WO1997000084A1 - Peptides non immunogenes bloquant le complexe majeur d'histocompatibilite (cmh) - Google Patents

Peptides non immunogenes bloquant le complexe majeur d'histocompatibilite (cmh) Download PDF

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Publication number
WO1997000084A1
WO1997000084A1 PCT/US1996/010396 US9610396W WO9700084A1 WO 1997000084 A1 WO1997000084 A1 WO 1997000084A1 US 9610396 W US9610396 W US 9610396W WO 9700084 A1 WO9700084 A1 WO 9700084A1
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Prior art keywords
peptide
amino acid
acid residues
linker
group
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PCT/US1996/010396
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English (en)
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Don C. Wiley
Marlene Bouvier
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President And Fellows Of Harvard College
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Publication of WO1997000084A1 publication Critical patent/WO1997000084A1/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
    • C07K14/72—Receptors; Cell surface antigens; Cell surface determinants for hormones
    • C07K14/721—Steroid/thyroid hormone superfamily, e.g. GR, EcR, androgen receptor, oestrogen receptor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • Antigenic peptides of T cells first bind to class I or class II major histocompatibility complex (MHC) molecules before interacting with T cell receptors on CD 8+ T cells or CD 4+ T cells to elicit immune responses.
  • MHC major histocompatibility complex
  • the present invention features MHC-blocking peptides which are designed based on novel modifications of antigenic peptides capable of binding to class I or class II MHC molecules for presentation to CD 8+ or CD 4+ T cells.
  • An aspect of this invention therefore relates to a synthetic peptide that blocks the interaction of a T cell receptor on CD 8+ T cells with an MHC molecule, the peptide containing 8, 9 or 10 amino acid residues and being identical to an antigenic peptide of the T cell receptor except that (i) a linker is covalently bonded to a first amino acid residue and a second amino acid residue of the peptide to form a 20- to 200-membered ring (preferably, a 40- to 120-membered ring), and that (ii) each of the first and second amino acid residues contains a side chain with a functional group selected independently from the group consisting of an amino group, a carboxyl group, a hydroxyl group, and a sulfhydryl group.
  • the first and second amino acid residues are covalently bonded to the linker via the just-mentioned functional groups.
  • each of the first and second amino acid residues is at one of positions 3-8 (e.g., 3-7 or 4-8); if the peptide contains 9 amino acid residues, each of the first and second amino acid residues is at one of positions 4-8; and if the peptide contains 10 amino acid residues, each of the first and second amino acid
  • residues is at one of positions 4-9 (e.g., 4-8 or 5-9).
  • first and second amino acid residues are apart by 2 or 3 amino acid residues.
  • Another aspect of this invention relates to a synthetic peptide that blocks the interaction of a T cell receptor on CD 8+ T cells with an MHC molecule, the peptide containing 8, 9 or 10 amino acid residues and being identical to an antigenic peptide of the T cell receptor except that (i) one, two, or three chains (preferably, two or three chains), each 10-200 atoms (preferably, a 20-100 atoms) in length, are respectively linked via covalent bonding to one, two, or three amino acid
  • each of the one, two, or three eunino acid residues has a side chain with a
  • each of the one, two, or three chains is covalently linked to the just-mentioned functional group of each of the one, two, or three eunino acid residues. Furthermore, if the peptide contains 8 amino acid residues, each of the one, two, or three eunino acid residues is at one of positions 3-8 (e.g., 3-7 or 4-8); if the peptide contains 9 eunino acid residues, each of the one, two, or three amino acid residues is at one of positions 4-8; and if the peptide contains 10 eunino acid residues, each of the one, two, or three eunino acid residues is at one of positions 4-9 (e.g., 4-8 or 5-9). When two or three chains are attached to the peptide backbone, it is preferred that the anchor positions be apart by 2 or 3 amino acid residues.
  • a further aspect of this invention relates to a synthetic peptide that blocks the interaction of a T cell receptor on CD 4+ T cells with an MHC molecule, the peptide containing 11-18 amino acid residues and being identical to an antigenic peptide of the T cell receptor except that (i) a linker is covalently bonded to a first amino acid residue and a second amino acid residue of the peptide to form a 20- to 200-membered ring (preferably, a 40- to 120-membered ring), and that (ii) each of the first and second amino acid residues contains a side chain with a functional group selected independently from the group consisting of an eunino group, a carboxyl group, a hydroxyl group, and a sulfhydryl group.
