US20030166860A1 - Peptide or protein containing a C '-D loop of the CD28 receptor family - Google Patents

Peptide or protein containing a C '-D loop of the CD28 receptor family Download PDF

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US20030166860A1
US20030166860A1 US10/310,674 US31067402A US2003166860A1 US 20030166860 A1 US20030166860 A1 US 20030166860A1 US 31067402 A US31067402 A US 31067402A US 2003166860 A1 US2003166860 A1 US 2003166860A1
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peptide
mabs
loop
binding
protein
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Thomas Hunig
Fred Luhder
Thomas Hanke
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TEGERNERO GmbH
TeGenero AG
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Priority claimed from DE2001160516 external-priority patent/DE10160516A1/de
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Assigned to TEGERNERO GMBH reassignment TEGERNERO GMBH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LUHDER, FRED, HUNIG, THOMAS, HANKE, THOMAS
Publication of US20030166860A1 publication Critical patent/US20030166860A1/en
Assigned to TEGENERO AG reassignment TEGENERO AG CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: TEGENERO GMBH
Priority to US11/581,933 priority Critical patent/US20070031407A1/en
Priority to US12/578,558 priority patent/US8586386B2/en
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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
    • C07K14/70521—CD28, CD152
    • 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
    • A61P37/04—Immunostimulants

Definitions

  • the invention relates to a protein or peptide containing a partial sequence of a member of the CD28 receptor family, a nucleic acid coding for such a peptide, a plasmid containing such a nucleic acid, hybridoma cells forming monoclonal antibodies (mAbs) binding to such a peptide, mAbs obtainable from such hybridoma cells, and methods of use of the peptide and the mAbs.
  • mAbs monoclonal antibodies
  • Monoclonal antibodies are antibodies being produced by hybrid cell lines (so-called hybridomas) typically resulting from the fusion of a B cell of animal or human origin producing antibodies with a suitable myeloma tumor cell.
  • the C′-D loop of CD28 comprises the amino acids 52 to 66 of the above CD28 sequence (numbering according to FIG. 7, see also Ostrov, D. A. et al.; Science (2000), 290:816-819).
  • the term C′-D loop will in the following also comprise any partial sequences thereof.
  • a loop or a binding site arranged therein is freely accessible, if there is for a defined binding partner no steric hindrance for the binding site in the loop by the sequences or molecules outside of the loop.
  • Activation of T lymphocytes is the increase of metabolic activity, increase of the cell volume, synthesis of immunologically important molecules and initiation of the cell division (proliferation) of T lymphocytes as a response to an external stimulation. Inhibition is the opposite process. For example are such processes caused by occupation of the CD28 molecule on T cells by special CD28-specific monoclonal antibodies.
  • the activation of the T lymphocytes with the described side effects is part of the physiologic immune reaction, in pathologic situations however there may be lost control thereof (lympho-proliferative diseases), or may be insufficient (immunodeficiency).
  • Modulation of the proliferation of T cells is either the increase of the activity (for a pathologically insufficient activation) or reduction or inhibition of the activity (for pathologically lympho-proliferative diseases).
  • Several sub-groups of the T cells means at least sub-groups of CD4 and CD8 T cells expressing CD 28.
  • An analogous peptide is a peptide the amino acid sequence of which differs from that one of the peptide to which it is analogous, which binds however a defined binding partner with at least the same affinity. Deviations in the sequence may be deletions, substitutions, insertions and elongations.
  • An analogous peptide will usually comprise a tertiary (partial) structure and/or exposition being very similar to the peptide, in a (cell surface) protein, and otherwise only needs to comprise or form a binding site for the defined binding partner in the section analogous to the immediate binding section of the peptide.
  • a mimicry compound of a mAb is a natural or synthetic chemical structure behaving in a binding assay as a defined mAb mimicrying the mimicry compound.
  • a mimicry compound of a C′-D loop is a natural or synthetic chemical structure to which specifically bind mAbs being superagonistic and specific for a member of the CD28 family.
  • mAbs comprises, in addition to structures of the usual Fab/Fc constructions, also structures consisting of or comprising the Fab fragment only. It is also possible to exclusively use the variable region, the fragment of the heavy chains being connected in a suitable manner, for instance also by means of synthetic bridge molecules, with the fragment of the light chain, in such a way that the binding regions of the chains form the antibody binding site.
