery gene. This CTL response thus limits the effectiveness of gene therapies.
  • agents are needed which inhibit this detrimental CTL response without affecting the general host immune defense system.
  • One means for therapeutically targeting the detrimental CTL response without interfering with the immune system's ability to mount general CTL response is to target an activation-specific marker.
  • T H cells and CD8-positive cytotoxic T (T CTL ) cells are predominantly produced in the thymus wherein they undergo both positive and negative selection.
  • T cell produced in this organ is unique by virtue of its polymorphic T Cell Antigen Receptor (TCR) that is matched to the resident Major Histocompatibility Complex Class I (MHC I) or Class II (MHC II) proteins for T CTL and T H cells, respectively.
  • TCR polymorphic T Cell Antigen Receptor
  • MHC I Major Histocompatibility Complex Class I
  • MHC II Class II
  • T cell bearing a TCR that appropriately fits to the foreign antigen-bearing cell will become activated.
  • the rest of the T cell population remains quiescent.
  • the activated T cell clonally proliferates, secretes growth factors and cytokines, and aids in the mounting of both humoral as well as cytotoxic immune responses .
  • the external generation of a "primary" activation signal within a T cell involves a variety of different proteins in addition to the TCR.
  • the CD3 physically associates with the TCR to form an antigen receptor complex.
  • the antigen receptor complex physically associates with either CD4 or CD8, depending on the type of T cell, and directly contacts the appropriate MHC molecule.
  • CD4 or CD8 depending on the type of T cell, and directly contacts the appropriate MHC molecule.
  • second signals can be provided by several other pathways such as CD28/B7, CD40/CD40L and/or CD2 (Bierer et al . Ann. Rev. Immunol. 1989 7:579-599; Linsley et al. J. Ex. Med.
  • MHC I is ubiquitous. It is a transmembrane-spanning heterodimer consisting of a large alpha chain and a shorter protein, known as B-2 microglobulin.
  • the alpha chain is comprised of three immunoglobulin-like subdomains referred to as the ⁇ -1, -2 and -3 subdomains .
  • the presented antigen is held in a cleft produced by two adjacent helices in the -2/ -3 subdomains.
  • the T Cell Antigen Receptor directly recognizes the antigen in the context of these helices.
  • CD8 binds to a distal region of the MHC class I. Its binding occurs across the ⁇ -1 subdomain of the alpha chain and the ⁇ -2 microglobulin.
  • the CTL response involves an initial clonal expansion process which generates the set of activated CD8 -positive T CTL cells.
  • This activated set of cells is responsible for targeted killing of cells bearing the "activating antigen" in the context of MHC I or of detecting and killing cells that do not bear the "self” MHC I.
  • activated/proliferating cells are highly sensitive to the influx of the "complete" set of activating signals. The sudden loss of one or more of the critical signals results in the induction of programmed cell death, known as apoptosis.
  • T cells are particularly sensitive to the regulatory signals that drive the activation forward. Crystal structure complexes of human CD8 (alpha chain homodimer) bound to MHC I have been described by Gao et al .
  • CDRl CDR2 and CDR3.
  • CDRl CDR2
  • CDR3 CDR3
  • CDR2 CDR3
  • CDR3 CDR3
  • CD8 In the unbound state of an antibody, the CDRs have mobility. When bound by an antigen, their mobility dramatically decreases.
  • Studies in human CD8 demonstrate its CDRs, when bound to MHC I, to also be more stabilized as compared to the unbound protein.
  • murine CD8 in the bound state the greatest degree of contact between CD8 and MHC I occurs across the CDRl and CDR3 domains of the protein. The carboxy terminal half of CDR2 is not in contact with the MHC I .
  • mic it is meant that the compounds present a similar surface and similar pattern of motion to the topology unique surface patterns.
  • interact it is meant that compounds are modeled to fit into spaces or holes in the surface patterns.