  • the first and second amino acid residues are covalently bonded to the linker via the just-mentioned functional groups and are located at the middle portion of the peptide backbone (i.e., they are not among the three eunino acid residues at either end).
  • the first and second amino acid residues are apart by two or more amino acid
  • a synthetic peptide that blocks the interaction of a T cell receptor on CD 4+ T cells with an MHC molecule, the peptide containing 11-18 amino acid residues and being identical to an antigenic peptide of the T cell receptor except that (i) one to five chains (preferably, two to four chains), each 10-200 atoms (preferably, a 20-100 atoms) in length, are respectively linked via covalent bonding to one to five amino acid residues (preferably, two to four amino acid residues) of the peptide, and that (ii) each of the one to five eunino acid residues has a side chain with a functional group selected independently from an amino group, a carboxyl group, a hydroxyl group, and a sulfhydryl group.
  • Each of the one to five chains is covalently linked to the just-mentioned functional group of each of the one to five amino acid residues, which are located at the middle portion of the peptide backbone (i.e., they are not among the three amino acid residues at either end).
  • the anchor positions be apart by two or more amino acid residues.
  • synthetic MHC-blocking peptide is a synthetic peptide which binds specifically to a class I or class II MHC molecule in a manner similar to an antigenic peptide of that T cell receptor, but does not activate the T cells.
  • an antigenic peptide of a T cell can be either a naturally occurring peptide or a variant thereof (e.g., containing an acetylated ⁇ -amino group, an amidated ⁇ -carboxyl group, a D- and/or ⁇ - or ⁇ -amino acid residue, or any suitable organic moiety); indeed, there are only two criteria, i.e., it is a peptide and it binds to a class I or class II MHC molecule in the manner described in
  • the anchor amino acid residue to which a linker or a chain is attached via the functional group on its side chain can be either of a naturally occurring amino acid or a synthetic eunino acid (e.g., a D-amino acid, a ⁇ - amino acid, or any suitable organic moiety).
  • a naturally occurring amino acid or a synthetic eunino acid e.g., a D-amino acid, a ⁇ - amino acid, or any suitable organic moiety.
  • Examples include, but are not limited to, lysine (Lys), ornithine (Orn), glutamic acid (Glu), aspartic acid (Asp), serine (Ser), threonine (Thr), tyrosine (Tyr), and cysteine (Cys).
  • L-amino acids are intended unless indicated otherwise.
  • an anchor amino acid residue is the same as its
  • an antigenic peptide has a Lys residue at the anchor position, then there is no need to replace that Lys residue with another anchor amino acid residue.
  • the position of an anchor amino acid residue is numbered in such a manner that the N-terminal residue is designated as position 1, its neighboring amino acid position 2, and so on.
  • two anchoring amino acids are apart by two or three amino acid residues, there are two or three eunino acid residues between them.
  • nonapeptide are apart by three amino acid residues (i.e., at positions 5, 6, and 7).
  • linker examples include, but are not limited to, a terminally functionalized poly(ethylene glycol) (PEG) such as PEG dicarboxylie acid, poly(D- or L-eunino acid), polysaccharide, or polynucleotide, which are reactive at both ends.
  • PEG poly(ethylene glycol)
  • similar polymer derivatives which are reactive only at one end e.g., monomethoxy PEG, or mPEG
  • the length of a chain refers to the number of atoms that make up its backbone.
  • Fig. 1 is a FAB mass spectrum for purified Tax 300 peptide (to be described below) showing a series of peaks for [M + H] + ions. Each peak is identified by a value of n representing the number of repeating monomer unit in PEG loops.
  • Fig. 2 is gel filtration chromatograms for HLA-A2 complexed with Tax 300, Tax 400, and Tax 600 peptides (all to be described below). Each complex eluted as a single peak is identified by an arrow.
  • Fig. 3 is a FAB mass spectrum for purified HLA-A2 complexed with Tax 300 peptide showing a series of peaks for [M + H] + peptide ions (compare with spectrum shown in Fig. 1).
  • T cell receptors on CD8 + and CD4 + T cells requires the recognition of antigenic peptides bound in the groove of MHC molecules on the surface of antigen-presenting cells.