  • the term antibody also comprises (complete) chimeric and humanized antibodies.
  • Superagonistic modulation of the proliferation of T cells means that no costimulation, i.e. no further binding event in addition to a binding of a mAb or of a mimicry compound to a member of the CD28 family is required for the stimulation or inhibition of the proliferation.
  • a screening method comprises the use of a target, for instance a partial sequence from CD28, one or more known or unknown substances being contacted with the target and a binding event being detected or not detected.
  • a target for instance a partial sequence from CD28
  • the substance is selected.
  • a deconvolution follows a selection of the mixture for the purpose of the determination of binding components in the selected mixture.
  • CD28 family is designated a group of T cell surface receptors having an immuno-regulatory activity. This may be either stimulating, as in the case of the CD28, or inhibiting, as in the case of the CTLA-4.
  • CD28, CTLA-4, PD-1 and ICOS To the CD28 family belong CD28, CTLA-4, PD-1 and ICOS.
  • a substrate can be soluble, insoluble and/or immobilized.
  • a substrate can be formed of any natural or synthetic molecules, for instance of amino acid chains, among others.
  • a protein or a peptide in the terminology of this text needs not necessarily be a protein or a peptide according to the conventional definition.
  • a protein or peptide according to the terminology used herein is also a protein or peptide in the usual terminology.
  • the activation of resting T cells for the proliferation and functional differentiation first requires the occupation of two surface structures, so-called receptors: i.e. of the antigen receptor having a different specificity from cell to cell and being necessary for the detection of antigens, for instance viral fission products; and of the CD28 molecule expressed in an identical manner on all resting T cells with the exception of one sub-group of the human CD8 T cells, said CD28 molecule binding in to ligands on the surface of other cells.
  • This is called the costimulation of the antigen-specific immune reaction by CD28.
  • these processes can be simulated by occupying the antigen receptor and the CD28 molecule by suitable mAbs.
  • neither the occupation of the antigen receptor nor of the CD28 molecule alone will lead to the T cell proliferation, the occupation of both receptors is however effective. This observation has been made for T cells of man, mouse and rat.
  • the invention is based therefore on the technical object to provide means, by use of which superagonistic compounds can be found which bind to one or several members of the CD28 family and have an improved stimulatory or inhibiting effect, as well as to specify such compounds.
  • the invention is based on the examination of the binding regions of superagonistic mAbs at CD28 as well as the interaction found in these experiments of the C′-D loop of CD28 with superagonistic mAbs. Further, the invention is based on the finding that a corresponding binding region for superagonistic mAbs can be found in the other members of the CD28 family, namely there, too, the C′-D loops. From this basic findings, various aspects for technical teachings of the invention can be deducted.
  • the invention teaches a protein or peptide comprising the C′-D loop of a member of the CD28 family, or comprising a peptide being analogous thereto or comprising a mimicry compound thereto, not however a member of the CD28 family.
  • the essential element of a protein or peptide according to the invention is the C′-D structure (or of an analogous/mimicry substance thereto), and that irrespective of whether and which sequences follow on both sides of the loop. It is only essential that the loop structure is sufficiently exposed, in order to offer access for superagonistic mAbs or mimicry compounds and to prevent in the case of the specific binding possibility a binding not for steric reasons.
  • a peptide in particular of an oligopeptide (4 to 9 amino acids) or a polypeptide (10-100 amino acids) or of a mimicry compound thereto, it is preferred that the ends thereof are each bound to a binding position of a substrate, the binding positions of the substrate being spatially arranged with regard to each other according to the binding positions for the C′-D loop, the C′-D loop or the peptide being analogous thereto or the mimicry compound thereto being fixed in a three-dimensional configuration according to the C′-D loop, the bound C′-D loop or the peptide being analogous thereto or the mimicry compound thereto being freely accessible for antibodies or mimicry compounds thereto, and the substrate not being a member of the CD28 family without a C′-D loop.
  • a three-dimensional structure permitting a binding with superagonistic substances is provided.
  • a peptide or protein according to the invention may comprise an amino acid sequence seq.-ID 41 (human CD28 loop), not however be human CD28, seq.-ID 42 (human CTLA-4 loop), not however be human CTLA-4, seq.-ID 43 (human ICOS loop), not however be human ICOS, or seq.-ID 44 (human PD-1 loop), not however be human PD-1.
