Immunotherapy against several tumors including lung cancer

Abstract

A method of treating a patient who has glioblastoma and/or gastric cancer includes administering to said patient a composition containing a population of activated T cells that selectively recognize cells in the patient that aberrantly express a peptide. A pharmaceutical composition contains activated T cells that selectively recognize cells in a patient that aberrantly express a peptide, and a pharmaceutically acceptable carrier, in which the T cells bind to the peptide in a complex with an MHC class I molecule, and the composition is for treating the patient who has glioblastoma and/or gastric cancer. A method of treating a patient who has glioblastoma and/or gastric cancer includes administering to said patient a composition comprising a peptide in the form of a pharmaceutically acceptable salt, thereby inducing a T-cell response to the glioblastoma and/or gastric cancer.

Claims

1. A peptide consisting of the amino acid sequence SLYKGLLSV (SEQ ID NO: 56) in the form of a pharmaceutically acceptable salt.

2. The peptide of claim 1, wherein said peptide has the ability to bind to an MHC class-I molecule, and wherein said peptide, when bound to said MHC, is capable of being recognized by CD8 T cells.

3. The peptide of claim 1, wherein the pharmaceutically acceptable salt is chloride salt.

4. The peptide of claim 1, wherein the pharmaceutically acceptable salt is acetate salt.

5. A composition comprising the peptide of claim 1, wherein the composition comprises an adjuvant and a pharmaceutically acceptable carrier.

6. The composition of claim 5, wherein the peptide is in the form of a chloride salt.

7. The composition of claim 5, wherein the peptide is in the form of an acetate salt.

8. The composition of claim 5 wherein the adjuvant is selected from the group consisting of anti-CD40 antibody, imiquimod, resiquimod, GM-CSF, cyclophosphamide, sunitinib, bevacizumab, interferon-alpha, interferon-beta, CpG oligonucleotides and derivatives, poly-(I:C) and derivatives, RNA, sildenafil, particulate formulations with poly(lactide co-glycolide) (PLG), virosomes, interleukin (IL)-1, IL-2, IL-4, IL-7, IL-12, IL-13, IL-15, IL-21, and IL-23.

9. The composition of claim 8, wherein the adjuvant is IL-2.

10. The composition of claim 8, wherein the adjuvant is IL-7.

11. The composition of claim 8, wherein the adjuvant is IL-12.

12. The composition of claim 8, wherein the adjuvant is IL-15.

13. The composition of claim 8, wherein the adjuvant is IL-21.

14. The peptide in the form of a pharmaceutically acceptable salt of claim 1, wherein said peptide is produced by solid phase peptide synthesis or produced by a yeast cell or bacterial cell expression system.

15. A composition comprising the peptide of claim 1, wherein the composition is a pharmaceutical composition and comprises water and a buffer.

16. The composition of claim 8, wherein the adjuvant is IL-1.

17. The composition of claim 8, wherein the adjuvant is IL-4.

18. The composition of claim 8, wherein the adjuvant is IL-13.

19. The composition of claim 8, wherein the adjuvant is IL-23.

20. The peptide of claim 1, wherein the pharmaceutically acceptable salt is trifluoro-acetate salt.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIGS. 1A through 1D: FIG. 1A) Exemplary mass spectrum from ABCA13-001 demonstrating its presentation on primary tumor sample NSCLC898. NanoESI-LCMS was performed on a peptide pool eluted from the NSCLC sample 898. The mass chromatogram for m/z 543.8318±0.001 Da, z=2 shows a peptide peak at the retention time 86.36 min. FIG. 1B) The detected peak in the mass chromatogram at 86.36 min revealed a signal of m/z 543.8318 in the MS spectrum. FIG. 1C) A collisionally induced decay mass spectrum from the selected precursor m/z 543.8318 recorded in the nanoESI-LCMS experiment at the given retention time confirmed the presence of ABCA13-001 in the NSCLC898 tumor sample. FIG. 1D) The fragmentation pattern of the synthetic ABCA13-001 reference peptide was recorded and compared to the generated natural TUMAP fragmentation pattern shown in FIG. 1C for sequence verification.

(2) FIGS. 2A and 2B: Expression profiles of mRNA of selected proteins in normal tissues and in 21 lung cancer samples

(3) FIG. 2A) ABCA13 (Probeset ID: 1553605_a_at)

(4) FIG. 2B) MMP12 (Probeset ID: 204580_at)

(5) FIGS. 3A through 3C: Presentation profiles for selected HLA class I peptides. A presentation profile was calculated for each peptide showing the mean sample presentation as well as replicate variations. The profile juxtaposes samples of the tumor entity of interest to a baseline of normal tissue samples.