  • Antigenic peptides bind in an extended conformation to class I and class II MHC
  • class II MHC molecules bind to longer antigenic peptides. This difference in length can be ascribed to structural differences between the two binding sites and the
  • Interaction of T cell receptors with both types of MHC complexes involves amino acid residues on both the peptide and MHC molecules.
  • amino acid residues from the central portion of the peptide, where side chains are most exposed play a more crucial role in this recognition event
  • amino acid residues having side chains pointing up are found along the entire sequence.
  • references for the structures of class I MHC molecules include: Madden, D.R., Garboczi, D.N. & Wiley, D.C. (1993) Cell 75, 693-708; Bjorkman, P.J., Saper, M.A., Samraoui, B., Bennett, W.S., Strominger, J.L. & Wiley, D.C. (1987) Nature 329, 506-512; Madden, D.R., Gorga, J.C., Strominger, J.L. & Wiley, D.C. (1991) Nature 353, 321-325; Silver, M.J., Guo, H.-C, Strominger, J.L. & Wiley, D.C.
  • cyclic peptides of this invention the cyclization reaction as described in Scheme II below is useful for the synthesis of cyclic peptides on polymer supports.
  • Linear chains can also be attached to an antigenic peptide following a strategy analogous to that described in Scheme II where mPEG carboxylic acid is reacted with the deprotected side chains of the lysine residues at anchor positions.
  • the strategy in Scheme II can also be extended to include other symmetrical PEG derivatives and complementary natural and nonnatural eunino acid residues on polymer supports for more general applications. For example, the use of PEG dieunines and PEG dithiols to link carboxyl and sulfhydryl groups, respectively.
  • amino acids such as Tyr, Ser, and Thr can react with PEG-epoxide and PEG-isocyanate under basic conditions to form stable ether and urethane linkages, respectively.
  • Cys and Orn and Lys can react with PEG-epoxide and PEG-isocyanate to yield stable thioether and urea linkages, respectively.
  • the peptides of this invention can be used to treat autoimmune diseases such as rheumatoid arthritis (HLA-DR1, -DR4, -DR5 [class II]), multiple sclerosis (HLA-DR2 [class II]); dermatitis herpetiformis (HLA-DR3 [class II]); ankylosing spondylitis (HLA-B27 [class I]); Reiter's diseases (HLA-B27 [class I]); myasthenia gravis (HLA-DR3 [class II]); and insulin dependent diabetes (HLA-DR3, -DR4 [class II]).
  • MHC alleles known to be strongly linked to the above mentioned autoimmune diseases such as rheumatoid arthritis (HLA-DR1, -DR4, -DR5 [class II]), multiple sclerosis (HLA-DR2 [class II]); dermatitis herpetiformis (HLA-DR3 [class II]); ankylosing spondylitis (HLA-B27
  • peptides having the correct sequence motif for binding specifically to these alleles can be designed and synthesized in the manners described herein.
  • VLFSSIDFRI class I or from myelin basic protein
  • ENPWHFFKNIVTPR can be used to treat multiple sclerosis.
  • the peptides of this invention can also be used to reduce or prevent graft rejection.
  • Graft rejection is a consequence of T cell-dependent immune responses: T cells from the host recognizes MHC molecules of the graft organ as foreign and proceeds to destroy it. One way to minimize graft rejection is to interfere with the
  • autoreactive T cells activation of autoreactive T cells by using a peptide designed specifically to be restricted to MHC alleles of the donor.
  • the dose of a peptide of the present invention for treating an autoimmune disease or minimizing graft rejection varies depending upon the manner of
  • the peptide may be administered by any route appropriate to the condition being treated. For example, it can be injected into the bloodstre ⁇ un of the subject being treated.
  • peptides of the present invention can also be used as a tool to investigate how T cell receptors interact with class I and class II MHC
  • HTLV-1 Tax peptide (LLFGYPVYV) (Utz, U., Koenig, S., Coligan, J.E. &
  • PEG 300 (Union Carbide) (3.99 g, 13.3 mmol) was placed in a oven-dried three-necked flask, equipped with a mechanical stirrer and a dropping funnel, and dissolved in freshly distilled toluene (40 mL) under dry nitrogen (Scheme I). Gehrhardt, H. & Mutter, M. (1987) Polymer Bull. 18, 487-493. Under intermittent cooling in a ice-water bath, a 2.5 M n-butyl lithium solution in hexane (11 mL, 27.5 mmol) (Aldrich Chemical Co.) was slowly injected.