  • Test compounds were assayed for their ability to block the generation and killing function of the CD8 -dependent CTL response. Test compounds were designed from both the human and murine structures and assayed in species relevant systems. It was found that synthetic mimicry of and/or interaction with of any of these surface features, whether by means of peptide or organic synthesis, resulted in highly specific antagonists of the activated CD8 complex.
  • the first site referred to as the "SHN" ridge is part of the CDR2 of CD8 and is in partial contact with MHC I .
  • This site resides at the top of the CDR2 loop.
  • Ser-58, Ser-59 and His-60 of this site are in direct contact with MHC I.
  • Asn-61 is pointed away from the class I.
  • SC8-29 is an all "d” amino acid analog consisting of the residues Ser-His-Asn.
  • the all "I” amino acid equivalent (SC8-2) had no activity.
  • the second surface is referred to as the KIT surface as amino acids lysine, isoleucine, threonine and tryptophan (KITW) were found to be prominently displayed. This portion of the surface is clearly away from the MHC I binding site and flanks a major channel running down the exposed face of the CD8 alpha subunit .
  • the Lys-62 and Thr-64 are used to create the surface of the ridge and lie- 63 and Trp-65 reach down toward the hydrophobic channel. This ridge is directly across the channel from the "RDT" ridge.
  • Target sites 3 and 4 referred to herein respectively as DEK and SSK, emanate from a surface region of the CD8 with the largest associated B-factors. These sites have been consolidated because they represent two halves of the same ridge. Furthermore, an analog spanning both site 3 and 4 (AC8-9) has been reported to inhibit the activation of the CTL response, but not the effector functions (Choksi et al . Nature Medicine 1998 4:309-314). The analog panels synthesized for these sites are shown in Table 3. TABLE 3 : Analogs to DEK and SSK
  • the fifth surface or site is referred to as the RDT ridge as amino acids arginine, aspartate and threonine are prominently displayed.
  • This ridge is situated vis-a-vis from the KIT ridge. Parts of this site are close to MHC I, but clearly not in contact with it.
  • An analysis of the B-factors associated with bound MHC I indicate that the ⁇ -2 region of MHC that is juxtaposed to the RDT site is one of the most flexible areas of the MHC protein.
  • the region equivalent to the RDT site in unbound CD8 has very little motion associated with it. In the structure bound to MHC I, however, the same ridge shows a significant degree of motion. Thus, the mobility of this ridge is clearly influenced by the binding of MHC.
  • the panel of analogs synthesized to probe this region of the protein is listed in Table 4. TABLE 4 : Analogs to RDT
  • Arg-79 and Asn-83 of this site are both facing in toward the channel and toward the MHC I ⁇ -3 domain, whereas Asp- 80, Thr-81 and Asn-82 are facing away from the channel and toward the ⁇ -2 domain of the MHC.
  • a conformationally restrained peptide encompassing one side of this surface such as cRDTc (SEQ ID NO:20) was demonstrated to have full inhibitory activity, while the unrestrained analog RDTN showed no biological activity.
  • Use of a " " amino acid to conformationally influence the main chain torsions in the analog T(d)NN also gave rise to an analog with full inhibitory activity, while the unrestrained TNN peptide had significantly less activity.
  • a preferred analog targeting the RDT ridge comprises cRDYc (SEQ ID NO: 22) .
  • mice that had been challenged with virus prior to their sacrifice usually showed a slightly stronger alloresponse .
  • the anti -viral response was completely abated.
  • the cys-T-D-R-cys analog which demonstrated only weak inhibition in vi tro, showed inhibition of the target-specific response in vivo .
  • a preferred RDT analog, cRDYc was also tested in vivo in an accelerated diabetes model in NOD mice. In this model, diabetogenic cells are passively transferred to naive recipients . All control mice developed diabetes before day 19. In contrast, all of the mice treated with cRDYc had a significantly delayed onset of diabetes ( ⁇ than 2 months) .
  • compounds designed to mimic the topology unique surfaces, SHN, KIT, DEK, SSK and RDT can be useful in specifically inhibiting detrimental CTL responses in both in vi tro and in vivo assays.