(6) FIG. 3A) ABCA13-001

(7) FIG. 3B) DST-001

(8) FIG. 3C) MXRA5-001

(9) FIG. 4: Exemplary results of peptide-specific in vitro immunogenicity of class I TUMAPs. Specific CD8+ T cells were stained with HLA multimers linked to two different fluorochromes. Dot plots show the MHC multimer-double-positive populations for the stimulating peptide (left panels) and the respective negative control stimulation (right panels).

(10) FIG. 5: Binding properties of POSTN-002 and MMP12-002 to the investigated HLA haplotypes: The diagram shows the binding scores of POSTN-002 and MMP12-002 to 5 of the 7 analyzed HLA-DR haplotypes.

(11) FIG. 6: Stability of HLA-POSTN-002 and MMP12-002 complexes after 24 h at 37° C.: The diagram shows the percentage of intact HLA-POSTN-002 and HLA-MMP12-002 complexes after 24 h at 37° C. with a corresponding HLA molecule.

(12) FIG. 7: Exemplary vaccine-induced CD4 T-cell response to CEA-006 in class II ICS assay. Following in vitro sensitization PBMCs of patient 36-031 were analyzed for CD4 T-cell responses to CEA-006 (upper panel) and mock (lower panel) at time point pool V8/EOS. Cells were stimulated with corresponding peptides and stained with viability, anti-CD3, anti-CD8, anti-CD4 and effector markers (from right to left: CD154, TNF-alpha, IFN-gamma, IL-2, IL-10), respectively. Viable CD4 T cells were analyzed for the proportion of cells positive for one or more effector molecules.

(13) FIG. 8: Immunogenicity of various class II peptides: The diagram shows the immune response rate to 5 various class II peptides detected in 16 patients for IMA950 peptides and in 71 patients for IMA910 peptides using ICS.

EXAMPLES

Example 1

(14) Identification and Quantitation of Tumor Associated Peptides Presented on the Cell Surface

(15) Tissue Samples

(16) Patients' tumor tissues were provided by University of Heidelberg, Heidelberg, Germany. Written informed consents of all patients had been given before surgery. Tissues were shock-frozen in liquid nitrogen immediately after surgery and stored until isolation of TUMAPs at −80° C.

(17) Isolation of HLA Peptides from Tissue Samples

(18) HLA peptide pools from shock-frozen tissue samples were obtained by immune precipitation from solid tissues according to a slightly modified protocol (Falk, K., 1991; Seeger, F. H. T., 1999) using the HLA-A*02-specific antibody BB7.2, the HLA-A, -B, -C-specific antibody W6/32, CNBr-activated sepharose, acid treatment, and ultrafiltration.

(19) Methods

(20) The HLA peptide pools as obtained were separated according to their hydrophobicity by reversed-phase chromatography (Acquity UPLC system, Waters) and the eluting peptides were analyzed in an LTQ-Orbitrap hybrid mass spectrometer (ThermoElectron) equipped with an ESI source. Peptide pools were loaded directly onto the analytical fused-silica micro-capillary column (75 μm i.d.×250 mm) packed with 1.7 μm C18 reversed-phase material (Waters) applying a flow rate of 400 nL per minute. Subsequently, the peptides were separated using a two-step 180 minute-binary gradient from 10% to 33% B at a flow rate of 300 nL per minute. The gradient was composed of Solvent A (0.1% formic acid in water) and solvent B (0.1% formic acid in acetonitrile). A gold coated glass capillary (PicoTip, New Objective) was used for introduction into the nanoESI source. The LTQ-Orbitrap mass spectrometer was operated in the data-dependent mode using a TOPS strategy. In brief, a scan cycle was initiated with a full scan of high mass accuracy in the orbitrap (R=30 000), which was followed by MS/MS scans also in the orbitrap (R=7500) on the 5 most abundant precursor ions with dynamic exclusion of previously selected ions. Tandem mass spectra were interpreted by SEQUEST and additional manual control. The identified peptide sequence was assured by comparison of the generated natural peptide fragmentation pattern with the fragmentation pattern of a synthetic sequence-identical reference peptide. FIGS. 1A through 1D show an exemplary spectrum obtained from tumor tissue for the MHC class I associated peptide ABCA13-001 and its elution profile on the UPLC system.

(21) Label-free relative LC-MS quantitation was performed by ion counting i.e. by extraction and analysis of LC-MS features (Mueller et al. 2007a). The method assumes that the peptide's LC-MS signal area correlates with its abundance in the sample. Extracted features were further processed by charge state deconvolution and retention time alignment (Mueller et al. 2007b; Sturm et al. 2008). Finally, all LC-MS features were cross-referenced with the sequence identification results to combine quantitative data of different samples and tissues to peptide presentation profiles. The quantitative data were normalized in a two-tier fashion according to central tendency to account for variation within technical and biological replicates. Thus each identified peptide can be associated with quantitative data allowing relative quantification between samples and tissues. In addition, all quantitative data acquired for peptide candidates was inspected manually to assure data consistency and to verify the accuracy of the automated analysis. For each peptide a presentation profile was calculated showing the mean sample presentation as well as replicate variations. The profile juxtaposes NSCLC samples to a baseline of normal tissue samples.