  • One or two amino acids may be added according to FIG. 7 to the 3′ end and/or the 5′ end.
  • partial sequences thereof may also be comprised in the peptides according to the invention, for instance according to the sequences seq.-ID 1 to 4, respectively.
  • the seq.-ID 5 to 10 indicate variants of the human CD28 loop.
  • the seq.-ID 12 to 17 indicate variants of the human CTLA-4 loop.
  • the seq.-ID 19 to 24 indicate variants of the human ICOS loop.
  • the seq.-ID 26 to 31 indicate variants of the human PD-1 loop.
  • One or more amino acids of the sequence 11 may be added according to FIG. 7 a to one of the sequences 1, 7 or 9.
  • One or more amino acids of the sequence 18 may be added according to FIG. 7 a to one of the sequences 2, 14 or 16.
  • One or more amino acids of the sequence 25 may be added according to FIG. 7 a to one of the sequences 3, 21 or 23.
  • One or more amino acids of the sequence 32 may be added according to FIG. 7 a to one of the sequences 4, 28 or 30.
  • sequences are sections according to the invention, to which superagonistic mAbs will specifically bind. It can in particular be seen, when comparing the sequences, that the primary structure of the loop is specific for the respective family members. By selection of the C′-D loop of a specific member and thus by application of substances having specificity for this selected loop, thus alternatively an activation or an inhibition of the proliferation can be obtained.
  • a (CD28-specific) protein or peptide according to the invention or a mimicry compound thereto can be identified by that one or more prospective proteins, peptides or mimicry compounds are subjected to a binding test with e.g. one of the mAbs 9D7 or 5.11A, and binding peptides are selected.
  • the mentioned mAbs are new superagonistic CD28-specific mAbs, which are described in detail in the experimental section hereof.
  • proteins, peptides or mimicry compounds according to the invention and being specific for the other members can be identified.
  • Such corresponding mAbs may be obtained in an analogous manner.
  • the invention further relates to a nucleic acid coding for a peptide according to the invention or for a protein comprising such a peptide, not however coding for a member of the CD28 family, and to a vector, e.g. plasmid, comprising such a nucleic acid, operably linked to a suitable promotor.
  • the peptide, protein according to the invention or a mimicry compound thereto according to the invention can be used in a method for producing mAbs which superagonistically modulate the proliferation of T cells of several to all sub-groups, a non-human mammal being immunized with the protein or peptide or the mimicry compound thereto, from the non-human mammal cells being taken, hybridoma cells being produced from the cells, and such obtained hybridoma cells being selected, the culture supernatant of which contains mAbs, which bind to the C′-D loop of the protein or peptide or the mimicry compound thereto, such hybridoma cells and mAbs obtainable with such hybridoma cells.
  • Human mAbs according to the invention can alternatively however also be produced by that B lymphocytes are selected which bind to the loop, and that their expressed immunoglobulin genes are cloned. Furthermore, human mAbs can be isolated from phage libraries. The average man skilled in the art is without any problems in a position, using his knowledge, to execute such alternative methods, so that no detailed description is needed here.
  • the invention also relates to the use of a peptide, of a protein according to the invention or of a mimicry compound thereto according to the invention in a screening method for the identification of substances superagonistically modulating the proliferation of T cells of several to all sub-groups, a prospective substance or a mixture of prospective substances being subjected to a binding assay with the peptide or protein or mimikry compound thereto, and substances binding to the peptide or protein or mimikry compound thereto being selected.
  • any conventional binding assay can be used.
  • a peptide, protein or mimicry compound thereto according to the invention as well as the mAbs or mimicry compounds thereto according to the invention have therapeutic relevance, since thereby lymphoproliferative diseases may be treated by inhibition of the proliferation, as well as immunodeficiency diseases by activation of the proliferation.
  • the induction of effector functions, e.g. secretion of effector substances, is also possible. This is achieved by selection or design of the mAb or of the mimicry compound according to a specificity and high affinity for a specific member of the CD28 family.
  • the process may be such that a second ligand in addition to the mAb or the mimicry compound with specificity for the special family member is searched, and the second ligand is linked, after an analysis of the relative spatial positions of the bound two ligands with respect to each other, by a bridging molecule with the mAb or the mimicry compound.