  • PEG 300 dimethyl ester (2.67 g, 6.0 mmol) was dissolved in 120 mL 1 M aqueous LiOH (120 mmol) and stirred at room temperature for 1.5 hours. The mixture was washed with DCM and the aqueous layer was acidified to pH 1 by the addition of concentrated hydrochloric acid. The aqueous solution was concentrated by
  • Cyclic peptides were synthesized manually on 4-hydroxymethylphenoxy (HMP) resin (Applied Biosysterns) using N a -9-fluorenylmethoxycarbonyl (Fmoc) eunino acids and N a -tert-butyloxycarbonyl (tBoc) eunino acid for the last residue (Scheme II). Side chains were protected with tert-butyl (tBu) groups except for lysine residues engaged in ring closure which were protected with
  • Linear Tax and Tax control peptides were synthesized on an automated synthesizer (Applied Biosystems 431A) using HMP resin and N a -Fmoc eunino acids.
  • Applied Biosystems 431A automated synthesizer
  • standard side chain protecting groups were used except for lysine residues which were protected with acetyl (Ac) groups.
  • Tax peptide Leu 1.95, Phe 1.00, Gly 0.98, Pro 0.96, Tyr 1.42, Val 1.86; and Tax control peptide: Leu 2.00, Phe 1.00, Lys 1.98, Pro 0.98, Tyr very low, Val 1.81.
  • the FAB mass spectra for Tax 400 and Tax 600 peptides showed expected series of peaks for [M + H] + ions centered around increasingly higher values of n.
  • Tax 300 peptide (1 mM) was incubated at 30°C with proline specific endopeptidase (Seikagaku Co.) at
  • Circular dichroism (CD) studies were done using a 1 mm cell on an Aviv 62DS spectropolarimeter equipped with a thermoelectric temperature controller. Thermal denaturation curves for HLA-A2 complexes (0.18 mg/mL) were obtained in triplicate by monitoring the change in CD signal at 218 nm in the range 20°C-90°C using a scan rate of 0.7 °C/min.
  • Averaged denaturation curves were fit by a nonlinear least squares analysis to determine melting temperatures. Bouvier, M. & Wiley, D.C. (1994) Science 265, 398-402.
  • cyclic peptides The key element in the design of cyclic peptides is the presence of large and floopy nonpeptidic loops favored to project out of the binding groove in such a way that the antigenic region of class I MHC complexes becomes inaccessible for recognition by T cell receptors.
  • Design was primarily guided from knowledge of the conformation of several nonamers, including the Tax peptide, bound in the groove of HLA-A2 as revealed by X-ray crystallography. Madden, D.R., Garboczi, D.N. & Wiley, D.C. (1993) Cell 75, 693-708.
  • Peptide side chains at positions 4 and 8 are generally shown pointing up and therefore ideal anchor sites for the substitution of lysine residues.
  • High molecular weight PEG dicarboxylic acids were used to covalently link the side chains of lysine residues resulting in large ring structures that include all residues predicted to contact the T cell receptor. The excellent water solubility of the
  • repeating oxyethylene group favors extension of PEG loops out of the binding site and towards T cell receptors.
  • the peptide amino and carboxyl termini and peptide anchor residues at position 2 (Leu) and position 9 (Val) have been unmodified to favor high-affinity binding and to retain specificity of interactions, respectively, between cyclic peptides and class I MHC molecules.
  • Tax peptide was synthesized on HMP resin (Scheme II) using a strategy that includes N a -Fmoc eunino acids, N a -Boc eunino acid for the last residue, and Dde
  • Fig. 1 shows a typical FAB mass spectrum for purified Tax 300 peptide revealing a series of distinct peaks corresponding to m/z for [M + H] + peptide ions. Each peak is separated by intervals of m/z 44, corresponding to the mass of the repeating oxyethylene group, and is identified by the appropriate n value.
  • HLA-A2 complexes were reconstituted from human heavy chain and b 2 m expressed in E. coll in the presence of excess cyclic peptides and purified by gel filtration chromatography (Fig. 2). Garboczi, D.N., Hung, D.T. & Wiley, D.C. (1992) Proc. Natl. Acad. Sci. USA 89,
  • spectrometry shows the expected series of peaks for [M + H] + peptide ions (compare Fig. 1 and Fig. 3) confirming the association of cyclic peptides with
  • the anchor amino acid residue of an antigenic nonapeptide of a T cell receptor on CD 8+ T cells can be at position 1, rather than position 4, 5, 6, 7, or 8.