(22) Presentation profiles of exemplary over-presented peptides are shown in FIGS. 3A through 3C.

Example 2

(23) Expression Profiling of Genes Encoding the Peptides of the Invention

(24) Not all peptides identified as being presented on the surface of tumor cells by MHC molecules are suitable for immunotherapy, because the majority of these peptides are derived from normal cellular proteins expressed by many cell types. Only few of these peptides are tumor-associated and likely able to induce T cells with a high specificity of recognition for the tumor from which they were derived. In order to identify such peptides and minimize the risk for autoimmunity induced by vaccination the inventors focused on those peptides that are derived from proteins that are over-expressed on tumor cells compared to the majority of normal tissues.

(25) The ideal peptide will be derived from a protein that is unique to the tumor and not present in any other tissue. To identify peptides that are derived from genes with an expression profile similar to the ideal one the identified peptides were assigned to the proteins and genes, respectively, from which they were derived and expression profiles of these genes were generated.

(26) RNA Sources and Preparation

(27) Surgically removed tissue specimens were provided by University of Heidelberg, Heidelberg, Germany (see Example 1) after written informed consent had been obtained from each patient. Tumor tissue specimens were snap-frozen in liquid nitrogen immediately after surgery and later homogenized with mortar and pestle under liquid nitrogen. Total RNA was prepared from these samples using TRI Reagent (Ambion, Darmstadt, Germany) followed by a cleanup with RNeasy (QIAGEN, Hilden, Germany); both methods were performed according to the manufacturer's protocol.

(28) Total RNA from healthy human tissues was obtained commercially (Ambion, Huntingdon, UK; Clontech, Heidelberg, Germany; Stratagene, Amsterdam, Netherlands; BioChain, Hayward, Calif., USA). The RNA from several individuals (between 2 and 123 individuals) was mixed such that RNA from each individual was equally weighted.

(29) Quality and quantity of all RNA samples were assessed on an Agilent 2100 Bioanalyzer (Agilent, Waldbronn, Germany) using the RNA 6000 Pico LabChip Kit (Agilent).

(30) Microarray Experiments

(31) Gene expression analysis of all tumor and normal tissue RNA samples was performed by Affymetrix Human Genome (HG) U133A or HG-U133 Plus 2.0 oligonucleotide microarrays (Affymetrix, Santa Clara, Calif., USA). All steps were carried out according to the Affymetrix manual. Briefly, double-stranded cDNA was synthesized from 5-8 μg of total RNA, using SuperScript RTII (Invitrogen) and the oligo-dT-T7 primer (MWG Biotech, Ebersberg, Germany) as described in the manual. In vitro transcription was performed with the BioArray High Yield RNA Transcript Labelling Kit (ENZO Diagnostics, Inc., Farmingdale, N.Y., USA) for the U133A arrays or with the GeneChip IVT Labelling Kit (Affymetrix) for the U133 Plus 2.0 arrays, followed by cRNA fragmentation, hybridization, and staining with streptavidin-phycoerythrin and biotinylated anti-streptavidin antibody (Molecular Probes, Leiden, Netherlands). Images were scanned with the Agilent 2500A GeneArray Scanner (U133A) or the Affymetrix Gene-Chip Scanner 3000 (U133 Plus 2.0), and data were analyzed with the GCOS software (Affymetrix), using default settings for all parameters. For normalisation, 100 housekeeping genes provided by Affymetrix were used. Relative expression values were calculated from the signal log ratios given by the software and the normal kidney sample was arbitrarily set to 1.0.

(32) Exemplary expression profiles of source genes of the present invention that are highly over-expressed or exclusively expressed in non-small-cell lung carcinoma are shown in FIGS. 2A and 2B.

Example 4

(33) In Vitro Immunogenicity for NSCLC MHC Class I Presented Peptides

(34) In order to obtain information regarding the immunogenicity of the TUMAPs of the present invention, we performed investigations using an in vitro T-cell priming assay based on repeated stimulations of CD8+ T cells with artificial antigen presenting cells (aAPCs) loaded with peptide/MHC complexes and anti-CD28 antibody. This way we could show immunogenicity for 9 HLA-A*0201 restricted TUMAPs of the invention so far, demonstrating that these peptides are T-cell epitopes against which CD8+ precursor T cells exist in humans (Table 4).