  • the determination of the position of two ligands with respect to each other after binding to a target can for instance be made by X-ray structure analysis or multi-dimensional NMR correlation spectroscopy, for instance 15 N/ 1 H NMR.
  • a second ligand can be determined by conventional screening methods, the special CD28 family member being used as a target.
  • the second ligand does not bind at the C′-D loop, but spaced thereto.
  • a peptide, protein or mimicry compound according to the invention thereto hot having an otherwise physiological effect competitively binds natural ligands of the members of the CD28 family, and thus creates a reverse effect by prevention of a pathologically caused natural activation or inhibition.
  • the invention relates on one hand also to the use of a peptide, protein or mimicry compound thereto according to the invention for producing a pharmaceutical composition for the modulation of the physiological T cell proliferation, wherein a such compound is optionally mixed with suitable carrier and auxiliary compounds and galenically prepared for the desired mode of administration, e.g. injection i.v or i.p.
  • the invention relates to the use of a mAb according to the invention or a mimicry compound thereto according to the invention for producing a pharmaceutical composition for the treatment of diseases with pathologically reduced CD4 T cell numbers, in particular AIDS, for producing a pharmaceutical composition for the treatment following stem cell transplantations after chemo or radio therapy of leukemic diseases, for producing a pharmaceutical composition for multiplying and/or qualitatively influencing immune reactions after vaccinations, and for producing a pharmaceutical composition for the treatment of autoimmune-inflammatory diseases.
  • Mixing and galenic preparation is performed in an according manner.
  • the invention finally relates to therapeutic methods, wherein to a person suffering from a proliferative or immunodeficient disease, a pharmaceutical composition according to the invention is administered.
  • FIG. 1 stimulation of T lymphocytes from the rat with various CD28-specific mAbs (a: costimulation, b: superagonistic, i.e. direct stimulation),
  • FIG. 2 a sequence comparison between mouse, rat and human CD28 in the section of the C′-D loop (in box),
  • FIG. 3 experimental results for the localization of the binding site of superagonistic mAbs at the CD28 molecule of the rat
  • FIG. 4 binding of various human CD28-specific mAbs to CD28 (a) and costimulatory (b) and superagonistic, i.e. directly stimulatory (c) activity of the mAbs of FIG. 4 a,
  • FIG. 5 binding tests that show that human CD28-specific superagonistic mAbs specifically bind to the C′-D loop
  • FIG. 6 a three-dimensional representation of CD28 with marking of the C′-D loop
  • FIG. 7 sequence alignment under emphasis of the C′-D loop or analogous structures, for various members of the CD28 family,
  • FIG. 8 experiments for the activation of cells by means of human CD28-specific mAbs and mutated mouse CD28 molecules
  • FIG. 9 representation of the sequences seq.-ID 33-40 ( a - h ), and
  • FIG. 1 shows the stimulation of freshly isolated T lymphocytes from the rat in the form of a 3H thymidine incorporation.
  • the approach corresponds to the one described in document WO98/54225, to which reference to a full extent is made here and in the following, and the scope of disclosure of which is hereby incorporated in the present text.
  • TCR T cell receptors
  • CD28-specific mAbs All the different CD28-specific mAbs used are shown. This series of various CD28-specific mAbs originate from an approach of the immunization and production of hybridoma cell lines described in WO98/54225 already. These are culture supernatants containing sufficient CD28-specific mAbs for a saturating binding to the 2 ⁇ 10 cultivated cells. From FIG. 1 a can be taken that all of these mAbs are able to activate in a costimulating manner, i.e. to induce in presence of the anti-TCR mAbs the thymidine incorporation. In FIG. 1 b is shown the stimulation in absence of TCR specific mAbs. This experiment has also been performed as described in document WO98/54225. It can be seen that only two mAbs are capable to stimulate the T lymphocytes in absence of a TCR signal. These mAbs have thus superagonistic activity.
  • CD28-specific mAbs bind to different sections of the CD28 molecule.
  • the mAbs were produced by immunization of mice with CD28 from the rat; as expected, they all do not react with mouse CD28 (not shown). Since the mAbs can thus only recognize such sections of the rat CD28 molecule which differ from that of the mouse, first a sequence comparison between CD28 from the mouse and the rat was performed (see FIG. 2, upper part). The differences between the two species are highlighted. For the designation of the amino acids, the one-letter code was used. As prototypes for a conventional rat CD28-specific mAb was used JJ319, for a superagonistic mAb JJ316 (see WO98/54225).