  • Compounds designed to mimic the murine CD8/MHC I surfaces including, but not limited to, those specifically exemplified herein are useful as reagents for enabling vector-driven gene delivery systems wherein detrimental CTL responses present a problem.
  • Such murine derived analogs as described herein or designed in accordance with methods described herein could be incorporated into kits comprising gene delivery systems for use in research and development of new gene therapies.
  • these unique surface patterns serve as templates for design of additional compounds which mimic the surface patterns and inhibit detrimental CTL response.
  • the ⁇ -2 microglobulin loop corresponds to MHC residues Asn-83, His-84, Val-85, Thr- 86, Leu-87, Ser-88 and Gln-89.
  • the LSQ portion of this loop provides part of the edge of the cavity created when CD8 binds to MHC.
  • the NHVT portion of the loop faces away from the CD8 surface.
  • the analogs LDT (a peptide similar in sequence to the active analog) NHVT, HVT and LSQ were assayed for their ability to inhibit human CTL target lysis responses.
  • the analogs were assayed at 200, 100 and 20 ⁇ g/ml .
  • the LSQ analog inhibited about 25 to 30% of the response.
  • Peptides derived from the side of the MHC loop facing away from the CD8 surface had no activity.
  • the ⁇ -specific side chain replacements on the CD8 template were then used to create the new model of the ⁇ heterodimer as described by Jameson (Nature 1989 341:465-467) and Jameson et al . (Nature 1994 368:744-746). After replacing the side chains, the model was subjected to alternating rounds of molecule motions. The modeling was performed using the Biopolymer module from the Sybyl computational chemistry suite of programs on a Silicon Graphics OCTANE computer. A Connolly Surface was calculated from the NMR-based structure using a hypothetical sphere with a radius of 2.8 A (twice the radius of a water molecule) .
  • NHT NHT
  • TNHTAK SEQ ID NO:23
  • IMNVK IMNVK
  • the second ridge is a segment of the CDRl, comprised of EVKSISK (21-271 SEQ ID NO: 25)
  • the third ridge is the most prominent (and the most highly charged) consisting of the amino acids SVDKKRN
  • the fourth ridge displays residues IILES (69-73; SEQ ID NO: 27) .
  • the fifth ridge is in a position equivalent to the RDT ridge on the ⁇ -chain. This prominently displayed surface is comprised of residues SSDSRRPFL (73-81; SEQ ID NO:28) .
  • the design of analogs to these ridges was performed in analogous fashion to analogs designed and described herein.
  • the inverse sequence Phe-Arg was predicted to lack several of the hydrogen bonds observed with the Arg-Phe peptide.
  • a dose-dependent inhibitory response was observed for both the Arg-Phe peptide and the semi -organic compound cbz-arginine .
  • the Phe-Arg analog has no activity. See Figure 1. Based upon these experiments, it is believed that other semi-organic compounds comprising a simple aromatic ring can be designed to interact with a surface feature of human CD8 specific to the interaction of human CD8 with MHC I thereby inhibiting a detrimental T lymphocyte response.
  • compositions comprising semi-organic compounds such as cbz-arginine or peptide mimetics such as described herein can then be prepared and administered to humans in accordance with well known techniques to inhibit detrimental T lymphocyte responses including, but not limited to, those responses which limit the effectiveness of gene therapies and tissue transplantation and which occur in patients with insulin-dependent diabetes mellitus (IDDM) .
  • IDDM insulin-dependent diabetes mellitus
  • This compound contains an ester linkage predicted by the computer model to have no biological purpose. However, this linkage is quite likely to limit the utility of cbz-arg in vivo . Accordingly, a series of semi-organic analogs without the ester linkage, but with a similar basic structure as depicted in Formula II (as shown below) , have been synthesized and tested for inhibitory activity.
  • analog of Formula VII is preferred.
  • additional analogs which interact with unique surface features of the CD8/MHC I complex wherein R 3 comprises one or more ring structures comprising 4 to 8 carbons and R x and R 2 have been modified to further enhance activity can also be produced combmatorially and used to inhibit detrimental Cytotoxic T lymphocyte responses.