(35) In Vitro Priming of CD8+ T Cells

(36) In order to perform in vitro stimulations by artificial antigen presenting cells loaded with peptide-MHC complex (pMHC) and anti-CD28 antibody, we first isolated CD8+ T cells from fresh HLA-A*02 leukapheresis products via positive selection using CD8 microbeads (Miltenyi Biotec, Bergisch-Gladbach, Germany) of healthy donors obtained from the Transfusion Medicine Tuebingen, Germany, after informed consent.

(37) Isolated CD8+ lymphocytes or PBMCs were incubated until use in T-cell medium (TCM) consisting of RPMI-Glutamax (Invitrogen, Karlsruhe, Germany) supplemented with 10% heat inactivated human AB serum (PAN-Biotech, Aidenbach, Germany), 100 U/ml Penicillin/100 μg/ml Streptomycin (Cambrex, Cologne, Germany), 1 mM sodium pyruvate (CC Pro, Oberdorla, Germany), 20 μg/ml Gentamycin (Cambrex). 2.5 ng/ml IL-7 (PromoCell, Heidelberg, Germany) and 10 U/ml IL-2 (Novartis Pharma, Nurnberg, Germany) were also added to the TCM at this step.

(38) Generation of pMHC/anti-CD28 coated beads, T-cell stimulations and readout was performed in a highly defined in vitro system using four different pMHC molecules per stimulation condition and 8 different pMHC molecules per readout condition.

(39) All pMHC complexes used for aAPC loading and cytometric readout were derived from UV-induced MHC ligand exchange (Rodenko et al., 2006) with minor modifications. In order to determine the amount of pMHC monomer obtained by exchange we performed streptavidin-based sandwich ELISAs according to (Rodenko et al., 2006).

(40) The purified co-stimulatory mouse IgG2a anti human CD28 Ab 9.3 (Jung et al., 1987) was chemically biotinylated using Sulfo-N-hydroxysuccinimidobiotin as recommended by the manufacturer (Perbio, Bonn, Germany). Beads used were 5.6 μm diameter streptavidin coated polystyrene particles (Bangs Laboratories, Illinois, USA).

(41) pMHC used for positive and negative control stimulations were A*0201/MLA-001 (peptide ELAGIGILTV from modified Melan-A/MART-1) and A*0201/DDX5-001 (YLLPAIVHI from DDX5), respectively.

(42) 800.000 beads/200 μl were coated in 96-well plates in the presence of 4×12.5 ng different biotin-pMHC, washed and 600 ng biotin anti-CD28 were added subsequently in a volume of 200 μl. Stimulations were initiated in 96-well plates by co-incubating 1×10.sup.6 CD8+ T cells with 2×10.sup.5 washed coated beads in 200 μl TCM supplemented with 5 ng/ml IL-12 (PromoCell) for 3-4 days at 37° C. Half of the medium was then exchanged by fresh TCM supplemented with 80 U/ml IL-2 and incubating was continued for 3-4 days at 37° C. This stimulation cycle was performed for a total of three times. For the pMHC multimer readout using 8 different pMHC molecules per condition, a two-dimensional combinatorial coding approach was used as previously described (Andersen et al., 2012) with minor modifications encompassing coupling to 5 different fluorochromes. Finally, multimeric analyses were performed by staining the cells with Live/dead near IR dye (Invitrogen, Karlsruhe, Germany), CD8-FITC antibody clone SK1 (BD, Heidelberg, Germany) and fluorescent pMHC multimers. For analysis, a BD LSRII SORP cytometer equipped with appropriate lasers and filters was used. Peptide specific cells were calculated as percentage of total CD8+ cells. Evaluation of multimeric analysis was done using the FlowJo software (Tree Star, Oreg., USA). In vitro priming of specific multimer+ CD8+ lymphocytes was detected by by comparing to negative control stimulations. Immunogenicity for a given antigen was detected if at least one evaluable in vitro stimulated well of one healthy donor was found to contain a specific CD8+ T-cell line after in vitro stimulation (i.e. this well contained at least 1% of specific multimer+ among CD8+ T-cells and the percentage of specific multimer+ cells was at least 10× the median of the negative control stimulations).

(43) In Vitro Immunogenicity for NSCLC Peptides

(44) For tested HLA class I peptides, in vitro immunogenicity could be demonstrated by generation of peptide specific T-cell lines. Exemplary flow cytometry results after TUMAP-specific multimer staining for two peptides of the invention are shown in FIG. 4 together with corresponding negative controls. Results for 25 peptides from the invention are summarized in Table 5.