  • FIG. 3 the mapping of the binding region is shown.
  • Expression plasmids were constructed, wherein one part of the extracellular domain of CD28 originates from the mouse, another one from the rat. This is shown by bars or lines, respectively; on the right-hand side thereof the binding of the mAbs JJ316 and JJ319 to mouse fibroblasts (L929 cells) is represented, which have been transfected with these expression plasmids.
  • the binding of both antibodies to the “right-hand” half of the sequence is mapped: Both will bind if this originates from the rat.
  • mice [0054] The next figures deal with superagonistic human-specific mAb. These have also been produced in mice, thus do not react with the CD28 molecule of the mouse.
  • the mice were immunized with human CD28-transfected A20/J mouse B lymphoma cells (see WO98/54225) and additionally boostered prior to the fusion with commercially available human CD28-Fc fusion protein (bought from R and D Systems) .
  • human CD28-specific mAbs binding to mouse L929 cells expressing human CD28, not however to untransfected L929 cells
  • FIG. 4 a shows that the used preparations of the three new mAbs bind comparatively well and also with comparable titer to human T lymphocytes.
  • An experiment is shown, wherein freshly isolated mononuclear cells from the human blood (so-called PBMC) were first treated with different dilution steps of the used mAbs on ice; then they were washed, and the bound mAb was made visible by a secondary antibody marked by a fluorescence dye, said secondary antibody specifically detecting the bound mouse mAbs.
  • PBMC mononuclear cells from the human blood
  • the binding of the titrated mAbs could be determined by electronic gating selectively for the CD4 T lymphocytes.
  • MFI is given the average fluorescence intensity being a measure for the amount of the bound CD28-specific mAb.
  • concentrations represent 3-fold dilutions of a standardized original preparation. It is fully normal that in this test the highest concentration gives a weaker signal than the following titration steps; this has to do with the avidity (bivalent binding) of mAbs and does not play any role in the context discussed here.
  • FIG. 4 b and c the capability of these three new CD28-specific mAbs to stimulate—in presence and absence of a TCR signal—freshly isolated human T cells to growth is compared. Again, a 3H thymidine incorporation is shown, as described above for the rat.
  • FIG. 4 b the wells were coated with a mAb which reacts with the human TCR/CD3 complex. Thus, the costimulation was measured. It can be seen that the proliferation without costimulation with one the mAbs fails to appear (negative control), all three antibodies are however capable to stimulate the cell division.
  • FIG. 4 c the absence of a TCR/CD3-specific mAb was selected. Only the antibodies 9D7 and 5.11A could stimulate in a superagonistic way.
  • FIG. 6 In FIG. 6 is shown a three-dimensional model of the CD28 molecule. The newly identified binding region is highlighted. It corresponds to the sequence in the box in FIG. 2. Concerning its structure, the extracellular domain of CD28 belongs to the so-called immunoglobulin super family being characterized by two superimposed 8 sheets as a basic structure. The labeling of these bands follows a pattern as given in the literature. It is important for the representation shown here that the region identified as an epitope for superagonistic CD28-specific mAbs in rat and mouse is described by “C′-D loop”.
  • mAbs having specificity for the C′-D loop of the CD28 molecule show superagonistic activity, thus can be used for the activation of T lymphocytes in the meaning of the document WO98/54225.
  • the superagonistic activity of C′-D loop-specific mAbs in rat and man shows that therein not the sequence of the epitope, but its position or shape is important.
  • CD28 belongs to a family of cell surface receptors with immuno-regulatory activity. This is either stimulating (CD28, ICOS) or inhibiting (CTLA-4, PD-1).
  • FIG. 7 the sequences of the known members of the CD28 family are shown in the sense of an “alignment”. The C′-D loop for CD28 is highlighted. Analogous loops of the other molecules (in box) are a correspondingly favorable target structure for the development of superagonistic ligands. It should be noted, with regard to FIG. 7, that “ ⁇ ” is a gap in the alignment, i.e. the amino acids following thereto are immediately connected to each other.
  • FIG. 8 shows first that without stimulation there is no IL-2 production (negative control).
  • FIG. 8 a shows the results when using the superagonistic mAb JJ316 of the rat
  • FIG. 8 b shows the results for the human C′-D loop-specific mAb 5.11A.