  • CTL response assays were performed to examine the effects of analogs on the generation of activated CTLs in response to an alloantigen and the ability of the analogs to inhibit CTL effector functions such as target lysis.
  • the primary spleen cells from C57BL/J6 mice were stimulated with mitomycin-treated irradiated (10,000 RADs) P815 cells at a 6:1 effector to stimulator ratio.
  • Stimulated spleen cells were then cultured in RPMI media supplemented with human recombinant IL-2 (1 U/ml) , 10% FCS, glutamic acid, penicillin and streptomycin.
  • the allogeneic CTL response was assayed in accordance with the protocol described by Matzinger (J. Immunol. Meth. 1991 145:185-192).
  • the effector cells were incubated with the [ 3 H] labeled targets (P815 cells) at a 50:1 ratio for 3 hours at 37°C and harvested using a PHD harvester.
  • spleen cells were treated with the peptides either at the time of the stimulation or at the time of the killing assay.
  • [ 3 H] incorporation by P815 cells that were cultured in the presence of the peptides for 3 days was determined. None of the peptides showed any signs of toxicity.
  • the murine retrovirus MuLV was inoculated (1 x 10 5 FFU) into C57BL/6 mice on day 0 of the study. Under these conditions, it is known that C57BL mice create a strong CTL response directed solely at the E55 envelope protein of the virus. Following the initial viral inoculation, the mice were allowed to develop a CTL response. This response typically takes 5 to 7 days. One day 9 of the study, a single bolus (i.v.) injection of the test analog was administered.
  • Small hydrophilic analogs such as peptides used in this study are generally very rapidly removed from the animal via renal clearance mechanisms. With a short serum half-life and an observed IC 50 of the mid-lower micromolar range, it is reasonable to assume that an inhibitory effect would only be seen at the end of the study if the analog can induce severe allergy or, more likely, clonal deletion of the activated CTLs.
  • the anti -viral CTL response was boosted by a re-challenge of MuLV on day 11. Because the CTL response to re-challenge is very rapid, a second bolus injection of the analog was administered on day 13. The mice were sacrificed on day 21 of the study. The CD8 positive cells of each animal are split into aliquots.
  • the first was used to assay for the virus-specific response to E55-positive target cells.
  • the second was used to show that the resting repertoire is fully functional by stimulating an allogeneic CTL response.
  • 5 groups of three C57BL/6 mice each were used as described in the following table .
  • test analog cRDYc SEQ ID NO: 22
  • the spleen cells from the donors were split into 2 groups. One group was left untreated and used in control animals. The second group was incubated for 20 minutes with 200 ⁇ g of the cRDYc analog prior to transfer into the animals. Treated animals also received 400 ⁇ g of the analog intravenously at approximately days 3 and 7 post transfer of the spleen cells .
  • Stimulated blood cells were cultured in RPMI media supplemented with human recombinant IL-2 (1 u/ml) , 10% FCS, glutamine, penicillin and streptomycin. After 7 days in culture the CTL response was assayed using a protocol developed by Matzinger

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Abstract

L'invention concerne des composés qui miment ou interagissent avec des caractéristiques de surface uniques du complexe CD8/MHC I, et qui sont utiles pour inhiber des réponses préjudiciables de lymphocytes T cytotoxiques.
EP00932013A 1999-05-04 2000-05-02 Conception de composes a base de structure qui inhibe reponses prejudiciables de lymphocytes t cytotoxiques Withdrawn EP1187625A1 (fr)

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US13236199P 1999-05-04 1999-05-04
US132361P 1999-05-04
US15015099P 1999-08-20 1999-08-20
US150150P 1999-08-20
US16263299P 1999-11-01 1999-11-01
US162632P 1999-11-01
PCT/US2000/011902 WO2000066146A1 (fr) 1999-05-04 2000-05-02 Conception de composes a base de structure qui inhibe reponses prejudiciables de lymphocytes t cytotoxiques

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