(45) TABLE-US-00010 TABLE 5 In vitro immunogenicity of HLA class I peptides of the invention Exemplary results of in vitro immunogenicity experiments conducted by the applicant for the peptides of the invention. <20% = +; 20%-49% = ++; 50%-70% = +++; and >70% = ++++ SEQ ID NO: Wells Donors 1 + ++ 2 + ++ 3 + ++ 4 + ++ 7 ++ ++++ 8 + ++ 9 + + 10 + ++ 11 ++ ++++ (100%) 15 ++ ++ 16 + ++ 19 + ++ 18 + +++ 21 ++ ++ 22 + +++ 24 + ++ 30 + ++ 31 + +++ 32 + +++ 33 + +++ 35 + ++ 37 + ++++ (100%) 38 + ++ 39 + ++ 40 + ++ 42 ++ ++++ (100%) 43 + +++ 44 + ++ 45 + + 46 + +++ 47 + ++ 48 + + 52 + + 53 ++ ++ 54 + ++ 55 + ++ 56 ++ ++++ (100%) 62 ++ ++++ 57 + ++ 59 + +++ 60 +++ ++++ (100%) 61 + +++ 63 + ++ 64 + +++ 65 ++ +++ 66 + +++ 67 + ++ 68 + + 69 ++ +++ 70 + +++ 71 + +++ 72 + +++ 73 + ++ 74 + +++ 75 + ++ 78 ++ ++ 79 + ++++ 80 + ++ 81 + ++ 85 ++ ++++ 86 + ++ 87 + +++ 88 + ++ 92 + ++

Example 5

(46) Syntheses of Peptides

(47) All peptides were synthesized using standard and well-established solid phase peptide synthesis using the Fmoc-strategy. After purification by preparative RP-HPLC, ion-exchange procedure was performed to incorporate physiological compatible counter ions (for example trifluoro-acetate, acetate, ammonium or chloride).

(48) Identity and purity of each individual peptide have been determined by mass spectrometry and analytical RP-HPLC. After ion-exchange procedure the peptides were obtained as white to off-white lyophilizates in purities of 90% to 99.7%.

(49) All TUMAPs are preferably administered as trifluoro-acetate salts or acetate salts, other salt-forms are also possible. For the measurements of example 4, trifluoro-acetate salts of the peptides were used.

Example 6

(50) UV-Ligand Exchange

(51) Candidate peptides for the vaccines according to the present invention were further tested for immunogenicity by in vitro priming assays. The individual peptide-MHC complexes required for these assays were produced by UV-ligand exchange, where a UV-sensitive peptide is cleaved upon UV-irradiation, and exchanged with the peptide of interest as analyzed. Only peptide candidates that can effectively bind and stabilize the peptide-receptive MHC molecules prevent dissociation of the MHC complexes. To determine the yield of the exchange reaction, an ELISA was performed based on the detection of the light chain (β2m) of stabilized MHC complexes. The assay was performed as generally described in Rodenko et al. (Rodenko B, Toebes M, Hadrup S R, van Esch W J, Molenaar A M, Schumacher T N, Ovaa H. Generation of peptide-MHC class I complexes through UV-mediated ligand exchange. Nat Protoc. 2006; 1(3):1120-32.).

(52) 96 well MAXISorp plates (NUNC) were coated over night with 2 ug/ml streptavidin in PBS at room temperature, washed 4× and blocked for 30 min at 37° C. in 2% BSA containing blocking buffer. Refolded HLA-A*0201/MLA-001 monomers served as standards, covering the range of 8-500 ng/ml. Peptide-MHC monomers of the UV-exchange reaction were diluted 100 fold in blocking buffer. Samples were incubated for 1 h at 37° C., washed four times, incubated with 2 ug/ml HRP conjugated anti-β2m for 1 h at 37° C., washed again and detected with TMB solution that is stopped with NH.sub.2SO.sub.4. Absorption was measured at 450 nm.