  • the respective cell lines are stimulated for the IL-2 production.
  • there is however no stimulation by “conventional” CD28-specific mAbs since these do not only not bind to the C′-D loop, but cannot detect the construct at all, because they are specific for rat or human-specific sequences not contained in the construct.
  • FIG. 9 a is shown the nucleic acid sequence of the variable region of the light chain of a mAb 9D7 according to the invention (seq.-ID 33).
  • FIG. 9 b shows the peptide coded thereby (seq.-ID 34).
  • FIG. 9 c shows the nucleic acid sequence of the variable region of the heavy chain of this mAb (seq.-ID 35).
  • FIG. 9 d is the peptide coded thereby (seq.-ID 36).
  • FIG. 9 e is represented the nucleic acid sequence of the variable region of the heavy chain of a mAb 5.11A according to the invention (seq.-ID 37).
  • FIG. 9 f shows the peptide coded thereby (seq.-ID 38).
  • FIG. 9 g shows the nucleic acid sequence of the variable region of the light chain of this mAb (seq.-ID 39).
  • FIG. 9 h shows the peptide coded thereby (seq.-ID 40).
  • FIG. 10 shows the humanized variable domain of the mAb 5.11A.
  • FIG. 10 a is the light chain
  • FIG. 10 b the heavy chain.

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US10/310,674 2001-12-04 2002-12-04 Peptide or protein containing a C '-D loop of the CD28 receptor family Abandoned US20030166860A1 (en)

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US11/581,933 US20070031407A1 (en) 2001-12-04 2006-10-17 Peptide or protein containing a C'-D loop of the CD28 receptor family
US12/578,558 US8586386B2 (en) 2001-12-04 2009-10-13 Peptide or protein comprising a C′-D loop of the CD28 receptor family

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DE10160516 2001-12-04
DE2001160516 DE10160516A1 (de) 2001-12-04 2001-12-04 Peptid oder Protein enthaltend ein C'-D Loop der CD28 Rezeptorfamilie
DE10200714 2002-01-10
DE10200714 2002-01-10

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US20040092718A1 (en) * 2002-03-13 2004-05-13 Thomas Hunig Use of a CD28 binding substance for making a pharmaceutical composition
US20060009382A1 (en) * 2003-09-22 2006-01-12 Thomas Hanke Use of a CD28 binding pharmaceutical substance for making a pharmaceutical composition with dose-dependent effect
US20060286104A1 (en) * 2005-05-11 2006-12-21 Tegenero Ag Superagonistic anti-CD28 antibodies
US20080044837A1 (en) * 2004-01-09 2008-02-21 Simon Davis Receptor Modulators
US20090104190A1 (en) * 2003-03-21 2009-04-23 John Wijdenes Humanized anti-cd4 antibody with immunosuppressive properties
US20110059082A1 (en) * 2008-03-13 2011-03-10 Matthias Germer Agent for treating disease
US20110059084A1 (en) * 2008-03-13 2011-03-10 Frank Osterroth Agent for treating disease
US20110059083A1 (en) * 2008-03-13 2011-03-10 Silke Aigner Agent for treating disease
US20110229465A1 (en) * 2008-09-29 2011-09-22 Frank Osterroth Composition for treating disease
US9995733B2 (en) 2009-11-30 2018-06-12 Biotest Ag Agents for treating disease
CN109195990A (zh) * 2016-03-30 2019-01-11 Musc研究发展基金会 通过靶向糖蛋白a重复优势蛋白(garp)治疗和诊断癌症以及单独或联合提供有效免疫疗法的方法

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EP2886645A1 (fr) * 2013-12-20 2015-06-24 Julius-Maximilians-Universität Würzburg Expansion de lymphocytes T humains in vitro par des anticorps monoclonaux anti-CD28 classiques liés à une bille
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WO2017079656A2 (fr) * 2015-11-04 2017-05-11 The Trustees Of The University Of Pennsylvania Protéines artificielles et compositions et méthodes associées
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US8586386B2 (en) 2013-11-19
EP1451224A2 (fr) 2004-09-01
AU2002357427A1 (en) 2003-06-17
EP1451224B1 (fr) 2012-08-15
PT1451224E (pt) 2012-10-09
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US20070031407A1 (en) 2007-02-08
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