  • peptide analogs obtained by back modification of the above-described MHC-blocking peptides e.g., replacement of at least one of the peptide bonds with -CH 2 -NH-, CH 2 -S-, or the like.

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Abstract

L'invention concerne un peptide synthétique, bloquant le complexe majeur d'histocompatibilité, identique à un peptide antigénique du récepteur des lymphocytes T, excepté que (i) un segment de liaison est lié de manière covalente à un premier reste d'acides aminés et à un second reste d'acides aminés afin de former un noyau et que (ii) chacun de ces restes d'acides aminés renferme une chaîne latérale contenant un groupe fonctionnel par l'intermédiaire duquel les restes d'acides aminés sont liés de manière covalente au segment de liaison; ou bien excepté que (i) une, deux ou trois chaînes sont liées respectivement par une liaison covalente à un, deux ou trois restes d'acides aminés du peptide, et que (ii) chacun de ces restes d'acides aminés possède une chaîne latérale contenant un groupe fonctionnel par l'intermédiaire duquel une, deux ou trois de ces chaînes sont liées de manière covalente.
PCT/US1996/010396 1995-06-16 1996-06-14 Peptides non immunogenes bloquant le complexe majeur d'histocompatibilite (cmh) WO1997000084A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999058557A2 (fr) * 1998-05-11 1999-11-18 Isis Innovation Limited Nouvelle molecule et methode diagnostique
WO2002052158A2 (fr) 2000-12-22 2002-07-04 Caterpillar, Inc. Transformateur de pression hydraulique
EP1711825A2 (fr) * 2004-01-07 2006-10-18 Ambit Biosciences Corporation Petites molecules conjuguees

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
ADVANCED DRUG DELIVERY REVIEWS, 1991, Vol. 6, SEHON, "Suppression of Antibody Responses by Conjugates of Antigens and Monomethoxypoly(ethylene Glycol)", pages 203-217. *
ANNUAL REVIEW OF IMMUNOLOGY, 1992, Vol. 10, JORGENSEN et al., "Molecular Components of T-Cell Recognition", pages 835-873. *
BIOCONJUGATE CHEMISTRY, 1995, Vol. 6, No. 2, ZALIPSKY, "Functionalized Poly (Ethylene Glycol) for Preparation of Biologically Relevant Conjugates", pages 150-165. *
JOURNAL OF BIOLOGICAL CHEMISTRY, 10 June 1977, Vol. 252, ABUCHOWSKI et al., "Alteration of Immunological Properties of Bovine Serum Albumin by Covalent Attachment of Polyethylene Glycol", pages 3578-3581. *
JOURNAL OF IMMUNOLOGY, 01 September 1987, Vol. 139, FOX et al., "Functionally Distinct Agretopic and Epitopic Sites. Analysis of the Dominant T Cell Determinant of Moth and Pigeon Cytochromes C with the Use of Synthetic Peptide Antigens", pages 1578-1588. *
PROC. NATL. ACAD. SCI. U.S.A., January 1995, Vol. 92, ROGNAN et al., "Rational Design of Nonnatural Peptides as High-Affinity Ligands for HLA-B*2705 Human Leukocyte Antigen", pages 753-757. *
PROC. NATL. ACAD. SCI. U.S.A., May 1996, Vol. 93, No. 10, BOUVIER et al., "Antigenic Peptides Containing Large PEG Loops Designed to Extend Out of the HLA-2 Binding Site Form Stable Complexes with Class I Major Histocompatibility Complex Molecules", pages 4583-4588. *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999058557A2 (fr) * 1998-05-11 1999-11-18 Isis Innovation Limited Nouvelle molecule et methode diagnostique
WO1999058557A3 (fr) * 1998-05-11 2000-02-10 Isis Innovation Nouvelle molecule et methode diagnostique
WO2002052158A2 (fr) 2000-12-22 2002-07-04 Caterpillar, Inc. Transformateur de pression hydraulique
EP1711825A2 (fr) * 2004-01-07 2006-10-18 Ambit Biosciences Corporation Petites molecules conjuguees
EP1711825A4 (fr) * 2004-01-07 2008-01-23 Ambit Biosciences Corp Petites molecules conjuguees

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