(53) TABLE-US-00011 TABLE 6 UV-Ligand exchange SEQ ID Average exchange NO. Peptide name yield in % Exchange yield 81 ANKS1A-001 78 ++++ 87 AURKB-001 54 +++ 85 BUB1B-001 59 +++ 48 SNRNP20-001 54 +++ 80 CEP192-001 56 +++ 90 COG4-001 57 +++ 89 IFT81-001 57 +++ 83 MDN1-001 67 +++ 82 CEP250-002 70 +++ 91 NCBP1-001 65 +++ 92 NEFH-001 50 ++ 84 OLFM1-001 48 ++ 86 PI4KA-001 51 +++ 11 SLC3A2-001 56 +++ 78 SLI-001 47 ++ 79 TLX3-001 70 +++ 2 MMP12-003 57 +++ 68 FAP-003 31 ++ 66 IGF2BP3-001 46 ++ 4 DST-001 50 ++ 5 MXRA5-001 57 +++ 31 GFPT2-001 43 ++ 1 ABCA13-001 93 ++++ 6 DST-002 59 +++ 40 MXRA5-002 56 +++ 49 SAMSN1-001 47 ++ 8 HNRNPH-001 26 ++ 69 WNT5A-001 37 ++ 15 IL8-001 41 ++ 50 STAT2-001 69 +++ 72 ADAM8-001 67 +++ 73 COL6A3-002 81 ++++ 18 VCAN-001 41 ++ 12 SMYD3-001 50 ++ 3 ABCA13-002 36 ++ 35 BNC1-001 43 ++ 7 CDK4-001 45 ++ 19 DROSHA-001 68 +++ 33 GALNT2-001 73 ++++ 13 AKR-001 13 + 39 LAMC2-001 61 +++ 56 RAD54B-001 48 ++ 24 COL12A1-002 55 +++ 43 CSE1-001 55 +++ 45 SEC61G-001 18 + 47 PCNXL3-001 87 ++++ 9 TANC2-001 71 ++++ 70 TPX2-001 56 +++ 17 HUWE1-001 45 ++ 54 TACC3-001 54 +++ 32 CERC-001 62 +++ 26 SERPINB3-001 47 ++ 58 CCNA2-001 54 +++ 44 DPYSL4-001 77 ++++ 27 KIF26B-001 68 +++ 51 CNOT1-001 57 +++ 11 SLC34A2-001 51 +++ 30 RGS4-001 49 ++ 20 VCAN-002 49 ++ 67 CDC6-001 48 ++ 74 THY1-001 65 +++ 10 RNF213-001 84 ++++ 61 RCN1-001 75 ++++ 37 FZD-001 52 +++ 71 HMMR-001 49 ++ 60 C11orf24-001 47 ++ 53 JUNB-001 51 +++ 25 ELANE-001 62 +++ 61 RCC1-001 77 ++++ 62 MAGEF1-001 83 ++++ 22 ACACA-001 61 +++ 21 PLEKHA8-001 47 ++ 57 EEF2-002 31 ++ 41 HSP-002 47 ++ 38 ATP-001 19 + 46 ORMDL1-002 61 +++ 59 NET1-001 82 ++++ 63 NCAPD2-001 76 ++++ 42 VPS13B-001 63 +++ 64 C12orf44-001 34 ++ 23 ITGA11-001 53 +++ 75 DIO2-001 50 ++ 28 ANKH-001 52 +++ 65 HERC4-001 61 +++ 16 P2RY6-001 91 ++++

(54) Candidate peptides that show a high exchange yield (i.e. higher than 40%, preferably higher than 50%, more preferred higher than 70%, and most preferred higher than 80%) are generally preferred for a generation and production of antibodies or fragments thereof, and/or T cell receptors or fragments thereof, as they show sufficient avidity to the MHC molecules and prevent dissociation of the MHC complexes.

Example 7

(55) Binding and Immunogenicity of Selected MHC Class II Peptides

(56) HLA class II proteins are divided into 3 major isotypes HLA-DR, -DP, DQ which are encoded by numerous haplotypes. The combination of various α- and β-chains increases the diversity of the HLA class II proteins found in an arbitrary population. Thus, the selected HLA class II TUMAPs have to bind to several different HLA-DR molecules (i.e. show promiscuous binding ability) in order to be able to contribute to an effective T-cell response in a significant percentage of patients.

(57) The promiscuous binding of POSTN-002 and MMP12-002 to various HLA-DR haplotypes and the stability of the formed complexes was assessed in an in vitro binding assay by an external service provider as follows.

(58) Materials and Methods

(59) List of Peptides

(60) TABLE-US-00012 Sequence No Peptide ID Sequence Origin Size 76 MMP12-002 INNYTPDMNREDVDYAIR IMA-942 18 77 POSTN-002 TNGVIHVVDKLLYPADT IMA-942 17
List of Investigated HLA-DR Haplotypes

(61) The 7 investigated HLA-DR haplotypes are selected according to their frequencies in HLA-A*02 and HLA-A*24 positive North Americans population (Table 7.1 and 7.2)

(62) Data are derived from the analysis of 1.35 million HLA-typed volunteers registered in the National Marrow Donor Program (Mori et al., 1997). The analyzed population was subdivided in the following ethnic groups: Caucasian Americans (N=997,193), African Americans (N=110,057), Asian Americans (N=81,139), Latin Americans (N=100,128), and Native Americans (N=19,203).

(63) TABLE-US-00013 TABLE 7.1 Haplotype frequencies in HLA-A*02 positive North Americans: The analyzed haplotypes are indicated in the rightmost column. Serological Haplotype Frequency [% of HLA-A*02 positive individuals] haplotype Native HLA-A HLA-DR Caucasian African Asian Latin American Analyzed 2 1 8.8 7.8 3.0 6.1 6.8 Yes 2 2 14.9 13.8 17.6 9.7 13.8 Yes 2 3 6.1 11.1 1.8 5.3 5.5 Yes 2 4 21.3 9.4 15.7 23.6 24.9 Yes 2 5 1.2 2.3 1.0 1.3 1.8 No 2 6 15.2 20.0 11.5 17.7 15.9 Yes 2 7 13.0 10.5 2.5 7.8 9.0 Yes 2 8 4.2 5.7 10.2 16.2 8.7 No 2 9 1.2 2.8 16.0 1.0 2.9 No 2 10 1.4 2.4 1.2 1.3 0.8 No 2 11 8.7 10.6 5.2 6.4 4.8 Yes 2 12 2.6 2.8 12.3 1.8 1.9 No 2 90 1.4 0.8 2.0 1.7 3.3 No SUM 100.0 100.0 100.0 100.0 100.0

(64) TABLE-US-00014 TABLE 7.2 Haplotype frequencies in HLA-A*24 positive North Americans: The analyzed haplotypes are indicated in the rightmost column. Serological Haplotype Frequency [% of HLA-A*24 positive individuals] haplotype Native HLA-A HLA-DR Caucasian African Asian Latin American Analyzed 24 1 8.2 7.9 5.4 4.1 4.6 Yes 24 2 15.7 18.8 24.6 10.7 14.8 Yes 24 3 6.0 7.5 1.4 3.7 4.0 Yes 24 4 14.9 14.4 19.8 25.8 21.6 Yes 24 5 2.0 1.6 1.4 2.7 1.0 No 24 6 17.0 18.7 9.6 20.5 20.7 Yes 24 7 9.2 7.9 2.5 4.8 4.3 Yes 24 8 4.0 3.8 5.7 12.4 11.3 No 24 9 1.4 1.7 9.9 0.7 5.8 No 24 10 1.6 1.2 0.8 2.0 0.6 No 24 11 16.5 8.0 5.2 9.0 5.4 Yes 24 12 1.8 7.5 11.5 2.2 2.4 No 24 90 1.6 1.0 2.2 1.3 3.3 No SUM 100.0 100.0 100.0 100.0 100.0
Principle of Test

(65) The ProImmune REVEAL® MHC-peptide binding assay determines the ability of each candidate peptide to bind to the selected HLA class II haplotype and stabilize the HLA-peptide complex. Thereby the candidate peptides are assembled in vitro with a particular HLA class II protein. The level of peptide incorporation into HLA molecules is measured by presence or absence of the native conformation of the assembled HLA-peptide complex at time 0 after completed refolding procedure (so called on-rate).

(66) The binding capacity of candidate peptide to a particular HLA molecule is compared to the one with known very strong binding properties (positive control) resulting in the corresponding REVEAL® MHC-peptide binding score. The positive control peptide is selected and provided by ProImmune based on their experience individually for each HLA haplotype.

(67) Besides the affinity of a peptide to a particular HLA molecule, the enduring stability of the formed HLA-peptide complex is crucial for the occurrence of an immune response. Accordingly presence of the formed HLA-peptide complex is measured after its incubation for 24 h at 37° C. Consequently the stability of the formed MHC-peptide complex is calculated as a ration of the binding scores at 24 h and the binding scores which are received right after the refolding (accordingly at time 0) in percent.

(68) Results

(69) The analysis of POSTN-002 and MMP12-002 in REVEAL® MHC-peptide binding assay showed that both peptides bind to various HLA haplotypes. POSTN-002 was shown to form a complex with 5 and MMP12-002 with 4 of 7 investigated HLA haplotypes (FIG. 5). Both peptides did not bind to HLA-DR3 and HLA-DR6. The detected binding scores were within the range of 0.02 to about 2.5% compared to the positive control, and clearly above scores of non-binding peptides.

(70) The stability analysis of the formed HLA-POSTN-002 and HLA-MMP12-002 complexes revealed that 3 and 2 of 6 investigated HLA-peptide complexes were stable after 24 h at 37° C., respectively (FIG. 6).

(71) A conclusion on the immugenicity of a peptide based on its binding capacity to a HLA molecule can be made by comparing the binding score of this peptide to the one with known immunogenicity. Therefore, five well investigated peptides with determined immunogenicity were selected for this comparison. The immunogenicity of these peptides was determined ex vivo in blood samples of vaccinated patients using intracellular cytokine staining (ICS) CD4 T-cells.

(72) In principle, ICS assays analyze the quality of specific T cells in terms of effector functions. Therefore, the peripheral mononuclear cells (PBMCs) were cultivated in vitro and subsequently restimulated by the peptide of interest, a reference peptide and a negative control (here MOCK).

(73) Following the restimulated cells were stained for FN-gamma, TNF-alpha, IL-2 and IL-10 production, as well as expression of the co-stimulatory molecule CD154. The counting of affected cells was performed on a flow cytometer (FIG. 7).

(74) The immunogenicity analysis revealed 100% immune response by vaccination with IMA950 peptides (BIR-002 and MET-005) in 16 patients and 44% to 86% immune response by vaccination with IMA910 peptides (CEA-006, TGFBI-004 and MMP-001) in 71 patients.

(75) To compare the binding scores of POSTN-002 and MMP12-002 to the binding scores of IMA910 and IMA950 peptides, all peptides were arranged in a table for each investigated HLA-DR haplotype according to the detected binding score (Tables 8.1 to 8.5).

(76) TABLE-US-00015 TABLE 8.1 Binding scores of POSTN-002 and MMP12-002 to HLA-DR1 compared to the binding scores of class II peptides with known immunogenicity: POSTN-002 and MMP12-002 are ranked 4 and 6, respectively. Relative Binding Score Peptide Rank Peptide Code Origin HLA-DR1 1 BIR-002 IMA950 40.06 2 CEA-006 IMA910 1.31 3 MET-005 IMA950 0.87 4 POSTN-002 IMA-942 0.24 5 MMP-001 IMA901 0.19 6 MMP12-002 IMA-942 0.04 7 TGFBI-004 IMA910 0.03

(77) TABLE-US-00016 TABLE 8.2 Binding scores of POSTN-002 and MMP12-002 to HLA-DR2 compared to the binding scores of class II peptides with known immunogenicity: POSTN-002 and MMP12-002 are ranked 3 and 1, respectively. Relative Binding Score Peptide Rank Peptide Code Origin HLA-DR2 1 MMP12-002 IMA-942 2.43 2 MMP-001 IMA901 0.7 3 POSTN-002 IMA-942 0.68 4 MET-005 IMA950 0.28 5 TGFBI-004 IMA910 0.28 6 BIR-002 IMA950 0.05 7 CEA-006 IMA910 0.03

(78) TABLE-US-00017 TABLE 8.3 Binding scores of POSTN-002 and MMP12-002 to HLA-DR4 compared to the binding scores of class II peptides with known immunogenicity: POSTN-002 and MMP12-002 are ranked 6 and 4, respectively. Relative Binding Score Peptide Rank Peptide Code Origin HLA-DR4 1 CEA-006 IMA910 39.65 2 BIR-002 IMA950 6.12 3 MET-005 IMA950 5.89 4 MMP12-002 IMA-942 0.74 5 MMP-001 IMA901 0.06 6 POSTN-002 IMA-942 0.02 7 TGFBI-004 IMA910 0.02

(79) TABLE-US-00018 TABLE 8.4 Binding scores of POSTN-002 and MMP12-002 to HLA-DR5 compared to the binding scores of class II peptides with known immunogenicity: POSTN-002 and MMP12-002 are ranked 5 and 6, respectively. Relative Binding Score Peptide Rank Peptide Code Origin HLA-DR5 1 BIR-002 IMA950 103.9 2 MMP-001 IMA901 47.82 3 CEA-006 IMA910 24.27 4 MET-005 IMA950 0.12 5 POSTN-002 IMA-942 0.08 6 MMP12-002 IMA-942 0.04 7 TGFBI-004 IMA910 0.04

(80) TABLE-US-00019 TABLE 8.5 Binding scores of POSTN-002 and MMP12-002 to HLA-DR7 compared to the binding scores of class II peptides with known immunogenicity: POSTN-002 and MMP12-002 are ranked 3 and 7, respectively. Relative Binding Score Peptide Rank Peptide Code Origin HLA-DR7 1 MET-005 IMA950 3.69 2 CEA-006 IMA910 0.63 3 POSTN-002 IMA-942 0.47 4 BIR-002 IMA950 0.27 5 TGFBI-004 IMA910 0.01 6 MMP-001 IMA901 0 7 MMP12-002 IMA-942 0

(81) The comparison of the binding scores of POSTN-002 and MMP12-002 to the binding scores of the other class II peptides with known immunogenicity showed that the binding capacities of both peptides are mostly located in the middle till the lower half of the tables with exception of HLA-DR2. The binding capacities of both peptides to HLA-DR2 are located in the upper half of the table with MMP12-002 being the top candidate. Based on this analysis it must be expected that both peptides, POSTN-002 and MMP12-002, induce an immune response as well.

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